Datasets:

j-chim

/

pii-pile-chunk3-300000-350000-tagged

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[ "Clark County Sheriff's Memo\n\nAn Internal Affairs investigation document from the Clark County Sheriff’s Office in Vancouver, WA explicitly stating the FBI considers the \"Proud Boys to be an extremist group with ties to white nationalism.”", "\n\nRelevant tagging includes: Proud Boys, FBI, Alt-Right, Nazi, Clark County, Extremism, White Nationalism, Nationalist" ]

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[ "Q:\n\nwhat do you call this gray line thing in html\n\nwhat do you call this \"gray line\" in html, where you can use like a separator?", "\nThanks\n\nA:\n\n<hr /> is this what you mean?", "\n\nA:\n\nthis is called a horizontal rule and can be created using the following:\n<hr />\n\nHowever, the fact that the line is gray is online its default behaviour. ", "Using CSS you can style it as you like. ", "\n\nA:\n\nYou're probably referring to <hr/>, which is a Horizontal Rule.", "\n\n" ]

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[ "Effect of experimental hyposalivation on the induction of dental caries in rats infected with Streptococcus mutans.", "\nThe effects of hyposalivation on the induction of dental caries were examined in specific pathogen-free Sprague-Dawley rats infected with Streptococcus mutans MT8148R and fed the caries-inducing diet 2000. ", "Hyposalivation was induced by either irradiation or surgical removal of salivary glands in 30-day-old rats. ", "After either procedure, severe dental caries was induced in the rats when examined at 84 days of age, and a statistically significant correlation was found between caries scores and flow rates of saliva. ", "However, the recovery of strain MT8148R from hyposalivated rats was not always high, and it is possible that microorganisms other than the inoculated S. mutans strain MT8148R may have played a role in promoting dental caries." ]

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[ "\nccflags-y := -Iinclude/drm\n\nvmwgfx-y := vmwgfx_execbuf.o vmwgfx_gmr.o vmwgfx_kms.o vmwgfx_drv.o \\\n\t vmwgfx_fb.o vmwgfx_ioctl.o vmwgfx_resource.o vmwgfx_buffer.o \\\n\t vmwgfx_fifo.o vmwgfx_irq.o vmwgfx_ldu.o vmwgfx_ttm_glue.o \\\n\t vmwgfx_overlay.o vmwgfx_marker.o vmwgfx_gmrid_manager.o \\\n\t vmwgfx_fence.o vmwgfx_dmabuf.o vmwgfx_scrn.o\n\nobj-$(CONFIG_DRM_VMWGFX) := vmwgfx.o\n" ]

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[ "\nSoulver – Notepad, meet calculator - tosh\nhttps://soulver.app/\n======\ndaturkel\nI personally use Numi, which is very similar. ", "I like the ability to assign\nvariables and reuse them (and change the value of the variable on the fly,\ninstantly redoing all other calculations).", "\n\n[https://numi.io/](https://numi.io/)\n\n~~~\njonstaab\nSeconded (though I'm tentatively switching to dc[0], reverse polish notation\nftw), can anyone who has used both Numi and Soulver point out the differences\nbetween the two? ", "They look super similar to me.", "\n\n[0]\n[https://www.computerhope.com/unix/udc.htm](https://www.computerhope.com/unix/udc.htm)\n\n~~~\nmarklgr\nI like dc too, and wrote this plugin for Vim: [https://github.com/fcpg/vim-\ncolddeck](https://github.com/fcpg/vim-colddeck)\n\nThe power of old tools :)\n\n~~~\ndmix\nFor me the currency conversion, easy ‘totalling’, syntax highlighting, and\nmixing Markdown text inline (which gets ignored) is the key feature for these\nnotepad/numi apps.", "\n\nThese still could be done in Vim but it’s more than just a unixy calculator or\ntext-editor spreadsheet.", "\n\n~~~\nmarklgr\nTo each his own I guess. ", "As far as I'm concerned, I'm mainly interested in the\none-column spreadsheet, tweaking a few input rows and checking how it impacts\nsome other rows. ", "I still use instacalc from time to time, but now I often\nreach for vim instead.", "\n\n------\ndljsjr\nI've been using Soulver for ages, I have Soulver 2 from the Mac App Store.", "\nIt's a terrific little scratch pad, I love the ability to naturally interleave\nnotes/language with arithmetic. ", "I was unaware that there was a Soulver 3,\nhowever, as apparently they are no longer using the MAS as a distribution\nchannel. ", "Just a little top level note for anybody else like me that came here\noff the vague title alone and wasn't aware of Soulver 3.", "\n\n~~~\nkennethfriedman\nAnd another FYI: Soulver 2 is still available on the Mac App Store for $9.", "\nWhereas Soulver 3 is on their website for $30.", "\n\n~~~\nancorevard\nWhy would anyone buy Soulver outside the Mac App Store? ", "Any compelling new\nfeatures that warrants the higher price and risk?", "\n\n~~~\ngumby\n> Why would anyone buy [any app] outside the Mac App Store?", "\n\nI almost never buy an app from the Mac App Store when it's also available\ndirectly. ", "I'd rather that the developer gets to keep the extra 30%.", "\n\nFree apps I typically get from the store when available for the convenience of\nthe updating system (though sparkle has made non-app store app updating pretty\npainless).", "\n\nI don't find v3 a compelling upgrade _for me_ but will upgrade anyway once\nsyncing to iOS works again (important feature for me) just to support the dev.", "\n\n~~~\nsovande\n> I almost never buy an app from the Mac App Store when it's also available\n> directly.", "\n\nUnpopular opinion, but I always try to buy Apps from the Mac App Store. ", "It is\neasy to purchase and with buyer protection. ", "You can easily install the app on\nanother Mac and it updates automatically and all my apps are in the same place\nwith just one account. ", "But most importantly, Mac App Store Apps must run in a\nsandbox which is much more secure, than just downloading an app from the\ninternet which might run with root privileges on your Mac.", "\n\nI did purchase Soulver 3 though because I wanted to support the developer as I\nhave been using Soulver 2 almost daily for 10 years. ", "But sure enough, the in-\napp purchase experience did not work and crashed when going to PayPal. ", "Ended\nup purchasing through the web-site. ", "The downside now, is that my Soulver 3 App\nhas megabytes of Paddle API frameworks embedded in it that is not used, and\nLittle Snitch reports that Soulver 3 tries to connect to paddle 2 times every\nfreaking time I start the app. ", "Very annoying and unnecessary.", "\n\nSoulver 3 has actually been a bit of a disappointment. ", "They rewrote the parser\nand math engine in Swift and a lot of functionality has been lost in the\nprocess. ", "I'm sure this will be addressed in further releases, but for now, it\nhas no iCloud sharing and you cannot share documents with the iOS app. ", "Bit\nflicking operators does not work anymore, which was so useful for programming.", "\nIt has gained support for date time calculation which is very nice, like\n'today + 30 days', but Numi does this better and also has a 'now' variable for\ncurrent time you can do calculations with. ", "The new Soulver 3 UI could be\nbetter and I especially find it annoying that the window has a rather large\nfixed min-width and I also don't like the different color for the right\ncolumn. ", "Numi is a a copy of Soulver, but has bypassed the original.", "\nUnfortunately, I found Numi after I purchased Soulver 3, but I have ditched\nSoulver 3 for Numi. ", "Numi has more functionality, looks much better and has\nfewer bugs. ", "Edit: I don't like that Numi is not available on the App Store\neither. ", "Numi is created by a developer from Belarus, which is a country only\nslightly better than DPRK and I would very much like to have Numi in a\nsandbox.", "\n\n~~~\ndnikolaeu\nHa-ha. ))) ", "C' mon man! ", "So superficial about Belarus. )) ", "I just don't want to\nbother with MAS, so it's much easier to automate all stuff. ", "Btw all recent\nupdates are notarized.", "\n\n~~~\nsovande\n> I just don't want to bother with MAS, so it's much easier to automate all\n> stuff.", "\n\nThat might sound good to you, but not to your users. ", "Please put it in a\nsandbox and on the MAS. ", "There is no reason for a calculator to _not_ run in a\nsandbox. ", "Discoverability and sales will probably improve as well on the App\nStore. ", "I for one, would purchase in an instance, whereas now the only purchase\noption is a paddle (sic) preorder button.", "\n\n> Btw all recent updates are notarized.", "\n\nThat is nice.", "\n\n------\njwr\nThe problem I have with this type of app is that I am never sure what will\nwork and what will not. ", "It's \"natural language\" only after you learn which\nsubset of language the app actually understands.", "\n\nI still can't find anything that beats my HP 50g (either physical or running\nin one of the emulators) for just about any kind of computation involving\nseveral pieces of data. ", "For more data, a spreadsheet is really hard to beat.", "\n\n~~~\nfilmgirlcw\nI mean, I use PCalc[1] all the time too, but I love Soulver b/c unlike Excel\n—- which is great but can be a lot —- it’s super easy to just jot stuff down\nand have it calculated, just like a spreadsheet.", "\n\nYou’re not wrong on the syntax stuff, but as long as the math operations are\nthere, it’ll do what you want. ", "The special stuff for currency or other\nconversions isn’t very hard to get the hang of once you start using an app.", "\n\nReally, the frustrating thing is when I’m on a machine that’s not mine and I\nhit my Soulver system-wide shortcut and can’t open up my scratchpad. ", "But\nthat’s my problem.", "\n\n[1]: [https://www.pcalc.com/](https://www.pcalc.com/)\n\n------\ngabipurcaru\nI wrote [https://dedo.io/](https://dedo.io/) as a web version of this, since\nthere's no good equivalent for linux\n\n~~~\nkeroro\nHave you seen NaSC?", "\n\n[https://parnold-x.github.io/nasc/](https://parnold-x.github.io/nasc/)\n\n~~~\njszymborski\nWow, that seems super cool.", "\n\nA little tangential, but also really cool how elementary os is really coming\nto be the MacOS alternative it has set out to be.", "\n\n------\nfilmgirlcw\nI’ve been using Soulver for like 12 years and it’s one of my favorite and\nmost-used apps.", "\n\nThere was a huge amount of time between Soulver 2 and 3 so I gladly paid for\nversion 3 (even though it doesn’t sync with iOS which isn’t a big deal, and\nsome features haven’t made their way over so I still keep 2 installed).", "\n\nThere might be decent alternatives but at this point, I’m so used to Soulver I\ndon’t want anything else. ", "Plus, the new Alfred workflow is really good.", "\n\n~~~\nfrereubu\nMe too, but don't you find the way Soulver 3 manages documents a bit weird? ", "I\nmuch preferred the old way where you could save document wherever you wanted,\nwhereas version 3 seems to want to control all of that for you. ", "Unlike the\nprevious version I couldn't wrap my head around how it was supposed to work\nquickly, and went back to version 2. ", "I was happy to pay for a new version just\nto make sure Soulver isn't abandoned because my working life would be\nnoticeably more difficult without it.", "\n\n~~~\nfilmgirlcw\nYeah it took me a bit of time and I admit I still use 2 a lot but I’m trying\nto force myself to use 3. ", "I think part of it is the 9 years or whatever that I\nused 2.", "\n\n------\njhallenworld\nMy editor JOE has a built-in calculator equivalent to a Casio scientific: for\nexample it can do statistics (sum, count, average, standard deviation) on a\nblock of numbers you select in the edit buffer. ", "I use this all the time.", "\n\nIn another project, I wrote a preprocessor for TeX- somewhat like Markdown, so\nthat you can make TeX documents with an easier syntax. ", "One of its features is\na built-in calculator/spreadsheet. ", "The idea is that \\\\{1+2+3} is expanded with\n6. ", "You can also assign and reference variables \\\\{a=3}. ", "If these appear in a\ntable, you can reference other cells: \\\\{RRD+7} \"Get first expression from\ncell two to the Right Right one Down and add 7 to it\".", "\n\n[https://github.com/jhallen/joes-\nsandbox/tree/master/doc/nice...](https://github.com/jhallen/joes-\nsandbox/tree/master/doc/nicetex)\n\nAnyway, I'd like this capability in the editor, will add it someday..\n\n~~~\nskrause\nIs this the same JOE editor I was using when I first started using Linux\naround 1999?", "\n\n~~~\njhallenworld\nYes.", "\n\n~~~\nvanderZwan\nThat puts the sentence _\" will add it someday..\"_ in perspective.", "\n\n~~~\njhallenworld\nEveryone should have a long term project..\n\n------\nstaticvoidmaine\nA great option which is similar but different and which I enjoy very much is:\n\n[https://speedcrunch.org/](https://speedcrunch.org/)\n\n~~~\ndankoss\nI second this, it's a great cross-platform scratchpad.", "\n\n------\nflixic\nAs Marco Arment once said, if Soulver isn’t open he’s not working. ", "Rings true\nfor me as well. ", "I almost always have it running to help me through some\ncalculation or more complex modeling. ", "Highly recommended.", "\n\n------\nvjeux\nI reimplemented a simplified version of it 7 years ago (wow, time flies) and\nopen sourced it, if people are interested.", "\n[https://github.com/vjeux/soulver.js](https://github.com/vjeux/soulver.js)\n\n~~~\njraph\nWatch out:\n\n> $22 for lunch + 10% sales tax\n\nDisplays $32.00 instead of $24.20 or something. ", "Other issues: it does not\nsupport units on the right nor euros (€).", "\n\nNice anyway :-)\n\n~~~\ncontinuational\nTo be pedantic, 10% = 0.10, which is has no unit, so it can't be added to a\ndollar amount.", "\n\n~~~\njraph\nSure, but 25 + 10% = 27.5 for:\n\n\\- Soulver, according to the screenshots (and the goal of this project seems\nto match Soulver's behavior),\n\n\\- the calculator on my phone,\n\n\\- KRunner, the launcher in KDE, and KCalc, its calculator\n\n\\- gcalc, the Gnome calculator\n\n\\- qalc, that shows \"25 * (110 * percent) = 27,5\".", "\n\n\\- The TI-106 solar calculator that I happen to have [1].", "\n\nThinking about it, we are probably talking about some kind of \"\\+ %\" operator,\nwhere x + y % = x + x × y / 100.", "\n\nInterestingly, 10% = 0 for the TI-106 (but 25*10% = 2.5). % ", "alone does not\nseem to mean anything for it.", "\n\nThis little calculator will probably outlive me.", "\n\n[1]\n[http://www.datamath.org/BASIC/LCD_Modern/TI-106_2.htm](http://www.datamath.org/BASIC/LCD_Modern/TI-106_2.htm)\n\n------\nbadatshipping\nThe funny thing is that Excel would basically meet this need perfectly if it\ndidn’t take 5 seconds to open.", "\n\n~~~\npetey283\nThis. ", "Excel as a notepad would be great. ", "Don't know enough about windows\ndesktop development to implement my own solution, but I'm surprised that\nnothing currently exists.", "\n\n~~~\nselimthegrim\n[http://blockpad.net](http://blockpad.net) might be what you are looking for\n\n------\ngumby\nI've used Soulver for several years and just upgraded so I guess I like it. ", "I\nhave to confess I originally bought it simply because I was delighted someone\nwas reimagining the calculator interface and I wanted to support that. ", "But I\ndo use it every day.", "\n\nIt's not my automatic go-to calculator (that's either dc or RPN pcalc). ", "But if\nI want to do any slightly complicated calculation but don't need the overhead\nof Excel/Numbers or Mathmatica (or am on my phone!) ", "it's really nice to lay\nout some variables (cost/m2, length width, blah blah) and be able to tweak\nthem. ", "And I can fiddle on my computer and then see the model on my phone where\nit's also easy to edit.", "\n\nNot a tool for everyone, but surprisingly good as both a programmer and\ngeneral purpose calculator.", "\n\n------\ndiimdeep\nReally like [https://calca.io](https://calca.io)\n\n~~~\nskuhn\nI really like Calca and still use it a bunch, but it has a few annoyances\n(some of which cause incorrect answers) and seems to get updated about once\nevery 4 years.", "\n\nPutting the answers inline rather than over in a separate column (ala Soulver\nand Numi) makes more sense to me.", "\n\n------\ndotmanish\nI've been a Soulver user since 2012, and it's been an integral part of my\nworks, even acting as a scratch pad for ideas with numbers.", "\n\nThe UX is the plus here - I am aware that there have been several other apps\nthat have offered a polished UX since then, but the convenience and my learned\naffinity to Soulver makes me keep it.", "\n\n------\nmadisp\nIt looks neat but I wish it had physics calculations - I want to be able to\nwrite something like\n\n10m * 1000kg * 9.8m/s^2 in kWh\n\nand see a correct result\n\n~~~\njsilence\nNot as polished as Soulver and Numi, but maybe Frink is something for you:\n[https://frinklang.org/](https://frinklang.org/)\n\n~~~\nroryokane\nAs a student project, I once prototyped a Soulver-like interface that used\nFrink for its calculations: [https://github.com/roryokane/CalcuDoc/wiki/About-\nCalcuDoc](https://github.com/roryokane/CalcuDoc/wiki/About-CalcuDoc). ", "You can\nsee screenshots and get the code from that link.", "\n\nI didn’t continue working on it after the class finished, though – I lost all\ninterest after I realized that the Frink programming language, despite being\nfree, is not open source.", "\n\n------\npaleogizmo\nI never knew there were so many people into notebook/repl style calculators,\nfor lack of an accepted term. ", "How did these never take over from the\nskeuomorphic style? ", "There clearly seems to be a market below the\nspreadsheet/Jupyter notebook use case.", "\n\n------\nfghorow\nSlightly off topic:\n\nBack in the early days of the Newton, there was an app that let you manipulate\nalgebraic expressions by dragging and dropping individual elements of the\nexpression. ", "Think factoring out a common factor represented by the expression\nsprouting parentheses with the factor out front. ", "There was a later effort\ncalled MathDrag'n but that seemed to run out of steam.", "\n\nDoes anyone know if a similar thing exists and is maintained now?", "\n\n~~~\nTimTheTinker\nThe old (pre-OS X) Macintosh app Graphing Calculator did this. ", "I really miss\nit.", "\n\n~~~\npvg\nIt's still around -\n\n[https://www.pacifict.com/WhatsNew.html](https://www.pacifict.com/WhatsNew.html)\n\n~~~\nTimTheTinker\nHey thanks!!", "\n\n------\npfranz\nWhat's new between Soulver 2 and 3? ", "I can't seem to find out any info.", "\n\nThis type of app seems like it would be useful, and I know I'm basically\nasking for free candy, but I don't find 30 day trials that useful. ", "I'll toy\naround with it now, but 35 days later think about it for serious work and ever\nreally get to evaluate it. ", "Or, I'll drop $30 on it now and never think about\nit again.", "\n\n------\nbitwize\nOrg-mode: Notepad, meet calculator, spreadsheet, mind map, literate\nprogramming tool, blogging/Web CMS, presentation builder...\n\n~~~\nanotheryou\nI really can't find a good way to recreate what I have with something like\nsoulver.", "\n\nWith tables I don't see the formulas at glance. ", "Only alternative would be a\nreal programming language but than something like time is a pain again.", "\n\n~~~\nsubjectsigma\nYou can evaluate emacs lisp everywhere in the editor with C-x C-e. C-u C-x C-e\npastes into the buffer. ", "IDK if that fits your use case or not but I hope it's\nhelpful.", "\n\n~~~\nanotheryou\nwhat does this correspond to? ", "I'm on spacemacs\n\n~~~\nsubjectsigma\neval-last-sexp, which I believe is , e s in Spacemacs. ", "Also, most Emacs\ndefaults like that are carried over to Spacemacs so you can try SPC h d k C-x\nC-e and get info that way.", "\n\n------\nstickfigure\nThis looks neat, but I'm struggling with the landing page.", "\n\nThere are a bunch of animated gifs that show off how Soulver works - great!", "\nBut just as they finish the exercise and show the result, they immediately\nblank and restart. ", "I don't get any time to figure out what just happened. ", "It's\nincredibly frustrating.", "\n\nPut a 5s pause at the \"complete\" frame.", "\n\n~~~\nroryokane\nIt’s also annoying that each example on the landing page only fades in when it\nis scrolled almost to the top of the window. ", "I have enough vertical space to\nsee two examples at once, but it always hides the bottom one to look\n“mysterious”. ", "This is especially disorienting when scrolling up or down a page\nat a time.", "\n\nApple’s marketing pages do this type of fade-in better – the fade-in happens\nquickly as soon as the page is scrolled to a certain point, and after that,\nthe faded-in item doesn’t fade out again unless you refresh the page.", "\n\n------\npkamb\nSoulver is great, but there's one feature that seriously makes me hate using\nit.", "\n\nI often open up \"scratchpad\" text documents. ", "I Paste some text, edit it,\nSelect All, then Cut. ", "I press CMD-W to close the window. ", "Because the document\nis blank, I'm not prompted to save the unsaved File.", "\n\nIf I try to do the same thing with Soulver, when I close the (blank) window\nthe app pops up a modal dialog asking me where I want to save the (blank,\nnever-saved, scratchpad-only) File. ", "So annoying.", "\n\nIt seriously prevents me from quickly opening up or using Soulver just because\nI don't want to deal with clicking through that modal once I'm done. ", "I'll just\nuse a Text document instead or put the math equation into the Chrome omnibox.", "\n\n~~~\nroryokane\nIn the save confirmation dialog of any Mac app, the keyboard shortcut Command-\nDelete (⌘⌫) chooses Delete for you. ", "I found such dialogs much less annoying\nafter I learned that.", "\n\nSo when you want to close a window without saving:\n\n1\\. Hit ⌘W\n\n2\\. Wait a moment for the dialog to open\n\n3\\. Hit ⌘⌫\n\n------\nxattt\nA tangent, but there is an unspoken need for natural language\nprocessing/interpretation in EHR charting for nurses.", "\n\nVery often, you enter values manually into a flow sheet around that status of\na patient (ie vitals, PQRST for pain, assessments) but you may also enter a\nsupporting note around the circumstances of your charting.", "\n\nIt would be beyond helpful to have an interpreter to pull in data within that\nnote to place it within the appropriate data fields. ", "It would eliminate a\nsignificant portion of duplicate charting.", "\n\nI am putting it out there, because this is beyond me to solve this issue from\na technical standpoint.", "\n\nSoulver looks like a tiny step in that direction/way of thinking.", "\n\n~~~\nzdragnar\nIs this really a good solution? ", "My biggest concern is more psychological than\ntechnical. ", "If the error rate of interpretation is too high, then it obviously\nwon't reduce the effort. ", "However, if the error rate is low, then the errors\nare much more likely to be overlooked.", "\n\nThe enemy of good may be perfect, but it seems that the closer to (without\nbeing) perfect the interpreter, the worse the outcome for the patient.", "\n\n------\nkalid\nShameless plug, I made [https://instacalc.com](https://instacalc.com)\n(pastebin for calcs) for back-of-the-envelope number crunching. ", "Fast, free,\ngets out of your way.", "\n\n------\nredwards510\nI'd love to see a VS Code extension that does this. ", "Anyone heard of one?", "\n\n------\nwernsey\nLike the concept, but I'm on Windows so I'll try out some of the alternatives\nmentioned in these comments.", "\n\nMy solution for Windows has been the NppCalc plugin for Notepad++. ", "It is not\nquite as advanced, but does have a lot of functions that the alternatives\ndon't (like some common encryption algorithms which came in useful recently)\n\n[https://sourceforge.net/p/nppcalc/wiki/Home/](https://sourceforge.net/p/nppcalc/wiki/Home/)\n\n------\nCriticalCathed\nI do this kind of thing a lot...this is a tool that I didn't know I needed.", "\nLike excel-lite.", "\n\nToo bad it's mac only. ", "And so is Numi.", "\n\nAny linux (preferred) or windows alternatives?", "\n\n~~~\nfloatboth\n[https://github.com/parnold-x/nasc](https://github.com/parnold-x/nasc) for GTK\n\n------\nlcnmrn\nEva(luate)\n[https://github.com/NerdyPepper/eva](https://github.com/NerdyPepper/eva)\n\n------\nnewscracker\nI've used this sometimes, and still use it sometimes (a few times a year,\nprobably). ", "But I find it not very intuitive (beyond the basics of typing some\nnames, numbers and operators in a list), and I couldn't figure out how to\n_easily_ do subtotals in a long list (I don't want to write a long formula\nadding every other item above). ", "Better documentation and examples could help.", "\n\n------\nmatchbok\nCool idea, but but does every website nowadays insist on lazy loading every\nsingle part of the site? ", "It just makes everything feel so _slow_.", "\n\n------\ncrooked-v\nI wish there was an app like this that would work with dense text with\nembedded math, so I could use it for tabletop game character sheets.", "\n\n~~~\nnekopa\nMaybe try to use this from a comment elsewhere in this thread:\n\nbuild your own reactive editor or content with data streams using TagleJS:\n[http://worrydream.com/Tangle/](http://worrydream.com/Tangle/) and it is open\nsource. :)", "\n\n------\nkragen\nI'm using a thing called microMath+ on Android (available on F-Droid) but it's\nkind of clumsy. ", "I haven't tried hacking on it yet to improve the UI, but I'm\nwondering if there might be something else out there that's already better.", "\n(Not proprietary software, obviously.)", "\n\n~~~\nroryokane\nI don’t see the app on F-Droid – the listing on\n[https://www.f-droid.org/en/packages/32/index.html](https://www.f-droid.org/en/packages/32/index.html)\nskips from “Microchip” to “Microphone”. ", "I can’t find the app’s website or code\nby searching the web either – all I found was this C++ project from 2012:\n[https://github.com/candycode/micromath](https://github.com/candycode/micromath).", "\n\n~~~\nkragen\nSorry, it's spelled with a Greek lowercase mu.", "\n\n~~~\nroryokane\nIt wasn’t clear what part of “microMath+” you meant should be replaced by μ,\nbut I eventually found the app. ", "It’s μMath+, on F-Droid at\n[https://www.f-droid.org/en/packages/com.mkulesh.micromath.pl...](https://www.f-droid.org/en/packages/com.mkulesh.micromath.plus/)\nand on GitHub at\n[https://github.com/mkulesh/microMathematics](https://github.com/mkulesh/microMathematics).", "\n\n~~~\nkragen\nThat's right. ", "I'm sorry I didn't post the correct name in the first place; I\ndon't have\n[https://github.com/kragen/xcompose](https://github.com/kragen/xcompose) set\nup on my hand computer (because it doesn't run X).", "\n\n------\neswat\nI don’t use Soulver that much anymore other than while travelling, but it’s\ngreat for tracking my travel budget on my phone: able to clearly list what\nI’ve bought, for how much, what the grand total is in my home currency and\nleave comments on things.", "\n\n------\nncmncm\nIt's funny that in the very first image showing how it works, they have a wage\ncalculation for four days worked, but there are five days.", "\n\n\"There are two hard problems in programming: naming, cache maintenance, and\noff-by-one errors.\"", "\n\nNot just in programming.", "\n\n------\nsmugshot\nyou can build your own reactive editor or content with data streams using\nTagleJS: [http://worrydream.com/Tangle/](http://worrydream.com/Tangle/) and it\nis open source. :)", "\n\nNot just calculator.", "\n\n~~~\nvanderZwan\nIsn't that a slightly different kind of thing though? ", "That makes a static\ndocument interactive.", "\n\n------\nxinan\nI feel that with non-standard syntax like $100 + 25% tip it become very\nconfusing whether the answer would be 100.25 or 125. ", "I’ll end up spending a\nlot of time trying to verify the answer.", "\n\n------\notoburb\nType annotated calculator. ", "If the author had a Windows version he would\nprobably sell many more licenses, but understandably that's probably not high\non their priority list.", "\n\n~~~\nimmigrantsheep\nYou got Speedcrunch which is both crossplatform and opensource\n\n~~~\notoburb\nI love Speedcrunch and it's an integral part of my Windows workflow, but not\nas flexible as Numi or Soulver. ", "I would incorporate either of those two into\nmy Windows workflow if they were available as such with the same\nresponsiveness and footprint.", "\n\n~~~\nzarathustraa\nFor Windows you might want to checkout OpalCalc. ", "The website is horrible, but\nthe product is actually good (if ugly).", "\n\n------\nElepsis\nHas anyone found anything remotely comparable for Android? ", "I'd love to have a\nSoulver or Numi analog on my phone. ", "I don't even need it to sync with\nanything.", "\n\n------\nwar1025\nI wish the gifs on the page would pause a little longer at the end. ", "It loops\nback to the beginning too fast for me to really grok what is happening.", "\n\n------\ntoypaj\nI've used this for years, and use it to tally up my outgoings quickly, and\nchanging a linked value will update all the related items\n\n------\njdlyga\nMac only? ", "Oh well\n\n------\nlloydatkinson\nMac only? ", "Really.", "\n\n~~~\njazzyjackson\nSince getting a Mac I've been finding that there's a whole market of mac only\napps and I get the sense that it's just choosing your demographic: people who\nbuy macs are more likely to pay for software.", "\n\n------\nNelsonMinar\nI've also been using Soulver for years, mostly on my iPhone. ", "I like how it's\nbasically Jupyter-for-arithmetic.", "\n\n------\nanotheryou\nfor Windows: OpalCalc\n\nmore than nostalgic website but actively maintained:\n[https://www.skytopia.com/software/opalcalc/](https://www.skytopia.com/software/opalcalc/)\n\ncalcing with time is a bit jumpy at times, but other than that I love it for\nquick napkin calcing stuff\n\ncosts 15 bucks\n\n------\ngarysahota93\nThis is awesome! ", "I was actually looking around for something a few days ago!", "\nPerfect timing.", "\n\n------\nfourier_mode\nUI is impressive!", "\n\nBut, how is the functionality provided better than tons of free spreadsheet\napps out there?", "\n\n~~~\nzarathustraa\nSpreadsheets force you to pick cells, and the formulas are hidden. ", "They are\nnon-linear, this is linear. ", "They also take a lot of screen space, this is\ntiny.", "\n\n------\njasonhansel\nAnyone know of a good Linux version? ", "For Windows, OpalCalc is pretty good.", "\n\n------\nvincent-toups\nC-X X-E evaluates any s-expression in any emacs buffer using emacs lisp.", "\n\n~~~\nrhymer\nOr C-x * for calc-dispatch? ", "I guess the point of this app is the input doesn't\nhave to be precise. ", "Not sure emacs can do that.", "\n\n------\ncr0sh\nPart of me thinks this needs to be a plugin or something for VS Code...\n\n------\ncvaidya1986\nLovely! ", "Congratulations :)\n\n------\nbroabprobe\nlooks like a great app but a little disappointing it requires MacOs 10.14.", "\nThere are a non-insignificant number of people still using older machines.", "\n\n------\nthomasfl\nJust like emacs in the 1980´s.", "\n\n------\n6thaccount2\nI usually use Mathematica for this kind of thing.", "\n\n~~~\n6thaccount2\nNot sure why I got downvoted here, so I'll explain that Mathematica makes a\nreally good proxy for this.", "\n\nI can do a decent amount of this in Notebooks or the terminal with\nWolframscript and I'm not limited to simple things either.", "\n\nI'm sure this tool is better if you just need something really simple as it is\nmuch cheaper and certainly lighter weight than Mathematica.", "\n\n------\ncoldacid\nWhy wouldn't I just use something like orgmode?", "\n\n~~~\noutworlder\nI'm also an Emacs user. ", "But there are people who don't use Emacs. ", "Or _gasp_\ndon't even have it installed! ", "Believe it or not.", "\n\n------\nindentit\nA paid, Mac only app which could fairly easily be implemented as a plugin to\nany popular text editor... I'm not sure I understand the appeal - what am I\nmissing here, please? :)", "\n\n~~~\npetepete\nThis is like comparing Dropbox to \"having an FTP account, mounting it locally\nwith curlftpfs, and then using SVN or CVS on the mounted filesystem\".", "\n\nYes, you could. ", "Or you could use something that's polished and works, with a\nclean UI and years of real world testing.", "\n\n~~~\nmikeash\nFor anyone missing the joke, when the Dropbox announcement was posted to HN,\nthat was exactly the reaction it got.", "\n\n" ]

{ "pile_set_name": "HackerNews" }

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[ "Yaya Diallo\n\nYaya Diallo is a musician and author from the Republic of Mali.", "\n\nBackground\n\nYaya Diallo was born in 1946 in the village of Fienso (French Sudan) now Mali, to a nomadic Fula father and a Minianka mother. ", " Yaya was raised in a culture that works, worships, lives and breathes to the beat of the drum. ", " Thanks to his mother, being from the illustrious Berthe family (hunters, county chiefs, musicians...), young Yaya had the opportunity to hear some of the best musicians of the former canton Zangasso. ", " The old musician, healer and sorcerer Nangape Kone became his protector and mentor.", "\n\nArriving in Montreal, Canada, in 1967, Yaya graduated from the University of Montreal in Chemistry in 1973. ", " Following a brief career as a chemist, Yaya returned to traditional African music. ", " He was a co-founder of the music and dance groups Djembe-Kan and Cleba and a member of the African Troubadours with the World Music Institute as well as a faculty member with the Creative Music Studio, Woodstock, NY, and the Omega Institute.", "\n\nYaya is currently teaching Applied World Percussion at Bellarmine University in Louisville, KY. ", "He also offers workshops in traditional African healing, music and dance for the community. ", " He was a seasonal lecturer at Carlton University, teaching Aural Training I & II from 1987 to 1992. ", " In the meantime Yaya worked for Multiculturalism at Schools and the Community (MASC) in Ontario and Quebec, Canada, teaching more than 6000 students per year. ", " From 1974 to 1986, he was a staff member of the Intercultural Institute of Montreal, Canada. ", " There he organized workshops and lectures about different aspects of diverse cultures living in Montreal. ", " Topics ranged from Alternative Medicine to Aging to Music in different cultures.", "\n\nHe has performed throughout the USA, Canada, Asia (Japan, Singapore), Europe (France, England, and Belgium).", "\n\nBiography \n\n1 Early Years\n1.1 Origin in Fienso\n\nIn his book, The Healing Drum, Yaya Diallo wrote a lot of things about his mother and her famous family of Zangasso. ", " He never wrote about his nomadic heritage. ", " That is a missing link in his life that people do not know. ", " Yaya Diallo's great grand father's name was Yoro Diallo. ", " When he stopped in Fienso he changed his family name and opted for Sountoura instead. ", " Sountoura and Diallo are the same name. ", " In some parts of West Africa, Fula people (Fulani; ; ) are not welcomed, especially the Diallo family. ", " Today in Mali, all people whose family name is Sountoura are Diallo, which is a living fact.", "\n\nIn order to be accepted in Fienso, Yaya Diallo's ancestors were sponsored by a Minianka family called Zango-o where the last name is Kone. ", " Even today, the two families have a special relationship, brotherhood and sisterhood.", "\n\nYaya Diallo's family was semi-nomadic. ", " One part stayed in Fienso and the second was nomadic in the hostile Miniankala. ", " Minianka farmers used to hate Fula people because the animals destroyed crops and young plants. ", " In order to travel, Fula people have to be initiated to the most secret societies. ", " Yaya Diallo's grandfather, Flantio became a powerful man who was feared by everyone. ", " When he touched you with his magic stick, you got diarrhea. ", " Flantio took back the name Diallo. ", " He married Yaya's grandmother, gNire Kone, from the powerful family Kone of the village Ziena. ", " She was a midwife.", "\n\nA marabout (seer) Fula made a prophecy to Flantio saying that one of his grandsons would be well known in the world using paper and sound. ", " This is similar to the one they made to his mother. ", " At that time, most of Minianka had never seen a piece of paper.", "\n\n1.2 His Father\n\nYaya Diallo's father, Sibo Diallo, was a Nia Messenger from his birthday until 1974 when he became Muslim. ", " He was a medium. ", " During the rituals of Nia Society he came into a trance while his youngest brother was playing Nia Ngoni (African bass guitar). ", " In his trance, Yaya's father could predict the future of the village people, family by family. ", " he predicted diseases, bad weather, disasters, death, gender of babies in their mother's womb with a surprising accuracy. ", " For each disease, he recommended the herbs to use. ", " Only the initiators understood his language. ", " In his daily life, he knew a lot of medicinal herbs. ", " He was a specialist of the digestive system and all diseases related to it. ", " He was the mentor of Nia Borotali (the messengers of Nia). ", " He could read and translate the 266 characters of Nia. ", " He died April 19, 1995 before Yaya Diallo. ", " In Africa, it is a blessing to have the last word of one's dying father, and Yaya had it and participated in the funerals. ", " Yaya Diallo's mother died on 2 February 1997.", "\n\n1.3 Nomadic life\n\n1950-1953\n\nEach male child in Diallo's family from the age of four to 21 years had to live a nomadic life; Each female child lived nomadically from the age of six until she was married at 16 or after.", "\n\nTo survive in nature, Yaya Diallo had to learn useful things. ", " At first he learned that to live, he should be strong; this is natural selection. ", " He should have some basic needs: Listening- he had to know the sound of hungry lions, hyenas, etc.; ", "Observation- he should look at what's around him, snakes, scorpions; Smelling- to protect himself, Diallo learned deadly smells. ", " Also, he learned the paradox of nature which is: the plant near a poisonous plant has the antidote of the poison. ", " We have a poison and its antidote. ", " Many human diseases have their medications in nature. ", " Yaya Diallo knows how to cure or stop the symptoms of some illnesses: diarrhea, flu, headaches, and the bites or stings of scorpions, snakes, bees, and wasps.", "\n\nAs Fula in Yaya Diallo's family, they breed cattle and sheep. ", " They were always moving, looking for some good place where the animals could get good grass and water; where there were no harmful insects that could give infectious diseases to the cattle. ", " They built temporary huts near a village. ", " Women go to the village to sell or trade dairy products like milk and butter and to buy the ingredients for food: rice, fish, and flour. ", " They cooked and slept in the temporary huts. ", " During the day, Yaya Diallo herded animals in order to feed them. ", " He had to follow the rhythm of the animals; that is a good school for patience.", "\n\nBy some nights, predators such as hyenas and lions came and attacked animals. ", " The shepherds had to hunt them away. ", " Those were the difficult times. ", " When one animal is killed, all the animals were stressed for days. ", " Sometimes they called musicians to play so animals went away.", "\n\nYaya Diallo was subdued to some familial taboos. ", " It is absolutely forbidden to cut down flowers and end the process of reproduction of green plants. ", " Never cut down trees without good reason.", "\n\n1.4 Family values\n\nTo be a successful man, one should put a lot of big, heavy necklaces around his wife's neck. ", " He has to hang big golden earrings from his spouse's ears. ", " To be wealthy and respected like a wealthy man, one should have a big herd of cattle and a lot of sheep. ", " At the school of Nature, Diallo had time to observe and learn. ", " Daily he met many animals: predators, birds, reptiles, herbivores, and all kinds of insects. ", " He also learned about plants. ", " All those factors justified why Diallo was a good biology student and his interests in medical herbs.", "\n\nIn 1953, Diallo went to French school at Zangasso, his mother's native village. ", " During school, Diallo was sedentary. ", " As soon as school stopped he joined the nomadic people. ", " When he came to North America, that was the end of his nomadic life, but as a musician he loves traveling. ", " He said, \"The school of traveling is unique. ", " You can not learn in books what you learn when you travel.\"", "\n \n1.5 Western education\n\nDiallo started French school in 1953. ", " At the time French school was considered a curse for villagers. ", " According to the prediction of villagers, Yaya Diallo could not stay in school for two years, \"he is not even good enough to be black, how can he succeed in the white man's school?\" ", "Since he went to the classroom he was ranked among the five best students out of 51 in total. ", " He successfully went through all kinds of difficulties. ", " In 1959, the last year of primary school in Zangasso, his teacher Arouna Dembele believed that Yaya Diallo could be one of the best Africans in Sudan to succeed in the contest required to go to Lycees and colleges. ", " He failed the contest, for some reasons he had explained in the Healing Drum, but he succeeded in completing the exams for the certificate of primary studies. ", " It was the first and last degree of the Federation of Mali (Mali-Senegal) which lasted only three months, from June to August. ", " This diploma is a historical document.", "\n\nFrom 1959 to 1960, he came back to school and succeeded in the contest and went to the College Moderne of Sikasso. ", " In the 7th grade there were 120 students coming from all schools of the Sikasso Region. ", " The best 30 students would go to the Lycee Henri Terrassons de Fougeres at Bamako. ", " That school became Lycee Askia Mohamed in 1962-63. ", " In spite of all kinds of difficulties, Yaya Diallo was ranked among the top thirty students (Healing Drum, pp.", " 143–145).", "\n\nHe successfully got the D.E.F: Diploma of Fundamental Studies in 1964. ", " In order to help his mother, he wanted to go to a special school to become a teacher, but his mother refused his request. ", " He was oriented to biological studies (mathematics, physics, chemistry, biology). ", " In 1966, he succeeded in both writing and oral exams and obtained the first part of Baccalaureal Francais (Malien).", "\n\nIn 1967, the last year of secondary school, he was one of the best students in biology for the last twenty years according to the biology teacher Madame Le Blanc. ", " That meant he could have a scholarship from the World Health Organization to go to medical school in France. ", " The teacher had made good recommendations to medical schools. ", " In April 1967, Yaya Diallo got the scholarship from Canada to become a Sanitary Engineer. ", " he accepted that offer. ", " With tears, his biology teacher did recommendations to Ecole Polytechnique de Montreal. ", " He came to Canada with the reputation of being horrible at drawing: arts or technical.", "\n\nHe came to Montreal on September 22, 1967, two weeks before the mid-term exams. ", " He studied in the metric system in Africa and had exams with the British system. ", " All his textbooks were in English, as well. ", " He lost one year trying to adapt to the new environment and system. ", " In 1968-69, he passed all exams except technical drawing. ", " His teacher PM Cote told him, \"There is no engineer without drawings.\" ", " He took the course again and failed. ", " Canada government recommended him to go to intensive drawing class. ", " He refused the request, lost his scholarship, and became an illegal alien. ", " His girlfriend's father, manager of Stuart Biscuit, found him a job in the factory. ", " He worked hard, got money and went to study organic chemistry in order to understand the chemical products in herbs and plants. ", " It was a blessing for him. ", " From 1969 to 1970 he was working full-time by night (4pm-2am) and school full-time (8am-3pm). ", " In October 1970, he stopped because there was the October Revolution in Montreal. ", " In 1973, Diallo got his diploma: specialized bachelor's in organic chemistry.", "\n\n2 Brief career as a chemist\n\n2.1 University of Montreal\n\nMay–September 1973\n\nAfter graduation he was hired by Dr. Robert Marchesseault, the Head of the Department of Chemistry, to work on a special project for Domtar Inc. Using Ziegler-Natta catalysts, Diallo was to determine how to make waterproof paper from rolls of paper in movement. ", " There was nothing new. ", " It was easier to make waterproof paper in a stable position rather than on the rolls of paper that are produced in factories. ", " The team had built a mechanical system for the purpose of conducting this experiment. ", " At one side, the paper unrolled, went in the solvent, and then entered in the catalysts in which it was injected with a gas, ethylene. ", " Ziegler-Natta catalysts controlled the size of the polymers (polyethylene) inside and outside the paper at the movement. ", " The paper went out of the products, travelled a distance of two feet, the time needed to be dried. ", " Then the dried paper wound around a bar to make a roll of waterproof paper. ", " Several tests were then performed. ", " Diallo put one piece of paper in water for one day and another for one week to find out if they absorbed water. ", " The final product was sent to Domtar at Pointe-Claire. ", " There, paper was submitted to a pressure of 1,000 pounds in order to homogenize the surface of the paper.", "\n\nTo prove the utility of the project, Diallo had to determine the time of the paper in the solvent, the time in the products, and the time the paper needed to be dried. ", " He also had to calculate the quantities of the solvent, of the products, and of the wastes as plastics. ", " Yaya said, \"I like this project. ", " I studied chemistry to get my hands wet. ", " I like the technical aspect of sciences. ", " I want to make products.\"", "\n\nHe interrupted his career to apply for the Canadian government waiver for illegal aliens.", "\n\n2.2 Interruption\n\nIn August, Diallo learned that the Canadians made an armistice for illegal aliens and especially for students. ", " He went to get registered as a student at H.E.C. (Hautes Etudes Commerciales), a business school. ", " He got the requested papers to stay in Canada. ", " He went through nightmares. ", " The officers of immigration were outraged because Diallo's case became very popular. ", " Look at the case: He came with a scholarship that he lost and still stayed in Canada. ", " He studied at the same university, got a social security number, worked at a factory and at the department of chemistry without questions. ", " People who know the man say, \"That is Yaya Diallo. ", " That is him.\"", "\n\nFor eight months, the immigration's officers gave him a hard time. ", " He had to come to their office twice a week and each time he met a new officer. ", " On March 1974, he received an order to leave Canada or he would be deported in two days. ", "He met the right people at the right time and was given permission to stay in Canada. ", "He had the choice to stay and study or to become an immigrant. ", " He became an immigrant in 1974 and a Canadian citizen in 1983.", "\n\n2.3 Second short career as a chemist\n\nIn 1975, Diallo was ready to go back home to Mali. ", " In the newspaper he saw a contest in which the winner would get a job at the Department of Geology at the University du Quebec in Montreal. ", " He took a piece of paper, identified 9 mistakes out of 10 in the formulation of the problem and won the contest. ", " He was hired to work with a double collector mass spectrograph. ", " In the Geology Department, Dr. Claude-Marcel Hillaire was in charge of the project. ", " Using the stable isotope, Carbon-13 for dating instead of Carbon-14 which was radioactive. ", " In the entire world, there were only four double collector mass spectrograph. ", " One was in London where they were conceived and built. ", "One was in Australia, another in Montreal, and the last, Yaya has forgotten where it was sold.", "\n\nUseful project for people living in desert countries:\n\nThe first step was to collect carbon dioxide from the sample. ", " Under a vacuum of 0.001 Torr, one attacked the sample with a weak acid such as phosphoric acid. ", " The carbon dioxide appeared as a gas. ", " This gas then went through a trap that was immersed in ice at 0 degrees to retain water vapor. ", " After that, it continued its way to the following trap which was kept at -80 degrees Celsius. ", " The dry vapor was trapped at -180 degrees Celsius where it was a solid. ", " that last trap was immersed in liquid nitrogen.", "\n\nOne fixed the sample and the standard called Chicago on the spectrograph. ", " The two gasses were injected in the machine that collected the mass 44 of the sample and the standard on one side while on the other side, it collected the mass 45 of the two gasses. ", " Based on the difference between the mass 44 of the sample and the standard side, and the difference between the mass 45 of the two gasses, one could calculate the relative age of the sample using a complex formula and Fortran IV on the computer. ", "This part was a nightmare.", "\n\nAccording to the literature, this new technique could be used to estimate the age of water trapped underground. ", " Every six months, a sample was taken and analyzed. ", " If the age was the same, that meant that there was no new source of water to that specific location. ", " Only by watching the differences between the mass 44 and 45 of the sample and the standard one, could one make a conclusion that water was unchanged. ", " People who use wells in the desert could be warned that one day they would lack water. ", " When the differences changed, that meant that there was new water, so people could use the water without worries. ", " This technique can be used to determine the age of nitrogen in plankton, as well. ", " Yaya Diallo was enthusiastic to work on the project. ", " One day the destiny called him (Healing Drum).", "\n\n3 Musical career\n\nYaya Diallo said, \"For my people, with its rich musical context, exposure to music begins in the wombs when pregnant mothers join in the community dance...when infants are then wrapped onto their mother's backs with a cloth and taken into the dancing circle with everyone else.\" ", " This statement is quoted by Mickey Hart in his book Planet Drum, pp.", " 88. ", " That was Yaya Diallo's first music and dance lessons. ", " During his early childhood, he was exploring the balafons which were kept in his paternal family. ", " In his native village, Fienso, he was learning Peenyi (Dounou), spiritual balafon, morals, proverbs, and philosophy with his mentor Nangape Kone. ", " Sounkalo Kone and Issa Koroma gave him djembe (daykaylaykay) lessons. ", " Yago Kone was his biology and Moukolo (equivalent of Congo) teacher. ", " In Zangasso his grandfather taught him hand and stick drum techniques. ", " After his death, his grandfather continued to teach him music and wisdom in his dreams. ", " That is the most important part of his musical education. ", " Sotigui Kone was his religious tama (talking) drum teacher. ", " When he was six years old, Yaya Diallo had his first drum sculpted by the blacksmith Nianso Koroma. ", " He formed his first music group with the goals and dreams to impress his grandfather. ", " he felt and was disappointed.", "\n\nIn order to live with Minianka people Yaya Diallo had to have several initiations. ", " He is always interested in the religious and mystical aspects of the music. ", " He learned the music and the instruments which go with each step of the rituals. ", " In different secret societies he was playing the instrument that sustained the rhythm or and tempo.", "\n\n3.1 Practice time\n\nListening is the most important tool for learning in oral traditions. ", " As a shepherd, Yaya Diallo was using his body, pieces of wood and stones as musicalt instruments. ", " By tradition he should play flute or sokou (one string violins) but he did not like those instruments which are easily portable. ", " During the day he was listening to the musicians from different villages who were playing for groups of collective farmers to motivate people to work fast. ", " He also listened to birds, insects, and by nights, orchestras of frogs when he was near a small river.", "\n\nIn Sikasso the capitol of balafons, he was in Heaven listening to the finest players in 1960-61. ", " In Bamako, djembe is the main instrument, for six years at the Lycee, he heard great djembe players. ", " As a students at the Lycee, it was not a good thing to listen to traditional music.", "\n\n3.2 Musical career in Montreal, Canada\n\n1976-77\n\nWhen Yaya Diallo quit his job, he met Alama Kanate from Côte d'Ivoire, with two Senegaleses Boubacar Gueye and Moustapha Seck. ", " They founded a band called Djeme-kan.", "\n\nThe group did small performances for weddings and cultural events without good results. ", " The Senegaleses abandoned the group and were replaced by a Congolese guitarist and singer, and Alain Tagny, a dancer from Cameroun. ", " After two successful nights at the National Bibliothèque de Montreal on St. Denis Street Alama Kanate claimed that the group belonged to him. ", " So Djeme-kan was divided in two parts.", "\n\n1977-78\n\nYaya Diallo and Alain Tagny created Cleba, meaning that the sun is shining for everyone, so white people were accepted in the group. ", " That music unit was successful and played for big events such as St. John Baptist Celebration on main stages. ", " In May 1978, the group did a tour in Saguenay-Lac-Saint-Jean outside of Montreal. ", " It was a fiasco. ", " Montreal Canadiens, the Montreal Hockey team, was in the finals against the New York Rangers. ", " nobody could compete with this team in Quebec. ", " The most important thing was that in the 1970s, French Canadians were not ready to see white men playing African instruments and white women dancing to African music. ", " When they came back to Montreal, people were not motivated to continue, so they quit the group.", "\n\n3.3 Hard time in his life\n\nOctober 1977-February 1978\n\nTo survive, Diallo had money from unemployment for ten months. ", " Very broke, he got training to sell Grolier Encyclopedias. ", " He had to knock at doors all day long and by night he met targeted families. ", " In small cities, people were not ready to see a black man walking on the streets in the darkness in their neighborhood. ", " That was a problem. ", " In February, he went to the north of Quebec called Abitibi where the average temperature was -40 degrees Celsius. ", "He had suffered for a week and had sold only two encyclopedias. ", " Back in Montreal, he quit the job.", "\n\n1978-79\n\nYaya Diallo was homeless, jobless, and hopeless in spite of two prophecies. ", " He was dating Helen Alemany, his son Teli Diallo's mother. ", " He was teaching drum classes at the space they had rented for Cleba. ", " He was jamming at La Grande Passe on Ontario Street and Chez Dumas on Emery Street. ", " In Montreal they called him a \"chum,\" meaning people who dream big but are not capable of doing anything great.", "\n\n1979-80\n\nAt the Centre Monchanin, now Intercultural Institute of Montreal, he started to teach African dance to a group of women. ", " At the end of the project, Diallo was hired to work at the center in 1980. ", " He worked part-time and became a staff member and Treasurer of the board from 1980 to 1987.", "\n\n1980-90\n\nWhile he was working at the Center, he met a multi-billionaire, Madame Dominique de Menil from Houston, Texas. ", " She invited Yaya Diallo to accomplish a difficult mission. ", " On June 20, 1981, she wanted to reward ten people or organizations in the world at her chapel; The Rothko- the Rothko Chapel Rewards in Recognition of commitment to truth and Freedom. ", " For the rituals, Yaya Diallo's recommendations were the best among several options. ", " For each nominee, Yaya Diallo had to play an appropriate beat according to the type of commitment. ", " For example, for Las madres de La Playa de Mayo Buenos Aires, Argentina, he played the rhythm for people who had lost men, women, children. ", " For Warren Robbins, son of Jewish immigrants from Ukraine, founder and director of the Museum of African Arts, Washington D.C., who had accomplished a mission impossible, Yaya Diallo played a special music for brave people. ", " When the journalist Zwelakhe Sisulu's name was announced, Diallo played a beat for courage and motivation. ", " Sisulu was also a National President of the Media Worker's Association South Africa, Johannesburg.", "\n\nDecember 1981\n\nIn Houston, Warren Robbins was impressed by Yaya Diallo's wisdom and invited him for some events in Washington D.C. Diallo met some leaders of the Black community (today called African Americans) especially the group of African Heritage. ", " he performed at an Evening of Balafon music feature Yaya Diallo and Pascal Milogo at the Smithsonian Museum in Washington on December 27, 1981. ", " This concert was sponsored by the National Museum of Art's African Art program.", "\n\nHe was invited to talk on the radio station, La Voix de l'Amerique hosted by George Collinet. ", " Unfortunately he did not meet with George Collinet who was on vacation. ", " His messages were heard in 250 countries. ", " \"Young people, build your own country, there is no room for everybody in the USA. ", " American youth should not be your role models.\"", "\n\nTo meet Africans living in Washington D.C. he did a Balafon concert at the popular Malian restaurant \"The Baobab.\"", "\n\n3.4 Creative Music Studio, Woodstock, NY, CMS:\n\nDiallo conducted drum workshops and did some concerts with his group from Montreal. ", " He performed at CMS Summer Festival '81: World music on Sunday July 12 '81 as Yaya Diallo from Mali. ", " People such as John Abercrombie, Karl Beger, Chick Corea, Dave Holland, Ingrid, Jack de Johnette, Pat Metheny, Charlie Haden, and Dewey Redman had performed at CMS. ", " Diallo was a faculty member from 1981 to its end.", "\n\n3.5 Introduction to jazz music\n\nBaikida Carrol, a jazz horn player from St. Louis, invited Yaya Diallo to join in one of his two groups to play at Public Theater NY, on Friday November 14, 198?. ", " The first team called Bush Wish included Nana Vasconcellos, Bresil, Yaya Diallo and others. ", " The second team was composed of Julius Hemphill and Antony Davis. ", "Randy Weston appeared both nights.", "\n\nEven that Yaya Diallo said that he knew nothing about jazz, he felt at home in jam sessions with Baikida Carrol, Julius Hempell, and Antony Davis, and others.", "\n\n3.6 Dream time\n\n1980-82\n\nIn 1980, Yaya Diallo made his first LP record, produced by Stephen Conroy through his company Onzou Records. ", " The LP release was done at the Art Gallery the same day of the opening of one of the most popular clubs, Izaza in Montreal. ", " With some good musicians of Montreal and two dancers, Yaya Diallo did an excellent performance at L'Improvu on Monday, March 2, 1981, during the second LP release. ", " The media, people wanted to see more from him. ", " From March 31 to April 5, Diallo came back to L'Improvu located at L'Iroquois, Place Jaques Cartier Vieux Montreal. ", " The performances were original and excellent. ", " The phenomenon of Yaya Diallo was born in Montreal. ", " Karl Parent, a journalist of CBC International was amazed by what he heard at L'Improvu and offered to Yaya Diallo the opportunity to make the music of a documentary film. ", "Yaya Diallo did the music of the documentary film Leopold Cedar Senghor, Former President of Senegal. ", " The film was presented at CBC TV on Tuesday, May 1981. (", "See TV program. ", "Ici Radio-Canada, Vol. ", "5, no. ", "22)\n\n1982-90\n\nAfter a short time of glory in Montreal, Diallo's music career was going nowhere. ", " He started working part-time at the Intercultural Institute of Montreal while he opened African dance classes at 310 West st. ", "Catherine, moved to Cooper Building on St. Laurent, and finally to Building Dance on Mont-Royal St and Pine Ave at Montreal. ", " He had three classes of 40 students each a week. ", " Meantime he created his band, Kanza, and had time to raise his first son Teli.", "\n\nIn June 1983, Yaya Diallo was invited through the Institute to participate in a symposium at Namur Belgium. ", " That symposium was organized for European scholars and experts in intercultural cooperation by University De La Paix. ", " The questions were: What are unifying myths of the world? ", "Who has the right to define the criteria of good life for the world?", "\n\nIn July, he went back to Namur, Belgium, to assist in an intercultural colloquium organized by 200 non-profit organizations coming from all over the world. ", " After a week of work using six languages, Yaya Diallo was in charge of writing a report in French of the symposium with his old friend Adama Samassekou who was living in Paris, France. ", " Yaya Diallo came back to Montreal with 10 cassettes and did the work by himself.", "\n\nIn Namur, Yaya Diallo had shared a room with Professor Alpha Oumar Konare who became President of Mali for two five-year terms (1992–2002) and was chairperson of the African Union. ", " His friend Adama Samassekou was Minister of Education in Mali. ", " He was Yaya's Diallo's third roommate. ", " Some non-profit organizations did not like Diallo's opinions and his conclusions of the symposium. ", " In September, Yaya Diallo wrote the most controversial and critical article about the international cooperation in French, entitled, La Cooperation est-elle possible? ", " (Is Cooperation Possible?) ", " This article is published in Interculture (October–December 1983, Vol. ", "XVI, No. ", "4 cahier 81, pp.", " 9–17).", "\n\nWith a grant from the Ministry of Multiculturalism of Canada, Diallo wrote the Profil Culturel Africain. ", " This document was first published in 1985 by the Intercultural Institute of Montreal. ", " Many teachers, researchers, students, and seekers of exoticism, as well as Africans searching for their roots have had recourse to it. ", " In spite of that relative success, it is completely out of print. ", " In October 2001, it was translated in English as At the Threshold of the African Soul. ", " The Fulani-Minianka Way, Intercultural Issue No. ", "141. ", " This document is the heart of the book, Healing Drum, African Wisdom Teachings. ", "Diallo's international reputation came from his writings and his name is associated with the Healing Drum, as writing books is his destiny. ", "Diallo said, \"I don't want to be associated with a record company.\"", "\n\nIn 1982, as a musician, Diallo played two weeks at CNE (Canadian National Exhibit) in Toronto. ", " In 1986, he played at the International Exhibit in Vancouver BC, at Folklife, and at Canadian Pavilion. ", " In 1987, he stopped working at the Institute and started to tour to schools with the program made by the former General Governor of Canada, Jeanne Sauve. ", " The same year, he started teaching two courses, Aural training I and II, at Carlton University. ", "Diallo also was one of the first artists of the program made by Jan Andrews and Jennifer Cayley: \"A Change to Give.\" ", " The organization became MASC, Multiculturalism at Schools and Communities. ", " Diallo worked for MASC from 1988-2004.", "\n\nDiallo did some performances with his band, Kanze, at the Festival Culture Canada 88, at Ottawa-Hull: more than five festivals Nuits d'Afrique with Ballattou; Festival 1001 Nuits; at Club Soda 1989, 1990, The Spectrum de Montreal.", "\n\nIn 1987, Diallo collaborated with others of so-called French-speaking countries to make the song \"Franc Parler\" for the Summit of Francophony at Quebec City.", "\n\nThe Healing Drum was published in 1989. ", "The president of Inner Traditions, his wife and his staff came to Montreal to meet the community. ", "He bought food for the people of Balattou, for two nights the kanza played. ", "We had a press conference with The Gazette, La Presse, and Voir. ", "After Montreal the company had planned tours Yaya Diallo. ", "He went to bookstores and Universities, he signed books and did lectures all over the United States. ", "Mickey Hart, the drummer of the Grateful Dead, wrote his two books, he has quoted Diallo's work several times in each book and gave his opinion on how good he thought The Healing Drum was. ", "The phenomenon of The Healing Drum was born. ", "For several years Diallo did workshops, lectures and debates. ", "The World Music Institute contacted him, he became a member of the artists they manage. ", "They booked him everywhere they could as a solo artist. ", "In 1993 they created the African Troubadours, and they too booked shows everywhere. ", "Other people like Everyone's Drumming with Dounoukan, Relaxation Company, Dombaa Folee had produced Diallo's music, and organized the promotion of the products.", "\n\n_\"Schools Kick off Black History Month.\" ", "Buckner Elementary School. ", "The Courier Journal, Neighborhoods, February 6, 2002, by Tonia Holbrook\n_Drumming in the New MIllenium. ", "At the Pyramids of Egypt. ", "West African Yaya Diallo Mali. ", "December 6, 1999.", "\n_\"Champ meeting, Former Heavyweight Champion Muhammad Ali Greeted Drummer Yaya Diallo at Dunbar Community Center in Lexington, KY.\" ", "February 1995. ", "The Courier Journal.", "\n_\"Yaya Diallo Tells African Stories at Yukon Storytelling Festival 1994,\" June 29, 1994, The Yukon News. ", "p. 19.", "\n_\"African Drumer Brings Music to Students.\" ", "Yaya Diallo works with Boyd County Middle School students. ", "He will be at school for several days as artist in residence. ", "The Daily Independent, Ashland, KY. ", "January 23, 2002. ", "pp.", " 1 and 12, by Beth Goins.", "\n_\"Yaya Diallo Performed at the Student Center as a Part of Celebrating Diversity\"; Kentucky Kernel, University of Kentucky, Lexington. ", "February 27, 1992.", "\n_African Dancing and Drumming. ", "When Yaya Diallo plays, the entire body hears. ", "Rowe Camp and Conference Center, Rowe Mass. No 12-14, 1999.", "\n_One Thunder. ", "Yaya Diallo and 80 drummers from all over the world. ", "World Trade Organization at Singapore. ", "December 13, 1996. ", "pp.", " 1 and 12. ", "Program: Television Corporation of Singapore.", "\n_Music for People. ", "Workshops in Music Making, Drumming, and Dancing. ", "Featuring David Darling, Yaya Diallo, Glen Velez, Uleikha. ", "October 4–5, 1995. ", "Sacred Heart University, Fairfield, Connecticut.", "\n_Workshops. ", "Yaya Diallo West African Drumming Performances and Workshops. ", "Multiculturalism at School and Communities. ", "MASC. ", "Guest Artist and Artist in Residence for 12 years (see brochure 2003-04, p. 15)\n_World Music Institute presents. ", "A world of percussion featuring Don Cherry, Ed Blackwell, Nana Vasconcelos, Yaya Diallo. ", "June 6, at Symphony Space Broadway and 95th St. NYC, NY.", "\n_Creative Music Studio. ", "Summer Festivals 81. ", "Yaya Diallo from Mali. ", "People as JOhn Abercrombie, Karl Beger, Chick Corea, Dave Holland, Ingrid, Jack de Johnette, Pat Metheny had performed at the same festivals.", "\n_Yukon Storytelling Festival 1994. ", "Mainstage Performance; The Heart of the Festival: Why will say, yes, yes. ", "Yaya Diallo and Jan Andrews. ", "This was offered at two levels. ", "Ages 5–7, and ages 8 and up.", "\n_African Family Festival at the Louisville Zoo. ", "May 29–31, 1999. ", "Don't miss the festival featuring Yaya Diallo in concert May 31, 5pm.", "\n_African Troubadours featuring Hassan Hakmoun, James Makubuya, Yaya Diallo. ", "Traditional music of Morocco, Uganda, Mali, sponsored by the World Music Institute. ", "Sterling and Francine; Clark Art Institute Williamstown Mass. www.clarkwilliams.edu.", "\n_World Music Institute. ", "African Troubadours, Hassan Hakmoun, James Makubuya, Foday Musa Suso, Yaya Diallo, had its debut as a touring unit during African American History month in 1994. ", "The four sites in California including Humbold State University, Arcadia, University of California, Berkeley; University of California, Santa Cruz, University of California San Diego; as well as Colorado State University, Fort Collings.", "\n_A World of Percussion: Sat. ", "June 8, 1995. ", "Featuring Don Cherry, Glen Velez, Foday Musa Suso, Adam Rudolph, Michel MerHej, Hanna MerHej, Yaya Diallo, Ayib Dieng and Zakir Hussain at Symphony Space, NYC, NY info. ", "World Music Institute NYC, NY.", "\n_An Evening of Balafon Music Featuring Yaya Diallo and Pascal Millogo at the Smithsonian Museum Washington DC. ", "Sunday, December 27, 1981. ", "Evening sponsored by National Museum of African Art Program.", "\n_Best Bets. ", "World Beat. ", "Yaya Diallo teams up with three other leading African musicians to form African Troubadors. ", "Museum of civilization hosts top African Musicians on Friday, January 31, 1997, Canada.", "\n_Troubadours Teach Culture. ", "Black HIstory month starts with music. ", "African Troubadours at the Canadian Museum of Civilization. ", "The concert features Hassan Hakmoun, James Makubuya, Adam Rudolph, Vieux Diop. ", "Another one of the key elements of the group is Mali's Yaya Diallo, who was in town yesterday to conduct workshops at a couple of schools before the big show. ", "The Ottawa Sun, Vol. ", "9, No. ", "61. ", "Ottawa Friday. ", "January 31, 1997. ", "By Ric Overall. ", "Canada.", "\nDrumming: Dancing is the Other Healing Art. ", "In Yaya Diallo's Tradition, music is a remedy for psychological and physical problems. ", "From page B1 Citilighte Thursday January 30, 1997, Ottawa. ", "Canada.", "\n_Lexington Wellness Center. ", "Percussion with Passion. ", "African master drums up enthusiasm. ", "Yaya Diallo demonstrated some of the finer points of African drumming in a workshop at the Lexington Wellness Center. ", "Drumming is more than the rhythm to the Mali native. ", "See Drumming B3, Local News, 23, 1997 Lexington, KY.", "\n_Mirror: Books Rhythm of life. ", "The Healing Drum African Wisdom teachings. ", "By his account, Yaya Diallo was born in foolish Union. ", "Mirror Montreal Canada. ", "August 16–23, 1990 Vol. ", "6, p. 27 By Andrew Jones.", "\n_Don't try to impress Yaya Diallo Ginaw Bone Indian. ", "Mali drummer Yaya Diallo teslls with one beat of the drum what level of drummer he is teaching. ", "The Harold-Times, Vol. ", "115, no. ", "75. ", "Bloomington, Indiana. ", "By Kathleen Mills.", "\n_NY Open Center NYC, NY. ", "Yaya Diallo African Drumming and Dance from Mali. ", "Saturday and Sunday July 28 and 29 pg. ", "48 Yaya Concert p. 50.", "\n_Harrison Festival of the Arts. ", "July 21, 1988 Yaya Diallo, The people who attended your workshops were very pleased, and the afternoon concert was great. ", "It was definitely one of the highlights. ", "Phyllis Wilson, Executive Director. ", "Hot Springs, BC, Canada.", "\n_The Healing Drum with Yaya Diallo Concert: Sounds of Africa. ", "December 19, 1999. ", "Drumming, Dance, and Singing workshops December 20–22, 1999. ", "Concert and Dance with Yaya Diallo and company December 23, 1999. ", "Sivananda Ashram Yoga Camp. ", "Val Morin Quebec Canada.", "\n_Omega Institute. ", "Celebrating 25 years, At the threshold of the African soul, Village Voice. ", "By Yaya Diallo. ", "Drum and Dance Workshops and Concert. ", "July 22–26, pp.", " 56. ", "Omega May–October 2002 Rhenebeck, NY.", "\n_Village Awards March 27, 2004 Community Service/Arts, Yaya Diallo; The Healing Drum by the Godfather of Village Awards, Councilman George Unseld (6th District) Louisville, KY.", "\n_Mike's Spicks. ", "Yaya Diallo leads workshops in West African drum and dance in Woodstock NY. ", "Roots of Rhythm: Get 50-60 men and women together, each thumping a drum, led by a master whose chops and knowledge go all the way back to the roots of rhythm and you've got the resonance of heaven, the apotheosis of good vibrations. ", "That's what any serious percussionist or student of African dance can expect this weekend as Yaya Diallo returns to the Woodstock to conduct another series of workshops. ", "By David Arneir a Woodstock pianist and percussionist, Yaya's Balafon student.", "\n_World Music Institute Features African Troubadours: Hassan Hakmoun, James Makubuya, Musa Foday Suso, Yaya Diallo at Town Hall NYC, NY. ", "June 1996.", "\n_He's got the beat. ", "Glengarry students treated to some African charisma. ", "Yaya Diallo introduced his drums to Iona Academy on March 8, Martintown Public School on March 9, and to Williamstown Public School, and Char-Lin District High School March.", "\n_Sivananda Yogalife. ", "Winter 2000. ", "Millennium World Peace Pilgrimage. ", "The Peace MIssion continues into the 21st Century. ", "African Music and Dance by Yaya Diallo, p. 9.", "\n_Sivananda Millennium World Peace Pilgrimage. ", "London, England. ", "October 25–30, 1999. ", "Featuring Yaya Diallo, Concerts, Drumming and Dance Workshop. ", "Sivananda Yoga Centre. ", "London, England.", "\n_Sivananda Millennium World Peace Pilgrimage. ", "At Sivananda Ashram Yoga Retreat. ", "Paradise Island, The Bahamas. ", "Featuring Yaya Diallo: Concerts, Drumming and Dance Workshop. ", "From December 25, 1999 – January 1, 2000.", "\n_American Orf-Schulwork Association, 2003. ", "National Conference at Louisville, KY. ", "Nov. 12-16, 2003. ", "Three events with master drummer Yaya Diallo from Mali.", "\n_The last concert and workshop sponsored by World Music Institute for African Troubadours including Yaya Diallo was on Feb. 25 at the U.C. San Diego; year 2000.", "\n_1988, The two founders of MASC, Jan Andrews and Jennifer Cayley, had organized a big festival called \"Culture Canada\" at Park Lauier Located at Hull Quebec. ", "Like other people working for MASC, Diallo was asked to offer his workshop \"Music without Money.\" ", "With Stones, pieces of wood, small pipelines, bamboo sticks, children learned how to make quickly the instruments, and how to play together as an orchestra. ", "The Queen Mother Elisabeth II of England in visit in Canada wanted to see the workshops made by people from different cultures. ", "The Queen accompanied by the Prime Minister of Canada, Bryan Mulroney arrived to Yaya Diallo workshop, she was happy to see how one could make children happy with stones, woods…. ", "She hanged her hand to shake Diallo's hand, Diallo did not understand, the cameras took the image of the Queen's hands hanging in the air. ", "That was the embarrassing part. ", "Back to Montreal, Diallo's friends teased him, are you a separatist French Canadian. ", "The RCMP did a background check of all participants. ", "They did the something with children's parents before they chose them. ", "For a week Diallo did workshops and shows on small stages. ", "The last day there was the big show where ten groups from different cultures had to play one piece of music together. ", "Diallo's band was composed of musicians from Haiti.", "\n_1987-89, in 1987 Yaya Diallo started teaching three classes enroll training I and II at Carleton University in Ottawa, meantime he was doing tours at several schools in Ontario, Ottawa region, and in Quebec Outtaouais. ", "While he was working with Mapou Ginin a local music and dance group from Haiti, living in Montreal. ", "In December 1988, he combined his group Kanza to make the first show ever by a local world music group living in Montreal. ", "At Club Sods of Montreal. ", "The door of club Soda was closed to the so-called world beat musicians. ", "The show was great, so there were no excuses to keep the door closed to foreign music Fanta Kone from Guadaloupe, Delphin Pandoue from Cote d' Ivoire, and Josiane Antourel from Martinique three female dancers approached Yaya Diallo to make some performances. ", "After six months of hard work, Diallo combined the three professional dancers with his band Kanza to make a comeback show in the Club Soda. ", "The show was phenomenal. ", "Diallo had the challenge to open one more Closed door, the spectrum de Montreal. ", "The mission was accomplished; the door was opened for local world beat music. ", "To get in, each bad had to say if you could open the door to Yaya Diallo, you should open it for everyone. ", "In August 1989, Josian Antoural invited Yaya Diallo to the \"Festival Village Marin.\" ", "Le Festival de la me (Festival of the Sea). ", "Several Caribbean Islands came to celebrate the Caribbean Sea. ", "Yaya Diallo said it was one of the best times in my life. ", "Diallo was surprised to find out that the beat that he was playing over and over again with his band in Fienso, Mali was the most popular beat in Martinique. ", "Diallo's song \"Mouwa\" was a hit in Martinique. ", "During each performance, there were more than five encores. ", "For two weeks Diallo played and listened to unknown top musicians of Caribbean Sea.", "\n_Centre College. ", "Danville, KY. ", "African voices festival celebrates African and African-American culture. ", "Events include and evening of music from Mali by Yaya Diallo, a musician and author. ", "He will do two workshops, drumming and dance in Vahikamp Theater and a concert of January 14. ", "Diallo will also talk and perform at a program titled \"The Healing Drum African Wisdom Teachings\". ", "Center News, January 6, 2011, Kathy Nelsen.", "\n\nBooks\n1985 At the Threshold of the African Soul: The Fulani-Minianka Way / A Village Voice\nA Journal published by the Intercultural Center of Montreal\n1989 The Healing Drum: African Wisdom Teachings (Destiny Books)\n2001 Reprint journal At the Threshold of the African Soul\n\nArticles and reviews\nIntroduction to Djembe Drum Music Articles\nBellarmine Article About Yaya Diallo\nFrom Africa to the World, Yaya Diallo Unleashes His Music\nThe History of African Music\nThe Meaning of Music\nEffects of Sound\nThe Destruction of African Culture\nDjembe Drum Music\nThe Spiritual Significance of Music\nNangape Reviews\nDounoukan Reviews\nLive at Club Soda Reviews\nThe Healing Drum Book Reviews\nThe Healing Drum CD Reviews\nThe Truth About The Healing Drum\nLa cooperation est-elle possible?", "\nKilling The Ego (Yoga Life)\n\nAwards\n\n1986—Awarded by the Commissioner General of Section for Canada, recognizing his services rendered to the Canada Pavilion during the 1986 World Exposition Vancouver, British Columbia.", "\n2005—Entertainer of the Year, awarded by the African People's Intercontinental Awards.", "\n2008—Mosaic Award, Louisville, KY.", "\n\nDiscography\n The Healing Drum: African Ceremonial and Ritual Music (1994) CD - Destiny Recordings , \n Dounoukan (1995) CD - Yaya Diallo\n Dombaa Fole: Medicine Music of Mali (1998) CD & audio Cassette - Relaxation Company , \n Nangape (2003) CD - Onzou Records\n Live at Club Soda (2003) CD - Onzou Records\n\nReferences\n\n1 The Power of Music; The Drums of his Country Saved Yaya Diallo ... The Magazine of Bellarmine University. ", " Spring 2009 pp.", " 22–25 by Carla Carlton\n\n2 Mosaic Awards, The Jewish Family and Vocational Service. ", " Louisville. ", " May 14, 2008.", "\n\n3 At the Threshold of the African Soul. ", " An'R Issue 18 August 2003 pp.", " 14\n\n4 At the Best the Healing Drum is Honest ... Beat Magazine, Vol. ", "no. ", "4, 1990 \"Book Beat\" by Jason Fine\n\n5 Yaya Diallo Heals the Spirit, The Oberlin Review, September 22, 1995, by Stephame\n\n6 West African Dance, Music, and Culture Take in Kentucky. ", " Yaya Diallo plays ... Summer 2005 Magazine: Arts AerooKenky pp 44–46 by Judy Cato.", "\n\nYaya Diallo\n7 \"Schools Kick off Black History Month.\" ", " Buckner Elementary School. ", " The Courier Journal, Neighborhoods, February 6, 2002, by Tonia Holbrook\n\n8 The Only Representative of Mother Africa in this set is Yaya Diallo ... Down Beat: The Contemporary Music Magazine. ", " April 1983. ", " pg.40. ", " Editor.", "\n\n9 Drumming in the New MIllenium. ", " At the Pyramids of Egypt. ", " West African Yaya Diallo Mali. ", " December 6, 1999.", "\n\n10 \"Champ meeting, Former Heavyweight Champion Muhammad Ali Greeted Drummer Yaya Diallo at Dunbar Community Center in Lexington, KY.\" ", " Feb 1995. ", " The Courier Journal.", "\n\n11 \"Yaya Diallo Tells African Stories at Yukon Storytelling Festival 1994,\" June 29, 1994, The Yukon News, p. 19.", "\n\n12 \"African Drumer Brings Music to Students.\" ", " Yaya Diallo works with Boyd County Middle School students. ", " He will be at school for several days as artist in residence. ", "The Daily Independent, Ashland, KY. ", " January 23, 2002, pp.", " 1 and 12, by Beth Goins.", "\n\n13 \"Yaya Diallo Performed at the Student Center as a Part of Celebrating Diversity;\" Kentucky Kernel, University of Kentucky, Lexington. ", " February 27, 1992.", "\n\n14 African Dancing and Drumming. ", " When Yaya Diallo plays, the entire body hears. ", " Rowe Camp and Conference Center, Rowe Mass. No 12-14, 1999.", "\n\n15 One Thunder. ", " Yaya Diallo and 80 drummers from all over the world. ", " World Trade Organization at Singapore. ", " December 13, 1996. ", " pp.", " 1 and 12. ", " Program: Television Corporation of Singapore.", "\n\n16 Music for People. ", " Workshops in Music Making, Drumming, and Dancing. ", " Featuring David Darling, Yaya Diallo, Glen Velez, Uleikha. ", " October 4–5, 1995. ", " Sacred Heart University, Fairfield, Connecticut.", "\n\n17 Workshops. ", " Yaya Diallo West African Drumming Performances and Workshops. ", " Multiculturalism at School and Communities. ", " MASC. ", " Guest Artist and Artist in Residence for 12 years (see brochure 2003-2004, p. 15)\n\nRhythm and Music Magazine\n18 Master Drummer Yaya Diallo. ", " Fool's Gold: Percussion Discussion. ", " Music Global sounds and ideas May/June 1996 pp.", " 14–17 by David N. Blank-Edelman.", "\n\n19 Yaya Diallo Entertainer of the Year 2005. ", " API Award. ", "African People's Intercontinental Awards. ", " June 4, 2005 at the Washington Convention Center. ", " Washington DC Program pp 11 and 12.", "\n\n20 Power of Listening! ", " Yaya Diallo. ", "Today's Black Woman. ", " May 1997 by Joy Jones.", "\n\n21 EBONY. ", " Ebony Bookshelf. ", " The Healing Drum, An exploration of the culture of Minianka people (Mali) April 1990.", "\n\n22 World Music Institute presents. ", " A world of percussion featuring Don Cherry, Ed Blackwell, Nana Vasconcelos, Yaya Diallo. ", " June 6, at Symphony Space Broadway and 95th St. NYC, NY.", "\n\n23 Creative Music Studio. ", " Summer Festivals 81. ", " Yaya Diallo from Mali. ", " People as JOhn Abercrombie, Karl Beger, Chick Corea, Dave Holland, Ingrid, Jack de Johnette, Pat Metheny had performed at the same festivals.", "\n\n24 Yukon Storytelling Festival 1994. ", " Mainstage Performance; The Heart of the Festival: Why will say, yes, yes. ", " Yaya Diallo and Jan Andrews. ", " This was offered at two levels. ", " Ages 5–7, and ages 8 and up.", "\n\n25 African Family Festival at the Louisville Zoo. ", " May 29–31, 1999. ", " Don't miss the festival featuring Yaya Diallo in concert May 31, 5pm.", "\n\n26 African Troubadours featuring Hassan Hakmoun, James Makubuya, Yaya Diallo. ", " Traditional music of Morocco, Uganda, Mali sponsored by the World Music Institute. ", " Sterling and Francine; Clark Art Institute Williamstown Mass. www.clarkwilliams.edu.", "\n\n27 World Music Institute. ", " African Troubadours, Hassan Hakmoun, James Makubuya, Foday Musa Suso, Yaya Diallo, had its debut as a touring unit during African American History month in 1994. ", " The four sites in California including Humbold State University, Arcadia, University of California, Berkeley; University of California, Santa Cruz, University of California San Diego; as well as Colorado State University, Fort Collings.", "\n\n28 A World of Percussion: Sat. ", "June 8, 1995 Featuring Don Cherry, Glen Velez, Foday Musa Suso, Adam Rudolph, Michel MerHej, Hanna MerHej, Yaya Diallo, Ayib Dieng and Zakir Hussain at Symphony Space, NYC, NY info. ", " World Music Institute NYC, NY.", "\n\n29 An Evening of Balafon Music Featuring Yaya Diallo and Pascal Millogo at the Smithsonian Museum Washington DC. ", "Sunday, Dec. 27, 1981. ", " Evening sponsored by National Museum of African Art Program.", "\n\n30 Best Bets. ", " World Beat. ", " Yaya Diallo teams up with three other leading African musicians to form African Troubadors. ", " Museum of civilization hosts top African Musicians on Friday, January 31, 1997, Canada.", "\n\n31 Troubadours Teach Culture. ", " Black HIstory month starts with music. ", " African Troubadours at the Canadian Museum of Civilization. ", " The concert features Hassan Hakmoun, James Makubuya, Adam Rudolph, Vieux Diop. ", " Another one of the key elements of the group is Mali's Yaya Diallo, who was in town yesterday to conduct workshops at a couple of schools before the big show. ", " The Ottawa Sun, Vol. ", "9, No. ", "61. ", " Ottawa Friday. ", " January 31, 1997. ", " By Ric Overall. ", " Canada.", "\n\n32 Drumming: Dancing is the Other Healing Art. ", " In Yaya Diallo's Tradition, music is a remedy for psychological and physical problems. ", " From page B1 Citilighte Thursday January 30, 1997, Ottawa. ", " Canada.", "\n\n33 Lexington Wellness Center. ", " Percussion with Passion. ", " African master drums up enthusiasm. ", "Yaya Diallo demonstrated some of the finer points of African drumming in a workshop at the Lexington Wellness Center. ", " Drumming is more than the rhythm to the Mali native. ", " See Drumming B3, Local News, 23, 1997 Lexington, KY.", "\n\n34 Mirror: Books\nRhythm of life. ", " The Healing Drum African Wisdom teachings. ", " By his account, Yaya Diallo was born in foolish Union. ", " Mirror Montreal Canada. ", " August 16–23, 1990, Vol. ", "6, pp.", " 27. ", "By Andrew Jones\n\n35 Don't try to impress Yaya Diallo Ginaw Bone Indian. ", " Mali drummer Yaya Diallo teslls with one beat of the drum what level of drummer he is teaching. ", " The Harold-Times, Vol. ", "115 no. ", "75. ", " Bloomington, Indiana. ", " By Kathleen Mills\n\n36 Shaman's Drum. ", " A Journal of Experential Shamanism. ", " The Healing Drum (Yaya Diallo) is more than a literary autobiography: it includes considerable ethnographic information about Minianka culture. ", " Number 21: Fall 1990. ", " Editor of Shaman's Magazine.", "\n\n37 East West. ", " The Journal of Natural Health and Living. ", " The Healing Drum. ", " Diallo tells his tale with lucidity and poignancy. ", " It is a story that entertains and opens. ", " February 1991. ", " By Anna Bond.", "\n\n38 Education Feature\nNative culture, Firsthand. ", " For H.H. Langford students. ", " \"My grandfather said: Maybe it's time for lessons...You play like that somebody will kill you, Yaya Diallo.\" ", "students 5-6 grades. ", " Langford, Ontario Canada. ", " January 26, 1994.", "\n\n39 NY Open Center NYC, NY. ", " Yaya Diallo African Drumming and Dance from Mali. ", " Saturday and Sunday July 28 and 29 pg. ", "48 Yaya Concert pg. ", "50.", "\n\n40 The Healing Drum: yaya Diallo MItchell Hall. ", " A music with powers to heal the troubled soul. ", " Montreal: The Gazette. ", " Saturday, May 12, 1990. ", " By Daniel Feist. ", " Special to the Gazette.", "\n\n41 Interculture October–December 1983. ", " Is Cooperation possible? ", "By Yaya Diallo pp.", " 9–14 Vol, XVI, No. ", "4 cahier 81\n\n42 Just Plain Folks 2004 Music Award. ", " Artist nominee Yaya Diallo Dounoukan Album. ", " Yaya Diallo, West Africa (Mali)\n\n43 Just Plain Folks 2004 Music Award. ", " Album nominee Dounoukan, Yaya Diallo, West Africa (Mali)\n\n44 Harrison Festival of the Arts. ", " July 21, 1988. ", "Yaya Diallo, The people who attended your workshops were very pleased, and the afternoon concert was great. ", " It was definitely one of the highlights. ", " Phyllis Wilson, Executive Director. ", " Hot Springs, BC, Canada.", "\n\n45 Yoga LIfe Summer 99. ", " Published the article killing the Ego pages 18–19 By Yaya Diallo.", "\n\n46 Yaya Diallo's focus and intent are similar to those of Nada Yoga- the Yoga of sound and vibrations. ", " The Ashram will be a good place for him to play. ", " Ashrams had welcomed performers including Ravi Shankar, Akbar Kahn, and Paul Horn. ", " Ashock Charles. ", " Toronto. ", " Yoga LIfe Summer 1999, pp.", " 18–19.", "\n\n47 The Heling Drum with Yaya Diallo Concert: Sounds of Africa. ", "December 19, 1999. ", " Drumming, Dance, and Singing workshops December 20–22, 1999. ", " Concert and Dance with Yaya Diallo and company December 23, 1999. ", " Sivananda Ashram Yoga Camp. ", " Val Morin Quebec Canada.", "\n\n48 Omega Institute. ", " Celebrating 25 years, At the threshold of the African sou, Village Voice. ", " By Yaya Diallo. ", " Drum and Dance Workshops and Concert. ", " July 22–26, pp.", " 56. ", " Omega May–October 2002 Rhenebeck, NY.", "\n\n49 Sahell 2000. ", " Yaya Diallo, The Minianka Messenger. ", " Bulletin de sensibilisation et d'information sur l'Afrique. ", " D.I.B. E.C. Vol. ", "1, No. ", "3 April 1990. ", " By Ali Nekaa.", "\n\n50 Village Awards March 27, 2004 Community Service/Arts, Yaya Diallo; The Healing Drum by the Godfather of Village Awards, Councilman George Unseld (6th District) Louisville, KY.", "\n\n51 The Midwest Book Review; the Book Watch, The Heling Drum by Diallo and Hall. ", " Hapa Trade Journal Recordings 0-89281-505-1 CD Vol. ", "6 No. ", "1; New Year 1995. ", " More than just drumming.", "\n\n52 Jazz A L'Improvu. ", " Yaya Diallo back to L'Improvu. ", " March 31 to April 5, 1981 at L'Iroquois. ", " Place Jacques Cartier Vieux Montreal. ", " Montreal, Quebec.", "\n\n53 Jazz Report. ", " Yaya Diallo The Healing Drum. ", " Music is essential in Minianka existence. ", " Together Diallo and Hall collaborated to produce a text that combines anthropology, sociology, philosophy, and music in a potent and thought-provoking read. ", " Mark Sutherland.", "\n\n54 Body, Mind, Spirit Magazine. ", " October 2003. ", " I have beens searching for an authentic CD with chanting and singing, and now I have found it. ", " The Healing Drum: African Ceremonial an Ritual Music By Yaya Diallo.", "\n\n55 Ethnomusicology: The Healing Drum. ", " This is not actually a scholarly book, but that is part of its strength: The subjects discussed in part one, about Minianka culture as a whole, are those covered in standard ethnographic studies. ", " Roderic Knight, Book Review pp.", " 121 Winter 1991.", "\n\n56 What if Papageno played the Balafon? ", "in the Magazine Place des Arts Montreal. ", "Music Allows Yaya Diallo to see into souls, to cure madness, among other illness. ", " Jan-Feb 1990, Vol. ", "1, No. ", "2, By Jean Bernier.", "\n\n57 Mixed Media\n\n58 Mik's Spicks. ", " Yaya Diallo leads workshops in West African drum and dance in Woodstock NY. ", " Roots of Rhythm: Get 50-60 men and women together, each thumping a drum, led by a master whose chops and knowledge go all the way back to the roots of rhythm and you've got the resonance of heaven, the apotheosis of good vibrations. ", " That's what any serious percussionist or student of African dance can expect this weekend as Yaya Diallo returns to the Woodstock to conduct another series of workshops. ", " By David Arneir a Woodstock pianist and percussionist, Yaya's Balafon student.", "\n\n59 World Music Institute Features African Troubadours: Hassan Hakmoun, James Makubuya, Musa Foday Suso, Yaya Diallo at Town Hall NYC, NY. ", " June 1996.", "\n\n60 To keep Mali's Cultural roots alive Yaya Dialo drummer on mission to Save Malian Culture heritage. ", " Monday August 17, 2009. ", " The Courier Journal, Louisville, KY. ", " pp. ", "A1 and A2. ", " By Christ Kenning.", "\n\n61 He's got the beat. ", " Glengarry students treated to some African charisma. ", " Yaya Diallo introduced his drums to Iona Academy on March 8, Martintown Public School on March 9, and to Williamstown Public School, and Char-Lin District High School March 10. ", " The Glengarry News, Alexandria, Ontario Canada, p. 34. ", "March 23, 1988. ", " by Lesly Cadham.", "\n\n62 Sivananda Yogalife. ", " Winter 2000. ", " Millennium World Peace Pilgrimage. ", " The Peace MIssion continues into the 21st Century. ", " African Music and Dance by Yaya Diallo. ", "p. 9.", "\n\n63 Sivananda Millennium World Peace Pilgrimage. ", "London, England. ", " October 25–30, 1999. ", " Featuring Yaya Diallo, Concerts, Drumming and Dance Workshop. ", " Sivananda Yoga Centre. ", " London, England.", "\n\n64 Sivananda Millennium World Peace Pilgrimage. ", " At Sivananda Ashram Yoga Retreat. ", " Paradise Island, The Bahamas. ", " Featuring Yaya Diallo: Concerts, Drumming and Dance Workshop. ", "December 25, 1999 – January 1, 2000.", "\n\n65 American Orf-Schulwork Association, 2003. ", " National Conference at Louisville, KY. ", " November 12–16, 2003. ", " Three events with master drummer Yaya Diallo from Mali.", "\n\n66 Centre College. ", " Danville, KY. ", " African voices festival celebrates African and African-American culture. ", " Events include and evening of music from Mali by Yaya Diallo, a musician and author. ", " He will do two workshops, drumming and dance in Vahikamp Theater and a concert of January 14. ", " Diallo will also talk and perform at a program titled, The Healing Drum African Wisdom Teachings. ", " Center News January 6, 2011, Kathy Nelsen.", "\n\n67 The last concert and workshop sponsored by World Music Institute for African Troubadours including Yaya Diallo was on February 25 at the U.C. San Diego; year 2000.", "\n\nExternal links\nFarafina Donia - A survival school for traditional African culture\n\nCategory:1946 births\nCategory:Living people\nCategory:African drummers\nCategory:Malian musicians\nCategory:Université de Montréal alumni\nCategory:Bamana people\nCategory:Balafonists\nCategory:People from Sikasso Region" ]

{ "pile_set_name": "Wikipedia (en)" }

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[ "Q:\n\nTastypie Authentication without default User model\n\nI am building an API with Django Tastypie and I am trying to implement the ApiKeyAuthentication.", "\nMy system doesn't use the built in User model that Django provides and all the examples seem to rely on that.", "\nI've created my own version of the User model called Author which is much simpler. ", "For the ApiKeyAuthorization I was hoping to be able to use the id of an Author rather than the username of the User model.", "\nIs there a way I can build this authorization system without using the User model?", "\n\nA:\n\nApiKeyAuthentication relies on Django's builtin User object. ", "It's a fairly simple class implementation, looking at its source should give you an idea how to write your own Authentication model.", "\n\n" ]

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[ "Topic: background checks\n\nOLYMPIA (AP) — Microsoft co-founder Bill Gates and his wife have donated $1 million to a Washington state campaign seeking to expand background checks on gun sales, bringing the total amount the campaign has brought in up to nearly $6 million. ", "The donation to the Initiative 594 campaign was given Friday but not made public until…\n\nThe Associated Press A new poll shows strong support among Washington voters for a ballot initiative that would require background checks on all firearm sales in the state. ", "The Elway Poll found that 70 percent of people were inclined to vote for Initiative 594. ", "The same poll showed that 46 percent of people were inclined to vote…\n\nSALEM, Ore. (AP) — An Oregon bill that would require background checks for private gun sales appears to be in trouble. ", "Senate President Peter Courtney has promised to allow a vote in the full Senate if the measure can get out of the Judiciary Committee. ", "But there wasn’t enough support in Judiciary, so on Thursday that…\n\nSupporters of universal background checks for gun sales on Wednesday submitted most of the signatures they need to qualify for a 2014 statewide initiative. ", "Jewish Federation shooting victim Cheryl Stumbo and other Initiative 594 backers showed up in Olympia with an estimated 250,401 signatures on more than 15,000 petitions, according to the Secretary of State’s office. ", "While…\n\nAbout The Today File\n\nThe Today File is a general news blog featuring real-time coverage of Seattle and the Northwest. ", "It is reported by the news staff of The Seattle Times and includes stories from The Associated Press and McClatchy-Tribune Information Services." ]

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[ "Q:\n\nCreating a dataframe and casting colums with inferSchema from a csv is way slower than creating one and casting with withColumn\n\nI'm trying to create a dataframe in Spark by reading a csv, the problem is that if I don't do anything in particular the dataframe will have every column type as string:\nroot\n |-- ticker: string (nullable = true)\n |-- open: string (nullable = true)\n |-- close: string (nullable = true)\n |-- adj_close: string (nullable = true)\n |-- low: string (nullable = true)\n |-- high: string (nullable = true)\n |-- volume: string (nullable = true)\n |-- date: string (nullable = true)\n\nIn order to solve this I add the option \"inferSchema\" as true, like this: \nval spark = SparkSession.builder\n.appName(\"Job One\")\n.master(\"local\")\n.config(\"spark.eventLog.enabled\", \"true\")\n.config(\"spark.eventLog.dir\", spark_events)\n.getOrCreate()\nimport spark.implicits._", "\n\nval df = spark.read\n .format(\"csv\")\n .option(\"inferSchema\", \"true\")\n .option(\"header\", \"true\") \n .option(\"mode\", \"DROPMALFORMED\")\n .load(historicalStockPrices)\n\ndf.printSchema()\n\nAnd this way I obtain this instead:\nroot\n |-- ticker: string (nullable = true)\n |-- open: double (nullable = true)\n |-- close: double (nullable = true)\n |-- adj_close: double (nullable = true)\n |-- low: double (nullable = true)\n |-- high: double (nullable = true)\n |-- volume: long (nullable = true)\n |-- date: string (nullable = true)\n\nWhich is what I want, but adding the option inferSchema makes so that the job takes 1.4 minutes instead of just 6 seconds when I don't add it.", "\nAnother method to obtain the columns with the types I want is by using withColumn, like this:\nval df2 = df\n.withColumn(\"open\",df(\"open\").cast(\"Float\"))\n.withColumn(\"close\",df(\"close\").cast(\"Float\"))\n.withColumn(\"adj_close\",df(\"adj_close\").cast(\"Float\"))\n.withColumn(\"low\",df(\"low\").cast(\"Float\"))\n.withColumn(\"high\",df(\"high\").cast(\"Float\"))\n.withColumn(\"volume\",df(\"volume\").cast(\"Long\"))\n\ndf2.printSchema()\n\nThe result of the whole operation this time is just 6 seconds again.", "\nWhat gives?", "\n\nA:\n\nThe answer to your question: When you specify .option(\"inferSchema\", \"true\") it needs to dynamically read the whole file as you do not specify a percentage. ", "That takes a while. ", "This is not done with big files often.", "\n\n" ]

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[ "As web technologies continue to grow and evolve, interest in technical SEO is growing along with it. ", "Columnist Patrick Stox looks ahead to see what advancements are on the horizon and how these may impact technical SEO.", "\n\nThe post What’s next for technical SEO? ", "appeared first on Search Engine…\n\nGoogle has made its review markup guidelines fairly clear and has even issued penalties to sites that utilize spammy or misleading structured data markup. ", "But columnist Andrew Shotland points out that many sites are still violating these guidelines, intentionally or unintentionally." ]

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[ "Featured Post\n\nAre people annoyed by Pre-Roll Ads?", "\n\nHow often do people click away from pre-roll video advertisements before a video’s content starts playing? ", "For a period of 48 hours tubemogul tracked 1 797 560 video streams (full-length videos were excluded).", "\nWhat is the result of this analysis?", "\n15.89% of viewers click away from a video rather...\n\n0\n\nAs Facebook, Twitter and other social media sites entered our lives, something has changed. ", "Seth Goldstein (Co-Founder of SocialMedia.com) is convinced that Social ads became Ads 2.0.", "\n\nThis presents advertisers with a huge challenge, but also an opportunity to engage online audiences in new and compelling ways. ", "Transparency, responsiveness, genuine dialogue, and ethics take center stage in the battle for revenue.", "\n\nSeth Goldstein`s presentation from 2010 IAB Annual Leadership Meeting can be seen on SlideShare." ]

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[ "How millennia of honed tradecraft will help us survive Thunderdome.", "\n\nAs long as there have been people, there have been spies. ", "The Arthashastra, an ancient Indian text, details how a spy might take the guise of a holy man and con his way into the confidence of the king’s court. ", "Darius I of the Achaemenid Empire employed spies called “the king’s ears” to keep tabs on provincial governors. ", "The Aztec Empire commissioned traveling merchants as a kind of ancient State Department, charging them with diplomacy and espionage.", "\n\nToday, we send Lacrosse satellites into orbit and relay signals down to Area 58. ", "Unmanned aerial vehicles with stealth technology map out nuclear facilities. ", "We have Gorgon Stares and biometrics, and whenever we need to know the general mood in Peshawar, we harvest data from social networks and feed it to “vengeful librarians.”", "\n\nBut what would happen if the satellites went dark? ", "What would have happened if the United States and Soviet Union had unleashed their full arsenals of intercontinental ballistic missiles and pressed the reset button on humanity, tabula rasa. ", "Chances are, survivors would keep doing what we’ve always done: Try to learn what the other tribe is doing, and how best to get the jump on him. ", "In other words, we’d keep on spying. ", "But what would espionage look like in the post-apocalypse (with or without zombies)? ", "Whether in the Capital Wasteland or the Mad Max deserts, people will always spy on one another. ", "Here’s how we’d do it.", "\n\nOnce the radiation reaches acceptable levels and politicians crawl out of “Area B” of the Mount Weather Emergency Operations Center, the first thing they’re going to want is a read of the new operating environment. ", "As Sun Tzu wrote, “What enables the wise sovereign and the good general to strike and conquer, and achieve things beyond the reach of ordinary men, is foreknowledge.” ", "Human intelligence (HUMINT) will be critical in establishing an understanding of the mutated hordes. ", "Only with such an understanding can the “rightful” government reassert authority. ", "The power of observation can provide the most basic understanding of an army or people. “", "When his troops lean on their weapons, they are famished. ", "When drawers of water drink before carrying it to camp, his troops are suffering from thirst.”", "\n\nWhen the spies who emerge from the ruins of Site R communicate with one another, cryptography will be essential. ", "This has been essential to intelligence operations since at least the time of the ancient Greeks. ", "The quality of encryption today is unrivaled and hard to grasp—even with hypothetical computers of unbridled speed, it has been estimated that to break PGP with brute force would take ten trillion years. (", "For comparison, the universe is only 13.75 billion years old.)", "\n\nPost-apocalypse, things would throttle back a bit, and we might revert to Spartan technology, or at least a variant of it. ", "The scytale, for example, (pronounced skittle-ly, as in: “This fruit candy tastes Skittle-ly.”) ", "was a baton with parchment wrapped around it, running up, like you might imagine the bandages of a mummy’s arm. ", "Unwrapped, the parchment would seem to be random letters; wrapped on a baton of exact diameter, however, letters would align and the message would reveal itself. ", "Phil Zimmerman might not be impressed, but it’s better than plaintext.", "\n\nLast year, the Central Intelligence Agency declassified the government’s oldest classified documents, dating back to World War I. Said then-Director Leon Panetta: “These documents remained classified for nearly a century until recent advancements in technology made it possible to release them.” ", "Any tool of espionage with that kind of shelf life has to be good. ", "In this case, the government was protecting information on steganography—that is, the use of invisible ink.", "\n\nThe ancient Romans discovered that print made with the milk of the tithymalus plant would dry invisible, but reveal itself if gently heated. ", "Different formulas were developed over the centuries to employ hidden messages, though inks could be formulated from ingredients as basic as lemon juice and water. ", "During the American Revolutionary War, General George Washington employed the use of secret ink called “sympathetic stain.” ", "When used in combination with a code, the ink was so effective that it took 150 years before anyone learned the identities of the spies under his aegis. ", "Once the grid is gone and we’re living in a zombie wasteland, such basic tradecraft as writing two messages on a single page—one with invisible ink and one with standard black ink—will again become a necessity. ", "The zombies won’t know what hit them. (", "Take note also that lemon groves will become a vital national asset.)", "\n\nAnother technique Washington employed (and Sun Tzu wrote about) was the use of the double agent. ", "Early in the Revolution, he recruited a former British soldier named John Honeyman to serve as a secret agent for the Continental Army. ", "Honeyman plied his trade as a butcher and craftsman, and stridently trafficked with the British, all the while gathering intelligence. ", "After collecting enough information, he arranged to be detained by the Continentals and brought directly to General Washington for “interrogation.” ", "The information he had gathered: The British and German troops at Trenton were preoccupied with the coming Christmas holiday, and susceptible to attack. ", "This information was valuable, but Washington raised the stakes by arranging for Honeyman to escape the stockade. ", "Honeyman then went to Colonel Johann Rall, the Hessian commander in Trenton, with intelligence he had “gathered”: The Continental forces under Washington were in disarray and mutinous, and posed little threat.", "\n\nThe Christmas celebration thus went forward, and that night, General Washington and his soldiers quietly crossed the Delaware River before mounting a decisive attack on the Hessians at the Battle of Trenton. ", "The United States of America exists today specifically because of an instance of effective tradecraft. ", "That’s not bad considering the Continental Army didn’t have a National Geospatial-Intelligence Agency. ", "The use of double agents will work well when Cormac McCarthy novels become nonfiction.", "\n\nTherefore, we can say with confidence that espionage in the grim future (if that’s what’s in store) will look a lot like that of the shiny past. “", "An army without secret agents is exactly like a man without eyes or ears,” wrote Sun Tzu. ", "In our horribly mutated future, a want for eyes and ears might well be the norm. ", "Burgeoning spy agencies might not have quantum computers or nanotechnology, but they will have something, in a sense, more valuable—something in many ways lost in the digital age—fundamental, proven, time-tested tradecraft. ", "To the mutants, zombies, smokers, and raiders: Bring it on.", "\n\nD.B. Grady is the pseudonym of author David Brown. ", "He is the co-author of The Command: Deep Inside the President’s Secret Army, and can be found at http://dbgrady.com or on Twitter at @dbgrady." ]

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[ "The present invention relates to a locking device for locking a movable member such as the backrest or a seat,\nIn a locking device in JP59-44364U, the front part of the seat is pivotally mounted to the front part of a support base, and the rear part of the seat is urged forward and upward by a spring. ", "In the adjusting metal tool on the lower surface of the rear part of the seat, a plurality of engagement holes communicates with one another via narrower communicating holes to form an adjusting hole. ", "The support base comprises an operating rod which has a larger-diameter portion which passes through the engagement hole, but does not pass through the communicating hole, and a smaller-diameter portion which passes through the smaller-diameter hole to move axially. ", "The smaller-diameter portion fits in the adjusting hole to allow the seat to be adjusted freely in an angle. ", "The smaller-diameter portion is shifted sideward from the adjusting hole to allow the larger-diameter portion to fit in the selected engagement hole, so that the seat is locked at a tilted position determined by the selected engagement hole.", "\nIn a conventional chair, an elevating device for the seat or an operating lever for operating a tilting device of the backrest is mounted to the seat, a support base for the backrest, backrest frame or a support member on the lower surface of the seat.", "\nFor example, JP2005-163966A discloses the mounting structure in which the end of an operating lever is bent like a crank which actuates a gas spring for urging the backrest to stand up. ", "The shaft of the operating lever is held by a holding tool screwed to the backrest frame.", "\nHowever, in the locking device in JP59-44364U, an operating rod is loaded by the weight of the occupant who sits on the chair, so that the operating rod is not moved. ", "To move the operating rod, it is necessary for the occupant to leave the seat or to stand up thereby causing poor operativity.", "\nIn JP2005-163966A, in order to mount the operating lever, it is necessary to fix the holding metal tool to the support member, which is complicated and needs time. ", "The number of parts is increased." ]

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[ "Monday, November 26, 2007\n\nToday, I received the best email message from a friend. ", "Mark, who usually does not forward emails, sent me the most beautiful, thought provoking poem that left me speechless. ", "A Black Woman's Smile by Ty Gray-El captures the very essence of Black women. ", "The poem illustrates the struggles Black women had to endure, the strength she gained as a result of her struggles, and the beauty she exhibit despite her struggles.", "\n\nSunday, November 25, 2007\n\nStarting Monday, November 26th, \"NBC News with Brian Williams\" will air a five-part series that takes a look at the issues facing African-American women. ", "The series will cover a wide-range of issues from the role African-American women will play in the 2008 Presidential race, to increased health risks. ", "Please visit the websitehttp://dailynightly.msnbc.msn.com/archive/2007/11/20/476352.aspx for a more detailed program description. ", "Check your local listings for air time.", "\n\nThis should be an interesting series, I'll watch the program before I form an opinion.", "\n\nThursday, November 22, 2007\n\nThanksgiving is a day to reflect on all of life's riches. ", "Riches not in term of material things, but of the love and joy experienced with family and friends. ", "Sharing love is one of God's greatest gifts. ", "I wish you all a day filled with love on this Thanksgiving day and throughout the year." ]

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[ "package blackfriday\n\nimport (\n\t\"bytes\"\n\t\"fmt\"\n)\n\n// NodeType specifies a type of a single node of a syntax tree. ", "Usually one\n// node (and its type) corresponds to a single markdown feature, e.g. emphasis\n// or code block.", "\ntype NodeType int\n\n// Constants for identifying different types of nodes. ", "See NodeType.", "\nconst (\n\tDocument NodeType = iota\n\tBlockQuote\n\tList\n\tItem\n\tParagraph\n\tHeading\n\tHorizontalRule\n\tEmph\n\tStrong\n\tDel\n\tLink\n\tImage\n\tText\n\tHTMLBlock\n\tCodeBlock\n\tSoftbreak\n\tHardbreak\n\tCode\n\tHTMLSpan\n\tTable\n\tTableCell\n\tTableHead\n\tTableBody\n\tTableRow\n)\n\nvar nodeTypeNames = []string{\n\tDocument: \"Document\",\n\tBlockQuote: \"BlockQuote\",\n\tList: \"List\",\n\tItem: \"Item\",\n\tParagraph: \"Paragraph\",\n\tHeading: \"Heading\",\n\tHorizontalRule: \"HorizontalRule\",\n\tEmph: \"Emph\",\n\tStrong: \"Strong\",\n\tDel: \"Del\",\n\tLink: \"Link\",\n\tImage: \"Image\",\n\tText: \"Text\",\n\tHTMLBlock: \"HTMLBlock\",\n\tCodeBlock: \"CodeBlock\",\n\tSoftbreak: \"Softbreak\",\n\tHardbreak: \"Hardbreak\",\n\tCode: \"Code\",\n\tHTMLSpan: \"HTMLSpan\",\n\tTable: \"Table\",\n\tTableCell: \"TableCell\",\n\tTableHead: \"TableHead\",\n\tTableBody: \"TableBody\",\n\tTableRow: \"TableRow\",\n}\n\nfunc (t NodeType) String() string {\n\treturn nodeTypeNames[t]\n}\n\n// ListData contains fields relevant to a List and Item node type.", "\ntype ListData struct {\n\tListFlags ListType\n\tTight bool // Skip <p>s around list item data if true\n\tBulletChar byte // '*', '+' or '-' in bullet lists\n\tDelimiter byte // '.' ", "or ')' after the number in ordered lists\n\tRefLink []byte // If not nil, turns this list item into a footnote item and triggers different rendering\n\tIsFootnotesList bool // This is a list of footnotes\n}\n\n// LinkData contains fields relevant to a Link node type.", "\ntype LinkData struct {\n\tDestination []byte // Destination is what goes into a href\n\tTitle []byte // Title is the tooltip thing that goes in a title attribute\n\tNoteID int // NoteID contains a serial number of a footnote, zero if it's not a footnote\n\tFootnote *Node // If it's a footnote, this is a direct link to the footnote Node. ", "Otherwise nil.", "\n}\n\n// CodeBlockData contains fields relevant to a CodeBlock node type.", "\ntype CodeBlockData struct {\n\tIsFenced bool // Specifies whether it's a fenced code block or an indented one\n\tInfo []byte // This holds the info string\n\tFenceChar byte\n\tFenceLength int\n\tFenceOffset int\n}\n\n// TableCellData contains fields relevant to a TableCell node type.", "\ntype TableCellData struct {\n\tIsHeader bool // This tells if it's under the header row\n\tAlign CellAlignFlags // This holds the value for align attribute\n}\n\n// HeadingData contains fields relevant to a Heading node type.", "\ntype HeadingData struct {\n\tLevel int // This holds the heading level number\n\tHeadingID string // This might hold heading ID, if present\n\tIsTitleblock bool // Specifies whether it's a title block\n}\n\n// Node is a single element in the abstract syntax tree of the parsed document.", "\n// It holds connections to the structurally neighboring nodes and, for certain\n// types of nodes, additional information that might be needed when rendering.", "\ntype Node struct {\n\tType NodeType // Determines the type of the node\n\tParent *Node // Points to the parent\n\tFirstChild *Node // Points to the first child, if any\n\tLastChild *Node // Points to the last child, if any\n\tPrev *Node // Previous sibling; nil if it's the first child\n\tNext *Node // Next sibling; nil if it's the last child\n\n\tLiteral []byte // Text contents of the leaf nodes\n\n\tHeadingData // Populated if Type is Heading\n\tListData // Populated if Type is List\n\tCodeBlockData // Populated if Type is CodeBlock\n\tLinkData // Populated if Type is Link\n\tTableCellData // Populated if Type is TableCell\n\n\tcontent []byte // Markdown content of the block nodes\n\topen bool // Specifies an open block node that has not been finished to process yet\n}\n\n// NewNode allocates a node of a specified type.", "\nfunc NewNode(typ NodeType) *Node {\n\treturn &Node{\n\t\tType: typ,\n\t\topen: true,\n\t}\n}\n\nfunc (n *Node) String() string {\n\tellipsis := \"\"\n\tsnippet := n.Literal\n\tif len(snippet) > 16 {\n\t\tsnippet = snippet[:16]\n\t\tellipsis = \"...\"\n\t}\n\treturn fmt.", "Sprintf(\"%s: '%s%s'\", n.Type, snippet, ellipsis)\n}\n\n// Unlink removes node 'n' from the tree.", "\n// It panics if the node is nil.", "\nfunc (n *Node) Unlink() {\n\tif n.Prev !", "= nil {\n\t\tn.Prev.", "Next = n.Next\n\t} else if n.Parent !", "= nil {\n\t\tn.Parent.", "FirstChild = n.Next\n\t}\n\tif n.Next !", "= nil {\n\t\tn.Next.", "Prev = n.Prev\n\t} else if n.Parent !", "= nil {\n\t\tn.Parent.", "LastChild = n.Prev\n\t}\n\tn.Parent = nil\n\tn.Next = nil\n\tn.Prev = nil\n}\n\n// AppendChild adds a node 'child' as a child of 'n'.", "\n// It panics if either node is nil.", "\nfunc (n *Node) AppendChild(child *Node) {\n\tchild.", "Unlink()\n\tchild.", "Parent = n\n\tif n.LastChild !", "= nil {\n\t\tn.LastChild.", "Next = child\n\t\tchild.", "Prev = n.LastChild\n\t\tn.LastChild = child\n\t} else {\n\t\tn.FirstChild = child\n\t\tn.LastChild = child\n\t}\n}\n\n// InsertBefore inserts 'sibling' immediately before 'n'.", "\n// It panics if either node is nil.", "\nfunc (n *Node) InsertBefore(sibling *Node) {\n\tsibling.", "Unlink()\n\tsibling.", "Prev = n.Prev\n\tif sibling.", "Prev !", "= nil {\n\t\tsibling.", "Prev.", "Next = sibling\n\t}\n\tsibling.", "Next = n\n\tn.Prev = sibling\n\tsibling.", "Parent = n.Parent\n\tif sibling.", "Prev == nil {\n\t\tsibling.", "Parent.", "FirstChild = sibling\n\t}\n}\n\nfunc (n *Node) isContainer() bool {\n\tswitch n.Type {\n\tcase Document:\n\t\tfallthrough\n\tcase BlockQuote:\n\t\tfallthrough\n\tcase List:\n\t\tfallthrough\n\tcase Item:\n\t\tfallthrough\n\tcase Paragraph:\n\t\tfallthrough\n\tcase Heading:\n\t\tfallthrough\n\tcase Emph:\n\t\tfallthrough\n\tcase Strong:\n\t\tfallthrough\n\tcase Del:\n\t\tfallthrough\n\tcase Link:\n\t\tfallthrough\n\tcase Image:\n\t\tfallthrough\n\tcase Table:\n\t\tfallthrough\n\tcase TableHead:\n\t\tfallthrough\n\tcase TableBody:\n\t\tfallthrough\n\tcase TableRow:\n\t\tfallthrough\n\tcase TableCell:\n\t\treturn true\n\tdefault:\n\t\treturn false\n\t}\n}\n\nfunc (n *Node) canContain(t NodeType) bool {\n\tif n.Type == List {\n\t\treturn t == Item\n\t}\n\tif n.Type == Document || n.Type == BlockQuote || n.Type == Item {\n\t\treturn t !", "= Item\n\t}\n\tif n.Type == Table {\n\t\treturn t == TableHead || t == TableBody\n\t}\n\tif n.Type == TableHead || n.Type == TableBody {\n\t\treturn t == TableRow\n\t}\n\tif n.Type == TableRow {\n\t\treturn t == TableCell\n\t}\n\treturn false\n}\n\n// WalkStatus allows NodeVisitor to have some control over the tree traversal.", "\n// It is returned from NodeVisitor and different values allow Node.", "Walk to\n// decide which node to go to next.", "\ntype WalkStatus int\n\nconst (\n\t// GoToNext is the default traversal of every node.", "\n\tGoToNext WalkStatus = iota\n\t// SkipChildren tells walker to skip all children of current node.", "\n\tSkipChildren\n\t// Terminate tells walker to terminate the traversal.", "\n\tTerminate\n)\n\n// NodeVisitor is a callback to be called when traversing the syntax tree.", "\n// Called twice for every node: once with entering=true when the branch is\n// first visited, then with entering=false after all the children are done.", "\ntype NodeVisitor func(node *Node, entering bool) WalkStatus\n\n// Walk is a convenience method that instantiates a walker and starts a\n// traversal of subtree rooted at n.\nfunc (n *Node) Walk(visitor NodeVisitor) {\n\tw := newNodeWalker(n)\n\tfor w.current !", "= nil {\n\t\tstatus := visitor(w.current, w.entering)\n\t\tswitch status {\n\t\tcase GoToNext:\n\t\t\tw.next()\n\t\tcase SkipChildren:\n\t\t\tw.entering = false\n\t\t\tw.next()\n\t\tcase Terminate:\n\t\t\treturn\n\t\t}\n\t}\n}\n\ntype nodeWalker struct {\n\tcurrent *Node\n\troot *Node\n\tentering bool\n}\n\nfunc newNodeWalker(root *Node) *nodeWalker {\n\treturn &nodeWalker{\n\t\tcurrent: root,\n\t\troot: root,\n\t\tentering: true,\n\t}\n}\n\nfunc (nw *nodeWalker) next() {\n\tif (!", "nw.current.isContainer() || !", "nw.entering) && nw.current == nw.root {\n\t\tnw.current = nil\n\t\treturn\n\t}\n\tif nw.entering && nw.current.isContainer() {\n\t\tif nw.current.", "FirstChild !", "= nil {\n\t\t\tnw.current = nw.current.", "FirstChild\n\t\t\tnw.entering = true\n\t\t} else {\n\t\t\tnw.entering = false\n\t\t}\n\t} else if nw.current.", "Next == nil {\n\t\tnw.current = nw.current.", "Parent\n\t\tnw.entering = false\n\t} else {\n\t\tnw.current = nw.current.", "Next\n\t\tnw.entering = true\n\t}\n}\n\nfunc dump(ast *Node) {\n\tfmt.", "Println(dumpString(ast))\n}\n\nfunc dumpR(ast *Node, depth int) string {\n\tif ast == nil {\n\t\treturn \"\"\n\t}\n\tindent := bytes.", "Repeat([]byte(\"\\t\"), depth)\n\tcontent := ast.", "Literal\n\tif content == nil {\n\t\tcontent = ast.content\n\t}\n\tresult := fmt.", "Sprintf(\"%s%s(%q)\\n\", indent, ast.", "Type, content)\n\tfor n := ast.", "FirstChild; n !", "= nil; n = n.Next {\n\t\tresult += dumpR(n, depth+1)\n\t}\n\treturn result\n}\n\nfunc dumpString(ast *Node) string {\n\treturn dumpR(ast, 0)\n}\n" ]

{ "pile_set_name": "Github" }

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[ "INTRODUCTION\n============\n\nIn neural networks, the relative weight of synaptic and intrinsic conductances varies depending on the type of neuron ([@B16]) as well as on the task performed ([@B63]; [@B4]). ", "Although spinal neurons have complex repertoires of intrinsic properties, such as plateau potentials and low threshold spikes (LTS; [@B57]), their contribution to the various functions executed by spinal circuits remains controversial. ", "Using an isolated carapace--spinal cord preparation in turtles, [@B1] showed that plateau potentials in motoneurons are overridden by synaptic activity during scratch. ", "However, inward persistent conductances in cat motoneurons innervating ankle extensor muscles are modulated by small changes in the angle of the ankle joint ([@B26]) and plateau potentials are recruited in frog motoneurons during the withdrawal reflex ([@B49]). ", "This suggests that the involvement of intrinsic properties is highly dependent on the particular function executed by spinal circuits.", "\n\nThe detection and feature extraction of sensory information during the initial steps of sensory processing involve complex transformations at the cellular level. ", "We hypothesize that as reported for some sensory modalities ([@B60]; [@B30]; [@B48]; [@B35]; [@B62]), intrinsic properties of dorsal horn neurons (DHN) actively shape somato-sensory information carried by primary afferent fibers. ", "To test this idea, we took advantage of an integrated spinal cord--hindlimbs preparation from turtles allowing the combination of patch-clamp recordings of DHN embedded in an intact network with accurate control of the extracellular milieu ([@B52]). ", "We found that plateau potentials and LTS -mediated by L- and T-type Ca^2+^channels, respectively- generated complex dynamics by interacting with naturally evoked synaptic potentials. ", "For example, the LTS underlined a form of plasticity of inhibitory receptive fields whereas the plateau potential transformed sensory signals in the time domain. ", "Thus, unlike some motor tasks involving massive activation of large-scale networks, intrinsic properties have a say on the integration of sensory information performed by DHN.", "\n\nMATERIALS AND METHODS {#s1}\n=====================\n\nAll experimental procedures were performed in accordance with the ethical guidelines established by our local Committee for Animal Care and Research at the Instituto de Investigaciones Biológicas Clemente Estable. ", "Every precaution was taken to minimize animal stress and the number of animals used. ", "Data were obtained from 40 juvenile turtles (*Trachemys dorbignyi*; 5--7 cm carapace length). ", "The animals were maintained in temperate aquaria (24--26°C) under natural illumination.", "\n\nINTEGRATED PREPARATION\n----------------------\n\nThe procedures to obtain the preparation are described in detail elsewhere ([@B52]). ", "Briefly, turtles rendered torpid by hypothermia induced by immersion in crushed ice for 1.5--2 h ([@B43]; [@B1]) were decapitated and the blood was removed by intraventricular perfusion with Ringer solution (6°C) of the following composition (in millimolar): 96.5 NaCl, 2.6 KCl, 31.5 NaHCO~3~, 4 CaCl~2~, 2 MgCl~2~, and 10 glucose. ", "The solution was saturated with 5% CO~2~ and 95% O~2~ to attain pH 7.6. ", "The animals were curarized (50--40 mg kg^-1^, I.M.) to avoid reflex responses to sensory stimulation. ", "The lumbo-sacral spinal cord was exposed on its dorsal side by remotion of a strip of carapace, and a chamber was formed by fixing two blocks of agar along the cord. ", "The posterior half of the body was then glued to a platform for recording and stimulation. ", "The spinal cord was continuously superfused with Ringer solution at a rate of 1 ml min^-1^. In some experiments, NiCl~2~ (200--900 μM), CsCl~2~ (1 mM), and nifedipine (10--50 μM, Sigma) were added to the Ringer solution. ", "At least 15 min elapsed before data collection after a change in composition of the superfusate. ", "All experiments were performed at room temperature (20--22°C).", "\n\nELECTROPHYSIOLOGICAL RECORDINGS AND STIMULATION\n-----------------------------------------------\n\nPatch-clamp whole-cell recordings were made blindly in the lumbar enlargement at depths of 150--500 μm from the dorsal surface of the cord. ", "The electrodes (7--20 MΩ) were pulled from thick wall glass tube (A-M Systems, Carlsborg, WA, USA) with a Flaming--Brown P-87 puller (Sutter Instruments, Co., USA) and filled with the following solution (in millimolar): 122 K-gluconate, 5 Na~2~-ATP, 2.5 MgCl~2~, 0.0003 CaCl~2~, 5.6 Mg-gluconate, 5 K-Hepes, 5 H-Hepes. ", "In some experiments, biocytin (10 mM) was also added to the patch solution. ", "Recordings were performed in the current clamp mode with an AxoClamp-2B amplifier (Axon Instruments, Union City, CA, USA) driven by a programmable stimulator (Master-8; A.M.P.I., Israel). ", "Data were filtered (DC-5 KHz), digitized (20 kHz sampling rate), and stored in a personal computer for offline analysis.", "\n\nThe passive and active properties of DHN were characterized by applying current pulses lasting from 500 ms to 5 s at different levels of holding current. ", "Action potential amplitudes were measured from peak to peak, input resistances determined in the linear region of the voltage-current relationship and liquid junction potentials (-14.6 mV) corrected off-line ([@B2]). ", "Numerical values are expressed as mean ± SEM.", "\n\nAfter the electrophysiological characterization of the recorded cell, the receptive field was studied by applying mechanical stimuli in the dorsal surface of the ipsilateral hindlimb. ", "To map the receptive field, stimuli were applied in 3 mm steps and repeated three times at each location. ", "Innocuous mechanical stimuli were produced by means of a fine artist brush and pinprick stimuli with the tip of a fine tweezers. ", "To ensure the same level of natural stimulation when performing pharmacology, we applied vibratory stimuli to the skin with a blunt probe (0.6 mm diameter) or a sharp tip attached to the cone of a loudspeaker. ", "A wave generator (Hewlett Packard 3312A) was used to drive the loudspeaker to produce sinusoidal stimuli of 60--70 Hz. ", "A homemade movement detector based on an infrared optocoupler was used to measure the displacement of the loudspeaker cone ([@B52]).", "\n\nRESULTS\n=======\n\nRESPONSE PROPERTIES OF BURSTING NEURONS TO NATURAL STIMULATION\n--------------------------------------------------------------\n\nAs previously described in slices ([@B58]; [@B56]), we found that some DHN in the integrated spinal cord-hindlimbs preparation showed burst firing when depolarized from hyperpolarized membrane potentials (**Figure [1Aa](#F1){ref-type=\"fig\"}**) or at the offset of hyperpolarizing current pulses (**Figure [2A](#F2){ref-type=\"fig\"}**). ", "As shown in **Figure [1](#F1){ref-type=\"fig\"}**, the same absolute level of current during the pulse generated a mild response at rest (**Figure [1Aa](#F1){ref-type=\"fig\"}**, left trace) but a strong burst of action potentials when bias current hyperpolarized the cell (**Figure [1Aa](#F1){ref-type=\"fig\"}**, right trace), suggesting the activation of an LTS ([@B27]). ", "Long-lasting current pulses in bursting neurons generated an initial high frequency of action potentials that subsided over many seconds to end in tonic firing (**Figure [1Ab](#F1){ref-type=\"fig\"}**). ", "Bursting cells (*n* = 50) were found in relatively superficial layers of the dorsal horn (78%, 150--300 μm below the surface), had action potential amplitudes of 74.7 ± 1.6 mV (*n* = 47), input resistances of 1.3 ± 0.1 GΩ (*n* = 48), and resting membrane potentials of -70.0 ± 1.4 mV (*n* = 41).", "\n\n![**", "Responses to mechanical stimulation in cells with LTS. (", "A)** A depolarizing current pulse produced low-frequency tonic firing when applied at rest \\[**(a)**, left\\] and a high-frequency burst when the cell was hyperpolarized with bias current \\[**(a)**, right\\]. ", "Application of a long-lasting current pulse (5 s) shows that the initial high-frequency burst is followed by sustained tonic firing **(b)**. **(", "B)** Responses of the cell shown in A to brush **(a)** and pinprick **(b)** applied in two different zones of the ipsilateral hindleg (1 and 2, dots in the cartoons). **(", "C)** Responses of a different bursting cell to brush **(a)** and pinprick **(b)**. ", "The corresponding receptive fields are shown in the insets. ", "In this and subsequent figures, dotted lines and arrows underneath the traces indicate the time of application of the brush and pinprick stimuli, respectively. (**", "Aa--Ab)** and **(Ca--Cb)** from the same cell.](fncel-07-00276-g001){#F1}\n\n![**", "Interaction between the LTS and synaptic activity elicited by natural stimulation. (", "A)** A hyperpolarizing current pulse applied at different levels of bias current. ", "Notice that the rebound response grew as the membrane potential was depolarized to generate a burst of action potentials (-58 mV). ", "The inset shows the superimposed rebounds generated at -69 and -65 mV (arrowhead). **(", "B)** In the cell shown in **(A)**, a barrage of IPSPs was generated when pinprick was applied to a spot within the receptive field (dot in cartoon). ", "As the membrane potential was depolarized, the IPSPs generated action potentials after some delay. ", "The inset shows that spiking resulted from post-inhibitory rebounds. **(", "C)** Cartoons showing the receptive field of a DHN with a naturally induced response similar to that shown in B, at two different membrane potentials. ", "The firing zone at rest \\[**(a)**, -68 mV\\] was smaller than at depolarized membrane potentials \\[**(b)**, -54 mV\\] as the LTS interacted with IPSPs.](fncel-07-00276-g002){#F2}\n\nThe responses to brush (**Figure [1Ba](#F1){ref-type=\"fig\"}**) or pinprick (**Figure [1Bb](#F1){ref-type=\"fig\"}**) of the skin in most bursting neurons (33 of 41) were dominated by a barrage of inhibitory post-synaptic potentials (IPSPs) intermingled with a few excitatory post-synaptic potentials (EPSPs). ", "At resting membrane potentials, IPSPs were identified as rapid hyperpolarizing deflections followed by a slower relaxation, whereas EPSPs were conversely recognized as fast depolarizing events. ", "In addition, as the membrane was hyperpolarized with holding current, IPSPs decreased in amplitude (see **Figure [2B](#F2){ref-type=\"fig\"}**) -reversing close to the Cl^-^ equilibrium potential (-78.3 mV at 20°C) -- whereas EPSPs were decreased in amplitude by depolarization. ", "In 19 of 29 cells, the inhibitory receptive fields were large, comprising the whole ipsilateral leg and had a small firing zone (**Figure [1Bb](#F1){ref-type=\"fig\"}**, upper trace and cartoon in inset). ", "The hyperpolarizing response elicited by brief stimulation within the inhibitory receptive field could last up to 2 s (see **Figures [1B](#F1){ref-type=\"fig\"}, [2B](#F2){ref-type=\"fig\"}**, and **[3](#F3){ref-type=\"fig\"}**) and may be due to repetitive firing of inhibitory interneurons. ", "The remaining neurons with LTS (8 out of 41) showed responses to brush (**Figure [1Ca](#F1){ref-type=\"fig\"}**) or pinprick (**Figure [1Cb](#F1){ref-type=\"fig\"}**) composed mostly by EPSPs. ", "In these cells, the excitatory receptive fields had a firing zone surrounded by a subthreshold zone (**Figure [1C](#F1){ref-type=\"fig\"}**, cartoons in insets).", "\n\n{#F3}\n\nINTERACTIONS OF THE LTS WITH NATURALLY EVOKED SENSORY INPUTS\n------------------------------------------------------------\n\nAlthough previous studies in slices showed that LTS could interact with synaptic inputs elicited by stimulation of dorsal roots ([@B56]), it is not clear whether LTS could shape the output of DHN when driven by meaningful sensory inputs. ", "We thus analyzed the interactions of naturally evoked sensory inputs with the intrinsic properties of bursting cells. **", "Figure [2](#F2){ref-type=\"fig\"}** shows the responses of a bursting cell to hyperpolarizing current pulses (**Figure [2A](#F2){ref-type=\"fig\"}**) and to natural stimulation (**Figure [2B](#F2){ref-type=\"fig\"}**) at different membrane potentials. ", "The presence of a sag during the pulse suggested that the post-inhibitory rebound was partly accounted for by the activation of a time-dependent anomalous rectification (**Figure [2A](#F2){ref-type=\"fig\"}**, left trace). ", "However, a substantial component of the response was mediated by the activation of an LTS since the rebound grew (**Figure [2A](#F2){ref-type=\"fig\"}**, middle trace, arrowhead) to become a burst of spikes with progressive application of depolarizing holding current (**Figure [2A](#F2){ref-type=\"fig\"}**, right trace). ", "The inset in **Figure [2A](#F2){ref-type=\"fig\"}** shows the superimposed rebound responses at -69 and -65 mV. At hyperpolarized and resting membrane potentials (**Figure [2B](#F2){ref-type=\"fig\"}**, left trace and middle trace, respectively), the cell responded to pinprick with a strong and long-lasting inhibition. ", "However, when the cell was held at depolarized membrane potentials (**Figure [2B](#F2){ref-type=\"fig\"}**, right trace), pinprick on the same spot of the skin (**Figure [2B](#F2){ref-type=\"fig\"}**, dot in cartoon) generated an early barrage of IPSPs followed by spike firing at the end of the response. ", "Notice that spiking did not arise from EPSPs but from the rebound produced by individual IPSPs as shown on a faster time scale in the boxed inset. **", "Figure [2C](#F2){ref-type=\"fig\"}** shows the effects of changing the membrane potential on the characteristics of the receptive field. ", "The large inhibitory receptive field measured at rest (**Figure [2Ca](#F2){ref-type=\"fig\"}**, -68 mV) changed to an extended firing zone when the bursting neuron was depolarized (**Figure [2Cb](#F2){ref-type=\"fig\"}**, -54 mV).", "\n\nThe voltage dependence of the responses induced by natural stimulation of the receptive field suggests that the delayed excitation following inhibition was mediated by the activation of T-type Ca^2+^ channels. ", "To confirm that the delayed excitation was due to the interaction of IPSPs and the LTS we used Ni^2+^ (200--900 μM) as a T-type Ca^2+^ channel blocker. ", "In all cases (*n* = 6), the rebound responses were reduced in the presence of Ni^2+^. **Figure [3](#F3){ref-type=\"fig\"}** shows that a delayed excitation in response to sinusoidal (70 Hz) stimulation with a sharp probe (**Figure [3A](#F3){ref-type=\"fig\"}**) disappeared when Ni^2+^ was added to the bath (300 μM, **Figure [3B](#F3){ref-type=\"fig\"}**). ", "Notice, however, that the inhibition induced by the same stimulus in the presence of Ni^2+^ was even larger than that of control, suggesting the blockade of the delayed excitation is because of the antagonism of post-synaptic T-type Ca^2+^ channels. ", "In line with this, Ni^2+^ selectively blocked the T-type Ca^2+^ channel component of the LTS generated at the offset of a hyperpolarizing current pulse (**Figure [3B](#F3){ref-type=\"fig\"}**, inset, *n* = 6). ", "The contribution of the time-dependent anomalous rectification to rebound responses induced by natural stimulation in bursting DHN seems to be small because Cs^2+^ (1 mM, *n* = 3) did not prevent delayed excitation (data not shown).", "\n\nRESPONSES OF DHN WITH PLATEAU PROPERTIES TO NATURAL STIMULATION\n---------------------------------------------------------------\n\nA second population of cells (*n* = 51) responded with incrementing firing frequency of action potentials and after-discharges in response to long-lasting depolarizing current pulses (**Figure [4Aa](#F4){ref-type=\"fig\"}**). ", "Neurons with plateau potentials localized more deeply in the dorsal horn (80%, 250 μm to 500 below the surface), had spike amplitudes of 79.6 ± 1.3 mV (*n* = 51), input resistances of 1.2 ± 0.1 GΩ (*n* = 51), and resting membrane potentials of -58.5 ± 1.3 mV (*n* = 47).", "\n\n![**", "Responses of plateau-generating neurons to sensory stimulation. (", "A)** Incrementing firing frequency and after-discharge generated by a depolarising current pulse **(a)**. ", "In the same cell, brushing the skin within different zones \\[**(b)**, 1 and 2\\] of the ipsilateral leg generated sub-threshold synaptic responses. **(", "B)** Most plateau neurons had an excitatory receptive field with a sub-threshold zone (1) and a firing zone (2). **(", "C)** Plateau-generating neuron that had a receptive field with excitatory (1, 2) and inhibitory (3) zones in response to innocuous **(a)** as well as noxious **(b)** mechanical stimuli. ", "Note that the firing zone was larger to pinprick **(b)** than to brush **(a)**.](fncel-07-00276-g004){#F4}\n\nAll plateau neurons responded to mechanical stimuli applied to the ipsilateral hindlimb and had large receptive fields. ", "The majority of cells (31 out of 35) were wide dynamic range (WDR) neurons since they responded to brush and pinprick of the skin (**Figure [4C](#F4){ref-type=\"fig\"}**). ", "In 11 of 47 cells, the response to skin brush consisted of subthreshold EPSPs mixed with some IPSPs (**Figure [4Ab](#F4){ref-type=\"fig\"}**), whereas in the remaining cells a firing zone within the receptive field was observed (**Figures [4B,C](#F4){ref-type=\"fig\"}**). ", "The responses were complex with concurrent activation of excitation and inhibition. ", "As the stimulus moved away from the firing zone, the inhibitory component of the response became stronger, to turn in some cells (6 out of 36) into a net hyperpolarization that defined an inhibitory zone within the receptive field (**Figure [4C](#F4){ref-type=\"fig\"}**).", "\n\nPLATEAU POTENTIALS INTERACT WITH NATURALLY EVOKED SENSORY INPUTS\n----------------------------------------------------------------\n\nPlateau properties have been implied in the generation of persistent activity in sensory systems ([@B34]; [@B41]) and during some motor tasks ([@B38]; [@B49]; [@B26]). ", "As previously described in slices ([@B54], [@B55]; [@B46]), a depolarizing current pulse in DHN with plateau properties can elicit persistent firing that can be turned off by transient hyperpolarization (**Figure [5A](#F5){ref-type=\"fig\"}**). ", "In these cells, persistent activity could also be triggered by natural stimulation within the excitatory receptive field (**Figure [5B](#F5){ref-type=\"fig\"}**, -63 mV). ", "Notice that although the persistent response was synaptically induced, it could be terminated by a hyperpolarizing current pulse. ", "Hyperpolarizing the membrane potential with bias current reduced the number of spikes and the overall duration of the response (**Figure [5B](#F5){ref-type=\"fig\"}**, -75 and -85 mV).", "\n\n{#F5}\n\nThe voltage-dependence of the responses to natural stimulation suggests that L-type Ca^2+^ channels in the post-synaptic membrane add substantially to the responses induced by brief stimulation of the receptive field. ", "Indeed, the persistent activity induced by mechanical stimulation within the excitatory receptive field was reversibly eliminated by nifedipine (**Figure [5C](#F5){ref-type=\"fig\"}**; 20--50 μM, *n* = 5). ", "Notice that the early, synaptically driven component of the response was unaffected by nifedipine.", "\n\nStimulation within different zones of the receptive fields of DHN with plateau properties generated complex dynamics. ", "For example, the after-discharges mediated by L-type Ca^2+^ channels (**Figure [6Aa](#F6){ref-type=\"fig\"}**) could be terminated by transient stimulation of the inhibitory zone of the receptive field (**Figure [6Ab](#F6){ref-type=\"fig\"}**, 5 out of 5 cells). ", "In fact, bistability could be produced by alternate stimulation within the excitatory and inhibitory zones of the receptive field (**Figure [6B](#F6){ref-type=\"fig\"}**, 4 out of 4 cells).", "\n\n{#F6}\n\nAnother interesting dynamic generated by the plateau potential occurred within the time domain. ", "As described previously in slices of the turtle ([@B54], [@B55]) and rat ([@B46], [@B47]) spinal cords, the repetition of a mild depolarizing current pulse in DHN with plateau properties (**Figure [7A](#F7){ref-type=\"fig\"}**) induced a \"windup\" of the response (**Figure [7Ba](#F7){ref-type=\"fig\"}**, 21 out of 29 cells). ", "The facilitation of the response could be explained by the \"warm-up\" of L-type Ca^2+^ channels as there was no cumulative depolarization between stimuli (**Figure [7Ba](#F7){ref-type=\"fig\"}**). ", "In 15 out of 19 cells, the wind up produced with current pulses could also be generated by natural stimulation of the skin. ", "For example, in the cell shown in **Figure [7Ba](#F7){ref-type=\"fig\"}**, repetitive pinprick within the subthreshold zone of the receptive field produced spike firing \"windup\" (**Figure [7Bb](#F7){ref-type=\"fig\"}**) similar to that induced with current pulses. ", "The offset of windup varied widely among plateau-generating cells, ranging from about 5 s to hundreds of seconds when persistent firing occurred. **", "Figure [7C](#F7){ref-type=\"fig\"}** shows a plateau neuron in which repetitive pinprick applied in the firing zone of the receptive field induced \"windup\" of the response followed by persistent firing at the resting membrane potential (**Figure [7C](#F7){ref-type=\"fig\"}**, -52 mV). ", "The same stimulation protocol applied at hyperpolarized membrane potentials (**Figure [7C](#F7){ref-type=\"fig\"}**, -83 mV) showed that the synaptic drive induced by natural stimulation did not increase with repetition, suggesting that windup to pinprick was mediated by the intrinsic properties of DHN. ", "To confirm this interpretation, we tested the effect of L-type Ca^2+^ channel blockade with nifedipine on windup generated by pinprick of the skin. ", "Nifedipine (20--50 μM, *n* = 5) reduced the incrementing firing frequency during a long-lasting depolarizing current step (**Figures [8A,B](#F8){ref-type=\"fig\"}**) and in the same cell wiped out the windup of the response to repetitive pinprick (**Figure [8C](#F8){ref-type=\"fig\"}**). ", "Collectively, our data show that the windup of the response is produced by the integration of inputs by the L-type Ca^2+^ channels over a slow time frame and not by a progressive increase in synaptic weight.", "\n\n{#F7}\n\n{#F8}\n\nDISCUSSION\n==========\n\nIntrinsic properties represent a major building block in small-scale networks of invertebrates ([@B20]; [@B40]). ", "Although neurons in vertebrates also have complex intrinsic dynamics ([@B33]), their relevance in large-scale networks has been questioned ([@B1]; [@B3]; [@B31]). ", "We show here that LTS and plateau potentials dynamically shaped naturally evoked sensory inputs in DHN immersed within an intact spinal network. ", "The interaction of intrinsic properties and synaptic potentials occurred within voltage and time windows defined by the properties of T-type and L-type Ca^2+^channels.", "\n\nLTS IN DHN: EXCITED BY INHIBITION\n---------------------------------\n\nMost DHN with LTS responded to natural stimulation with a robust barrage of IPSPs resulting in receptive fields with large inhibitory components. ", "Interestingly, the interaction of the synaptic potentials and the LTS within a narrow range of membrane potentials produced post-inhibitory rebounds that paradoxically transformed an inhibitory input into a delayed excitatory output. ", "Rebound excitation after inhibition by noxious stimuli in the hindpaw has been reported in a subset of DHN recorded extracellularly in rats ([@B42]) and in cat spinoreticular neurons after powerful IPSPs elicited by sciatic nerve stimulation ([@B59]). ", "Thus, rebound excitation seems a general computational element during the analysis of somato-sensory information in the spinal cord. ", "The temporal sequence of inhibition-excitation has been generally assumed to arise from the logic of circuitry ([@B32]). ", "Neurons with rebound responses to hyperpolarizing current pulses and inhibitory receptive fields were found in a hemisected spinal cord-hindlimb preparation of the neonatal rat ([@B36]) and *in vivo* in superficial DHN of the mouse ([@B22]), although in these studies the possible interaction with LTS was not explored. ", "Our study shows that depending on the recent history of DHN (e.g., the actual membrane potential at which inhibition occurs) rebound excitation can be fully accounted for by the interaction of sensory inputs and the properties of the post-synaptic membrane.", "\n\nThe function of the intrinsic delayed excitation produced by the LTS in DHN is puzzling. ", "In the auditory system, post-inhibitory rebound excitation has been implied in temporal computation of auditory signals ([@B32]). ", "Indeed, rebound excitation in a subset of neurons in the superior paraolivary nucleus and the inferior colliculus is produced by intrinsic mechanisms activated by hyperpolarization induced by acoustic stimulation ([@B15]; [@B28]). ", "It is then possible, that the interaction between sensory-induced inhibition and the LTS in DHN similarly encode temporal features of the stimulus.", "\n\nDelayed excitation is one of the functional building blocks in neuronal networks and has been proposed as an intrinsic mechanism for integration of excitatory inputs ([@B20]; [@B64]). ", "As proposed for the slow post-inhibitory rebound in lateral pyloric neurons of the stomatogastric ganglion ([@B21]), the delayed excitation induced by naturally evoked inhibition in DHN could be an intrinsic mechanism for integration of inhibitory inputs. ", "Post-inhibitory rebounds have been also implied in the production of different forms of rhythmic motor patterns ([@B20]). ", "In the neonatal rat, a post-inhibitory rebound mediated by low voltage-gated Ca^2+^ channels is engaged in spinal motoneurons during locomotion ([@B7]). ", "In addition, a subset of interneurons, in the turtle spinal cord are rhythmically hyperpolarized during fictive scratch and swimming ([@B5], [@B6]). ", "Although we never observed rhythmic activity in our study, DHN with LTS may be elements of the pre-motor network devoted to early stages of sensory-motor integration. ", "Indeed, DHN with LTS are small interneurons with an axon bearing profuse collaterals in the dorsal horn ([@B56]; [@B52]).", "\n\nPLATEAU POTENTIALS INTEGRATE SOMATOSENSORY INPUTS IN A SLOW TIME SCALE\n----------------------------------------------------------------------\n\nIn the somatosensory system, prolonged after-discharges in WDR neurons have been related to pain mechanisms ([@B66]). ", "Noxious stimuli applied to the skin in mammals produce prolonged post-discharges ([@B51]; [@B9]; [@B53]) and psychophysical studies showed that pain perception greatly outlasts the stimulus ([@B9]). ", "Although local recurrent networks are a widely accepted theory to explain persistent neuronal activity ([@B38]), anatomical evidence supporting this kind of circuits in the spinal cord is lacking. ", "We demonstrate here that persistent firing induced by natural stimulation can be accounted for by the activation of a plateau potential mediated by L-type Ca^2+^ channels. ", "The time- and voltage-dependent facilitation of the plateau potential was also responsible for the windup of the response, a form of short-term synaptic plasticity induced by repetitive noxious stimulation ([@B45]). ", "Because the windup is considered an intermediate step in the development and maintenance of a central sensitization to pain ([@B37]; [@B65]), the plateau potential could be a key element of the mechanisms that generate long-lasting phenomena such as hyperalgesia. ", "In line with this, *in vivo* extracellular recordings in the rat showed that the windup of both the response of deep DHN and the nociceptive flexion reflex were sensitive to L-type Ca^2+^channel blockers ([@B18]). ", "In addition, allodynia is reversed *in vivo* after blocking the expression of Ca~v~1.2 channels ([@B17]). ", "Remarkably, Cav1.2 mRNA is increased in a neuropathic pain model ([@B17]), a change probably related to the increased proportion of DHN able to display plateau potentials ([@B53]).", "\n\nThe plateau potential could also play an important part in the processing of non-noxious sensory information as in some cases it was activated by innocuous stimuli. ", "In mammals, some neurons display prolonged after-discharges in response to innocuous stimulation ([@B50]) and in humans, innocuous stimuli can generate prolonged post-stimulus sensations ([@B50]). ", "It has been suggested that persistent neural activity to brief stimuli represents a universal form of working memory mechanism ([@B39]; [@B38]). ", "Thus, the plateau potential in DHN may work as an intrinsic mnemonic mechanism underlying prolonged post-stimulus sensory perceptions. ", "The intrinsic dynamics provided by L-type Ca^2+^channels may also be a key component of sensory-motor integration at the spinal cord level. [", "@B11] proposed that the prolonged post-discharges and temporal facilitation to repetitive stimulation at low frequencies (0.2 Hz) in a set of interneurons is related to the residual excitability after the end of scratching. ", "In fact, recent findings suggest that increased activity of the pre-motor network contributes to scratch initiation ([@B23]). ", "DHN with plateau properties are likely components of pre-motor networks as they have axon collaterals in the ventral horn ([@B55]). ", "Therefore, after-discharges and windup induced by L-type Ca^2+^ channels may contribute to short-term storage and accumulation of sensory information required for the execution of motor tasks.", "\n\nPLASTICITY OF THE RECEPTIVE FIELDS MEDIATED BY INTRINSIC PROPERTIES\n-------------------------------------------------------------------\n\nThe receptive field of sensory neurons is not a rigid attribute but changes dynamically to adjust to changing demands ([@B13]; [@B10]). ", "For example, receptive fields in WDR neurons of monkeys expand or contract depending on the attentional state of the animal ([@B14]; [@B24]; [@B25]). ", "The mechanisms underlying the plasticity of receptive fields are poorly understood and have been related mainly to dynamic adjustments of synaptic strength. ", "Our results suggest that both LTS and plateau potentials may mediate some forms of receptive field plasticity on a relatively fast time scale. ", "The shift from an inhibitory to an excitatory receptive field depended on whether the membrane potential of the post-synaptic cell allowed the interaction between the IPSPs and the LTS and not on plasticity of the synaptic input itself. ", "The dynamics of plateau potentials in DHN could also be an intrinsic mechanism for plasticity of receptive fields in the domain of time. ", "As we showed here, frequency-dependent facilitation of L-type Ca^2+^ channels enabled previously sub-threshold EPSPs to generate spike firing, expanding the firing zone with the contraction of the low-probability firing fringe of the receptive field, a form of short-term plasticity of excitatory receptive fields. ", "In addition to an excitatory receptive field, WDR neurons in mammals frequently exhibit an inhibitory receptive field (see [@B67]). ", "In some DHN of the cat ([@B8]) and rats ([@B53]) prolonged after-discharges could be terminated by a transient stimulus within the inhibitory receptive field and turned on again by stimulation of the excitatory zone of the receptive field. ", "The deactivation of plateau potentials by inhibitory synaptic inputs could be the mechanism generating this phenomenon and could contribute to the hypoalgesic influence elicited by stimuli applied outside the excitatory receptive field ([@B44]).", "\n\nBecause the receptive field plasticity mediated by both LTS and plateau potentials was exquisitely sensitive to the membrane potential at which naturally evoked synaptic inputs occurred, the modulation of membrane potential by monoamines released from the brainstem ([@B19]; [@B61]; [@B68]), and GABA and glycine released from the medulla ([@B29]) may be a suitable mechanism to dynamically adjust the receptive fields to match ongoing tasks.", "\n\nCONCLUSION\n==========\n\nUnlike motoneurons during scratching ([@B1]; [@B3]), our findings in an integrated spinal cord-hindlimbs preparation show that synaptic activity elicited by natural stimulation in DHN does not override intrinsic membrane properties. ", "Thus, whereas intrinsic properties do not seem to contribute to behaviors that require massive activity of large-scale spinal circuits ([@B4]), for tasks involving a small number of cells, such as the detection and coding of sensory information, spinal networks may function as those in invertebrates, where intrinsic conductances are main determinants for network output ([@B12]).", "\n\nAUTHOR CONTRIBUTIONS\n====================\n\nThe study was done in the department of Neurofisiología Celular y Molecular, Instituto de Investigaciones Biológicas Clemente Estable. ", "Cecilia Reali: conception and design of the experiments; collection, analysis, and interpretation of data; writing of the manuscript; Raúl E. Russo: conception and design of the experiments, collection, analysis, and interpretation of data, writing of the manuscript. ", "All authors approved the final version of the manuscript and are accountable for all aspects of the work.", "\n\nConflict of Interest Statement\n==============================\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.", "\n\nThe work described here was supported by Grant \\# FCE_2920 from ANII and by PEDECIBA.", "\n\n[^1]: Edited by: *Enrico Cherubini, International School for Advanced Studies, Italy*\n\n[^2]: Reviewed by: *Marco Beato, University College London, UK; Andrea Nistri, Scuola Internazionale Superiore di Studi Avanzati, Italy*\n\n[^3]: This article was submitted to the journal Frontiers in Cellular Neuroscience.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Ultimo aggiornamento: Martedì 28 Agosto 2018, 13:31\n\n© RIPRODUZIONE RISERVATA\n\nera conosciuta a Cassino come una donna energica e risoluta. ", "Dipendente per anni della clinica Sant’Anna, amava scandire le sue giornate tra il lavoro e gli affetti più cari, costituiti dai nipoti, i figli dei suoi fratelli Guerino e Vittorio. ", "Pur essendo una bella donna aveva scelto di rimanere sola. ", "Aveva rinunciato al matrimonio e alla maternità. ", "Il motivo di quella scelta si è saputo solo ora. ", "La donna custodiva dentro di sé un segreto che non ha mai svelato a nessuno. ", "Neanche in punto di morte. ", "Ha preferito portarlo via con sé., ", "morta all’età di 74 anni a marzo dello scorso anno, non immaginava che presto il suo segreto sarebbe stato rivelato al mondo. ", "A farlo sarebbe stata, detta Maria, la figlia partorita nel 1966 e lasciata in un convento a Londra. ", "Maria, oggi 52enne, da ben quattordici anni stava cercando Oltremanica la madre naturale.", "A portare alla luce la storia di Gilda e a svelare il segreto, che da mezzo secolo l’ex dipendente della clinica S. Anna portava gelosamente nel suo cuore, ci hanno pensato i giornalisti, conduttori della trasmissione televisiva Long Lost Family, analogo format della trasmissione italiana “Così lontani. ", "Così vicini” condotta su Rai Uno da Romina Power e Al Bano Carrisi. ", "A Cassino la notizia si è diffusa da qualche giorno. ", "Da quando sui teleschermi di ITV, televisione del Regno Unito, è stato trasmesso il secondo episodio dell’ottava serie di Long Lost Family interamente realizzato tra Cassino, nel popolare quartiere Fraschetti, dove abita Silvana, la cugina che è stata la prima a sapere dell’esistenza di Maria e a fare da tramite con la redazione della trasmissione per riabbracciarla, e Arpino, location scelta dai giornalisti per l’incontro con i parenti ritrovati. ", "A raccontare la storia è Silvana Costantino, nipote di Gilda.", "«Mia zia – riferisce – non ha mai parlato con nessuno dell’esistenza di questa figlia. ", "Quando abbiamo saputo la notizia siamo rimasti basiti».", "«Il destino ha giocato a favore. ", "In prossimità del primo anniversario della morte di zia Gilda, mi chiama una mia amica e mi avvisa di aver condiviso sulla mia pagina Facebook un annuncio in inglese. ", "Io, non conosco l’inglese. ", "Ho atteso l'arrivo di mia nuora per la traduzione. ", "Accanto alla frase c’era il simbolo di Montecassino. ", "L’annuncio diceva: ‘Siamo amici di Gilda Costantino. ", "Abbiamo lavorato con lei a Londra. ", "Vogliamo incontrarla’. ", "Io ho risposto: ‘Sono la nipote’. ", "Da quel momento sono stata contattata in privato. ", "Mi hanno detto che c’era Antonella Lualda Maria Roberts che, dopo aver cercato in tutto il Regno Unito la madre naturale, si era rivolta alla trasmissione».", "«Per quasi tre mesi ci sono stati contatti con Long Lost Family. ", "Noi parenti non sapevamo nulla. ", "Siamo caduti dalle nuvole. ", "Sapevamo che mia zia aveva lavorato a Londra in una casa di cura per cinque anni. ", "Poi aveva fatto rientro a Cassino. ", "Il giorno scelto per l’incontro era il compleanno di Maria. ", "Il luogo Arpino. ", "Ha incontrato prima me – racconta Silvana – poi il resto della famiglia: i cugini Ada e Mario. ", "Abbiamo saputo, così, che zia Gilda era andata a Londra per partorire. ", "Quando è partita aspettava già. ", "Quando è nata ha battezzato la bimba con il nome di Antonella Lualda e l’ha lasciata in un convento, dove una suora le ha dato anche il nome Maria. ", "Lei ha sempre saputo di essere adottata. ", "Alla morte dei genitori adottivi ha trovato i certificati di nascita in casa in cui mia zia dichiarava che il padre era di Cassino, ma morto in un incidente stradale lungo la Casilina”. “", "E’ stato emozionante conoscere e abbracciare una cugina di cui non sapevamo l’esistenza. ", "Ci messaggiamo ogni giorno. ", "Lei scrive che ci vuole bene e ha nostalgia di noi»." ]

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[ "Description\n\nWhen your baby experiences nasal congestion, provide simple relief with the Nasal aspirator. ", "The two piece design is easy to clean, and gentle suction is safe to use on newborns\n\nSuggested Use\n\nWash before initial use, do not boil. ", "Hold baby upright. ", "Squeeze aspirator bulb, place tip into nostril and tilt to side. (", "Never point tip directly in center of nostril. ", "Do not push past the over-insertion guard) Slowly release the bulb allowing suction to draw mucus out." ]

{ "pile_set_name": "Pile-CC" }

[ 0.009433962264150943, 0, 0, 0, 0, 0 ]

[]

[ "// Protocol Buffers - Google's data interchange format\n// Copyright 2008 Google Inc. All rights reserved.", "\n// https://developers.google.com/protocol-buffers/\n//\n// Redistribution and use in source and binary forms, with or without\n// modification, are permitted provided that the following conditions are\n// met:\n//\n// * Redistributions of source code must retain the above copyright\n// notice, this list of conditions and the following disclaimer.", "\n// * Redistributions in binary form must reproduce the above\n// copyright notice, this list of conditions and the following disclaimer\n// in the documentation and/or other materials provided with the\n// distribution.", "\n// * Neither the name of Google Inc. nor the names of its\n// contributors may be used to endorse or promote products derived from\n// this software without specific prior written permission.", "\n//\n// THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS\n// \"AS IS\" AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT\n// LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR\n// A PARTICULAR PURPOSE ARE DISCLAIMED. ", "IN NO EVENT SHALL THE COPYRIGHT\n// OWNER OR CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL,\n// SPECIAL, EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT\n// LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE,\n// DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY\n// THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT\n// (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE\n// OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE.", "\n\n#ifndef GOOGLE_PROTOBUF_UTIL_CONVERTER_DEFAULT_VALUE_OBJECTWRITER_H__\n#define GOOGLE_PROTOBUF_UTIL_CONVERTER_DEFAULT_VALUE_OBJECTWRITER_H__\n\n#include <memory>\n#ifndef _SHARED_PTR_H\n#include <google/protobuf/stubs/shared_ptr.h>\n#endif\n#include <stack>\n#include <vector>\n\n#include <google/protobuf/stubs/callback.h>\n#include <google/protobuf/stubs/common.h>\n#include <google/protobuf/util/internal/type_info.h>\n#include <google/protobuf/util/internal/datapiece.h>\n#include <google/protobuf/util/internal/object_writer.h>\n#include <google/protobuf/util/internal/utility.h>\n#include <google/protobuf/util/type_resolver.h>\n#include <google/protobuf/stubs/stringpiece.h>\n\nnamespace google {\nnamespace protobuf {\nnamespace util {\nnamespace converter {\n\n// An ObjectWriter that renders non-repeated primitive fields of proto messages\n// with their default values. ", "DefaultValueObjectWriter holds objects, lists and\n// fields it receives in a tree structure and writes them out to another\n// ObjectWriter when EndObject() is called on the root object. ", "It also writes\n// out all non-repeated primitive fields that haven't been explicitly rendered\n// with their default values (0 for numbers, \"\" for strings, etc).", "\nclass LIBPROTOBUF_EXPORT DefaultValueObjectWriter : public ObjectWriter {\n public:\n // A Callback function to check whether a field needs to be scrubbed.", "\n //\n // Returns true if the field should not be present in the output. ", "Returns\n // false otherwise.", "\n //\n // The 'path' parameter is a vector of path to the field from root. ", "For\n // example: if a nested field \"a.b.c\" (b is the parent message field of c and\n // a is the parent message field of b), then the vector should contain { \"a\",\n // \"b\", \"c\" }.", "\n //\n // The Field* should point to the google::protobuf::Field of \"c\".", "\n typedef ResultCallback2<bool /*return*/,\n const std::vector<string>& /*path of the field*/,\n const google::protobuf::Field* /*field*/>\n FieldScrubCallBack;\n\n // A unique pointer to a DefaultValueObjectWriter::FieldScrubCallBack.", "\n typedef google::protobuf::scoped_ptr<FieldScrubCallBack> FieldScrubCallBackPtr;\n\n DefaultValueObjectWriter(TypeResolver* type_resolver,\n const google::protobuf::Type& type,\n ObjectWriter* ow);\n\n virtual ~DefaultValueObjectWriter();\n\n // ObjectWriter methods.", "\n virtual DefaultValueObjectWriter* StartObject(StringPiece name);\n\n virtual DefaultValueObjectWriter* EndObject();\n\n virtual DefaultValueObjectWriter* StartList(StringPiece name);\n\n virtual DefaultValueObjectWriter* EndList();\n\n virtual DefaultValueObjectWriter* RenderBool(StringPiece name, bool value);\n\n virtual DefaultValueObjectWriter* RenderInt32(StringPiece name, int32 value);\n\n virtual DefaultValueObjectWriter* RenderUint32(StringPiece name,\n uint32 value);\n\n virtual DefaultValueObjectWriter* RenderInt64(StringPiece name, int64 value);\n\n virtual DefaultValueObjectWriter* RenderUint64(StringPiece name,\n uint64 value);\n\n virtual DefaultValueObjectWriter* RenderDouble(StringPiece name,\n double value);\n\n virtual DefaultValueObjectWriter* RenderFloat(StringPiece name, float value);\n\n virtual DefaultValueObjectWriter* RenderString(StringPiece name,\n StringPiece value);\n virtual DefaultValueObjectWriter* RenderBytes(StringPiece name,\n StringPiece value);\n\n virtual DefaultValueObjectWriter* RenderNull(StringPiece name);\n\n // Register the callback for scrubbing of fields. ", "Owership of\n // field_scrub_callback pointer is also transferred to this class\n void RegisterFieldScrubCallBack(FieldScrubCallBackPtr field_scrub_callback);\n\n // If set to true, empty lists are suppressed from output when default values\n // are written.", "\n void set_suppress_empty_list(bool value) { suppress_empty_list_ = value; }\n\n private:\n enum NodeKind {\n PRIMITIVE = 0,\n OBJECT = 1,\n LIST = 2,\n MAP = 3,\n };\n\n // \"Node\" represents a node in the tree that holds the input of\n // DefaultValueObjectWriter.", "\n class LIBPROTOBUF_EXPORT Node {\n public:\n Node(const string& name, const google::protobuf::Type* type, NodeKind kind,\n const DataPiece& data, bool is_placeholder, const vector<string>& path,\n bool suppress_empty_list, FieldScrubCallBack* field_scrub_callback);\n virtual ~Node() {\n for (int i = 0; i < children_.size(); ++i) {\n delete children_[i];\n }\n }\n\n // Adds a child to this node. ", "Takes ownership of this child.", "\n void AddChild(Node* child) { children_.push_back(child); }\n\n // Finds the child given its name.", "\n Node* FindChild(StringPiece name);\n\n // Populates children of this Node based on its type. ", "If there are already\n // children created, they will be merged to the result. ", "Caller should pass\n // in TypeInfo for looking up types of the children.", "\n void PopulateChildren(const TypeInfo* typeinfo);\n\n // If this node is a leaf (has data), writes the current node to the\n // ObjectWriter; if not, then recursively writes the children to the\n // ObjectWriter.", "\n void WriteTo(ObjectWriter* ow);\n\n // Accessors\n const string& name() const { return name_; }\n\n const vector<string>& path() const { return path_; }\n\n const google::protobuf::Type* type() const { return type_; }\n\n void set_type(const google::protobuf::Type* type) { type_ = type; }\n\n NodeKind kind() const { return kind_; }\n\n int number_of_children() const { return children_.size(); }\n\n void set_data(const DataPiece& data) { data_ = data; }\n\n bool is_any() const { return is_any_; }\n\n void set_is_any(bool is_any) { is_any_ = is_any; }\n\n void set_is_placeholder(bool is_placeholder) {\n is_placeholder_ = is_placeholder;\n }\n\n private:\n // Returns the Value Type of a map given the Type of the map entry and a\n // TypeInfo instance.", "\n const google::protobuf::Type* GetMapValueType(\n const google::protobuf::Type& entry_type, const TypeInfo* typeinfo);\n\n // Calls WriteTo() on every child in children_.", "\n void WriteChildren(ObjectWriter* ow);\n\n // The name of this node.", "\n string name_;\n // google::protobuf::Type of this node. ", "Owned by TypeInfo.", "\n const google::protobuf::Type* type_;\n // The kind of this node.", "\n NodeKind kind_;\n // Whether this is a node for \"Any\".", "\n bool is_any_;\n // The data of this node when it is a leaf node.", "\n DataPiece data_;\n // Children of this node.", "\n std::vector<Node*> children_;\n // Whether this node is a placeholder for an object or list automatically\n // generated when creating the parent node. ", "Should be set to false after\n // the parent node's StartObject()/StartList() method is called with this\n // node's name.", "\n bool is_placeholder_;\n\n // Path of the field of this node\n std::vector<string> path_;\n\n // Whether to suppress empty list output.", "\n bool suppress_empty_list_;\n\n // Pointer to function for determining whether a field needs to be scrubbed\n // or not. ", "This callback is owned by the creator of this node.", "\n FieldScrubCallBack* field_scrub_callback_;\n\n GOOGLE_DISALLOW_EVIL_CONSTRUCTORS(Node);\n };\n\n // Populates children of \"node\" if it is an \"any\" Node and its real type has\n // been given.", "\n void MaybePopulateChildrenOfAny(Node* node);\n\n // Writes the root_ node to ow_ and resets the root_ and current_ pointer to\n // NULL.", "\n void WriteRoot();\n\n // Creates a DataPiece containing the default value of the type of the field.", "\n static DataPiece CreateDefaultDataPieceForField(\n const google::protobuf::Field& field, const TypeInfo* typeinfo);\n\n // Adds or replaces the data_ of a primitive child node.", "\n void RenderDataPiece(StringPiece name, const DataPiece& data);\n\n // Returns the default enum value as a DataPiece, or the first enum value if\n // there is no default. ", "For proto3, where we cannot specify an explicit\n // default, a zero value will always be returned.", "\n static DataPiece FindEnumDefault(const google::protobuf::Field& field,\n const TypeInfo* typeinfo);\n\n // Type information for all the types used in the descriptor. ", "Used to find\n // google::protobuf::Type of nested messages/enums.", "\n const TypeInfo* typeinfo_;\n // Whether the TypeInfo object is owned by this class.", "\n bool own_typeinfo_;\n // google::protobuf::Type of the root message type.", "\n const google::protobuf::Type& type_;\n // Holds copies of strings passed to RenderString.", "\n vector<string*> string_values_;\n\n // The current Node. ", "Owned by its parents.", "\n Node* current_;\n // The root Node.", "\n google::protobuf::scoped_ptr<Node> root_;\n // The stack to hold the path of Nodes from current_ to root_;\n std::stack<Node*> stack_;\n\n // Whether to suppress output of empty lists.", "\n bool suppress_empty_list_;\n\n // Unique Pointer to function for determining whether a field needs to be\n // scrubbed or not.", "\n FieldScrubCallBackPtr field_scrub_callback_;\n\n ObjectWriter* ow_;\n\n GOOGLE_DISALLOW_EVIL_CONSTRUCTORS(DefaultValueObjectWriter);\n};\n\n} // namespace converter\n} // namespace util\n} // namespace protobuf\n\n} // namespace google\n#endif // GOOGLE_PROTOBUF_UTIL_CONVERTER_DEFAULT_VALUE_OBJECTWRITER_H__\n" ]

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[ "Application of optimal design methodologies in clinical pharmacology experiments.", "\nPharmacokinetics and pharmacodynamics data are often analysed by mixed-effects modelling techniques (also known as population analysis), which has become a standard tool in the pharmaceutical industries for drug development. ", "The last 10 years has witnessed considerable interest in the application of experimental design theories to population pharmacokinetic and pharmacodynamic experiments. ", "Design of population pharmacokinetic experiments involves selection and a careful balance of a number of design factors. ", "Optimal design theory uses prior information about the model and parameter estimates to optimize a function of the Fisher information matrix to obtain the best combination of the design factors. ", "This paper provides a review of the different approaches that have been described in the literature for optimal design of population pharmacokinetic and pharmacodynamic experiments. ", "It describes options that are available and highlights some of the issues that could be of concern as regards practical application. ", "It also discusses areas of application of optimal design theories in clinical pharmacology experiments. ", "It is expected that as the awareness about the benefits of this approach increases, more people will embrace it and ultimately will lead to more efficient population pharmacokinetic and pharmacodynamic experiments and can also help to reduce both cost and time during drug development." ]

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[ "Donal Monaghan\n\nDonal Monaghan (1950 – 3 January 2016) was an Irish Gaelic footballer who played as a right corner-back for the Donegal county team.", "\n\nBorn in Donegal, Monaghan first played competitive Gaelic football at the age of fifteen when he first linked up with the Donegal minor team, before later lining out with the under-21 side. ", "He made his senior debut in the 1968-69 National Football League. ", "Monaghan went on to play a key part for Donegal in a team that made a provincial breakthrough, and won two Ulster medals and one All Stars Award. ", "His uncle, Johnny Monaghan, played Gaelic football with Fermanagh in the 1930s.", "\n\nMonaghan represented the Ulster inter-provincial team on a number of occasions and was a Railway Cup runner-up in 1975. ", "At club level he won one championship medal with Four Masters.", "\n\nMonaghan retired from inter-county football after the 1978 championship, while a knee ligament injury brought his club football career to an end in 1984.", "\n\nReferences\n\nCategory:1950 births\nCategory:Living people\nCategory:Donegal inter-county Gaelic footballers\nCategory:Four Masters Gaelic footballers\nCategory:Ulster inter-provincial Gaelic footballers" ]

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[ "Whether you’re expecting and want to remember that beautiful baby bump or have been thinking about getting family photos taken, Fall is truly one of the best times to preserve your family memories through photography. ", "Lisa Seidel of Portraits by Lisa specializes in spirited heirloom images of children and families and has come up with an […]\n\nIt’s no secret that I am a huge swaddling advocate. ", "Throughout my book I reiterate the benefits of swaddling and topping that list is the fact that most newborns love and are content with the secure feeling of being swaddled. ", "In the hospital (where nurses swaddle for a living!) ", "your baby was very likely happy as a […]\n\nBaby Nurse Question: I want my baby to be warm enough at night in her crib but my pediatrician says I should not put blankets on her. ", "Is there another solution? ", "This is such a common concern among new parents and the answer is, yes, there’s a solution. ", "As I highlight in The Baby Nurse […]\n\nAlthough this contest is a little off topic from my usual pregnancy, birth and newborn posts, I thought it was a great opportunity to share with those of you who are local readers. ", "I’ve always believed summer camps to be such a great way to boost kids’ social and team-building skills, get them out enjoying […]\n\nI am excited to share I’ll be speaking at Magic Beans in Brookline and Isis Parenting in Boston the week of March 21. ", "I’ll be covering a range of topics from baby preparation to newborn care and sharing Baby Nurse Tips and secrets you won’t want to miss. ", "I hope to see you there! ", "Wednesday, […]\n\nSubscribe to our newsletter\n\nOur Philosophy\n\nThe team at Boston Baby Nurse & Nanny knows that welcoming a new caregiver into the home is a big decision for parents. ", "That’s why, for over a decade now, we’ve committed to providing families with the absolute best in newborn support, overnight care, sleep coaching and an award winning nanny placement service. ", "At Boston Baby Nurse & Nanny we have a genuine desire to be known for our high standards, our integrity and our dedication to the families we serve. ", "This commitment to excellence has made us Boston’s most trusted and sought after childcare resource." ]

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[ "\n2 Cal.3d 508 (1970)\n467 P.2d 836\n86 Cal. ", "Rptr. ", "4\nIn re LAWRENCE O'NEIL SMITH on Habeas Corpus.", "\nDocket No. ", "Crim. ", "13961.", "\nSupreme Court of California. ", "In Bank.", "\nApril 30, 1970.", "\n*509 COUNSEL\nEdward J. Horowitz, under appointment by the Supreme Court, for Petitioner.", "\nThomas C. Lynch, Attorney General, William E. James, Assistant Attorney General, and Russell Iungerich, Deputy Attorney General, for Respondent.", "\nOPINION\nMOSK, Acting C.J.\nIn this habeas corpus proceeding petitioner attacks the validity of a prior narcotics conviction used to increase the prison term imposed for a subsequent narcotics offense.", "\nIn 1954 petitioner was convicted on a plea of guilty of violating Health and Safety Code section 11721 (use of or addiction to narcotics).[1] In 1956 *510 he was convicted by a judge sitting without a jury of violating Health and Safety Code section 11500 (possession of narcotics other than marijuana). ", "The trial court found that the 1954 narcotics conviction had been proved, and petitioner was sentenced to the term prescribed by law.[2] We affirmed the conviction. (", "People v. Smith (1958) 50 Cal.2d 149 [323 P.2d 435].)", "\nPetitioner now contends the 1954 conviction cannot be used to aggravate the maximum sentence for the 1956 narcotics conviction because Health and Safety Code section 11721 has since been held unconstitutional by the United States Supreme Court. ", "Petitioner relies on Robinson v. California (1962) 370 U.S. 660 [8 L.Ed.2d 758, 82 S.Ct. ", "1417]. ", "In that case the court held that insofar as section 11721 punished a person for being addicted to the use of narcotics, the statute imposed cruel and unusual punishment under the Eighth Amendment, made applicable to the states by the Fourteenth Amendment. (", "Robinson v. California, supra, 370 U.S. at pp. ", "666-667 [8 L.Ed.2d at pp. ", "762-763].) ", "The court, however, did not strike down that portion of section 11721 which makes unlawful the use of narcotics. (", "In re Carlson (1966) 64 Cal.2d 70, 72 [48 Cal. ", "Rptr. ", "875, 410 P.2d 379].)", "\nIn the Carlson case we stated at page 73: \"If the sole sufficient ground for petitioner's section 11721 conviction was the unconstitutional portion of that statute, or if, as in Robinson, that portion was a possible alternate sole sufficient ground, then the writ which he seeks should issue. (", "See In re Newbern, 53 Cal.2d 786, 792 [3 Cal. ", "Rptr. ", "364, 350 P.2d 116].) ", "On the other hand, the writ should not issue if that conviction had, as a sufficient ground, something other than the illicit portion of the statute. (", "In re Bell, 19 Cal.2d 488, 498-499 [122 P.2d 22].)\" (", "See also In re Becerra (1963) 218 Cal. ", "App.2d 746, 747 [32 Cal. ", "Rptr. ", "910].) ", "We stated further at page 75: (1) \"The presumption of regularity which attached to a judgment collaterally attacked (see Johnson v. Zerbst, 304 U.S. 458, 468 [58 S.Ct. ", "1019, 82 L.Ed. ", "1461, 146 A.L.R. 357]; In re Bell, supra, 19 Cal.2d 488, 500) places upon a petitioner the burden of proving that his conviction was based not upon the constitutional but upon the unconstitutional provisions of the statute under which he was convicted. (", "See In re Bell, supra, at pp. ", "501, 504.) (", "2) In attempting to sustain this burden he is not confined to the evidence presented at trial but may have resort to `any *511 necessary additional evidence bearing on the infringement' of his rights. (", "In re Bell, supra, 19 Cal.2d 488, 501.)\"", "\n(3) The evidence before us demonstrates that petitioner has not met this burden. ", "Although the complaint filed against petitioner in 1954 has since been destroyed by court order,[3] the Attorney General has submitted evidence that petitioner was charged with and therefore pleaded guilty to both the use of and addiction to narcotics.[4] The declaration of Philip E. Grey, Assistant City Attorney of Los Angeles, states that at the time petitioner was arraigned and convicted, a prepared form of complaint was used in prosecutions for violations of section 11721 which charged that the defendant \"did wilfully and unlawfully use and be addicted to the unlawful use of narcotics.\" ", "The declaration further states that \"[i]t was not the practice of deputies assigned to prosecute cases under Section 11721 to amend the complaint form ... to charge only that the accused was addicted to the unlawful use of narcotics.\" ", "The declaration of John L. Denny, the deputy city attorney assigned to represent the People when petitioner was arraigned, states that the declarant is \"of the unalterable opinion that during the year of 1954, [he] never used any complaint form alleging a violation of Section 11721 of the Health and Safety Code other than such printed forms, since if [he] had done so it would have been such an unusual occurrence that [he] ... would remember it to this day.\"", "\nPetitioner has presented no evidence sufficient to overcome the presumption of regularity which attached to the judgment or the showing offered by the Attorney General that he pleaded guilty to both the use of and addiction to narcotics.[5] His sole allegation in this regard is that he \"was arrested on or about October, 1954 and was convicted for being addicted to the use of narcotics (violation of Section 11721 Health & Safety Code) which addiction was determined by the opinion of an investigating officer of the Los Angeles Police Department.\" ", "This allegation is not inconsistent with a plea of guilty to a joint charge of use of and addiction to narcotics.", "\nPetitioner has placed some reliance on the 1954 arrest report. ", "In that *512 report petitioner is quoted as saying: \"I've been using heroin for the past four years. ", "I had my last fix of heroin Monday [two days before his arrest] at about 3:00 in the afternoon. ", "I shot a half a cap of H at that time.\" ", "The report also contains the following statement by the arresting officers: \"Officers, while conducting a narcotic investigation in the vicinity of 102 and Graham, stopped the above suspect after observing him talk to several unknown people, who left immediately. ", "Examination revealed that he was a user of narcotics, and old scar tissue as well as fresh needle marks were observed over the inside veins of both left and right arms.\" ", "The statements in the arrest report at best are only inconclusive as to whether petitioner was arrested for and subsequently pleaded guilty to the use of or addiction to narcotics.", "\nPetitioner further contends he was not represented by counsel during the 1954 proceedings. ", "He alleges that \"[t]o the best of his memory and knowledge petitioner was not represented by counsel at the court proceedings held in 1954 nor did he intelligently and understandingly waive his right to counsel.\" ", "This allegation is refuted by the record. ", "The docket sheet shows that at the time of petitioner's arraignment and trial he was represented by an attorney.", "\nThe order to show cause is discharged and the petition for a writ of habeas corpus is denied.", "\nMcComb, J., Peters, J., Tobriner, J., Burke, J., Sullivan, J., and Ford, J.,[*] concurred.", "\nNOTES\n[1] At the relevant time Health and Safety Code section 11721 provided in part: \"No person shall unlawfully use or be addicted to the unlawful use of narcotics. ", "Any person convicted of violating any provision of this section is guilty of a misdemeanor....\"\n[2] At the time petitioner was convicted of possession of narcotics (Health & Saf. ", "Code, § 11500), the maximum penalty for a first offense was 10 years in prison. ", "The maximum sentence for a second or subsequent offense was 20 years in prison. (", "Health & Saf. ", "Code, § 11712, repealed in 1959; now see Health & Saf. ", "Code, § 11500.)", "\n[3] The destruction of municipal court criminal records over five years old is authorized by Penal Code section 1428b.", "\n[4] When the original complaint charging violation of Health and Safety Code section 11721 is unavailable, it is permissible to prove the form of the charge by other evidence. (", "See In re Carlson (1966) 64 Cal.2d 70, 74-75 [48 Cal. ", "Rptr. ", "875, 410 P.2d 379].)", "\n[5] In affirming petitioner's 1956 narcotics conviction, we stated: \"It [the trial court] also found that he was previously convicted of narcotic addiction (Health & Saf. ", "Code, § 11721), a misdemeanor....\" (People v. Smith (1958) 50 Cal.2d 149, 150 [323 P.2d 435].) ", "We have reviewed the record of the 1956 conviction, but we can find no reference by either the trial court or the parties to the specific part of section 11721 to which petitioner pleaded guilty in 1954. ", "Accordingly, our statement that petitioner was \"convicted of narcotic addiction\" cannot be dispositive.", "\n[*] Assigned by the Acting Chairman of the Judicial Council.", "\n" ]

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[ "1. ", "Introduction {#sec1-materials-11-01813}\n===============\n\nSignificant numbers of people around the world have suffered from bone defects that are mainly due to trauma, bone-related diseases, and improper bone tissue growth. ", "This situation has worsened during the recent era primarily because of a burgeoning global population suffering from a proportionately greater number of bone-related diseases, like age-related bone loss \\[[@B1-materials-11-01813]\\]. ", "In addition, there are the effects of increasing sports-related injuries and traffic accidents, which have heightened the demand for bone tissue replacement \\[[@B2-materials-11-01813]\\]. ", "At present, treatments for bone defects/substitutes include autografts and allografts, both having some important limitations. ", "Limitations that are associated with autografts are mostly linked with a shortage of material available for autografting (i.e., from the iliac crest) and are also (rarely) linked with donor site morbidity. ", "Disease transmission risks and poor immune response describe the main limitations associated with allografts. ", "These limitations have provoked greater research efforts in bone tissue engineering with an aim to utilise a synergistic combination of different materials for functional bone regeneration \\[[@B3-materials-11-01813]\\]. ", "In a typical bone tissue engineering protocol, a three-dimensional (3D) porous scaffold is initially made and is then loaded with specific living cells and/or tissue-inducing growth factors to initiate and promote tissue regeneration or replacement \\[[@B2-materials-11-01813],[@B4-materials-11-01813]\\]. ", "The initiative of bone tissue engineering has escalated research in the field of biomedical sciences, i.e., it has resulted in a more biologically focused and coherent way of designing and developing 3D scaffolds with an appropriate/desired porosity so that they can serve as reinforcement, support, and in some special cases, firmly establish tissue regeneration and replacement. ", "A perfect scaffold is one that has an interconnected porous structure to guide new tissue in-growth and regeneration \\[[@B2-materials-11-01813]\\]. ", "Large numbers of people, every year, find themselves in need of different kinds of biomaterials, like that needed for dental filling material and for hip joint replacements. ", "After the procedure of blood transfusion, bone grafting has turned out to be the second most recurrently performed clinical procedure each year. ", "However, the harsh reality is that many patients still accept the amputation of diseased/damaged bone/organ as an ultimate treatment, because of the unavailability of suitable bone graft substitute materials \\[[@B5-materials-11-01813],[@B6-materials-11-01813]\\].", "\n\nAt present, various biomaterials are designed and fabricated using polymers, metals, ceramics, or their composites. ", "Bioceramics and their composites have increasingly become an established class of materials applied as human body implants in the form of 3D scaffolds, as they have the necessary properties for biological activity in regard to cell adhesion, migration, and proliferation \\[[@B2-materials-11-01813],[@B4-materials-11-01813],[@B7-materials-11-01813]\\]. ", "Amongst the different types of bioceramics available, those having a similar chemical identity to that of bone (i.e., calcium phosphate-based ceramics, like hydroxyapatite) have been found to be the most successful, however, their inherently low fracture toughness and strength have historically hampered their use in load-bearing applications \\[[@B8-materials-11-01813],[@B9-materials-11-01813],[@B10-materials-11-01813],[@B11-materials-11-01813],[@B12-materials-11-01813]\\].", "\n\nThis review intends to explore the ways in which the historically poor strength of pure hydroxyapatite implants has been improved through the use of different carbonaceous structures that have the potential to greatly enhance the strength of hydroxyapatite-based composites, manufactured either in the form of a bulk scaffold or as a coating. ", "The article will describe the efforts that have been put together to present the abilities of different carbonaceous structures, especially those in nanoform, to favour crack bridging and deflection in relation to strengthening and toughening effects in a HAp matrix. ", "The biomimetic roles of HAp and carbonaceous structures are also discussed in relation to developing a sound bio-mechanically active implant interface. ", "These roles of carbonaceous materials provide for potential uses in many different biomedical related applications.", "\n\nHistorical Perspective\n----------------------\n\nIn the past decades, scientists have focused their research efforts on designing and developing artificial bone, with the objective of creating functional bone regeneration candidates. ", "The historical development of the various stages (\"generations\") of biomaterials that resulted can be analysed through a consideration of their relative biomedical and mechanical properties. ", "The first generation of biomaterials was mostly related with the development of high strength bioinert materials, which included the development of metallic materials (such as stainless steel and titanium alloys), ceramic materials (like alumina, zirconia), and polymeric materials (like polyethylene and silicone rubber). ", "These biomaterials were used to make devices, which are commonly known as prostheses. ", "At that time, scientists were only focused on an objective to achieve an appropriate combination of physical properties to match those of the substituted tissue (i.e., the defective site) with a minimal toxic response in the host \\[[@B13-materials-11-01813]\\]. ", "Almost all of the biomaterials of the first generation had a common attribute, i.e., they were bioinert, and hence not able to develop a biological bond to bone or promote repair of bone. ", "Moreover, they were non-degradable in vivo, which meant that secondary surgery was required if the implant failed and/or needed revision \\[[@B6-materials-11-01813],[@B7-materials-11-01813]\\]. ", "By the end of the 1980's, approximately 50 types of implanted prostheses were in clinical use, which were made using 40 different biomaterials. ", "Many people at that time had had successful surgeries, which saw their lives enhanced due to the use of implants made from 'bioinert' biomaterials. ", "However, it was found (specifically in hip and knee implants) that over time there was a tendency for bone to become slowly resorbed at the prosthesis-bone interface, owing to a phenomenon that is known as \"bulk modulus mismatch\". ", "This is also known commonly as stress shielding, i.e., almost all of the mechanical load is carried by the higher modulus implant device, which initiates the localised osteoporosis-like symptoms leading to gradual bone resorption, deterioration of bone strength at the implant-bone interface, hence leading to ultimate failure via loosening. ", "At that time, prominent materials scientists of the 1980s, such as Bonfield, began working on the concept of designing biomaterials that would diminish bone resorption due to stress shielding at the prosthesis-bone interface \\[[@B14-materials-11-01813]\\].", "\n\nLater stages of research into biomaterials development were largely associated with advances in the field of artificial bone materials, which moved towards the use of bioactive or biodegradable materials. ", "This era came to be known as that of the second-generation biomaterials. ", "Bioactive ceramic materials (e.g., hydroxyapatite) and biodegradable polymeric materials (e.g., polylactic acid and polyglycolic acid) are important materials comprising the second-generation biomaterials group. ", "Unlike the previous generation of materials, second-generation biomaterials possessed the property to develop strong bonds to surrounding bone tissue and they were biodegradable/bioresorbable. ", "However, both generations of materials were clinically found to be merely functional/structural substitutes i.e., could only bear the load (in the case of the bioinert materials) or (in the case of the osteoconductive materials) provide a scaffold or \"structure\" in which bone formation had to be induced by natural bodily processes rather than by the implant itself. ", "Some were also found to be insensitive to physiological changes in vivo, such as in the case of stress shielding by bioinert implants \\[[@B5-materials-11-01813],[@B11-materials-11-01813],[@B14-materials-11-01813],[@B15-materials-11-01813],[@B16-materials-11-01813]\\].", "\n\nWith the inception of multidisciplinary developments in the fields of molecular biology, materials science and manufacturing engineering, many innovative and advanced artificial substitutes having unique functionalities were developed, which are capable of bone repair/regeneration. ", "This has led up to the stage where an important area of research known as tissue engineering was created \\[[@B17-materials-11-01813],[@B18-materials-11-01813],[@B19-materials-11-01813],[@B20-materials-11-01813]\\]. ", "Tissue Engineering develops scaffolds for placement in defect sites, which not only provide mechanical integrity but also encourage/actively induce stem cell proliferation. ", "A typical procedure of tissue engineering consists of manufacturing a scaffold using suitable biomaterials and subsequently subjecting them to seeding/culturing of stem cells (already harvested from the patient) after which the scaffold is implanted. ", "It can be applied in situations where a temporary functional repair is required or for permanent repair/regeneration. ", "For a successful scaffold material, it is necessary to have an appropriate degradation rate, as very slow rates of degradation retard bone growth, while overly fast rates will result in loss of mechanical integrity. ", "Therefore, it is necessary for a bone scaffold to possess the desired biological, mechanical, and topological properties, as well as favourable osteoconductive properties, thereby facilitating bone remodelling from artificial bone into natural bone \\[[@B5-materials-11-01813],[@B6-materials-11-01813],[@B7-materials-11-01813],[@B14-materials-11-01813],[@B15-materials-11-01813],[@B16-materials-11-01813],[@B21-materials-11-01813]\\].", "\n\nIn general, calcium, hydroxyapatite (HAp) based bioceramics show excellent biocompatibility, corrosion resistance, and very good compressive strength, which have made them a suitable candidate for implants. ", "However, amongst the list of different calcium phosphates used biomedically, HAp has attracted the most interest from the scientific community due mainly to its features of promoting osseointegration and new bone formation processes, as well as its low toxicity, and resemblance to mineral bone. ", "Research studies so far suggest that, among the list of calcium phosphate compounds, HAp-based materials have been the most successful in bone grafting applications.", "\n\n2. ", "Hydroxyapatite {#sec2-materials-11-01813}\n=================\n\nThe enhancement of advanced materials for biomedical applications is a critical issue challenging modern-day materials science and engineering, especially when it comes to the development of materials to be used in vivo. ", "Historically, hydroxyapatite (HAp), Ca~10~(PO~4~)~6~(OH)~2~ has been the best bone substitute, because it can achieve a sound, firm bond with bone tissue, and furthermore, it can demonstrate osteoconductive behaviour and have no undesirable effects on the human body \\[[@B15-materials-11-01813],[@B22-materials-11-01813],[@B23-materials-11-01813],[@B24-materials-11-01813],[@B25-materials-11-01813],[@B26-materials-11-01813]\\]. ", "The term \"hydroxyapatite\" implies the presence of hydroxyl (OH) groups while \"apatite\" (derived from the Greek word \"apatos\") meaning \"to deceive\" was historically used to identify mineral apatites, as they were often mistaken for precious gems, like topaz) \\[[@B27-materials-11-01813]\\]. ", "Apatites, in general, are known by the chemical formula M~10~(XO~4~)~6~Z~2~, in which M^2+^ is a metal and XO~4~^3−^ and Z^-^ are anions. ", "In the unit cell of HAp, the M^2+^ is Ca^2+^, XO~4~^3−^ is PO~4~^3-^ and Z^−^ is OH^-^. The Ca:P mole ratio in HAp is 1.67. ", "HAp crystallises in a hexagonal system with crystallographic parameters: a = 9.418 Ǻ, c = 6.881 Ǻ, and β = 120°. ", "The crystalline network of HAp is a compact assembly of tetrahedral PO~4~ groups, in which phosphorus atoms are found in the centre of tetrahedra having four oxygen atoms at the top. ", "Each PO~4~ tetrahedron delineates two types of distinct channels. ", "The first channel is surrounded by Ca^2+^ ions, denoted as Ca(I) (4 per unit cell). ", "The second type of channel contains six other Ca^2+^ ions, denoted as Ca(II). ", "These channels host OH^−^ groups along the c axis to balance out the positive charge \\[[@B28-materials-11-01813]\\].", "\n\nAs long ago as 1926, diffraction and chemical studies of teeth and bone revealed that their inorganic phases were basically calcium hydroxyapatite \\[[@B29-materials-11-01813]\\]. ", "In bone, the mineral phase consists broadly of hydroxyapatite but there is also a variety of impurity ions present in the HAp lattice, such as carbonate, magnesium, and sodium ions. ", "Carbonate is one of the most abundant impurity ions with its content being about 4--8 wt.%. ", "This is the reason that bone/hard tissue can be regarded as carbonate-substituted HAp (CHAp) \\[[@B30-materials-11-01813],[@B31-materials-11-01813]\\]. [", "Figure 1](#materials-11-01813-f001){ref-type=\"fig\"} represents the micron and sub-micron features of bone tissue, in which hydroxyapatite platelets can be seen. ", "The biological behaviour of HAp-based ceramics relies on many factors, such as chemical and phase transformation, microstructure, pore size, and pore volume. ", "In surgery, usage of both porous, as well as dense bioceramics, is common, as it depends upon the function and level of implantation that is required by the patient. ", "It is most commonly dealt with on a case-to-case basis rather than in general. ", "Experimentally porous ceramics have a low strength (although strength is found to be dependent upon the level of porosity), and hence such ceramics are found clinically to be more appropriate for drug delivery or for implantation into low load-bearing tissues (like maxillofacial applications) \\[[@B22-materials-11-01813],[@B32-materials-11-01813],[@B33-materials-11-01813]\\]. ", "Osteointegration depends heavily on the pores in implants, more specifically, the pore size, volume, and their interconnectivity. ", "It was observed that for bone ingrowth into an implant (successful osseointegration) the minimum pore size should be around 100--135 µm, and there is also found to be a direct relation between porosity/pore interconnectivity with the process of bony ingrowth into the implant, as the porosity/pore interconnectivity increases bone ingrowth, especially fixation processes, which become more operative. ", "Moreover, protein adsorption favours separation of osteogenic cells. ", "Subsequently, the presence of small, submicron pores, specifically those about the size of blood plasma proteins, favours biointegration. ", "Thus, it is preferred to have a bimodal distribution of pore-sizes in bioceramics \\[[@B20-materials-11-01813],[@B23-materials-11-01813],[@B33-materials-11-01813],[@B34-materials-11-01813]\\].", "\n\nSmall HAp granules are also of interest biomedically, as they find wide application in maxillofacial surgery and implantable drug delivery systems. ", "There are numerous ways to produce HAp granules, like hydrothermal synthesis and pelletising. ", "It was observed through scientific study that spherical HAp particles tend to promote osteointegration and diminish inflammatory processes \\[[@B20-materials-11-01813],[@B35-materials-11-01813]\\]. ", "Ceramics can also serve as a basis for producing composite materials. ", "There is considerable research effort focused on synthesising HAp-matrix composites that achieve reinforcement of the ceramic materials through the use of fine particles, micro lamellae, or fibres, These can raise the strength and toughness of such materials to the level necessary for hard tissue (bone) replacement implants in more load bearing areas \\[[@B24-materials-11-01813],[@B36-materials-11-01813]\\].", "\n\nResearchers have synthesised hydroxyapatite using different techniques, such as hydrothermal synthesis, precipitation, and hydrolysis, as well as employing natural resources, like bovine bones \\[[@B37-materials-11-01813],[@B38-materials-11-01813],[@B39-materials-11-01813],[@B40-materials-11-01813]\\], fish bones \\[[@B41-materials-11-01813],[@B42-materials-11-01813],[@B43-materials-11-01813]\\], marine shells \\[[@B44-materials-11-01813],[@B45-materials-11-01813],[@B46-materials-11-01813]\\], and eggshells \\[[@B45-materials-11-01813],[@B47-materials-11-01813],[@B48-materials-11-01813],[@B49-materials-11-01813]\\]). ", "Historically, the usage of xenogeneic bone, like Kiel bone (actual bone harvested from calf or ox) and Boplant (actual bone harvested from a calf) in biomedical applications, were thought to be the alternate to auto- or homografts, mainly due to limited supply of grafts, site morbidity, and the difficulty/expense of multiple surgical processes \\[[@B22-materials-11-01813]\\]. ", "A study by Callan and Rohrer \\[[@B39-materials-11-01813]\\] also reported patient fears about human tissue transfer, due to the advent of AIDS, especially in dental surgery. ", "They reported that clinicians were actively looking for alternative allograft materials and proposed a naturally derived xenogeneic hydroxyapatite (HAp). ", "The xenogeneic bone grafting material that was used was a fully crystalline naturally porous bovine-derived hydroxyapatite (with all collagenous protein removed), having a particle size in the range of 250--450 µm. ", "Although the organic matter had been previously removed, the bone microstructure was retained. ", "Hydroxyapatite, either synthetic or naturally produced, has been used in wide variety of biomedical applications mainly due to its property of being able to form a bone-like apatite layer at the bone tissue interface \\[[@B17-materials-11-01813],[@B50-materials-11-01813],[@B51-materials-11-01813]\\]. ", "As mentioned previously, despite these favourable bioactive characteristics of HAp, its poor mechanical properties, like low fracture strength and toughness, preclude its usage for high load bearing applications, such as an implant for the hip or knee. ", "Therefore, to make HAp more suitable for such applications, it needs to be reinforced with various biocompatible materials for improving its strength and toughness. ", "This hence necessitates HAp being prepared as a biocomposite material.", "\n\nStrengthening and Toughening of Hydroxyapatite---And Its Importance\n-------------------------------------------------------------------\n\nThe understanding and the application of strengthening and toughening mechanisms are very crucial for designing new and optimised materials. ", "A common engineering goal for a structural material is to be both strong and tough, yet often, increase in strength is coupled with a reduction of toughness and vice versa. ", "Strength is simply the material's ability to withstand stress without being subjected to non-recoverable deformation or fracturing, whereas toughness can be regarded as the resistance to crack propagation \\[[@B52-materials-11-01813],[@B53-materials-11-01813]\\]. ", "Every material contains some form of defects (e.g., pores and cracks) and designing with brittle materials, such as alumina (defect-tolerant design philosophy), is challenging as they are influenced by such defects. ", "Fracture mechanics is a valuable tool for design engineers, as it helps in identifying and evaluating conditions under which a crack/defect will propagate to cause a failure, usually by relating three important parameters i.e., the size of the largest/critical flaw, the applied stress, and the fracture toughness ([Figure 2](#materials-11-01813-f002){ref-type=\"fig\"}). ", "Fracture toughness (or plane strain fracture toughness to use its full title) is a material property that can be obtained through experimental methods, like a three-point bending test, such that crack propagation is instigated. ", "Design engineers can mathematically evaluate critical flaw size or critical stress levels using Equation (1) (fracture toughness equation), once the fracture toughness values are obtained. ", "$$\\ K_{IC} = Y\\sigma\\sqrt{\\pi a}\\ $$ where *K~IC~* is the fracture toughness, *Y* is the geometrical factor, *σ* is the applied stress, and a is the crack length \\[[@B54-materials-11-01813]\\].", "\n\nCeramic materials are known for their brittleness (lack of ability to plastically deform) \\[[@B52-materials-11-01813],[@B54-materials-11-01813],[@B55-materials-11-01813],[@B56-materials-11-01813]\\]. ", "In fracture mechanics theory (Griffith's theory) fractures inside ceramic materials originate from micro-cracks rather than from atomic bond breaking \\[[@B57-materials-11-01813]\\]. ", "Most importantly, these micro-flaws are omnipresent (microscopic flaws, including micro-cracks and internal pores, result from the cooling of the melt or during diffusion-based processes) in the body of a ceramic, and upon loading/stressing these microcracks tend to extend. ", "Similarly, in the case of bioactive ceramics, despite the excellent biological properties, they lack slip systems in their crystals, so whenever they are subjected to an external load, stress relaxing phenomena, like plastic deformation and grain boundary sliding that can occur in metals, do not occur, resulting in poor load-bearing properties for such bioactive ceramics \\[[@B6-materials-11-01813]\\]. ", "Hence, general failure mechanisms of ceramic materials are based on the unstable propagation of flaws (pores, cracks, or inclusions), as they are unable to relieve the stress build up at the tip of flaws (through plastic deformation, as, for example, a ductile metal would), and consequently, a ceramic body's strength is dependent upon the combination of the size of the flaw and the applied stress. ", "This explains why they are commonly referred to as notch-sensitive. ", "The flaws in ceramics tend to act as stress concentrating points, i.e., they amplify the stress at the crack tip, which eventually leads to material failure at an applied stress point that is much lower than the theoretical stress \\[[@B57-materials-11-01813]\\] i.e., a significant decrease in the values of actual strength when being compared with theoretical values \\[[@B57-materials-11-01813]\\]. ", "The theoretical strength of pristine glasses is about 7000 MPa, but practically their strength is merely 1% of the theoretical value (35--70 MPa) \\[[@B58-materials-11-01813]\\]. ", "The dimensions (in micron or nanometre), geometry (penny-like round) and orientation (parallel to applied load) of cracks regulate the magnitude of this amplification of stress. ", "This concentration of stress at the crack tip is commonly denoted by a stress concentration factor, which is the ratio between the maximum stress developed at the microstructural defect to the nominal stress in the body.", "\n\nIt is important to highlight the difference between the stress intensity factor and the stress concentration factor. ", "The stress concentration factor, as defined earlier, is the ratio of maximum (which develops at the crack or flaw) to nominal stress in the body and it is dependent upon the geometry of the flaw or crack. ", "Theoretically, the most important factor that is responsible for severe concentration of stress is a sharp crack (zero tip radius). ", "In contrast, the stress intensity factor is used to predict the stress intensity near the crack/flaw tip that was developed due to remote or residual load or simply it evaluates/calculates the local driving force for crack propagation. ", "This factor is dependent together on the geometry of crack and the applied load. ", "The stress intensity factor is calculated for a given geometry and load and compared with a threshold value of stress intensity factor above which cracks will propagate in the given material. ", "This threshold value of the stress intensity factor is known as fracture toughness or critical stress intensity factor. ", "In Equation (1), the product \"$\\sigma\\sqrt{\\pi a}\"~$is the stress intensity factor, which represents how much the applied stress σ, gets intensified at the tip of the crack having a length a, so, technically, in brittle materials, for the fracture to occur, the stress that is developed at the crack tip must be greater than the fracture toughness values \\[[@B54-materials-11-01813],[@B55-materials-11-01813],[@B59-materials-11-01813]\\]. ", "For bioceramics, where fracture events can be catastrophic, the approach based on utilising fracture toughness values, is the only method that can predict ceramic fracture.", "\n\nWhen the stress developed at the crack tip exceeds the fracture toughness value of the material, the crack will fracture. ", "It is important here to discuss the fracture process of this crack first, as the complete fracture is just a coalescence of the propagating crack with other ones. ", "Fracture mechanics defines this process as a competition between two phenomena i.e., intrinsic (damage) processes and extrinsic crack-tip shielding mechanisms. ", "Intrinsic damage processes, such as micro-void coalescence, promote the propagation of a crack tip by operating ahead of it and are dependent upon the nature of microstructure (or nanostructure) or any second phase ahead of crack tip (usually by cracking/debonding), while the extrinsic crack-tip-shielding mechanisms attempt to inhibit/resist this propagation of the crack tip and operate behind the crack tip. ", "One of the principal methods of increasing fracture toughness is by increasing the microstructural resistance, which will enlarge the plastic zone ahead of the crack tip, eventually making initiation as well as propagation of the crack difficult. ", "This is termed intrinsic toughening and is relevant to ductile materials. ", "For ceramics/bioceramics, extrinsic toughening is perhaps the primary source of toughening, as intrinsic toughening would involve altering the bond strength, which is not feasible. ", "Extrinsic toughening is generally based on diverse microstructural mechanisms that play their role (behind the crack tip) in reducing the damaging force developed at the crack tip; this is usually known as crack-tip shielding and can also involve processes like crack bridging by fibres and in situ phase transformation. ", "Intrinsic toughening mechanisms affect crack initiation as well as crack propagation. ", "They are an inherent property of the material and are found to be active in the material irrespective of the crack size and its geometry. ", "Extrinsic mechanisms, which are only effective for crack growth, come in to play in the event of the crack wake and they are dependent on the size and geometry of the crack \\[[@B52-materials-11-01813],[@B53-materials-11-01813],[@B60-materials-11-01813],[@B61-materials-11-01813]\\]. ", "In the domain of biofabrication using bioceramics, designers are constantly challenged with the issue of low strength and toughness, for which extrinsic toughening is the only solution that is usually done by reinforcing bioceramics using biocompatible and effective materials \\[[@B6-materials-11-01813],[@B17-materials-11-01813]\\].", "\n\nMany successful approaches have been undertaken to toughen the ceramic material. ", "The common strengthening and toughening mechanisms are:\n\n1\\. Modulus/load transfer; i.e., the use of high elastic modulus fibres in a relatively low elastic modulus matrix \\[[@B62-materials-11-01813]\\].", "\n\n2\\. Pre-stressing; which involves placing a portion of the ceramic under a residual compressive stress.", "\n\n3\\. Crack shielding; mainly involving transformation toughening, in which reinforcement particles undergo sudden volumetric change due to an applied stress, which in turn, compresses the flaws in ceramic materials.", "\n\n4\\. Crack deflection or impediment; mainly involving the modification in the microstructure of ceramic materials, like dispersing foreign particles, which tend to impede or deflect an advancing crack.", "\n\n5\\. Crack bridging; implying the addition of some secondary phase, usually fibrous structures, which bridge the flaws in the ceramic, resulting in enhanced strength.", "\n\n6\\. Fibre pull out; is associated with fibre debonding and the corresponding frictional sliding, which enhances the fracture toughness. ", "Some part of the energy is consumed due to friction as fibre, particle, or grain slides against adjacent microstructural features, resulting in enhanced fracture toughness.", "\n\n[Figure 3](#materials-11-01813-f003){ref-type=\"fig\"} represents an opaque and see-through image of the body containing fibrous reinforcement. ", "These pictures clearly outline different strengthening and toughening mechanisms. [", "Figure 4](#materials-11-01813-f004){ref-type=\"fig\"} represents a series of progressive SEM imaging of bovine (rib) bone sintered at high temperatures to burn out all of the collagen protein and lipid residues to yield crystalline hydroxyapatite.", "\n\n3. ", "Carbon and Its Structures {#sec3-materials-11-01813}\n============================\n\nCarbon, one of the most abundant elements on earth, is the essential building block of all living organisms. ", "The use of carbon/carbonaceous structures for biomedical applications is a novel trend as new diverse applications are continually being conceived. ", "Carbon has many different allotropic forms and after hydrogen, is the material that can form the most compounds of any of the elements. ", "Some well-known allotropes of carbon are graphite, diamond, glassy carbon, pyrolytic carbon, fullerenes (C~60~, C~70~), hexagonal diamond (lonsdaleite), and carbon nanotubes \\[[@B63-materials-11-01813]\\]. ", "A broad classification of carbon allotropes is presented in [Figure 5](#materials-11-01813-f005){ref-type=\"fig\"}, while [Figure 6](#materials-11-01813-f006){ref-type=\"fig\"} shows pictures of the different carbonaceous structures possible.", "\n\nCarbonaceous materials have been finding ever-increasing applications in areas spanning the electronics, mechanics, civil engineering, and medical disciplines. ", "Carbonaceous structures, especially carbon fibres, have a unique set of characteristics, namely, high elasticity modulus, as well as specific thermophysical, electrophysical, and sorption properties. ", "This encourages the ever-expanding introduction of carbon composites into the most topical and knowledge-intensive branches of science and technology \\[[@B64-materials-11-01813],[@B65-materials-11-01813]\\]. ", "The biocompatibility of carbonaceous structures with native tissues of the body invites opportunities for medical applications (creation of artificial heart valves, the fixation of bone fractures, burns and diabetic ulcers, the creation of sorbing elements, and air filters). ", "The creation of composites that are based on HAp and carbonaceous structures is a promising strategy for improving the mechanical characteristics of HAp-based implants \\[[@B17-materials-11-01813],[@B51-materials-11-01813],[@B66-materials-11-01813],[@B67-materials-11-01813],[@B68-materials-11-01813]\\].", "\n\nCarbonaceous structures, if used in a limited/low quantity, tend to disperse more evenly and uniformly, leading them to develop good interfacial bonding within the ceramic matrix. ", "It was observed in scientific studies that structures, like graphene and graphene oxide, were effective in enhancing fracture toughness, hardness, and wear resistance of ceramics, which is mainly due to their large surface area and wrinkled surfaces, as such surfaces would give rise to creative mechanical interlocking with the matrix \\[[@B69-materials-11-01813]\\]. ", "Carbonaceous structures possess large elastic modulus (900--1000 GPa) values, which are significantly higher than those that were measured for bio-ceramic-constructed forms (40--50 GPa). ", "As a result of this, when a crack propagates in these composite materials, the stress in the matrix can be efficiently transferred to the carbonaceous structures. ", "At this point of crack propagation, carbonaceous structures will be subjected to stretching and fracturing at their ultimate strain values or will be dragged out from the matrix as the stress exceeds the critical interface bonding strength. ", "In any of these scenarios, a significant amount of the fracture energy will hence be consumed. ", "As the crack spreads further, a mechanism of crack bridging may start to appear, due to other carbonaceous structures being present in the matrix. ", "The carbonaceous structures may start to act like ''elastic bridges\" to impede the further expansion of the crack \\[[@B59-materials-11-01813],[@B70-materials-11-01813]\\]. ", "In addition, to the bridging effect, there can be a crack deflection phenomenon operating, in which the crack interferes with the carbonaceous material, and instead of following its original path of propagation, it is deflected towards the ceramic/carbonaceous material interface. ", "However, if the external energy is inadequate to debond the carbonaceous structure/matrix junction, the crack (crack tip) will become seized, i.e., a condition is achieved, like a shielding effect, which enhances fracture toughness by avoiding further fracturing of the matrix. ", "These above-mentioned mechanisms make further propagation of a crack difficult as most of the external energy is consequently absorbed with little energy remaining for additional spread of the crack. ", "Consequently, the crack spreads in a step-like pattern and progressively decelerates, or even ceases, thus increasing the fracture toughness. ", "This provides a strengthened material capable of load-bearing applications. ", "Therefore, introducing a secondary phase like a carbonaceous structure, which can form a strong interfacial bond with the ceramic materials, can play an effective role in impeding crack propagation and producing more robust and stronger bioceramics.", "\n\nOptimisation experiments have indicated that the quantity of carbonaceous material is very important for mechanical properties, as when the content level approaches a certain threshold value, the optimum mechanical properties can be achieved, however, beyond that threshold value, mechanical properties begin to deteriorate \\[[@B71-materials-11-01813]\\]. ", "This is attributed to the unwanted agglomeration of carbonaceous structures at high content levels, due to strong van der Waals forces, p-p stacking, and the deficiency of functional sites in carbonaceous structures. ", "Apart from that, dispersion in a ceramic matrix is also inherently difficult, which can result in defects and weak interface bonding, eventually leading to a poor reinforcing effect. ", "Hence, for achieving optimum properties of ceramic-based composites, optimisation of content, as well as the dispersion of the reinforcing phase, are all important requirements. ", "So far, well dispersed carbonaceous structures/ceramic composite powders have been attained either by physical mixing or by colloidal processing. ", "In a typical physical mixing, carbonaceous structures were initially ultrasonicated and then mixed with the ceramic powder by milling (usually ball milling) in a solvent. ", "Ultrasonication of carbonaceous structure ensures disaggregation, which makes it suitable for mixing. ", "In a typical colloidal processing protocol, both carbonaceous material and ceramic particles are modified in a way to induce opposite charges on their surfaces, due to which carbonaceous structures can then easily and effectively be dispersed in the ceramic powder via electrostatic attraction, albeit with ultrasonication and stirring being needed to effect efficient mixing. ", "These modifications are brought about usually by surface functionalisation via acidification and oxidation or by using surfactants. ", "As a result, through appropriate processing techniques, carbonaceous structures can mechanically strengthen a hydroxyapatite matrix via crack bridging and deflection mechanisms \\[[@B6-materials-11-01813],[@B57-materials-11-01813],[@B72-materials-11-01813]\\].", "\n\n3.1. ", "Pyrolytic Carbon {#sec3dot1-materials-11-01813}\n---------------------\n\nPyrolytic carbon is highly fatigue resistant and it possesses elastic modulus values that are similar to that of bone. ", "Historically, pyrolytic carbon was widely used for implant coating/construction, as such coatings tended to resist blood clotting on their surface and to make a frictionless surface, which is very useful in cases where the implant needs to have some sort of relative motion with other implants/surfaces. ", "This material was also used for coating orthopaedic implants, like those that are used for finger joint implants, but was limited in their use in orthopaedic implants due to poor bone bonding properties \\[[@B73-materials-11-01813],[@B74-materials-11-01813]\\]. ", "Hetherington et al. ", "\\[[@B75-materials-11-01813]\\] tried to investigate the bone response to HAp-coated pyrolytic carbon, as they plasma-sprayed HAp on pyrolytic carbon implants. ", "Cylindrical samples of pyrolytic carbon, HAp-coated pyrolytic carbon, and HAp-coated titanium were implanted in the femurs of beagle dogs. ", "After eight weeks, the beagles were euthanized, and the implants excised and investigated, which led to the discovery that the pyrolytic carbon had almost nil attachment strength (1.59 MPa), while the other two showed similar interfacial strengths (\\~8.71 MPa). ", "This study showed that HAp favours a durable bond with the adjacent tissue. ", "Similarly, Lin and Jiarui \\[[@B73-materials-11-01813]\\] have reported HAp coating on pyrolytic carbon via electrophoretic deposition (EPD) in glycol and ethanol separately (as the dispersion medium), as they were studying the effect of dispersing media on coating quality. ", "However, this coating was characterised for its chemical and biological properties only, and not for its mechanical properties.", "\n\n3.2. ", "Carbon Fibres {#sec3dot2-materials-11-01813}\n------------------\n\nCarbon fibres (CF) are crystalline filaments of carbon, having a regular hexagonal pattern of carbon sheets. ", "Carbon fibres are widely used as a reinforcing material in polymer and ceramic matrices due to their high elasticity modulus, high strength-to-weight ratio, sorption, and thermophysical properties. ", "The biomedical properties of CFs make them a very important material, as due to their inherent biocompatibility (both in vitro and in vivo), they have been used in making artificial heart valves, in treating bone fractures and purulent wounds, and in making biocomposites. ", "They are usually manufactured via high-temperature conversions during the pyrolysis of carbon-rich (mostly polymeric) precursors \\[[@B76-materials-11-01813]\\].", "\n\nN. A. Zakharova et al. ", "\\[[@B77-materials-11-01813]\\] reported the successful manufacturing of composites comprising micrometre-sized carbon fibres (CFs) and biocompatible nanocrystalline calcium hydroxyapatite, containing 1.0, 2.0, and 5.0 wt.% CFs. ", "This study was based on the principle of co-precipitation of HAp-carbon fibre with hydroxyapatite from a solution of calcium and orthophosphate ions and it was noted that the presence of carbon fibres noticeably affected hydroxyapatite crystallization from a system comprising Ca(OH)~2~--H~3~PO~4~--CF--H~2~O. Researchers found a progressive decrease in HAp sizes in response to increasing carbon fibre percentage, mainly because the presence of more carbon fibres meant more nucleation sites available, which indirectly lead to the formation of finer sized HAp particles. ", "Slosarczyk et al. ", "\\[[@B78-materials-11-01813]\\] manufactured a HAp---carbon fibre composite by hot pressing (using a temperature of 1100 °C, pressure of 25 MPa and an argon atmosphere). ", "The composite was found to possess enhanced fracture strength and toughness. ", "It was reported from this study that the effect of hot pressing and carbon fibre presence both played a substantial role in the strengthening and toughening effects that were observed.", "\n\nDorner-Reisel et al. ", "\\[[@B79-materials-11-01813]\\] studied the microabrasion resistance of non-reinforced and CF-reinforced hydroxyapatite. ", "The composite was made using commercial grade HAp and CF via hot pressing (using a pressure of 25 MPa, temperature of 1000 to 1150 °C, pressing time of 15 min, and an argon atmosphere). ", "Apart from the chemical and structural characterisation, a ball crater test was utilised to ascertain the microabrasion resistance of the composite. ", "It was observed that 20 vol.% of added CF increased the resistance of the composite against microabrasion. ", "Cracking at the interface of the carbon fibres and the HAp matrix was observed after a wear test due to thermal mismatch. ", "To prevent this, the investigators coated the CF with pyrolytic carbon.", "\n\nVery recently, Boehm et al. ", "\\[[@B80-materials-11-01813]\\] tried to investigate the full potential of reinforcing with carbon fibre by undertaking surface functionalisation of the CF. ", "They worked on the concept of improving the wettability (which helps in precipitation) of a carbon fibre by activating their surface, which eventually leads to better adhesion of the fibre with the matrix. ", "Fibres were modified using aqua regia and then calcium adhesion was performed while using CaCl~2~, which proved influential for the precipitation of calcium phosphate crystals on the fibre surface. ", "This type of fibre modification process has great potential for making a strong composite for load-bearing applications.", "\n\n3.3. ", "Nano Carbonaceous Materials {#sec3dot3-materials-11-01813}\n--------------------------------\n\nNano carbonaceous materials involve the use of several different types of materials with varied appearance and properties. ", "Some important materials, for example, are carbon nanotubes, graphene, graphene oxide, and buckyballs. ", "All these materials exhibit unusual electrical, mechanical, optical, thermal, and magnetic properties as compared to their bulk form, mainly due to quantum effects and large surface-to-volume ratios. ", "Due to such unique properties, they are currently being used in a number of applications, such as in sensors and smart materials. ", "When employed as second-phase materials for composites, nanotubes and sheet-like structures of carbon are successful due mainly to their large specific surface areas \\[[@B69-materials-11-01813]\\].", "\n\n### 3.3.1. ", "Carbon Nanotubes {#sec3dot3dot1-materials-11-01813}\n\nCarbon nanotubes (CNTs) are a type of one-dimensional nano-scaled material, having a tubular structure made by rolling single/multi-layer graphite sheets. ", "CNTs, after their accidental discovery in 1991 by the Japanese physicist, Iijima, have piqued the interest of the scientific community mainly because of their unique structural and physicochemical properties. ", "They possess large specific surface areas (50--1315 m^2^ g^−1^), a high aspect ratio (as they have their diameters at the nano-scale but their lengths, are, by contrast, at the micron-scale), high tensile strength, high resilience, and flexibility. ", "The strength of CNTs is approximated to be roughly 100 times that of steel, but its density is just a fraction of that of steel. ", "The reason for these highly favourable mechanical properties is due to the CAC (Carbon Atomic Chain) covalent bond that exists in the carbon rings, as these bonds are considered to be very stable chemical bonds. ", "On the basis of this physical structure, carbon nanotubes can be single-walled carbon nanotube (SWNT) (single tube)---or multi-walled carbon nanotubes (MWNTs) (concentric cylinders of carbon) \\[[@B71-materials-11-01813],[@B81-materials-11-01813],[@B82-materials-11-01813],[@B83-materials-11-01813]\\].", "\n\nThere are many different processes to prepare carbon nanotubes, however, arc-discharge \\[[@B84-materials-11-01813],[@B85-materials-11-01813]\\], laser ablation \\[[@B81-materials-11-01813],[@B84-materials-11-01813],[@B86-materials-11-01813],[@B87-materials-11-01813]\\], and chemical vapour deposition (CVD) \\[[@B85-materials-11-01813],[@B88-materials-11-01813],[@B89-materials-11-01813]\\] are the most common. ", "For large quantities on a commercial scale, CVD is widely used for the preparation of CNTs. ", "In a typical CVD process, the hydrocarbon feedstock is reacted with a metal catalyst at elevated temperatures to yield carbon nanotubes, however, the quality, quantity and dimensions of CNTs are heavily dependent on the reaction conditions. ", "Owing to their unique properties, especially their property to act as carriers for bone morphogenetic proteins, they are regarded as highly successful candidates for reinforcing hydroxyapatite and numerous scientific studies have been performed to ascertain their strengthening and toughening effects in bio-ceramics. ", "Most biomedical research using such composites shows that CNT-based biocomposites are appropriate for cell growth and enzyme activity \\[[@B71-materials-11-01813],[@B82-materials-11-01813]\\].", "\n\nChen et al. ", "\\[[@B90-materials-11-01813]\\] developed a strong CNTs-reinforced hydroxyapatite composite coating on titanium (Ti-6Al-4V) alloy. ", "The composite coating was made while using a sophisticated technique known as \"laser surface alloying\". ", "Initially, commercial grade HAp and CNTs were mechanically ball milled in varying percentages of CNTs (0%, 5%, 10%, and 20%). ", "A Nd: YAG laser, (output power 400 W) was used to apply the coating. ", "After mechanical characterisation a significant increase in hardness was observed but only a slight improvement in modulus. ", "In general, it was found that approx. ", "7 vol.% of carbon nanotubes increased fracture toughness by 50% and flexural strength by 28%. ", "In comparison, Lahiri et al. ", "\\[[@B91-materials-11-01813]\\] reported an increase of 92% and 25% in fracture toughness and elastic modulus values with the addition of 4 wt.% CNTs. ", "Lahiri presented an increase of 260% in fracture toughness and of 50% in flexural strength in hydroxyapatite-nanorods/CNTs by the addition of 3 wt.% CNTs manufactured using spark plasma sintering. ", "It was also reported that vacuum hot-pressing of hydroxyapatite ceramics also improved the mechanical properties \\[[@B92-materials-11-01813]\\].", "\n\nKealley et al. ", "\\[[@B93-materials-11-01813]\\] developed a HAP-CNT composite via a chemical precipitation technique. ", "Commercial CNTs (2 wt.%) were added during the precipitation stage of HAp manufacturing. ", "The powder that was obtained was subjected to hot isostatic pressing at 900 °C under an argon atmosphere. ", "In situ neutron diffraction was utilized to confirm that CNTs and hydroxide bonds were present in the composite. ", "Kaya \\[[@B94-materials-11-01813]\\] developed a CNT-reinforced HAp coating, in which the addition of only 2 wt.% CNTs was found to significantly improve the hardness (i.e., by 10-fold), elastic modulus (by six-fold), and shear strength (by 3-fold) of the coating. ", "Moreover, CNTs were also found to prevent spalling of the coating. ", "CNTs were initially acid-treated to adjust the surface charge, which helped in the dispersion of CNTs in the HAp. ", "Meng et al. ", "\\[[@B95-materials-11-01813]\\] utilized nano-sized HAp particles with needle-like morphology to make a HAP-CNT composite via hot pressing. ", "The composite was found to have enhanced mechanical properties. ", "CNTs were initially functionalized to introduce -COOH groups on its surface, which helped in developing strong interactions between these and the Ca ions on the HAp particles. ", "The composite demonstrated an approx. ", "50% increase in fracture toughness and a 28% increase in flexural strength with the addition of 7 vol.% CNTs. ", "Sarkar et al. ", "\\[[@B96-materials-11-01813]\\] utilized surfactant-modified CNT to make HAp-CNT composites via a spark plasma sintering process while using surfactant-modified CNT and HAp nanopowders. ", "HAp was synthesised using a microwave-assisted process and was ball milled with 2.5 vol.% of CNTs. ", "The resultant powder was spark plasma-sintered at various temperatures, where the temperature of 1100 °C produced the maximum fracture toughness of 1.27 MPa.m^1/2^.\n\nBalani et al. ", "\\[[@B97-materials-11-01813]\\] developed CNT-reinforced HAp coatings using plasma spraying. ", "The powder feedstock for plasma spraying was comprised of 4% CNTs blended with HAp, which was sprayed on titanium Ti-6Al-4V substrate (power 20--25 kW). ", "The coating was found to be highly crystalline and non-toxic with a ca. ", "56% improvement in fracture toughness. ", "Li et al. ", "\\[[@B98-materials-11-01813]\\] utilised a double in situ process to develop HAp-CNT composites. ", "In the double in situ process, CNTs were initially synthesised and modified using HAp via CVD, and then were further encapsulated using HAp via a sol-gel process. ", "The modification of CNTs with HAp proved to be helpful in developing a strong interfacial bond and a homogenous dispersion in the matrix, which led to enhanced biological as well as mechanical properties, as the flexural strength was found to be higher (1.6 times) than that of pure HAp. ", "Kim et al. ", "\\[[@B99-materials-11-01813]\\] reinforced HAp with different percentages of multiwalled carbon nanotubes and utilised the spark plasma sintering (SPS) technique for consolidation. ", "Sintering at 900 °C, the composite attained maximum density, fracture toughness, and Vickers microhardness, but sintering beyond this temperature led to a degradation of the properties. ", "It was also observed that increasing nanotube concentration was directly increasing the hardness and fracture toughness. ", "A pull out mechanism was widely observed and declared to be the origin of the elevated fracture toughness values.", "\n\n### 3.3.2. ", "Graphene {#sec3dot3dot2-materials-11-01813}\n\nGraphene is a leading nanomaterial that commands a strong research following due to its diverse applications and properties. ", "This material has also been of strong interest to biomaterial scientists due to its two-dimensional structure and large contact area, which makes it an ideal material for making composites. ", "It is composed of a single layer of carbon (sp^2^-hybridized) atoms arranged in a honeycomb lattice-like arrangement. ", "Graphene is the basic building block of all graphitic materials and possesses exceptional mechanical properties like tensile strength of ca. ", "130 GPa and a Young's modulus ca. ", "0.5--1 TPa \\[[@B100-materials-11-01813],[@B101-materials-11-01813]\\]. ", "It has been found that graphene can stimulate a toughening effect in a HAp matrix even at a low content level; however, it would be appropriate to term this reinforcing graphene as \"graphene nanosheets (GNS)\". ", "This is because GNSs usually have thicknesses near 8--10 nm and are usually made up of a few graphene layers. ", "GNS show similar properties to that of graphene (monolayers), in that they have strong mechanical, high electrical, and enhanced biological properties. ", "From graphene can be derived two further important materials i.e., graphene oxide (GO) and reduced graphene oxide (RGO), which both have unique properties. ", "Many biomaterial scientists have developed graphene-HAp based biocomposites for different biomedical applications, especially those that can be used for orthopaedic applications \\[[@B102-materials-11-01813]\\].", "\n\nLiu et al. ", "\\[[@B103-materials-11-01813]\\] developed graphene/hydroxyapatite composites using precipitation methods, as a result of which nucleation and growth of rod-like HAp nanoparticles on the graphene surface was observed, which occur most likely as the result of a charge balancing mechanism. ", "After using arc spark plasma sintering, there was a significant increase in the fracture toughness (203%) with 1.0 wt.% graphene. ", "In contrast, Zhang et al. ", "\\[[@B104-materials-11-01813]\\] reported a maximum of 80% increase in the fracture toughness of HAp-1 wt.% CNT composite made via spark plasma sintering. ", "This rise in fracture toughness was attributed to different strengthening and toughening mechanisms, like crack bridging, crack deflection, and pull-out effects. ", "An in vivo study \\[[@B105-materials-11-01813]\\] on mice showed that the addition of graphene did not alter biocompatibility. ", "Therefore, it is a very promising strategy to incorporate graphene as a second phase reinforcement in HAp, as it can enhance the mechanical properties of HAp without compromising the biological properties.", "\n\n### 3.3.3. ", "Graphene Oxide {#sec3dot3dot3-materials-11-01813}\n\nGraphene oxide (GO) is an important derivative of graphene. ", "It can be referred to as the oxygenated counterpart of graphene as it consists of graphene sheets covered with oxygen-based functional groups, like hydroxyls (on its planes), epoxide (on its planes), and carboxyl and carboxyl groups (on its edges). ", "Its particularly large surface area, biostability, biocompatibility, antibacterial properties, ease of chemical functionalisation, favourable dispersion behaviour, and mechanical properties are the main reasons for its widespread applications in diverse fields. ", "The presence of functional groups on its surface facilitates in achieving dispersion stability and enhancement of interfacial bonding, which eventually leads to better load transfer in composites \\[[@B106-materials-11-01813],[@B107-materials-11-01813],[@B108-materials-11-01813]\\]. ", "As compared to CNT, high-quality GO can be manufactured on a commercial scale at a lower cost. ", "All of these properties and its relatively low cost of production have made GO an important material for nanoscale reinforcement in biocomposites. ", "Several studies were conducted to synthesise HAp-GO based composites, as the incorporation of GO in HAp will ensure a good dispersibility and enhancement of mechanical strength. ", "Historically, Schafhaeutl \\[[@B109-materials-11-01813]\\] had reported GO for the first time in 1840 (while working carbon for making cast iron, steel and malleable iron) and then Brodie \\[[@B110-materials-11-01813]\\] in 1859 (while discussing and evaluating the atomic density of graphite). ", "At present, GO is mostly synthesised using a process proposed in 1958 by Hummers and Offeman \\[[@B111-materials-11-01813]\\] in which graphite is initially oxidised (using concentrated sulfuric acid, sodium nitrate, and potassium permanganate) to achieve GO having an increased interlayer distance addition of oxygen-containing functional groups. ", "If this graphite oxide is subjected to ultrasonication, then it will dislodge the graphitic sheets to achieve graphene oxide (GO). ", "There is also a modified Hummers method in which NaNO~3~ was eliminated to make the process safer and environmentally friendly, but the main strategy is the same. ", "GO can also be reduced to achieve graphene, but due to partial reduction instead of graphene, \"reduced graphene oxide\" (RGO) usually results. [", "Figure 7](#materials-11-01813-f007){ref-type=\"fig\"} depicts how GO and RGO can be obtained from graphite.", "\n\nLi et al. ", "\\[[@B112-materials-11-01813]\\] reported a significant reduction in surface cracks and an improvement in resistance to coating detachment in the HAp based coating by adding graphene oxide (GO) via a cathodic electrophoretic deposition process on a titanium substrate. ", "Nano GO and HAp were commercially sourced and mixed together in varying percentages of GO (2% and 5%) via an ultrasonic process to ensure a homogenous distribution. ", "The coating was achieved while using the electrophoretic deposition method with 30 V of constant voltage in a HAp-GO suspension. ", "The coating was found to have superior corrosion resistance and in vitro biocompatibility, along with enhanced coating adhesion properties (ca. ", "75% increase with 2% GO and ca. ", "110% increase with 5% GO, when compared to the adhesion strength of pure HAp). ", "Fathyunes and Khalil-Allafi \\[[@B113-materials-11-01813]\\] utilized ultrasound-assisted pulse electrodeposition to develop microstructurally refined and compact GO-HAp coatings on titanium substrates. ", "The utilization of ultrasonic power (\\>60 W) was found to be effective for the incorporation/penetration of GO sheets into the coating. ", "GO was synthesised using the modified Hummers' method. ", "The electrodeposition method was performed using an electrolyte containing Ca(NO~3~)~2~, NH~4~H~2~PO~4~, and H~2~O~2~, with the addition of a 100 μg/mL GO suspension, which resulted in the development of the GO-HAp coating. ", "The complete process of electrodeposition was aided by ultrasonication with the HAp-GO coating being found to have higher hardness and modulus values (3.08 GPa of nano-hardness and 41.26 GPa of elastic modulus at the ultrasonic power of 60 W) together with enhanced corrosion resistance. ", "Li et al. ", "\\[[@B114-materials-11-01813]\\] successfully developed a GO-HAp composite using an in situ one-step mineralization method. ", "GO was synthesised using the modified Hummers and Offema method. ", "To perform the in situ mineralisation, GO and calcium chloride were ultrasonically mixed in a mixture of water and ethylene glycol and then disodium hydrogen phosphate solution was added, which stimulated the mineralisation of HAp, as confirmed by transmission electron microscopy (TEM), X-ray diffraction (XRD), Energy dispersive spectrometry (EDS), and Atomic Force Microscopy (AFM). ", "Mechanical testing of GO-HAp and GO sheets/papers revealed higher modulus values (16.9 GPa), higher tensile strength (75.6 MPa), but reduced fracture toughness values (214.9 kJ m^-3^), as compared to GO alone. ", "The modulus values of GO-HAp were found to be analogous to those measured for the human femur bone (13--15 GPa) and human tibia bone (13--16 GPa).", "\n\n### 3.3.4. ", "Reduced Graphene Oxide {#sec3dot3dot4-materials-11-01813}\n\nOne attractive feature of GO is its ability to undergo (partial) reduction by removing oxygen-containing groups to yield graphene-like sheets. ", "This recently developed material is a type of graphene and it has many terms describing it like \"functionalized graphene\", \"reduced graphene\", or \"chemically modified/converted graphene\", but, in general, it is known as \"Reduced Graphene Oxide\" or RGO. ", "The scientific aim of the reduction process of graphite/graphene oxide is to make pristine graphene, however, there always remain some defects and functional groups (residual) defects that can harshly alter the structure of the carbon plane. ", "The reduction process can be chemical, thermal, or electrochemical. ", "RGOs possess a honeycomb crystal lattice and they are found to have unique properties, like high electrical and thermal conductivity, biocompatibility, high surface area (\\>2600 m^2^ g^−1^), and chemical stability \\[[@B108-materials-11-01813],[@B115-materials-11-01813]\\].", "\n\nLiu et al. ", "\\[[@B103-materials-11-01813]\\] developed HAp-RGO nanocomposites while using a liquid penetration technique. ", "RGO was synthesised using the modified Hummer's method and it was made into a suspension by dispersing in water. ", "In the RGO suspension, HAp nanorods were wet-chemically synthesised to produce a HAp-RGO composite. ", "HAp-RGO composite powders with varying percentages of RGO were pelletised using Spark Plasma Sintering. ", "The composite's fracture toughness values reached up to 3.94 MPa.m^1/2^; much higher than that for pure HAp. ", "Crack tip shielding, crack deflection, and bridging were considered to be the reasons for the higher observed fracture toughness values, which were brought about by the inclusion of the RGO in the composite.", "\n\nBaradaran et al. ", "\\[[@B116-materials-11-01813]\\] developed HAp-RGO composites, in which HAp was used in the form of nanotubes. ", "GO was prepared while using the simplified Hummer's method, while HAp nanotubes were made using a surfactant-free solvothermal process. ", "HAp-RGO composites were synthesised using a hydrothermal process during which GO was reduced to RGO then formed into the hybrid material. ", "The powder was pelletised using hot isostatic pressing using 160 MPa pressure at 1150 °C. ", "The composite showed an increase in the fracture toughness and elastic modulus of 40% and 86% respectively when compared to pure HAp. ", "Biological testing revealed the promotion of osteoblast and proliferation activity on the composite. ", "Similarly, Elif et al. ", "\\[[@B117-materials-11-01813]\\] successfully reinforced HAp with RGO. ", "RGO was made from GO, which was initially made using Hummer's method, and then it was reduced using plant extracts to yield RGO. ", "HAp-RGO composites were made using a liquid penetration method and were subjected to pelletising and sintering. ", "It was observed that a small quantity (1%) of RGO had caused an increase of 3.2 times in the compressive strength of the composite as compared to the equivalent pure HAp sample. ", "An increase in biocompatibility was also observed.", "\n\n### 3.3.5. ", "Nanodiamonds {#sec3dot3dot5-materials-11-01813}\n\nNanosized diamond particles (Nanodiamond (ND)) are known for their mechanical, biological, and tribological properties, which include biocompatibility, high hardness, a low friction coefficient and chemical stability. ", "This unique set of properties in ND has ignited intense interest for its applications as a secondary phase for reinforcing a bioceramic, especially a HAp matrix. ", "On a commercial scale, NDs are formed by the detonation of carbon-based explosives and they are hence known as detonation nanodiamonds. ", "In a detonation nanodiamond, there can be impurity species like O, N, Fe, Cr, Ca, and some functional groups like N--H, C--O--C, C--OH, C=O present which is given as the reason for the surface's chemical multi-functionality. ", "Nanodiamonds have also been used to produce mechanically strong HAp based coatings for load-bearing biomedical applications. ", "The addition of nanodiamonds in HAp based coatings may also increase coating adhesion and prevent metal ion release from metal surfaces. ", "Nanodiamonds have also been explored for their application in drug delivery applications \\[[@B118-materials-11-01813],[@B119-materials-11-01813],[@B120-materials-11-01813]\\].", "\n\nPramatarova et al. ", "\\[[@B121-materials-11-01813]\\] developed and studied biomedical coatings that were based on hydroxyapatite reinforced with detonation nanodiamonds (DND). ", "The coating was grown biomimetically using supersaturated simulated body fluids on different substrates (Ti, Ti alloy, glass). ", "DNDs were created by the detonation of carbon-containing explosives and the generated shockwave at high temperatures and pressures, which produced very fine particles of DND (approx. ", "size: 4-6 nm). ", "These DNDs were added to an SBF solution, from which the growth of an HAp-DND coating was stimulated on different substrates. ", "Upon comparison, it was found that the composite coating was more compact than that of pure HAp but was porous. ", "Cell culture testing revealed DND was not toxic to living cells. ", "Similarly, Chen et al. ", "\\[[@B122-materials-11-01813]\\] synthesised a biomedical HAp--nanodiamond based coating and deposited it using plasma spraying on a titanium substrate. ", "The nanosized HAp powder was synthesised using the wet chemical route, with the powder being subsequently added in 3.0 wt.% PVA to make the slurry. ", "The ND suspension was made separately using commercial ND particles and a solvent (a 1:1 water/ethanol mixture). ", "The coating was achieved via spark plasma sintering using a 0.5 wt.% and 2.0 wt.% ND suspension. ", "The coating proved to be of uniform structure with low porosity and had enhanced mechanical properties when compared to the equivalent pure HAp-based coatings.", "\n\nSimilarly, Pecheva et al. ", "\\[[@B123-materials-11-01813]\\] incorporated ND particles into SBF solution to make a coating on a titanium substrate using an electrodeposition method for which they used a three-electrode electrolytic cell. ", "ND particles were made via a shock-wave propagation method and were added into an SBF solution. ", "The coating obtained was found to be of a homogenous structure, free from residual stresses and possessing high hardness and ductility values. ", "Li et al. ", "\\[[@B124-materials-11-01813]\\] reported a novel approach in which NDs were first biofunctionalized by attaching bone morphogenetic protein 2 to them and then made a composite with HAp. ", "Detonation NDs for this study were made using a shock wave propagation method and were then converted into a suspension (NDS-PBS (phosphate buffered saline)). ", "The composite powder was coated using a vacuum cold spray method.", "\n\n### 3.3.6. ", "Fullerenes {#sec3dot3dot6-materials-11-01813}\n\nFullerenes and their derivatives are found to have varied biomedical applications mostly in drug delivery systems. ", "Fullerenes were discovered in 1985 and possess a carbon cage structure with immense scope for chemical derivatisation \\[[@B125-materials-11-01813]\\]. ", "Fullerenes are entirely composed of carbon in the form of hollow spheres (or can be ellipsoidal in nature) or adopt related geometries. ", "Highly symmetrical spherical fullerenes with icosahedral symmetry are known as Buckyballs or C~60~ \\[[@B126-materials-11-01813]\\]. ", "Fullerenes are usually characterised by their hydrophobicity, three-dimensionality, electronic configuration, and good biological properties. ", "The major issues related to the usage of fullerenes are its insolubility in aqueous media and aggregation \\[[@B127-materials-11-01813]\\]. ", "One strategy to avoid such issues is chemical modification after which fullerene can be converted into fullerenol (a polyhydroxylated structure, C~60~(OH)~x~). ", "This type of chemical modification is based on the addition of hydroxyl groups to the fullerene, which causes it to form into loosely associated, amorphous nano-aggregates. ", "Djordjevic et al. ", "\\[[@B128-materials-11-01813]\\] synthesised a hydroxyapatite/fullerenol nanocomposite via sonochemical processing; however, no mechanical characterisation was performed to access the strengthening effect. ", "It was observed that the fullerenol nanoparticles had modified the surface of hydroxyapatite as the zeta potential values of the nanocomposite were ten times lower when compared to pure hydroxyapatite. ", "This was attributed to the possibility of developing hydrogen bonding between surface phosphate groups in hydroxyapatite and hydroxyl groups in fullerenol.", "\n\n### 3.3.7. ", "Carbon Nanofibres {#sec3dot3dot7-materials-11-01813}\n\nCarbon nanofibres (CNFs) are linear sp^2^ carbon-based short fibres, having an aspect ratio greater than 100. ", "They are generally vapour-grown or PAN (Polyacrylonitrile) based. ", "CNFs possess excellent mechanical properties, biocompatibility, and non-toxicity, which render them suitable for reinforcement purposes in biomedical materials. ", "Satoshi et al. ", "\\[[@B129-materials-11-01813]\\] reported an increase of the mechanical properties in HAp based biocomposites due to carbon nanofibres (CNFs) reinforcement. ", "The CNFs/HA composite was made via ball-milling techniques, followed by sintering using hot-pressing. ", "It was observed that the addition of 10 vol.% CNFs resulted in a bending strength (i.e., 90 MPa), which was in the range of that of cortical bone. ", "It was also found that the fracture toughness of CNFs/HAp composites was ca. ", "1.6 times higher than that of microporous HAp, but having the same level of bioactivity. ", "Wu et al. ", "\\[[@B130-materials-11-01813]\\] developed a carbon nanofibre (CNF)/hydroxyapatite (HAp) composite, having strong interfacial bonding and high mechanical strength. ", "The CNF was made using carbonisation of electrospun polymeric (polyacrylonitrile) precursor nanofibres. ", "CNF mat was alkali-treated to introduce carboxylic groups onto its surface, and was then immersed in SBF solution to precipitate HAp on its surface. ", "The fracture strength of 41% CNF-reinforced composites was found to be 67.3 MPa.", "\n\n4. ", "Other Systems Involving Carbon Structures and Hydroxyapatite {#sec4-materials-11-01813}\n===============================================================\n\nResearchers in the past have explored the strategy of reinforcing hydroxyapatite with suitable carbonaceous structures; however, there are numerous studies in which some other components have been added into the composite for biological and/or mechanical enhancement of the composite.", "\n\nHerkendell et al. ", "\\[[@B131-materials-11-01813]\\] highlighted the issue of bacterial infections during bone surgeries and emphasized the addition of a bactericidal component in the biomaterial to deal with the issue. ", "They developed a CNT-reinforced HAp composite containing small amounts of silver (Ag), which is known for its antibacterial properties. ", "A HAp--4 wt.% CNT--10 wt.% Ag composite demonstrated high density and a maximum fracture toughness enhancement of up to 244%. ", "The composite was found to have good anti-bacterial properties together with high interfacial strength. ", "With the addition of different trace metallic elements, researchers have found significant improvements in the biological properties of the HAp-based bioceramics. ", "These have exploited the fact that the HAp crystal lattice is labile to these cations \\[[@B132-materials-11-01813],[@B133-materials-11-01813],[@B134-materials-11-01813]\\]. ", "Different bioactive metallic ions have been investigated with HAp based composites, like Sr^2+^, Mg^2+^, Mn^2+^, Ag^+^, Zn^2+^, and Y^3+^. Among these, for instance, Mn^2+^ was found to influence the osteoblast differentiation and bone resorption and to promote biological activity and the ability to promote bone. ", "Similarly, Zn^2+^ was found to stimulate new bone formation, increasing bone density, inhibiting osteoclastic proliferation and bone resorption in vivo. ", "Elements incorporated into HAp, such as Ag^+^ ions, need to be considered with some caution, however, because the presence of silver in vivo may lead to a medical condition known as Argyria in which permanent deposition of silver can occur in tissues causing cosmetic disfigurement if it is subcutaneous. ", "This is discussed in detail in the paper by Hadrup and lam \\[[@B135-materials-11-01813]\\].", "\n\nChen et al. ", "\\[[@B136-materials-11-01813]\\] developed a chitosan- CNT-HAp nanocomposite using an in-situ precipitation method. ", "Chitosan is a fibre extracted from chitin, which develops in a crustacean's exoskeleton. ", "Chitosan is biocompatible and is biomedically exploited for various applications, such as bone tissue engineering \\[[@B137-materials-11-01813],[@B138-materials-11-01813],[@B139-materials-11-01813],[@B140-materials-11-01813]\\] and drug delivery technology \\[[@B141-materials-11-01813],[@B142-materials-11-01813],[@B143-materials-11-01813]\\]. ", "Multiwalled CNTs of 10 nm diameter were utilized and added into chitosan using ultrasonication. ", "The composite was found to have good biocompatibility and also a maximum increase of ca. ", "110% in elastic modulus and 210% in compressive strength as the CNTs/chitosan wt. ", "ratios rise from 0 to 5%. ", "Yoon et al. ", "\\[[@B144-materials-11-01813]\\] developed a gelatin-functionalised CNTs-HAp composite to mimic the natural structure of collagen fibrils in natural bone. ", "In natural bone, collagen fibrils are interdigitated with HAp crystals and are responsible for strength and flexibility. ", "Gelatine is a biocompatible, biodegradable, and high molecular weight polypeptide, which is already in medical usage, like wound dressings. ", "Initially, in this reported research, a CNT/gelatin hybrid was made by covalently grafting gelatin molecules onto the surface of CNTs via the formation of amide linkages, then HAp crystals were assembled onto the CNT/gelatin hybridised surface. ", "The structure of this composite is composed of CNT as a core and gelatin-HA as multi-layered shells. ", "This hybrid material was found to be biocompatible and with enhanced mechanical properties.", "\n\nKalmodia et al. ", "\\[[@B145-materials-11-01813]\\] manufactured a HAp -Alumina (Al~2~O~3~) -multiwalled carbon nanotubes (CNTs) composite. ", "Previous, separate studies showed an enhancement of fracture toughness of the HAp matrix using individual Al~2~O~3~ reinforcement \\[[@B146-materials-11-01813],[@B147-materials-11-01813]\\] and CNT reinforcement \\[[@B72-materials-11-01813],[@B93-materials-11-01813],[@B98-materials-11-01813],[@B99-materials-11-01813]\\]. ", "In this study, researchers were interested in investigating the combined reinforcing effect of CNT and Al~2~O~3~ in a HAp matrix. ", "The composite was made while using spark plasma sintering and it was found to be biocompatible and also demonstrated favourable cell adhesion and proliferation properties. ", "The highest hardness was recorded in a HAp-Al~2~O~3~ sample, but enhanced fracture toughness was observed when CNTs were added. ", "Khanal et al. ", "\\[[@B72-materials-11-01813]\\] utilised nylon along with carboxyl-functionalized CNTS (single walled) in a HAp matrix to enhance fracture toughness. ", "The process comprised precipitation of HAp particles, which were then mixed with predefined quantities of CNTs and nylon. ", "The fracture toughness values of the 1 wt.% carboxyl-functionalised single-walled CNTs and nylon were found to be 3.60 MPa.m^1/2^.\n\nMurugan et al. ", "\\[[@B148-materials-11-01813]\\] found an enhancement in the biological and mechanical properties of mineralised hydroxyapatite reinforced by GO and oxidised CNF. ", "GO was made using Hummer's method, while commercial CNF was treated while using NaOH. ", "Among the different percentages trialled, 1% oxidised CNF and 1% GO-based composite were found to have the best properties for orthopaedic applications, like mechanical strength, which was 468 ± 4 HV (by Vicker's micro-hardness), along with favourable bactericidal properties.", "\n\n5. ", "Biomimetic Role of Hydroxyapatite and Carbon Composite Materials Intended as Biomaterials {#sec5-materials-11-01813}\n============================================================================================\n\nGustave Eiffel designed The Eiffel Tower after being inspired by the load distribution features from observing the \"trabeculae\" of human thigh bone (the longest and strongest bone in the body). ", "In the biomedical field, using knowledge that is gained from biomimetics and biomineralisation can lead to biomaterials that are closer in function to natural boney tissues \\[[@B149-materials-11-01813]\\]. ", "For an ideal implant material that can provide a natural environment for surrounding tissues and cells, it is necessary to meet the biochemical requirements of bone tissue engineering and to have the necessary mechanical properties to provide a framework for surrounding cells/tissue to interact with its surface. ", "The environment leading to new tissue growth should eventually lead toward bone remodelling and new bone formation \\[[@B16-materials-11-01813],[@B150-materials-11-01813],[@B151-materials-11-01813],[@B152-materials-11-01813]\\]. ", "Designers for implant material(s) need to consider several different factors, which can either be extrinsic or intrinsic ([Figure 8](#materials-11-01813-f008){ref-type=\"fig\"}), however most of the extrinsic factors are outlined by medical professionals. ", "An implant material is anticipated to complete the process of bone regeneration and healing after which implant removal becomes desirable from a clinical and biomechanical point of view. ", "So, in such situations, bioactive and biodegradable materials are required to avoid a second surgery to remove them. ", "Bioactive and biodegradable ceramics possess the unique ability of developing a bond to bone tissue, making them useful as 3D scaffolds and coatings \\[[@B16-materials-11-01813],[@B151-materials-11-01813],[@B152-materials-11-01813]\\]. ", "Some of the most researched bioactive ceramics for bone augmentation are hydroxyapatite \\[[@B34-materials-11-01813],[@B153-materials-11-01813]\\], β-tricalcium phosphate (β-TCP) \\[[@B154-materials-11-01813],[@B155-materials-11-01813]\\], and bioactive glass \\[[@B156-materials-11-01813],[@B157-materials-11-01813],[@B158-materials-11-01813]\\]. ", "They possess different rates and extents of resorption, however, all of them are biocompatible and osteoconductive.", "\n\nHydroxyapatite is found to have low biodegradability due to its low solubility (Ksp ≈ 6.62 × 10^−126^) and it develops a bone-like calcium phosphate coating on the implant surface, which helps in bonding to the surrounding tissues \\[[@B159-materials-11-01813],[@B160-materials-11-01813]\\]. ", "Kim et al. ", "\\[[@B161-materials-11-01813]\\] demonstrated how electrostatic interactions of the HAp surface, with Ca^2+^ and PO~4~^3−^ ions promotes bone like apatite formation. ", "The study was carried out using SBF. ", "When an HAp surface is exposed to SBF, the surface displays negative charge and interacts with the Ca^2+^ ions, thereby forming a Ca-rich amorphous calcium phosphate layer, which resulted in the alteration of charge i.e., now the surface become positively charged. ", "The process proceeds with the electrostatic interaction with PO~4~^3−^ ions and forms the Ca-deficient amorphous calcium phosphate, which ultimately matures into bone-like apatite. ", "Brandt et al. ", "\\[[@B162-materials-11-01813]\\] reported hydroxyapatite implantation in rabbit femoral bone for 12 weeks, in which it was found that HAp exhibited bone formation, minimal degradation, and slow resorption. ", "Following implantation, serum proteins are known to be readily adsorbed on the implant surface, which favourably alters the interfacial properties of the scaffold leading to initial in vivo resorption mostly from cellular activity. ", "Tissue remodelling (bone formation and resorption) is carried out by osteoblast (bone forming) and osteoclast (bone resorbing) cells. ", "When a hydroxyapatite-based implant is inserted into the physiological environment, a foreign body response is initiated, which follows a series of different phenomena, namely: injury (surgeons initially have to \"injure\" certain tissues and remove them to some extent to fix implant), protein matter interaction, blood clotting, inflammatory responses, fibrous tissue formation, and tissue remodelling. ", "The resorption of HAp in the physiological environment creates space for newly developing tissues, which not only grows along the surface of the implant, but also infiltrates into the scaffold. ", "This infiltration is accompanied with blood vessels (and oxygen supply for regenerating tissues), which eventually allows bone formation to progress. ", "The initial degradation of HAp-based implants is highly dependent upon its properties, like porosity, surface roughness, and the site of implantation, as they directly affect the phenomena occurring near the implant surface (fluid exchange and nature of surrounding medium) \\[[@B152-materials-11-01813]\\]. ", "Moreover, one of the most important parameters for bone augmentation is the volume of new bone formed, which is highly dependent on an adequate blood supply. ", "Foreign body response near the implant results in a different physiological environment as there is found to be enhanced concentrations of reactive oxygen, proteolytic enzymes, fibrotic proteins, giant cells, as well as a reduced pH in the vicinity of the implant. ", "The osteoinductive properties of bone-like materials are largely dependent upon calcium (Ca^2+^) and phosphate (PO~4~^3-^) ions, as during in vivo bone resorption, osteoclasts resorb calcium (Ca^2+^) and phosphate (PO~4~^3-^) ions from bone matrix, which results in a local increase of ion concentration. ", "This ionic gradient assists in bone formation by the proliferation and differentiation of osteoblast cells. ", "Then, the presence of interconnected macro and micro porosity (and its distribution) in HAp-based implants plays a significant role in boney tissue ingrowth, as it is responsible for oxygen and blood exchange during cell and bone growth \\[[@B160-materials-11-01813]\\].", "\n\nFor designing an effective biologically active surface in an implant material that can orchestrate these physiological healing process, the strong effect of altered environment near the implant is considered. ", "In general, cellular response, which includes cell adhesion, proliferation, migration, and differentiation, is heavily influenced by the implant's surface chemistry, surface finish (the degree of roughness), topography, and wettability. ", "There are several mechanisms responsible for effective cell adhesion to a biomaterial surface, including weak van der Waal's forces and electrostatic attraction; mechanical clinching to surface topographical structures and specific interactions between cell surface receptors and specific ligand molecules, as different cells react differently to the various surface features \\[[@B16-materials-11-01813],[@B151-materials-11-01813],[@B163-materials-11-01813]\\]. ", "Jarcho \\[[@B164-materials-11-01813]\\] reported after clinical studies that HAp could develop direct physiological bonding to bone, with good biocompatibility and no inflammatory response. ", "Initially, the surface undergoes partial solubility, which leads to direct deposition of calcified bone matrix. ", "In vitro studies have shown that the presence of micro and macro porosities in HAp influence the degradation behaviour of HAp, but not the bonding of bone tissue. ", "Wenisch et al. ", "\\[[@B165-materials-11-01813]\\] studied the degradation of hydroxyapatite implanted in a sheep for six weeks, via transmission electron microscopy. ", "The degradation was found to be osteoclast-mediated. ", "Guda et al. ", "\\[[@B166-materials-11-01813]\\] conducted a clinical animal study to find the effect of pore size on bone regeneration and reported that large uniform pore sizes result in enhanced bone regeneration.", "\n\nSimilarly, in the case of carbonaceous matter included in biomedical materials, their properties are mostly related to their surface features. ", "Rajzer et al. ", "\\[[@B167-materials-11-01813]\\] reported microscopic studies both in vivo and in vitro on two types of carbon fibres, in which one was HAp-modified, while the other type was a porous carbonaceous material. ", "It was found out that cell adhesion was more effective on porous fibres when compared to the HAp-modified carbon fibres, which is most likely due to the increased surface area. ", "Similarly, the significant amount of porosity also enhanced the tissue and cell growth within the implant structure, which has been observed to be the case with porous mineralized structures. ", "As far as the biocompatibility of carbonaceous structures, especially carbon fibres, is concerned, it is known to be well tolerated by the body without any foreign reaction. ", "More interestingly, the newly developed bony structure on the carbon scaffolds was found to be morphologically and functionally similar in form to the replaced natural bone. ", "However, it was observed that in the case of fibrous carbon the cellular responses were inversely dependent upon the crystallinity i.e., amorphous fibres were judged to be excellent for implants rather that high crystallinity ones. ", "Some studies \\[[@B168-materials-11-01813],[@B169-materials-11-01813]\\] have revealed the adequate haemocompatibility; reduced thrombus formation in amorphous carbon. ", "Du et al. ", "\\[[@B170-materials-11-01813]\\] reported osteoblast cells attachment and proliferation on the surface of diamond like carbon (amorphous carbon) that was deposited on silicon substrates. ", "Perkin and Naderi \\[[@B171-materials-11-01813]\\] reviewed and declared carbon nanostructures safe for clinical uses. ", "They observed that, if the carbon structure is fixed in a solid composite structure, the effect of toxicity is reduced. ", "Moreover, if the nanostructure detaches from the solid composite, then functionalisation will prevent its bio-accumulation. ", "Schipper et al. ", "\\[[@B172-materials-11-01813]\\] reported a clinical study in which functionalized-SWCNTs were injected into the bloodstream of mice. ", "No toxic effect was noted for four months following treatment. ", "Usui et al. ", "\\[[@B173-materials-11-01813]\\] reported bone regeneration properties of MWCNTs, along with high bone tissue compatibility, as stimulated by human bone protein. ", "Blazewicz \\[[@B174-materials-11-01813]\\] reported that highly carbonized (more crystalline) carbon fibres showed gradual fragmentation in biological environment as compared to low carbonised carbon fibres (i.e., with smaller crystallite sizes), which were easily resorbed and integrated in the body. ", "Mild toxicity was also reported for CNTs mainly due to oxidative stress and inflammation \\[[@B175-materials-11-01813]\\]. ", "Peterson \\[[@B176-materials-11-01813]\\] conducted an animal study on epoxy/carbon fibre-composite and reported that carbon fibres can undergo osseointegration with live bone.", "\n\nThere is a continued interest in making biocomposites with exceptional bone bonding abilities, for which both the scaffold matrix and its reinforcement are selected very prudently. ", "The essential property that is required from a biocomposite is to demonstrate the formation of bone-like apatite on its surface. ", "For designers, biocompatibility is not the only important parameter to consider for an ideally functioning implant material. ", "It is also the strength, distribution of reinforcement, surface chemistry, porosity, microstructure, and surface roughness that comprise the other considerations related to the implant material. ", "When a biocomposite is made using hydroxyapatite and carbonaceous structures (mainly for the purpose of overcoming the strength issues of hydroxyapatite), it is required that the resulting composite should also maintain adequate bone bonding properties, as otherwise the purpose of using a biologically inspired implant is incomplete. ", "Hence the role of the reinforcing carbon is to maintain or minimally disrupt these bioactive properties of hydroxyapatite. ", "As reported earlier, researchers have added different carbonaceous structures into hydroxyapatite, like nanocarbon forms, diamond and each resulting composite were found to possess different properties. ", "In general, it is agreed that the carbon is bio-inert and has no toxic effect on living tissues \\[[@B177-materials-11-01813]\\]. ", "Researchers have also evaluated the combined effects of HAp and carbon, either in the form of solid composites or as coatings. ", "Mostly, nanostructures of carbon with HAp were evaluated for their biological properties. ", "Khalid et al. ", "\\[[@B178-materials-11-01813]\\] studied the interaction of functionalized-MWCNTs (f-MWCNTs) and f-MWCNTs-reinforced HAp composite with human osteoblast (sarcoma cell lines) in vitro. ", "No damaging effect was noted on the survival of osteoblast cells, whereas it was noted that an increasing concentration of functionalized-MWCNTs had a cytotoxic effect. ", "In a similar in vitro study, Khalid and Suman \\[[@B179-materials-11-01813]\\] reported no detrimental effect of f-MWCNTs HAp nanocomposites on a mouse fibroblast cell line. ", "Liu et al. ", "\\[[@B180-materials-11-01813]\\] demonstrated enhanced biocompatibility and cell growth properties by modifying pure carbon nanofibres using calcium phosphate. ", "Similarly, Huang et al. ", "\\[[@B163-materials-11-01813]\\] developed homogenous nanostructured calcium phosphate coatings on chemically modified carbon fibres using a biomineralisation process, which had promising biological properties. ", "Han et al. ", "\\[[@B181-materials-11-01813]\\] enhanced cell attachment and proliferation by modifying carbon fabric with calcium phosphate. ", "Chlopek et al. ", "\\[[@B182-materials-11-01813]\\] reported a modification of a carbon-carbon composite using hydroxyapatite powder. ", "Upon testing them in an artificial biological environment, it was observed that the composite with a HAp-enriched surface provided favourable conditions for bone apatite growth. ", "Newman et al. ", "\\[[@B183-materials-11-01813]\\] developed a high porosity mechanically strong composite while using β-tricalcium phosphate/hydroxyapatite. ", "A high-quality coating that is based on CNTs was applied to the composite for biomedical applications. ", "Martinelli et al. ", "\\[[@B184-materials-11-01813]\\] reported promising bone regeneration properties of nano HAP-CNT thin films developed on biomedical stainless steel via an in vitro osteogenesis study. ", "Murugan, Murugan and Sundramoorthy \\[[@B185-materials-11-01813]\\] developed a biological coating based on hydroxyapatite/polycaprolactone-graphene oxide on Ti alloy. ", "In vitro testing of this coating revealed outstanding cell viability, while in vivo testing in a rat model revealed bone formation after 28 days of implantation.", "\n\n6. ", "Conclusions and Future Aspects {#sec6-materials-11-01813}\n=================================\n\nIn this review, the reinforcing effects of different carbonaceous structures in a HAp matrix (as scaffolds or coatings for orthopaedic applications) were discussed. ", "The current demand on bone tissue engineering is to produce a scaffold or coating that should by itself be strong enough to bear loads, and to also possess favourable biocompatibility and bioactivity properties. ", "This objective can be analysed in two parts as the first one deals with the mechanical properties, while the other deals with the biomedical/biocompatibility properties and out of the two, the maintenance of good biomedical properties is of the utmost importance i.e., it is crucial to select a material having exceptional biomedical properties, and then it is necessary to evaluate its overall strength and toughness. ", "To produce such a robust material, scientists mostly rely on apatites/hydroxyapatite because of the highly favourable biomedical properties of these ceramics and then need to take steps to enhance its strength and toughness. ", "However, reinforcement to enhance mechanical properties must be done without any compromise to the biological properties. ", "Out of the many different materials, which can enhance the mechanical properties of HAp matrix, carbonaceous structures are always preferred in the biomedical science community because of their strength and biocompatibility. ", "In this paper, it was highlighted that different structures, quantities, and modifications of carbon can be useful in increasing the strength and toughness of the HAp matrix. ", "The biodegradability, osteoconductivity, and interface features of implant materials were also discussed, which suggests that the strategy to reinforce carbonaceous structure within the matrix of HAp will not disturb the bone regeneration properties of the composite.", "\n\nAs for future prospects, it is apparent that previous researchers have been focussed on achieving the maximum strength in a HAp matrix with use of the minimum amount of reinforcing the material, for which nano-reinforcements or nanofillers are a suitable choice. ", "Moreover, it can also be observed that the morphology of reinforcing materials is also very important as in the case of nano carbonaceous materials where fibrous and sheet-like morphologies are found to be of value. ", "When considering this, it can be suggested that future studies should exploit the combined effect of different carbonaceous materials. ", "An interesting and important aspect deduced from previous work is that the full exploitation of HAp-carbonaceous structures-based composites has still not been achieved yet. ", "This is because modifications in both the HAp and carbonaceous components, like functionalisation and mineralisation, still need to be considered to a greater extent to further improve the properties of the resulting composites. ", "Finally, it is also recommended to utilise other carbonaceous structures, like carbon nanobuds (its structure is a like a hybrid of fullerene and CNT and it appears that a fullerene-like bud is attached to the wall of CNT), carbon nanoform, Q-carbon (non-crystalline carbon, having mixed sp^2^ and sp^3^ bonding), carbyne (long chains of carbon), and lonsdaleite (hexagonal diamond). ", "In this way, a new generation of biomaterials can be produced, which greatly improves on previous ones.", "\n\nThe authors acknowledge the University of Waikato for all the essential resources/facilities for this work, especially Humair Ahmed Siddiqui who gladly acknowledges the University of Waikato for a University of Waikato Doctoral Scholarship. ", "Humair Ahmed Siddiqui would also like to acknowledge NED University of Engg. ", "and Tech. ", "for facilitating higher studies.", "\n\nH.A.S. wrote the article with K.L.P. and M.R.M. providing research supervision, scientific/engineering feedback and editing suggestions for the article content and wording.", "\n\nThis research received no external funding.", "\n\nThe authors declare no conflicts of interest.", "\n\n{#materials-11-01813-f001}\n\n{#materials-11-01813-f002}\n\n{#materials-11-01813-f003}\n\n{#materials-11-01813-f004}\n\n{#materials-11-01813-f005}\n\n{#materials-11-01813-f006}\n\n{#materials-11-01813-f007}\n\n{#materials-11-01813-f008}\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Uploading Videos to YouTube\n\nYou should have no problem finding the Upload button on YouTube — it’s on every page! ", "You’ll find it in the top right corner, to the left of the Sign In button (if you’re not logged in to YouTube), or to the left of the bell-shaped notification icon on the top right of the window (if you are logged in). ", "To upload your video content:\n\nSign in to your YouTube Account.", "\n\nClick the Upload button.", "\n\nDoing so brings up the Upload window.", "\n\nThe YouTube upload ­window.", "\n\nSelect the video-upload privacy option that you want from the Privacy pull-down menu.", "\n\nThe menu is automatically populated with your default privacy setting. ", "If you’re happy with the default setting, you don’t have to do a thing; just move on to the next step.", "\n\nStill in the Upload window, use one of the following three methods to select the video file you want to use:\n\nSelect files to upload: Hover the mouse cursor over the big up-arrow button and click it when it turns red. ", "Then use the Look In dialog box to navigate to — and then select — the file you want to upload.", "\n\nDrag and drop video files: This one’s as simple as it sounds: Just drag a video file to the Upload window and drop it when the drag-and-drop video file’s overlay turns green.", "\n\nImport your videos from Google+: This option is to the top right of the main Upload window. ", "Start by clicking the Import button there, and then select and upload the video file from your Google+ account.", "\n\nIf your method requires it, click OK to upload.", "\n\nYour files are on their way to YouTube.", "\n\nGet ready to enter your metadata.", "\n\nWith your videos selected and the upload under way, you’ll be presented with a new Video Manager editor screen that shows important details about the video. ", "If you’re uploading more than one video, YouTube will show you the progress for each upload.", "\n\nEntering metadata through Video Manager.", "\n\nThe Video Manager editor screen that you see during the upload process is the same one displayed under the Video Manager section of Creator Studio. ", "Having the video manager editor screen here as well allows you to go back later and modify the video settings. ", "This includes such tasks as changing the video description, tags, and shortlinks.", "\n\nDummies Insider\n\nSign up for insider news on books, authors, discounts and more content created just for you." ]

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[ "Serta® iComfort i5000 Bonded Leather High-Back Executive Chair, Onyx Black/Silver Item # 559623\n\n\n\n\n\n$429.99 each (Reg) $379.99 Sale (Save $50) Check Printer Compatibility Available for future delivery Free Store Pickup in 1 Hour Sold in stores selected store Check your store availability Qty Serta® iComfort i5000 Bonded Leather High-Back Executive Chair, Onyx Black/Silver Complete your home office with this onyx black Serta iComfort i5000 Series high-back executive chair. ", "Built-in lumbar support and a thick foam padding deliver comfort during extended working hours, while the arched aluminum base with oversized casters provides stability and mobility. ", "This Serta iComfort i5000 Series high-back executive chair features pneumatic seat-height adjustment and tilt control for added ergonomic support. ", "559623 was removed. ", "Thank you, you will now be redirected to comparisons. ", "Just a moment while we prepare the page Check In-Store Availability\n\nDescription Complete your home office with this onyx black Serta iComfort i5000 Series high-back executive chair. ", "Built-in lumbar support and a thick foam padding deliver comfort during extended working hours, while the arched aluminum base with oversized casters provides stability and mobility. ", "This Serta iComfort i5000 Series high-back executive chair features pneumatic seat-height adjustment and tilt control for added ergonomic support. ", "Overall Chair Dimensions: 46-3/4\"H x 29-1/2\"W x 33\"D.\n\nWeight capacity tested to support 300 lb.", "\n\nWaterfall seat cushion helps reduce strain on your legs for enhanced comfort.", "\n\nMeets and/or exceeds ANSI/BIFMA performance standards.", "\n\nAssembly required.", "\n\ni5000 Series high-back chair comes in onyx black. ", "Product Details Item # 559623 OfficeMax # 25606292 Manufacturer # 48596 Color (Seat) Onyx width 29-1/2 in. ", "height 46-3/4 in. ", "depth 33 in. ", "Weight Capacity (Seat) 300 lb Height (Minimum) - Floor To Seat 43-3/4 in. ", "Height (Maximum) - Floor To Seat 46-3/4 in. ", "Length (Seat) 23-1/2 in. ", "Height Range (Floor To Seat) 43-3/4 in. - ", "46-3/4 in. ", "Color (frame) Silver Width (Seat) 19 in. ", "chair back style High-Back Material of Seat Bonded Leather Material Family (Seat) Faux Leather Adjustments Seat Height; Tilt Lock; Tilt Tension Material of Frame Aluminum collection name iComfort i5000 Series recommended daily usage Professional (8-10 Hours) assembly Assembly Required style name iComfort i5000 Series High-Back Chairs Warranty 10-Year Limited Certifications Meets/Exceeds ANSI/BIFMA Standards arm type Padded lumbar support Yes seat glide No Swivel Yes Waterfall Seat Yes rolling Yes quantity 1 brand name Serta dimensions 46-3/4 in. ", "X 29-1/2 in. ", "X 33 in. ", "manufacturer OFFICE DEPOT Type Executive Chair Show More ▾ Customer Reviews\n\n559623\n\nSerta\n\nYou have not selected any items to share. ", "Please click on Cancel and try again.", "\n\nYour email has been sent.", "\n\nYou have not selected any items. ", "Please select items and try again.", "\n\n0" ]

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[ "LONDON (Reuters) - Nearly 40 years after the 1979 Islamic revolution saw the exit of Western oil companies from Iran, the Iranian oil sector faces yet another costly disruption after a series of interruptions from war, sanctions and diplomatic isolation.", "\n\nFILE PHOTO: Malta-flagged Iranian crude oil supertanker \"Delvar\" is seen anchored off Singapore March 1, 2012. . ", "REUTERS/Tim Chong/File Photo\n\nWashington will reapply sanctions to Iran’s oil sector on Nov. 4, after ending its participation in an international deal governing Iran’s nuclear sector. ", "Iran’s oil buyers outside the United States will stop or reduce purchases because of secondary sanctions applied on foreign companies that use the U.S. banking system.", "\n\nHaving lifted a self-imposed revolutionary ban on foreign investors in 1995, Iran has struggled to attract external investment for any sustained period.", "\n\nThe isolation caused by poor relations with the United States and, in recent years, Tehran’s efforts to develop a nuclear capability have prevented Iran building output capacity.", "\n\nBut huge reserves run by the National Iranian Oil Co have helped it cling to its position as one of the world’s five largest oil producers.", "\n\nThe United States stopped buying Iranian oil or investing in Iran’s oil industry in 1979 and has not resumed since.", "\n\nIran produces nearly 4 percent of the world’s daily oil supply and over the last 30 years has exported on average two-thirds of that.", "\n\nThe mid-1970s were the heyday of the Iranian oil sector, when its output accounted for 10 percent of global production.", "\n\nIt has never returned to the record 6 million barrels per day (bpd) it pumped in 1974.", "\n\nIn that year it pumped 70 percent of the amount produced by OPEC’s biggest producer, its regional political rival Saudi Arabia, and more than three times as much as its neighbor Iraq.", "\n\nIn 2012, when a first round of international nuclear sanctions was imposed, Iran’s output was only a third of Saudi Arabia’s, rising to 41 percent last year and just a little higher than Iraq’s.", "\n\nOutput dropped to a low of 1.5 million bpd in 1980, the year after Shah Mohammed Reza was overthrown, an event that caused the second oil shock across the economies of the West.", "\n\nIt took 23 years for Iran to restore 4 million bpd in 2003, with a post-revolutionary peak last year just short of 5 million bpd of crude and condensate combined.", "\n\nIran’s exports halved during the depths of the 2012-2016 international sanctions on its nuclear program.", "\n\nIt is unclear what proportion of Iranian crude sales will vanish from international markets after Nov. 4. ", "The United States said on Friday it would temporarily spare from sanctions eight jurisdictions that import Iranian oil. ", "The European Union would not be one of the eight, U.S. Secretary of State Mike Pompeo said.", "\n\nThis isn’t Iran’s first round of sanctions. ", "It has devised ways to export oil under the radar, evading detection by switching off the transponders of its fleet of nearly 40 supertankers, using alternatives to the U.S. dollar for payment, or selling crude to private refiners, in small, harder-to-track parcels." ]

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[ "Case Report {#sec1_1}\n===========\n\nA previously healthy 2-year-old female toddler from Sudan was admitted to the pediatric ward with the chief complaints of fever, weight loss, fatigability, pallor, and generalized lymphadenopathy. ", "The symptoms started 2 months before presentation. ", "Upon admission, the patient looked unwell, irritable, pyretic, pale, and had tachycardia. ", "Anthropometric measurements were within normal values for age and sex. ", "Widespread lymph node enlargement was observed in the head and neck region, as well as the presence of bilateral axillary nodes, and inguinal nodes (Fig. [", "1](#F1){ref-type=\"fig\"}). ", "The liver was felt 4 cm and the spleen 9 cm below the costal margins. ", "Laboratory tests revealed anemia with a hemoglobin of 4.7 g/dL, high reticulocyte count 19.3%, red blood cells (RBC) 0.81 × 10^6^/µL, mean cell volume 130.8 fL, leukocyte count of 16.5 × 10^3^/µL with 78% neutrophils, 8% lymphocytes, 7% eosinophils, and 7% basophils. ", "The platelets were normal: 244 × 10^3^/µL. The peripheral blood smear showed marked red blood cell agglutination along with polychromatic and spherocytic cells and nucleated RBC, consistent with acute hemolysis. ", "The direct antiglobulin test (Coombs) was strongly positive a finding suggestive of autoimmune hemolytic anemia. ", "The blood chemistry revealed increased levels of lactate dehydrogenase 426 U/L, low albumin levels 1.4 g/dL with normal serum bilirubin and liver enzymes. ", "The erythrocyte sedimentation rate was elevated to 50 mm by the end of first hour and the C-reactive protein was 10.6 mg/dL. The microbiology screen was negative when the body fluids were tested. ", "The serology test was unremarkable for Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, *Brucella*, and toxoplasma. ", "Herpes simplex virus IgG and IgM tests were positive. ", "The tuberculin skin test was negative. ", "The chest and abdominal CT scan revealed perihilar lymphadenopathy, para-aortic lymphadenopathy, and hepatosplenomegaly. ", "The bone marrow aspirate revealed reactive hypercellular bone marrow with Mott cells (active plasma cells) and abnormal histiocytes with a high hemophagocytic activity (Fig. [", "2](#F2){ref-type=\"fig\"}). ", "A lymph node biopsy from the anterior cervical group (Fig. [", "3](#F3){ref-type=\"fig\"}) showed that the sinusoids were extended and filled with S100 and CD68-positive but CD1a-negative histiocytes with abundant cytoplasmic fat globules and exhibited emperipolesis (viable lymphocytes inside the cytoplasm of histiocytes). ", "The histiocytes were surrounded predominantly by a lymphocytic and plasmocytic infiltrate with formation of Russell bodies (plasma cells with large inclusions containing immunoglobulins).", "\n\nThe patient received one unit of packed RBC which temporarily raised her hemoglobin level to 6.1 g/dL; however, with the ongoing hemolysis, the hemoglobin dropped to 3.8 g/dL. Treatment was then started with 2 mg/kg/day of prednisolone. ", "The patient showed a rapid clinical and laboratory improvement. ", "The fever subsided by the third day of steroid therapy, and the lymph nodes became softer to palpation toward the end of the first week of the treatment. ", "The hemoglobin increased to 8.7 g/dL and the level reached 11.3 g/dL upon discharge. ", "The steroid treatment was tapered, and it was discontinued 4 months after presentation. ", "The patient achieved clinical and laboratory remission with no evidence of hemolysis and had a negative direct Combs test.", "\n\nDiscussion {#sec1_2}\n==========\n\nRosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymph adenopathy, is a rare, mostly benign histiocytic disorder \\[[@B1], [@B2]\\]. ", "It is characterized by the proliferation and accumulation of histiocytes in the lymph nodes, but can also involve extranodal sites \\[[@B3], [@B4]\\]. ", "Although this disorder was described, initially by Rosai and Dorfman in young Africans, the disease is reported worldwide, and no racial group is spared. ", "The etiology of the disease remains uncertain. ", "The presence of autoimmune antibodies during the disease activity along with the several reports confirming serological evidence of recent bacterial or viral infection mainly herpes viruses suggests a possible link with an immune deregulatory activity secondary to infection \\[[@B5], [@B6], [@B7]\\]. ", "The serological evidence of recent herpes simplex infection, may suggest a possible correlation with the RDD in our patient.", "\n\nAcute life-threatening autoimmune hemolytic anemia has been described in several reports \\[[@B8], [@B9], [@B10]\\]. ", "However, only 4 pediatric patients \\[[@B11], [@B12], [@B13]\\], including our case, with significant acute autoimmune hemolytic anemia, have been identified (Table [1](#T1){ref-type=\"table\"}). ", "All patients had lymphadenopathy and symptoms of anemia upon presentation, along with low hemoglobin, high reticulocytes, and a strong positive direct antiglobulin test. ", "In addition to blood transfusion, management of RDD has ranged from only steroid treatment, as in our patient, to the use of chemotherapeutic agents in resistant cases. ", "The disease outcome among patients appears to be similar. ", "However, a 7-year-old boy from Nigeria had a disease course complicated by sickle-cell anemia, infections, and cardiac failure secondary to dilated cardiomyopathy (Table [1](#T1){ref-type=\"table\"}).", "\n\nThe value of this report lies in the association of autoimmune hemolytic anemia with RDD in the presence of serological evidence of a recent herpes simplex virus, which further supports the hypothesis of an altered immunological process triggered by a viral illness.", "\n\nStatement of Ethics {#sec1_3}\n===================\n\nThe authors have no ethical conflicts to declare.", "\n\nDisclosure Statement {#sec1_4}\n====================\n\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.", "\n\n{#F1}\n\n{#F2}\n\n{#F3}\n\n###### \n\nSummary of clinical and laboratory findings in children with Rosai-Dorfman disease and anemia\n\n Patient \\[Ref.\\] Age/gender Race Clinical presentation Hgb level, g/dL Treatment Outcome\n ------------------- ------------- ---------------- ------------------------------- ----------------- --------------------------------------------------------------- --------------------------------------------------------------------------\n 1 \\[[@B7]\\] 10 years/M Black/Indian LNP, HSM, pallor 6.4 Vincristine, cyclophosphamide, prednisolone DCT negative, Hgb 10, HSM regressed, responded partially to chemotherapy\n \n 2 \\[[@B8]\\] 7 years/M Black/Nigerian SCD, intermittent LNP, pallor 2.6 Chronic blood transfusion, frequent admission and antibiotics DCT remained positive, infectious complications, dilated cardiomyopathy\n \n 3 \\[[@B9]\\] 18 months/M Black/Sudanese Fever, LNP, HSM, pallor 4.3 Prednisolone DCT n.a., ", "HSM regressed responded partially, steroid for 1 year\n \n 4 \\[this report\\] 2 years/F Black/Sudanese Fever, LNP, HSM, pallor 4.7 Prednisolone for 4 months DCT negative, Hgb 11.3, HSM regressed, responded well\n\nHgb, hemoglobin; SCD, sickle cell disease, LNP, lymphadenopathy; HSM, hepatosplenomegaly; DCT, direct Coombs test; n.a., ", "not applied.", "\n" ]

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[ "A 'DIRTY protest' in the republican wing of Maghaberry prison cost the taxpayer almost £270,000.", "\n\nIn May 2011 around 30 inmates in Roe House engaged in a no-wash protest, smearing excrement on walls, refusing to wash or shave and emptying urine into the prison landings.", "\n\nThe action started in opposition to strip searches and didn't end until November the following year.", "\n\nThe prisoners claimed that authorities reneged on an agreement brokered in August 2010 to end a policy of routine full body searches and replace them with electronic scans.", "\n\nIn response to an assembly question by DUP Fermanagh and South Tyrone MLA Maurice Morrow, the extent of damage caused by the Roe House protest was revealed by justice minister Claire Sugden\n\nThe total cost of repair work, carried out between January 2013 and January 2014, was £268,884.", "\n\n\"Floor, wall and ceiling finishes to cells and landings, cell doors and furniture were damaged/contaminated. ", "Some in-cell sanitary ware was also damaged,\" the minister said.", "\n\n\"Repairs were carried out to all cells and landings, including redecoration of walls, windows and ceilings, replacement floor coverings, refitting sanitary ware and decontamination, refurbishment and redecoration of all cell doors and frames.\"" ]

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[ "“Before I start with this week I would like to address the conversation back at my ‘BBQ’ with Lisa Vanderpump at the table,” says Kyle. “", "Unless a parent brings up their children themselves, children are ALWAYS off limits. ", "Yolanda had told Erika and me ON camera that Bella and Anwar have Lyme disease. ", "Obviously it is not a secret if you tell people on camera.”", "\n\nCLICK CONTINUE READING FOR MORE!", "\n\n“I asked the question to Lisa (knowing she is friends with Mohamed) what was going on with Bella and Anwar. ", "That was not asked in a malicious way – at all – and certainly was not an outrageous question,” maintainsKyle. “", "The reply I got prompted me to ask more because it was confusing. ", "I already stated in a previous blog that I regret continuing to ask Lisa. ", "However, I certainly meant no harm toward Bella and Anwar. ", "Yolanda has since said ‘kids are off limits,’ but she is the one who brought her kids up in the first place. ", "If Yolanda had told me privately, and asked me not to mention it, I NEVER would have.”", "\n\nMoving on to Kathryn‘s lunch, Kyle says the afternoon turned “uncomfortable” when her sister, aka Kim Richards, became a topic of conversation.", "\n\n“I don’t like to hear Lisa Rinna speak against my sister,” says Kyle. “", "It bothers me that she claims to have empathy for anyone who suffers from addiction and then says terrible things about Kim. ", "I have tried to keep the situation between Rinna and Kim separate from our friendship. ", "However, she tends to bring it up again and again making that difficult. ", "I understand she is entitled to her feelings, but there is a time and place. ", "If she cared about our friendship at all, it would not be with me sitting right there, while saying such hurtful remarks about Kim as well as in her interviews.”", "\n\nKyle shares, “Kathryn defending my sister while sharing the loss of her father was touching. ", "A moment so personal we were all brought to tears and felt that much closer to Kathryn.”", "\n\nAbout Erika Girardi‘s BBQ, Kyle jokes, “OK, so if my BBQ wasn’t really a BBQ, what was Erika’s? ", "I walked in and was expecting a Ferris wheel.”", "\n\nKyle points out the hypocrisy in Yolanda‘s argument against Lisa Rinna, “Yolanda clearly is still upset with Rinna and rightfully so. ", "However, I do have to agree with Rinna. ", "By Yolanda saying she ‘could’ say she is bipolar but ‘wouldn’t do that’ IS already putting that out there. ", "It’s exactly like Lisa Rinna saying she didn’t say Yolanda had Munchausens but ‘engaged’ in a conversion about it… well, here we are six months later, hearing and talking about it.”", "\n\nKyle calls out Lisa and Yolanda‘s “let’s hug and move on” nonsense as “false and abrupt.”" ]

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[ "Health care privatization in Latin America: comparing divergent privatization approaches in Chile, Colombia, and Mexico.", "\nThe public-private mix in Chile, Colombia, and Mexico was very similar until the early 1980s when Chile undertook health care privatization as part of comprehensive health care reform. ", "Since then, health care privatization policies have diverged in these countries. ", "In this study we characterize health care privatization in Latin America and identify the main factors that promoted and hindered privatization by comparing the experiences of these countries. ", "We argue that policy elites took advantage of specific policy environments and the diffusion of privatization policies to promote health care privatization while political mobilization against privatization, competing policy priorities, weak market and government institutions, and efforts to reach universal health insurance hindered privatization. ", "The privatization approaches of Chile and Colombia were classified as \"big-bang,\" since these countries implemented health care privatization more rapidly and with a wider scope compared with the case of Mexico, which was classified as gradualist, since the privatization path followed by this country adopted a slower pace and became more limited and focalized over time. ", "We conclude that the emphasis on policy-driven privatization diminished in the 1990s and 2000s because of increased public health care financing and a shift in health care reform priorities. ", "Health care privatization in the region, however, continued as a consequence of demand-driven privatization." ]

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[ "-- Quest: C:\\QUESTS\\WORKING\\C0B10Y05.Qbn.", "\n-- StartsBy: NPC\n-- Questee: member\n-- Questor: temple\n-- Repute: 10\n-- QuestId: 5\n-- Edited for Daggerfall Unity by Jay_H\nMessages: 13\nQuest: C0B10Y05\nDisplayName: The Cursed Weapon\n-- Message panels\nQRC:\n\nQuestorOffer: [1000]\n<ce> %pcn, we have a\n<ce> very dangerous mission for you. ", "The\n<ce> temple has come into the possession\n<ce> of an evil, magical weapon long\n<ce> sought by the orcs. ", "The temple has\n<ce> already been attacked twice by the\n<ce> creatures. ", "It needs to be taken to\n<ce> a safehaven. ", "Will you to this for\n<ce> us? ", "The temple will pay _gold_ gold.", "\n\nRefuseQuest: [1001]\n<ce> I am saddened that your\n<ce> loyalty to the temple is\n<ce> so low. ", "But in light of\n<ce> the danger, I forgive you.", "\n\nAcceptQuest: [1002]\n<ce> Take this _evilitem_.", "\n<ce> In ___dungeon_,\n<ce> you will find _custodian_,\n<ce> a servant of this temple for many\n<ce> years. %", "g will safeguard the item\n<ce> and keep it out of the hands of the\n<ce> orcs. ", "We have bound it in spells to\n<ce> protect you from its evil effects.", "\n<ce> However, these spells will wear off\n<ce> in =traveltime_ days.", "\n\nQuestComplete: [1004]\n<ce> Ah, this is the evil\n<ce> _evilitem_ that _qgiver_\n<ce> spoke of. ", "I shall keep it\n<ce> here, where there are many\n<ce> defenses to keep it safe.", "\n<ce> _qgiver_ said that I\n<ce> should pay you _gold_ gold\n<ce> pieces for safe delivery.", "\n\nRumorsDuringQuest: [1005]\nThe orcs have been attacking __qgiver_ caravans.", "\n\nRumorsPostfailure: [1006]\nThe orcs finally got that _evilitem_.", "\n\nRumorsPostsuccess: [1007]\nThe _evilitem_ is safe from the hands of the orcs.", "\n\nQuestorPostsuccess: [1008]\nI heard that you got rid of the _evilitem_. ", "Now, what can I help you with?", "\n\nQuestorPostfailure: [1009]\nI trusted you with the _evilitem_ and look what happened.", "\n\nQuestLogEntry: [1010]\n%qdt:\n _qgiver_ of __qgiver_,\n in ___qgiver_, gave me an\n evil _evilitem_ to\n deliver to the ___dungeon_\n so that the orcs could not\n get it. ", "I have =traveltime_ days\n to make the delivery.", "\n\nMessage: 1011\n<ce> You must be the bearer of\n<ce> Manshrieker, the holy orc\n<ce> weapon of war. ", "Kill the\n<ce> human! ", "We must have that\n<ce> _evilitem_.", "\n\nMessage: 1012\n<ce> The evil _evilitem_, sparks and disintegrates.", "\n<ce> You suddenly feel very sick.", "\n\n\n-- Symbols used in the QRC file:\n--\n-- %g occurs 1 time.", "\n-- %pcn occurs 1 time.", "\n-- %qdt occurs 1 time.", "\n-- =traveltime_ occurs 3 times.", "\n-- ___dungeon_ occurs 2 times.", "\n-- ___qgiver_ occurs 3 times.", "\n-- _custodian_ occurs 1 time.", "\n-- _evilitem_ occurs 10 times.", "\n-- _gold_ occurs 4 times.", "\n-- _qgiver_ occurs 3 times.", "\n\nQBN:\nItem _evilitem_ weapon\nItem _gold_ gold\n\nPerson _qgiver_ face 1 group Questor\nPerson _custodian_ face 1 group Group_5.0\n\nPlace _dungeon_ remote dungeon\n\nClock _traveltime_ 00:00 0 flag 1 range 0 2\n\nFoe _orc1_ is Orc_shaman\nFoe _orc2_ is Orc_warlord\nFoe _orc3_ is 2 Orc_sergeant\nFoe _orc4_ is 3 Orc\n\n--\tQuest start-up:\n\tstart timer _traveltime_ \n\treveal _dungeon_ \n\tlog 1010 step 0 \n\tget item _evilitem_ \n\tplace npc _custodian_ at _dungeon_ \n\n_traveltime_ task:\n\tend quest \n\n_S.01_ task:\n\ttoting _evilitem_ and _custodian_ clicked \n\tgive pc _gold_ \n\tend quest \n\nuntil _S.01_ performed:\n\tcreate foe _orc2_ every 21 minutes 20 times with 5% success \n\tcreate foe _orc4_ every 41 minutes 20 times with 5% success \n\tcreate foe _orc1_ every 21 minutes 20 times with 5% success \n\tcreate foe _orc3_ every 31 minutes 20 times with 5% success \n\nvariable _gem1_\nvariable _bear_\nvariable _gem3_\nvariable _gem4_\n_S.06_ task:\n\tinjured _orc2_ saying 1011 \n\tinjured _orc4_ saying 1011 \n\tinjured _orc3_ saying 1011 \n\tinjured _orc1_ saying 1011 \n\n_S.07_ task:\n\twhen _traveltime_ and not _S.01_ \n\tmake pc ill with Witches'_Pox\n\tsay 1012 \n\t--moved saying 1012 to its own line" ]

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[ "Trio: Season 1, #19/20\n\nSo, i’m uploading the first bad one and the second bad one, because they’re bad for totally different reasons and between the two of them you can almost see the good that i intended. ", "In the first one i’ve got too much voice and too much guitar and it’s all just much too much, and in the second one i don’t have much voice left at all despite having solved the other issues – but the voice makes a big difference. ", "Fuck. ", "Now i’m not going to be able to hit my high note tomorrow for practice-juries. ", "Or, is that today… I’m such a stubborn little fucker. ", "Trio will be the death of me, i’m sure of it.", "\n\nReccomended: Trio A – Tired Of Sex (Weezer), Up & Down, Buildings and Bridges (Ani), The Trouble with Poets (Mulvey), Lost (original key)\n\nNot For the Faint of Heart or Ear: Trio B – The Trouble with Poets (Mulvey), Lost (original key), Up & Down, Tired of Sex (Weezer)\n\nLinks from Crushing Krisis to retailer websites may be in the form of affiliate links. ", "If you purchase through an affiliate link I will receive a minor credit as your referrer. ", "My credit does not affect your purchase price. ", "Affiliate programs and affiliations include, but are not limited to: Amazon Services LLC Associates Program (in the US, UK, Canada, France, Germany, Italy, and Spain), eBay Partner Network, and iTunes Affiliate Program. ", "Note that URLs including the \"geni.us\" domain name are affiliate short-links." ]

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[ "This Shimano Claris 8-Speed Double 34.9mm Band On Front Derailleur good value front derailleur for road use. ", "With a wide pivot link increasing rigidity while reducing flex for improved shifting response. ", "The aluminium outer link to save weight and improve rigidity while, a durable plated steel chain cage can take a thousands of miles of shifting.", "\n\nPart of Shimano's component groupset designed for road bikes featuring flat handlebarsWide link derailleur design for rigidity and precise, accurate shifts every timeMaximum flexibility - versions available for double and triple chainsetsMatt black and polished finish looks good on any bike\n\nLightweight front mech designed with modern trail bikes in mind, the Shimano M8025 Deore XT Double Front Mech provides revolutionary front shifting thanks to an all new design including side swing technology for increased tyre clearance. ", "The M8025 features a more standard pull design than the newer XT front mechs for use with standard frame routing designs. ", "The Deore XT 11 Speed Front Mech is\n\nFashion-forward footwear is the feature of every outfitGet trend-led treads in our edit of this seasons most talked about shoes. ", "Brogues and loafers put the sharp in shoes, while preppy plimsolls and trusty trainers make sure your off-duty style stays on-trend. ", "This season desert boots and skinny jeans are your day-to-night staple, and Chelsea boots best for chanelling preppy.", "\n\nShimano Band On Adapter For Front Derailleur Front Derailleurs on USA sites\n\nThe microSHIFT Marvo XE Front Derailleur is a performance upgrade for most cyclist at a fraction of the price of more well known brands. ", "microSHIFT's -inchShift and Go-inch shifting has become a standard among the cycling industry since its introduction in 1999. ", "So, if your riding style calls for simple accurate shifts, microSHIFT will be a good choice. ", "We provide world class quality and top\n\nRide that sweet, plush, responsive wave by lacing into the Cloudsurfer from On. ; ", "On footwear inspires a more efficient running style by promoting a more forward foot strike, as well as a centered and energized running position. ; ", "Benefits: On delivers a blend of the injury protection found in traditional running shoes, with the natural ride of its lightweight counterpart. ; ", "Ideal for all types of\n\nUnlike most message films which date themselves almost immediately, Lewis Milestones low-key unpolished and deeply-felt screen adaptation of the Erich Maria Remarque anti-war novel has lost little of its original impact. ", "Years after its release it was still being banned in countries mobilising for war. ", "The plot follows a group of young German recruits in World War I through their passage from\n\nPart of the Right as Rain collection this useful 100% waterproof jacket with front pockets is a useful piece to have to hand when the weathers not all it could be. ", "An internal drawstring adds some shape too.", "\n\nWhat if there were a list? ", "A list that said: Our finest actors werent allowed to act. ", "Our best writers arent allowed to write. ", "Our funniest comedians arent allowed to make us laugh. ", "What would it be like if there were such a list? ", "It would be like America in 1953. ", "In 1953, a cashier poses as a writer for blacklisted talents to submit their work through, but the injustice around him pushes him\n\nEquipped with a curved front glass panel and black silicone seals, Aqueon Deluxe LED Bow Front Aquarium Kit Black 16 Gallon has an added unique aesthetic that make this a non-traditional aquarium. ", "An LED strip light is included with a day white lamp that has an open slot for an additional lamp." ]

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[ "This invention relates to chemical and genetic methods for stabilizing Helicobacter urease.", "\nHelicobacter pylori is a gram-negative bacterium and a gastroduodenal pathogen that causes gastritis, gastric and duodenal ulceration, and possibly gastric carcinoma in humans (Graham et al., ", "Am. ", "J. Gastroenterol. ", "82:283-286, 1987; Homick, N. Eng. ", "J. Med. ", "316:1598-1600, 1987; Lee et al., ", "Microb. ", "Ecol. ", "Health Dis. ", "1:1-16, 1988; Cover et al., ", "Annu. ", "Rev. Med. ", "40:269-285, 1989; Buck, Clin. ", "Microbiol. ", "Rev. 3:1-12, 1990). ", "The bacterium produces large amounts of the enzyme urease, which is a multimeric nickel metallohydrolase that cleaves urea to ammonia and carbon dioxide (Hu et al., ", "Infect. ", "Immun. ", "58:992-998, 1990). ", "H. pylori urease is localized both in the cytosol and on the extracellular surface of the bacterium (Hawtin et al., ", "J. Gen. Microbiol. ", "136:1995-2000, 1990). ", "Extracellular urease may protect the bacteria in the highly acidic stomach by hydrolyzing urea to ammonia, thereby creating a buffering cloud of ammonia that neutralizes the acid around the bacteria (Ferrero et al., ", "Microbiol. ", "Ecol. ", "Health Dis. ", "4:121-134, 1991; Mobley et al., ", "In Helicobacter pylori: Basic Mechanisms to Clinical Cure, Hunt et al. (", "Eds.) ", "Kluver Acad. ", "Pub., ", "Dordrecht, 1994). ", "Urease may also contribute to the pathogenicity of H. pylori by direct toxicity of ammonia and monochloramine to cells lining the gastric mucosa.", "\nH. pylori urease is immunogenic to humans and antigenicity is highly conserved among H. pylori strains (Ferrero et al., ", "Mol. ", "Microbiol 9:323-333, 1993; Gootz et al., ", "Infect. ", "Immun. ", "62:793-798, 1994). ", "Antigenic conservation among ureases is the basis of protection of mice against H. felis infection when vaccinated with H. pylori urease (Ferrero et al., ", "Mol. ", "Microbiol 9:323-333, 1993). ", "Antigenic cross-reactivity has also been demonstrated between H. pylori and H. mustelae ureases (Gootz et al., ", "Infect. ", "Immun. ", "62:793-798, 1994).", "\nUrease enzymatic activity is toxic to animals and humans (Thomson et al., ", "Am. ", "J. Med. ", "35:804-812, 1963; Mobley et al., ", "Microbiol. ", "Rev. 53:85-108, 1985; LeVeen et al., ", "Biomed. ", "Pharmacother. ", "48(3-4):157-166, 1994). ", "Anti-urease antibodies bind to urease, but generally do not inhibit urease enzymatic activity. ", "For example, there is one report that claims to show inhibition of urease activity by monoclonal antibodies to urease (Nagata et al., ", "Infect. ", "Immun. ", "60:4826-4831, 1992). ", "We tested monoclonal and polyclonal antibodies to urease and urease subunits, and found no inhibition of urease activity. ", "Thomas et al. (", "J. Clin. ", "Microbiol. ", "30:1338-1340) measured urease inhibitory activity in serum samples from children infected with H. pylori, and found that among thirteen serum samples showing urease binding activity, only one sample showed any urease inhibitory activity. ", "These observations show that the catalytic and immunogenic domains of urease are different. ", "This is further supported by a recent report that antigenic reactivity of a urease preparation was retained under storage conditions in which enzymatic activity was lost (Perez-Perez, Infect. ", "Immun. ", "62:299-302, 1994). ", "These results suggest that immunogenicity can be separated from potentially toxic enzymatic activity, which is an important characteristic of a potential vaccine.", "\nSpecific human antibody responses to urease are absent or weak in a high proportion, if not the majority, of infected individuals. ", "Antibodies to urease administered to animals together with live Helicobacter protect against infection (Blanchard et al., ", "Infect. ", "Immun. ", "63:1394-1395, 1995). ", "Together, these observations support the basis for the effectiveness of urease as a vaccine that induces a high-grade, urease-specific immune response protective against H. pylori.", "\nNine genes have been identified in the H. pylori urease gene cluster (Cussac et al., ", "J. Bacteriol. ", "174:2466-2473, 1992; Labigne et al., ", "J. Bacteriol. ", "173:1920-193, 1992). ", "These include the urease structural genes, encoding UreA and UreB, and the accessory genes, encoding Ure I, E, F, G, and H. These genes have been shown to be essential for urease activity. ", "Hu et al. (", "Infect. ", "Immun. ", "60:2657-2666, 1992) expressed genes encoding the UreA and UreB subunits of H. pylori urease in E. coli and showed that these two genes alone are sufficient to encode a fully assembled apoenzyme, which was structurally and immunologically identical to native urease, but catalytically inactive, due to the absence of nickel ions. ", "Addition of nickel ions alone did not restore catalytic activity. ", "Similar results were reported with other bacterial ureases. ", "In other studies, recombinant Klebsiella aerogenes apourease, which differs substantially from H. pylori urease in subunit structure and overall amino acid sequence, was shown to be activated in vitro by incubation with carbon dioxide or bicarbonate, together with nickel ions (Park et al., ", "Science 267:1156-1158, 1995). ", "Based on crystallographic analysis, the K. aerogenes urease bi-nickel center is thought to include His 272, His 246, His 136, His 134, Asp 360, and Lys 219 of the Ure C subunit. ", "By analogy, the H. pylori urease metallocenter may be described as including His 248, His 138, His 136, Asp 362, and Lys 219 of the Ure B subunit." ]

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[ "Modern machine learning capabilities are rapidly changing and improving how some of the most complex and data-intensive computing problems are solved. ", "A performance of a machine learning model is governed mainly in the manner(s) in which the machine learning model is trained using data samples as machine learning training input and based on the hyperparameters of the machine learning model set prior to the training of the model. ", "As referenced in passing the hyperparameters of the machine learning models are parameters whose values are set prior to the commencement of the machine learning process rather than derived by the machine learning model during training. ", "Example include the number of trees in a random forest or the number of hidden layers in a deep neural net. ", "Adjusting the values of the hyperparameters of a machine learning model by any amount typically results in a large impact on a performance of the machine learning model.", "\nHowever, many existing machine learning models are not implemented with optimal hyperparameters well-suited for achieving the best predictive performances. ", "Rather, the many existing machine learning models are implemented with default hyperparameters that have not been optimized for a specific computing problem for which the machine learning models are being used.", "\nAdditionally, any existing system that enables optimization of hyperparameters of a machine learning model typically includes an extremely complex interface that may require significant coding capabilities and comprehension of the underlying software and hardware components of the system. ", "Thus, making it difficult to efficiently and effectively enable optimizations and subsequent improvements of the machine learning models.", "\nThus, there is a need in the machine learning field to create an improved optimization platform to test and improve machine learning models (e.g., in-product machine learning models) and an associated Application Program Interface that enables developers to efficiently and effectively interact with a robust system implementing the evaluation framework. ", "The embodiments of the present application described herein provide technical solutions that address, at least, the need described above, as well as the technical deficiencies of the state of the art described throughout the present application." ]

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[ "Share This Story!", "\n\nImmune system may play crucial role in mental health\n\nLast time you had a bad cold, you likely had less energy than usual. ", "You lay around and didn't have any enthusiasm for your usual activities. ", "After it dragged on for a day or two, a sense of helplessness\n\nImmune system may play crucial role in mental health\n\nConsidering inflammation has helped neuroscientists cast a broader net when searching for causes of and possible treatments for mental illness, mood disorders and neurodevelopmental conditions.", "\n\nA growing body of research in conditions from bipolar to schizophrenia to depression suggests a tighter link than expected between ailments of the mind and body. ", "Activation of the immune system seems to play a crucial role in both.(Photo: PhotoDisc)\n\nLast time you had a bad cold, you likely had less energy than usual. ", "You lay around and didn't have any enthusiasm for your usual activities. ", "After it dragged on for a day or two, a sense of helplessness probably set in. ", "It was hard to remember what feeling good felt like or how you could ever bound off the couch again.", "\n\nIn short, for a few days, you probably felt a lot like someone with depression.", "\n\nAnd increasingly, scientists think it's no coincidence that a mental illness feels like a physical one.", "\n\nA growing body of research on conditions from bipolar disorder to schizophrenia to depression is starting to suggest a tighter link than was previously realized between ailments of the mind and body. ", "Activation of the immune system seems to play a crucial role in both.", "\n\n\"We just didn't understand how much of a role the immune system plays in how we think and feel and act,\" says Andrew Miller, a professor of psychiatry at Emory University. \"", "An overactive immune system or when there's something going on in the immune system, it can have consequences on the brain.\"", "\n\nAn immune response, including inflammation, new research suggests, may help explain why:\n\n• About one in four people hospitalized with schizophrenia had a urinary tract infection when admitted to the hospital;\n\n• Mothers with auto-immune conditions such as lupus are more likely to have a child on the autism spectrum;\n\n• People with higher rates of inflammation are more likely to show signs of depression than those with healthy immune function. ", "A study in mice presented earlier this month at the Society for Neuroscience's annual convention showed that the immune changes came before the emotional ones.", "\n\n\"One of the things we need to stop thinking is that mental health is just a disorder of the brain,\" says researcher Georgia Hodes, of the Icahn Medical Institute at Mount Sinai Hospital, who conducted the mouse study. \"", "There's plenty of evidence in a number of different mental illnesses that they have components to them that relate to the entire body.\"", "\n\nMerely adding inflammation to their thinking has helped neuroscientists cast a broader net when searching for causes of and possible treatments for mental illness, mood disorders and neurodevelopmental conditions such as autism, researchers say.", "\n\nAnd this mind-immune system connection might help explain why mental health treatments don't work for some people. ", "Perhaps, researchers now think, those people would be better off with approaches that target their immune systems rather than their brain chemicals.", "\n\nFor those with schizophrenia and urinary tract infections, for instance, acute psychotic symptoms often improve after a few days on antibiotics, according to Brian Miller, an assistant professor of psychiatry at Georgia Regents University in Augusta, who is studying the connection between the conditions. ", "This isn't to suggest that all people with schizophrenia should be on antibiotics, Miller says, but patients with both might get as much or more relief from antibiotics as antipsychotics.", "\n\nOther studies show that the level of an inflammatory protein called interleukin 6 may help predict someone's emotional state. ", "Manipulating the levels of this protein changes behavior on depression and anxiety tests in mice, says Larry Swanson, a neuroscientist at the University of Southern California, and immediate past president of the Society for Neuroscience.", "\n\nResearchers are still working out the connection between the immune system and autism, says Judy Van de Water, an immunologist at the MIND Institute at the University of California-Davis. ", "There is some indication, she says, that the people with autism who have the most behavioral problems, such as irritability and hyperactivity, also show the highest levels of inflammation. ", "She says she hopes that better understanding the role of inflammation in autism will lead to treatments.", "\n\nThe immune system's role might also fit into the \"second-hit\" idea of mental illness, where two or more factors, such as genetics, immune challenges and, say, a hit to the head, combine to cause brain problems. ", "That may explain why traumatic brain injuries often lead to depression, says Jonathan Godbout, a neuroscientist and associate professor at the Institute for Behavioral Medicine Research at The Ohio State University Wexner Medical Center.", "\n\nA serious infection during pregnancy or early in life might make someone more vulnerable to problems later, says Godbout. \"", "It's like a priming or sensitization. ", "There are secondary triggers that can reactivate something and make it worse.\"", "\n\nWhat is clear, says Andrew Miller of Emory, is that the body and mind both influence one another. \"", "It's a two-way street — what happens psychologically can affect you physiologically and then feed back and affect you psychologically. ", "The brain and immune system — their interactions are quite meaningful for health and illness.\"", "\n\nThe immune system and the brain may be connected in ways that scientists have not previously realized.(Photo: Photo Disc)\n\nTips for keeping down inflammation, which might help promote good mental health:\n\n• Keep stress to manageable levels (inflammation probably causes stress and stress can cause inflammation; both are bad for the body and the brain.)", "\n\n• Exercise.", "\n\n• Maintain a healthy weight (excess fat leads to inflammation).", "\n\n• Get adequate sleep — 7½ to eight hours a night, on average.", "\n\n• Avoid serious infections while pregnant and in early childhood.", "\n\n• There is a little evidence that anti-inflammatory drugs, including aspirin, might help improve mood, though that research is very preliminary and these drugs are probably not strong enough to treat full-blown illnesses, say researchers." ]

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[ "Q:\n\nIf then join else other join\n\nI am trying to figure out a query which joins several tables (cca 8). ", "At one point I need to join one of two tables. ", "So lets call the result until this point A. Now I want to join B, or C. When I use B, I get smaller result, or no result. ", "If there is no result after the join, I need to join C instead.", "\nTo summarize, intersection of (A,C) gives bigger result and I only want to join C if intersection of (A,B) is empty.", "\nWhat would be a smooth way to say this in mysql?", "\n\nA:\n\nOnly join if the first join primary key is null:\nSELECT *\nFROM A\nLEFT JOIN B ON A.id = B.id\nLEFT JOIN C ON B.id IS NULL AND A.id = C.id\n\n" ]

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[ "---\nabstract: 'We discuss a Nambu–Jona-Lasinio (NJL) type quantum field theoretical approach to the quark matter equation of state with color superconductivity and construct hybrid star models on this basis. ", "It has recently been demonstrated that with increasing baryon density, the different quark flavors may occur sequentially, starting with down-quarks only, before the second light quark flavor and at highest densities also the strange quark flavor appears. ", "We find that color superconducting phases are favorable over non-superconducting ones which entails consequences for thermodynamic and transport properties of hybrid star matter. ", "In particular, for NJL-type models no strange quark matter phases can occur in compact star interiors due to mechanical instability against gravitational collapse, unless a sufficiently strong flavor mixing as provided by the Kobayashi-Maskawa-’t Hooft determinant interaction is present in the model. ", "We discuss observational data on mass-radius relationships of compact stars which can put constraints on the properties of dense matter equation of state.'", "\naddress:\n- '$^{1}$Institute for Theoretical Physics, University of Wroclaw, 50-204 Wroclaw, Poland'\n- '$^{2}$Bogoliubov Laboratory for Theoretical Physics, JINR Dubna, 141980 Dubna, Russia'\n- '$^{3}$EISLAB, Lule[å]{} University of Technology, 97187 Lule[å]{}, Sweden'\nauthor:\n- 'D. Blaschke$^{1,2}$, T. Klähn$^1$, R. [Ł]{}astowiecki$^1$ and F. Sandin$^{3}$'\ntitle: 'How strange are compact star interiors ?'", "\n---\n\nIntroduction\n============\n\nThe question of strangeness in compact star interiors is a multifaceted one [@Weber:2004kj] and has been discussed controversially ever since the first discussion of hyperons [@Ambartsumyan:1960] and kaon condensates [@Brown:1988ik; @Brown:1992ib; @Glendenning:1998zx] for the degenerate matter phases of neutron star cores. ", "Present-day state-of-the-art calculations of hyperonic matter within the Brueckner-Bethe-Goldstone scheme [@Baldo:1999rq] reveal the problem that due to the softening of the high-density equation of state (EoS) the maximum mass of hyperonic stars is below the measured mass of binary radiopulsars $M_{\\rm BRP}=1.35 \\pm 0.04~M_\\odot$ [@Thorsett:1998uc]. ", "As a possible solution to this problem a sufficiently early onset of quark deconfinement in neutron star matter at baryon densities $n= 0.3 - 0.5$ fm$^{-3}$ has been suggested [@Baldo:2003vx]. ", "In the present contribution we will not touch the question of absolutely stable strange quark matter [@Witten:1984rs] in compact stars but rather focus the discussion on models for hybrid stars with deconfined quark matter cores and recent observational constraints for their masses ($M$) and radii ($R$), see [@Lattimer:2006xb; @Klahn:2006ir].", "\n\nThe status of the theoretical approach to the neutron star matter equation of state is very different from that for the high-temperature case at low or vanishing net baryon densities, where [*ab initio*]{} lattice QCD simulations provide EoS with almost physical quark masses systematically approaching the continuum limit [@Bazavov:2009zn]. ", "This guidance is absent at zero temperature and high baryon number densities, where a variety of models exists on different levels of the microphysical description which make different predictions for the state of matter. ", "A common feature is that the transition from hadronic to quark matter cannot yet be described on a unique footing where hadrons would appear as bound states (clusters) of quarks and their possible dissociation at high densities as a kind of Mott transition [@Mott:1968] like in nonideal plasmas [@Redmer:1997] or in nuclear matter [@Ropke:1982; @Typel:2009sy]. ", "Early nonrelativistic potential model approaches [@Horowitz:1985tx; @Ropke:1986qs] are insufficient since they cannot accomodate the chiral symmetry restoration transition in a proper way. ", "Therefore, at present the discussion is restricted to so-called two-phase aproaches where the hadronic and the quark matter EoS are modeled separately followed by a subsequent phase transition construction to obtain a hybrid EoS.\n\nWidely employed for a description of quark matter in compact stars are thermodynamical bag models of three-flavor quark matter with eventually even density-dependent bag pressure $B(n)$, as in Ref. [", "@Baldo:2003vx]. ", "A qualitatively new feature of the phase structure appears in chiral quark models of the Nambu–Jona-Lasinio type which describe the dynamical chiral symmetry breaking of the QCD vacuum and its partial restoration in hot and dense matter, see Ref. [", "@Buballa:2003qv] for a review. ", "In contrast to bag models, in these approaches at low temperatures the light and strange quark degrees of freedom may appear sequentially with increasing density [@Gocke:2001ri; @Blaschke:2008vh; @Blaschke:2008br], so that strangeness may even not appear in the quark matter cores of hybrid stars, before their maximum mass is reached. ", "Once chiral symmetry is restored, a rich spectrum of color superconducting quark matter phases may be realized in dense quark matter, depending on it’s flavor composition and isospin asymmetry [@Alford:2007xm] with far-reaching consequences for hybrid star phenomenology, e.g., $M-R$ relationships and cooling behavior.", "\n\nWe will consider here a color superconducting three-flavor NJL model with selfconsistently determined density dependences of quark masses and scalar diquark gaps, developed in Refs. [", "@Ruester:2005jc] and [@Blaschke:2005uj] which differ in the fact that the former includes the flavor-mixing Kobayashi-Maskawa-’t Hooft (KMT) determinant interaction [@Kobayashi:1970ji; @'tHooft:1976up] while the latter does not. ", "Only recently it became clear [@Agrawal:2010er] that this flavor mixing is crucial for the possible stability of strange quark matter phases in hybrid stars.", "\n\nRole of the Kobayashi-Maskawa-’t Hooft (KMT) interaction\n========================================================\n\nOur description of quark matter is based on the grand canonical thermodynamic potential  [@Buballa:2003qv; @Ruester:2005jc; @Blaschke:2005uj; @Abuki:2005ms; @Klahn:2006iw] $$\\begin{aligned}\n \\Omega(T,\\{\\mu\\}) &=& \\frac{\\phi^2_u+\\phi^2_d+\\phi^2_s}{8 G_S}\n +\\frac{K\\phi_u\\phi_d\\phi_s}{16G^3_S} \n -\\frac{\\omega^2_u+\\omega^2_d+\\omega^2_s}{8 G_V}\n +\\frac{\\Delta^2_{ud}+\\Delta^2_{us}+\\Delta^2_{ds}}{4 G_D} \n\\nonumber \\\\\n &-&\\int\\frac{d^3p}{(2\\pi)^3}\\sum_{n=1}^{18}\n \\left[E_n+2T\\ln\\left(1+e^{-E_n/T}\\right)\\right] \n + \\Omega_{lep} - \\Omega_0~,\n\\label{potential}\\end{aligned}$$ where $E_n=E_n(p,\\,\\mu;\\,\\mu_Q,\\mu_3,\\mu_8,\\,\\phi_u,\\phi_d,\\phi_s,\\,\n\\omega_u,\\omega_d,\\omega_s,\\,\\Delta_{ud},\\Delta_{us},\\Delta_{ds})$ are the quasiparticle dispersion relations, obtained by numerical diagonalization of the quark propagator matrix in color-, flavor-, Dirac- and Nambu-Gorkov spaces. ", "The values of the meanfields (order parameters) are obtained from a minimization of $\\Omega(T,\\{\\mu\\})$, which is equivalent to the selfconsistent solution of the set of corresponding gap equations. ", "$\\Omega_{lep}$ is the contribution from leptons ([*e.g.*]{}, electrons, muons and the corresponding neutrino flavors) and the subtraction of $\\Omega_0$ garantees that in the vacuum $\\Omega(0,\\,0)=0$. Eq. (", "\\[potential\\]) is obtained in the meanfield approximation to the path integral representation of the partition function for the three-flavor NJL model Lagrangian with the interaction channels $$\\begin{aligned}\n {\\cal L}_{\\bar{q}q} &=& G_S \\sum_{a=0}^8 \\Big[({\\bar q}\\tau_a q)^2\n + ({\\bar q} i\\gamma_5\\tau_a q)^2\\Big] \n + G_V({\\bar q} i\\gamma_0 q)^2\n\\nonumber \\\\\n &-&K\\left[{\\rm det}_f(\\bar{q}(1+\\gamma_5)q)\n +{\\rm det}_f(\\bar{q}(1-\\gamma_5)q)\\right],\n\\label{qbarqlag} \\\\\n {\\cal L}_{qq} &=& G_D\\!\\!\\!\\!\\!\\!\\sum_{a,b = 2,5,7}\\!\\!\\!\\!\\!\\! ", "\n (\\bar{q} i\\gamma_5 \\tau_a \\lambda_b C\\bar{q}^T)\n (q^T C i\\gamma_5\\tau_a\\lambda_b\\,q),\n\\label{qqlag}\\end{aligned}$$ where $\\tau_a$ and $\\lambda_b$ are the antisymmetric Gell-Mann matrices acting in flavor and color space, respectively. ", "The scalar ($G_S$), diquark ($G_D$), vector ($G_V$) and KMT ($K$) couplings are to be determined by hadron phenomenology, see [@Rehberg:1995kh].", "\n\n\\[!ht\\] ![", "Left: Equations of state for neutron star matter in beta-equilibrium. ", "The hadronic phase is described by the DBHF EoS (solid line) and the quark matter EoS correspond to the NJL model (\\[potential\\]) for different choices of the diquark coupling strength $\\eta_D=G_D/G_S$ for given vector coupling $\\eta_V=G_V/G_S=0.1$ and KMT coupling $K$. Phase transitions from two-flavor (2SC) to three-flavor (CFL) quark matter are marked by full dots whereas phase transitions from hadronic to quark matter are indicated by open dots. ", "Right: Hybrid equations of state for symmetric matter compared to the flow constraint [@Danielewicz:2002pu] from heavy-ion collisions. ", "Except $\\eta_D=1.35$, for which the onset of the 2SC phase has a too low critical density, the parametriztions fulfil the flow constraint, see also [@Lattimer:2006xb; @Klahn:2006ir; @Klahn:2006iw]. ", "The 2SC-CFL transition lies outside the tested density region.[]{data-label=\"f:EoS\"}](D_comp.eps \"fig:\"){width=\"50.00000%\"} ![", "Left: Equations of state for neutron star matter in beta-equilibrium. ", "The hadronic phase is described by the DBHF EoS (solid line) and the quark matter EoS correspond to the NJL model (\\[potential\\]) for different choices of the diquark coupling strength $\\eta_D=G_D/G_S$ for given vector coupling $\\eta_V=G_V/G_S=0.1$ and KMT coupling $K$. Phase transitions from two-flavor (2SC) to three-flavor (CFL) quark matter are marked by full dots whereas phase transitions from hadronic to quark matter are indicated by open dots. ", "Right: Hybrid equations of state for symmetric matter compared to the flow constraint [@Danielewicz:2002pu] from heavy-ion collisions. ", "Except $\\eta_D=1.35$, for which the onset of the 2SC phase has a too low critical density, the parametriztions fulfil the flow constraint, see also [@Lattimer:2006xb; @Klahn:2006ir; @Klahn:2006iw]. ", "The 2SC-CFL transition lies outside the tested density region.[]{data-label=\"f:EoS\"}](Flow_V010_DBHF.eps \"fig:\"){width=\"50.00000%\"}\n\nAs pointed out in [@Buballa:2003qv], due to the mixing of the light and strange flavor sectors by the KMT interaction, the difference in the critical chemical potentials for the chiral phase transitions in these sectors (which coincide with the onset of 2SC and CFL phases, respectively) gets diminished. ", "This entails that the phase transition between hadronic matter (described by a realistic nuclear EoS, e.g., the DBHF one, see [@Klahn:2006iw]) and superconducting quark matter may eventually proceed directly into the CFL phase, provided the diquark coupling is sufficiently strong, see the left panel of Fig.", " \\[f:EoS\\]. ", "For consistency with nuclear matter phenomenology, one may check that the corresponding isospin symmetric EoS would not predict a too low transition density and is not in contradiction with the flow constraint from heavy-ion collisions [@Danielewicz:2002pu], see the right panel of Fig.", " \\[f:EoS\\].", "\n\n\\[!ht\\] ![", "Compact star sequences for different values of the diquark coupling strength $\\eta_D$. For $\\eta_D=1.2$ no stable configurations with quark matter exist while for the strong coupling $\\eta_D=1.35$ there is an early onset of 2SC quark core configurations at $M=0.6~M_\\odot$ followed by a stable branch of hybrid stars CFL quark matter cores in the mass range $0.9<M/M_\\odot<1.46$. For comparison recent mass radius constraints are shown coming from RX J1856 [@Trumper:2003we; @Klahn:2006ir], M13 [@Gendre:2003pw] and $\\omega$ Cen [@Gendre:2002rx], see also [@Lattimer:2006xb]. []{", "data-label=\"f:M-R\"}](MR_Mn_V010_DBHF.eps \"fig:\"){width=\"\\textwidth\"}\n\nIn Fig.", " \\[f:M-R\\] we show the $M-R$ and $M-n_c$ relationships for nonrotating compact star sequences obtained as solutions of the Tolman-Oppenheimer-Volkoff equations for the hybrid EoS shown in the left panel of Fig.", " \\[f:EoS\\] where the diquark coupling $\\eta_D=G_D/G_S$ is a free parameter and the vector coupling is set to $\\eta_V=G_V/G_S=0.1$. For sufficiently large $\\eta_D>1.2$ there is a stable branch of hybrid stars with color superconducting quark matter core. ", "These solutions are more compact and have a higher central density $n_c$ than the purely hadronic stars with the same mass. ", "In the parameter range $1.25<\\eta_D<1.3$, mass twin solutions are possible, for which the more compact configuration has a CFL quark matter core. ", "Such solutions have not been possible without the KMT interaction term, when the occurrence of CFL quark matter marks the onset of gravitational instability and thus sets the limit for the maximum mass of the hybrid star [@Klahn:2006iw; @Blaschke:2007tt]. ", "The question arises whether other flavor-mixing interactions have to be invoked. ", "It seems necessary in a next step to include channels which appear after Fierz transformation of the KMT interaction and couple chiral condensates with diquark condensates [@Steiner:2005jm]. ", "This may lead to a new critical point in the QCD phase diagram [@Hatsuda:2006ps] and, depending on the sign of the coupling, to a further reduction of the strange chiral condensate which enforces the flavor mixing effect studied here.", "\n\nThe observational constraints for masses and radii are not yet settled. ", "There is a lower limit for the $M-R$ relation from RXJ 1856.5-3754 [@Trumper:2003we] which requires either a large radius $R>14$ km for a star with $M=M_{\\rm BRP}$ or a mass larger than $\\sim 2~M_\\odot$ for a star with 12 km radius. ", "Both is difficult to accomodate with the present EoS. $M-R$ relations for the quiescent binary neutron stars in globular clusters M13 [@Gendre:2003pw] and $\\omega $ Cen [@Gendre:2002rx] point to rather compact stars as described by those sequences obtained here. ", "The presented microscopic EoS features an intermediate softening of the EoS due to diquark condensation in the density range $\\sim 0.4 - 0.8$ fm$^{-3}$ and predicts two stable branches in an overlapping range of masses (twins) as a robust feature of compact star $M-R$ relationships. ", "The hypothesis of the existence of a “third family” of supercompact stars is testable in future observational campaigns devoted to determine the masses [@Freire:2009dr] and $M-R$ relationship for compact stars [@Ozel:2009da] with high precision and thus to constrain the dense matter EoS.\n\nConclusions\n===========\n\nThe effect of the flavor-mixing KMT determinant interaction on the sequential occurrence of superconducting two- and three-flavor quark matter phase transitions in the EoS for cold dense matter has been studied in an NJL-type model. ", "It is found that at sufficiently strong diquark coupling the deconfinement phase transition in neutron star matter leads directly from the hadronic phase to the CFL phase and occurs at low enough density to entail the formation of stable branch of CFL core hybrid stars in the $M-R$ diagram of compact stars. ", "This branch may either continuously join that of normal neutron stars or eventually form a “third family” branch, separated from that of the neutron stars by a sequence of unstable configurations. ", "The possibility of such a characteristic feature of mass twins in the $M-R$ diagram suggested by advanced microscopic QCD motivated hybrid EoS with superconducting dense quark matter phases should be kept in the focus of observational programs to deduce the cold dense EoS exploiting measured $M-R$ relationships for compact stars.", "\n\nAcknowledgments {#acknowledgments .unnumbered}\n===============\n\nDB and RL acknowledge the hospitality of the Yukawa Institute for Theoretical Physics Kyoto, partial support by the Yukawa International Program for Quark-Hadron Sciences and discussions during the Workshop program “New Frontiers in QCD” where this work was completed. 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[ "Q:\n\nxpath to check the correct sequence of book-parts with @seq\n\nI am very new in XML development and I just read online materials to get me going so I'm really not an expert. ", "I have a problem with my schematron file. ", "\nProblem: The schematron needs to check if every book-part is in sequence through @seq. ", "However, my current schematron tagging doesn't work for nested book-parts. ", "\nXML: \n<book>\n <meta>....</meta>\n <body>\n <book-part seq=\"1\">....</book-part>\n <book-part seq=\"2\">....</book-part>\n <book-part seq=\"3\">\n <book-part-meta>....</book-part-meta>\n <book-body>\n <book-part seq=\"4\">....</book-part>\n <book-part seq=\"5\">....</book-part>\n <book-part seq=\"6\">....</book-part>\n </book-body>\n </book-part>\n <book-part seq=\"7\">\n <book-part-meta>....</book-part-meta>\n <book-body>\n <book-part seq=\"8\">....</book-part>\n <book-part seq=\"9\">....</book-part>\n <book-part seq=\"10\">....</book-part>\n </book-body>\n </book-part>\n <book-part seq=\"11\">....</book-part>\n <book-part seq=\"12\">....</book-part>\n </body>\n</book>\n\nSchematron tagging:\n<rule context=\"book-part[@seq]\">\n <report role=\"error\" test=\"preceding::book-part[@seq] and number(@seq) !", "= (number(preceding::book-part[1]/@seq) + 1)\">Book-parts must be in sequence</report>\n </rule>\nThe schematron errors book-part seq=\"4\" and book-part seq=\"8\". ", "It seems that there is a problem with the first nested book-part. ", "Is there someone that could help me with this?", "\n\nA:\n\nYou are mixing hierarchy levels here. ", "What you need in this case is not only preceding:: but also parent::. (", "For consistency, I think it should begin from 1 again on the sublevel, but that is only my personal opinion and not the point here.) ", "You can test if @seq is correct by comparing it to the number of preceding and ancestor book-parts together:\n<pattern id=\"test\">\n <rule context=\"book-part[@seq]\">\n <report role=\"error\"\n test=\"number(@seq) !", "= count(ancestor::book-part[@seq] | preceding::book-part[@seq]) + 1\"\n >Book-parts must be numbered in sequence</report>\n </rule>\n</pattern>\n\nI would treat the other condition (preceding book parts must have @seq) in a separate rule:\n<pattern id=\"test2\">\n <rule context=\"book-part[@seq]\">\n <report role=\"error\"\n test=\"preceding::book-part[not(@seq)] | ancestor::book-part[not(@seq)]\"\n >Book-parts must be numbered</report>\n </rule>\n</pattern>\n\n" ]

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[ "The invention is directed to messaging systems.", "\nA messaging system allows a user to direct a message from a source location, e.g., a messaging server, on the messaging system to a destination location, e.g., another messaging server, on the messaging system. ", "Locations on the messaging system are connected by messaging links. ", "Typically, these links include computer data connections such as network connections in a networked computer system. ", "The message is delivered by transferring the message across one or more of the links to a mailbox located at the destination. ", "The delivery is typically facilitated by router computers and gateway computers that allow the message to be transferred across numerous and disparate interlinked networks, including the Internet.", "\nFrom time to time, a link in a messaging system develops a deficiency that causes a message delivery failure or a message delivery delay or both. ", "A delivery failure is a failure of a message to arrive at the mailbox to which the message is directed. ", "A delivery delay is a delay in the arrival of the message at the mailbox. ", "A delivery failure or a delivery delay can occur if, e.g., the messaging system develops a computer hardware deficiency or a configuration deficiency that causes a message destination to become insufficiently connected with the messaging system. ", "Such a failure or delay can also be caused by a deficiency involving computer software used in the messaging system. ", "In addition, a message delivery delay can occur due to a significant increase in the link's message traffic, i.e., the volume of messages transferred across the link during a time period. ", "Furthermore, if the link includes cables or wires, a delivery failure or delay can occur as a result of damage or wear involving the cables or wires." ]

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[ "Q:\n\nAD Server Connection Probem\n\nOk so i have a Linux server handling the DHCP, and FTP server i have and Network Shares. ", "Then i have a Server (Windows R2) with just the AD. ", "None of the client computers can connect to the Domain. ", "The way i fixed this before, was the DHCP was on the Windows Server, back then when i had it on there. ", "Today i moved the DHCP to the Linux computer and now, like stated before, clients cant connect. ", "I want to know if moving the DHCP was the error? ", "When using an AD, does the same computer have to run the DHCP? ", "or is there something else thats not letting the clients connect?", "\nIm subnetting my network:\nScope is 192.168.1.0 /28\nRange: 192.168.1.2-192.168.1.14 (leaving 192.168.1.0 as the Network, 192.168.1.1 as the Router/DNS/Default Gateway, 192.168.1.15 as the broadcast address)\nServer addresses:\nLinux: 192.168.1.6\nWindows: 192.168.1.2\nrest are for clients, i am thinking of changing the ip of my linux server to 1.3, just to have them close together...\n\nA:\n\nOK, so the reason none of your Windows clients can talk to the domain is that you are serving them the wrong DNS server address from your DHCP server.", "\nYou need to provide the DNS addresses of the DNS server(s) in your AD domain. ", "Which, in an installation this small, is almost certainly running on your domain controller. ", "In particular, you should not hand out any DNS server address that isn't a DNS server in the domain.", "\n\n" ]

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[ "PHYLOGENY OF THE CONJUGATING GREEN ALGAE BASED ON CHLOROPLAST AND MITOCHONDRIAL NUCLEOTIDE SEQUENCE DATA(1).", "\nThe conjugating green algae represent a lineage of charophyte green algae known for their structural diversity and unusual mode of sexual reproduction, conjugation. ", "These algae are ubiquitous in freshwater environments, where they are often important primary producers, but few studies have investigated evolutionary relationships in a molecular systematic context. ", "A 109-taxon data set consisting of three gene fragments (two from the chloroplast and one from the mitochondrial genome) was used to estimate the phylogeny of the genera of the conjugating green algae. ", "Maximum likelihood (ML), maximum parsimony (MP), and Bayesian inference (BI) were used to estimate relationships from the 4,047 alignable nucleotides. ", "This study confirmed the polyphyly of the Zygnemataceae and Mesotaeniaceae with respect to one another. ", "The Peniaceae were determined to be paraphyletic, and two genera traditionally classified among the Zygnematales appear to belong to the lineage that gave rise to the Desmidiales. ", "Six genera, Euastrum, Cosmarium, Cylindrocystis, Mesotaenium, Spondylosium, and Staurodesmus, were polyphyletic in this analysis. ", "These findings have important implications for the evolution of structural characteristics in the group and will require some taxonomic changes. ", "More work will be required to delineate lineages of Zygnematales in particular and to identify structural synapomorphies for some of the newly identified clades." ]

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[ "Mitochondria targeting delivery of nucleic acids.", "\nMitochondria are intracellular organelles involved in energy production, which play important roles in metabolism. ", "Consequently, mutation in mitochondrial DNA may have adverse effects on the host organism. ", "This hypothesis is supported by increasing number of reports that associate various diseases with the mutation of the mitochondrial genome. ", "Therefore, new therapy methods for targeting mitochondria genome should be developed for the treatment of these diseases. ", "The current progress in mitochondrial targeting gene delivery is discussed and future direction is suggested. ", "Recent research progress in this field is briefly introduced, and successes and obstacles in research are discussed. ", "Delivery of antisense DNA using lipophilic cation showed possible therapeutic effect in vitro. ", "Delivery of tRNA is also another possible approach to correct tRNA mutations. ", "However, research into the delivery of protein expression system using liposome and polymer has been very limited. ", "The results suggest that more research is required to address the problems in mitochondrial targeting gene delivery. ", "Here, we suggest 'multifunctional multilamella vesicular or multifunctional multi-vesicular (MMV)' for efficient mitochondrial targeting DNA delivery." ]

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[ "Introduction {#S1}\n============\n\nInherited diseases account for a substantial number of hospital admissions of children but also affect adults. ", "Despite progress in science, efficient treatments that go beyond supportive care are not available for most of these diseases. ", "Gene replacement therapies bear a high potential to address the medical need in affected patients and have been introduced to clinical testing about 20 years ago ([@B1]). ", "After many draw-backs in the past an increasing number of reports of successful gene therapies in patients with hemophilia ([@B2]), Leber's congential amaurosis (LCA) ([@B3]), or X-linked adrenoleukodystrophy ([@B4]) were recently published. ", "In November 2012, Glybera^®^ (alipogene tiparvovec) was the first human gene therapy to receive a market approval from the European Medicines Agency (EMA) suggesting that the field has reached a turning point which may give raise to additional approved gene therapies in the future ([@B5]).", "\n\nMost strategies applied for gene replacement focus on two types of vectors to reach stable transfer of functional gene products into selected target tissues, namely lentiviral vectors for *ex vivo* gene transfer into hematopoietic cells or other stem cells, or adeno-associated virus (AAV) for *in vivo* gene transfer to various target tissues such as muscle, the liver, the retina, lung, or the brain. ", "Despite successes reported for AAV gene therapy approaches it has become clear that humoral and cellular immune responses against both the vector as well as the transgene may negatively impact on safety and efficacy of gene therapy approaches ([@B6]). ", "Humoral responses against AAV frequently occur in the population, increase by age and are efficiently induced following a single administration of AAV-based therapies. ", "Neutralizing antibodies against AAV have been shown to negatively influence transduction rates and may counter-act therapy approaches with systemic delivery of AAV in particular. ", "More recently, pre-existing antigen-specific T cells recognizing AAV capsid proteins have been suggested to be an independent factor leading to reduced transduction rates on one hand and immune-mediated clearance of transduced cells expressing capsid proteins on the other hand, which led to immune-related adverse events in patients ([@B7], [@B8]). ", "The first results showing that human CD8^+^ T cells to AAV capsid could limit the efficacy of the gene transfer originated form an initial trial of AAV gene transfer to the liver for treatment of hemophilia ([@B7]). ", "Here it could be shown that expression of the initially expressed factor IX (F.IX) disappeared after several weeks, accompanied by a transient elevation of transaminases of the liver that were shown to be mediated by antigen-specific T cells directed against AAV but not the therapeutic F.IX that eliminated vector-transduced hepatocytes. ", "In addition, extensive T cell monitoring from multiple studies performed in gene transfer to the muscle indicate that there is a dose dependent increase in treated patients showing T cell reactivity against the AVV capsid. ", "Interestingly, currently available data suggest that gene transfer to immune-privileged body compartments such as the eye and central nervous system so far did not lead to detectable immune responses to the capsid or the transgene. ", "In summary, the immunogenicity data found in the clinical studies conducted with AAV-based vectors in human and available in literature, confirm that immune responses against AAV capsid proteins can vary widely and amongst others are influenced by the target organ, route of delivery, and dosing schedule ([@B9]). ", "Also antigen-specific T cells against the encoded therapeutic gene have been described and may reduce efficacy of gene therapy ([@B10]). ", "All these findings explain why approaches to better understand or block immune responses following gene transfer with viral vectors have recently come into focus in the field ([@B11]).", "\n\nAdeno-associated virus-specific T cells have been shown to be directed against AAV capsid proteins inducing transient hepatitis following i.v administration of AAVs targeting the liver ([@B7]). ", "Although transient toxicity may be acceptable for regenerating tissues such as the liver in regard of safety, immune-mediated removal of AAV-transduced cells may become a major obstacle for gene transfer into toxicity relevant organs such as the brain or the heart. ", "AAV-specific immunity may also lead to safety concerns as well as efficacy loss in replacement of the retinal pigment epithelium-specific 65-kDa protein gene in the retina in patients with LCA as re-therapy in the other eye may be mandated ([@B12]).", "\n\nThe currently available data on AAV-therapy induced immunity supports the notion that detailed knowledge of the presence of antigen-specific T cells prior to gene therapy as well as the occurrence of vector- and transgene-specific immunity following therapy may guide clinical decision making in the future ([@B6], [@B9]). ", "Examples for proactive use of immunological data for the benefit of patients could be: (i) the selection of patients that have a high likelihood to exert the wanted effects, (ii) identification of patients that may need an adaption of the therapy (e.g., lower doses, improved vector), or (iii) receive concomitant immune-suppression until immunogenic capsid proteins are cleared. ", "It may also be used to (iv) identify patients at risk for adverse immune reactions following second administration of the vector, or (v) be early indicators of loss of function of the encoded gene product.", "\n\nIn order to confirm the hypothesis that data generated by immunological monitoring can indeed impact on clinical decision making to enhance AAV-mediated gene therapy, more systematic analyses of AAV-specific T cell immunity are mandated and have even been recommend by NIH Recombinant DNA Advisory Committee ([@B13]). ", "The fact that T cell assays may have a higher complexity and variability as compared to assays to quantify soluble analytes explains why all investigators that perform correlative biomarker studies should know, control and report on the variables of assay conduct that are known to critically affecting immune assay performance. ", "The critical variables were identified by large scale proficiency programs conducted by the Cancer Research Institute's Cancer Immunotherapy consortium (CRI-CIC), the Cancer Immunotherapy Immunoguiding Program (CIMT-CIP) ([@B14]), and the Human Immunophenotyping Consortium ([@B15]). ", "In addition analytical labs are advised to optimize and standardize sample logistics and assay conduct prior to testing specimens from clinical trials even at the earliest stage of clinical development in which hypothesis generation represents the primary aim of immune assay use. ", "Assay qualification and validation become mandatory requirements when a hypothesis generated in exploratory research from early clinical development has to be confirmed in advanced clinical development ([@B16]). ", "This gradual evolution of immune assays from first exploratory use toward validated assays performed under Good Clinical Laboratory Practice (GCLP) standards may be supported by assay harmonization at any stage (Figure [1](#F1){ref-type=\"fig\"}).", "\n\n{#F1}\n\nImmune Assay Harmonization and Variables that Impact on Assay Performance {#S2}\n=========================================================================\n\nA plethora of assays exists to evaluate specific T cell responses, wanted or unwanted. ", "These assays differ in their sensitivity to detect low frequency T cells, quantity of information obtainable, ability to determine structural and/or functional features of T cells, and their complexity in qualification and validation demands ([@B17]). ", "For years the field of T cell monitoring has been plagued by a seemingly inherent variability in assay results, even between assays evaluating the same sample in the same laboratories or by different laboratories. ", "A divergence of Standard Operating Procedures (SOPs), the introduction of new reagents and tools by manufacturers, preferences by the assay performing scientist, varying availability of equipment or the qualification, and training status of personnel, has further complicated the issue. ", "Due to the lack of stringent QC procedures as required for clinical diagnostic tests, many assay \"cooks\" brewed their own results \"soups\" following their recipe without knowledge of how good or how bad that soup \"tasted.\" ", "An additionally complicating fact is the limited availability of test samples, and the intrinsic biological variability in performance of such samples, a factor well known today that has caused a shift in considerations concerning sample handling for T cell monitoring ([@B18][@B19]--[@B20]).", "\n\nThis heterogeneous landscape of assays and protocols exists in cancer immunology, infectious diseases, transplantation immunology, and gene therapy. ", "As outlined earlier a multitude of gene therapy approaches exist that (i) address several unrelated diseases, (ii) apply various viral vectors and serotypes, (iii) target different tissues (e.g., liver, muscle, retina, central nervous system), (iv) are applied using different administration routes and (v) deliver various therapeutic gene products. ", "The fact the gene therapy comes in different flavors mandates a product specific adaption of the immunological monitoring that acknowledges therapy-related peculiarities and integrates available knowledge on immunogenicity and epitope hierarchy of both the applied vectors and therapeutic transgenes. ", "The fact that there is not one single assay format that is applicable for all gene therapy trials poses a challenge on the gene therapy community to agree on some standards that may be used across a variety of clinical products and studies to generate results that may be comparable across institutions.", "\n\nFirst activities examining the differences in T cell assay performance between laboratories evolved more than 10 years ago from cancer immunologists and researchers in the HIV field that initiated proficiency panel projects for ELISPOT ([@B21], [@B22]). ", "This concept was soon adopted by two non-profit organizations from the cancer research field, the CIMT-CIP and CRI-CIC, and elevated to highly efficient programs that address proficiency testing of assay performance of individual labs and the identification of variables influencing the assay outcome at large ([@B14]). ", "By sending out pretested samples in a blinded fashion to a large number of laboratories which had to test those sample with a given T cell assay following their own protocol, and report the results back to a central site including details about how they performed the assay, CRI-CIC and CIMT-CIP were able to not only give feedback on the performance of each individual laboratory in comparison to the other participating laboratories, but also identified critical protocol variables that influence the results reported back. ", "These studies indicated that independent of SOPs applied, the results of a significant proportion of labs accumulated around an overall median value in results, while others were outliers. ", "With the help of protocol information provided, initial recommendations for SOP adaptations were deduced and introduced to the field for the next testing round, where it could be confirmed whether these recommendation can indeed improve performance. ", "This iterative testing process allowed the identification of protocol steps that, independent of the SOP applied, could elevate the assay performance of labs ([@B23][@B24][@B25]--[@B26]). ", "These findings are summarized in harmonization guidelines which are now increasingly used by laboratories (Figure [2](#F2){ref-type=\"fig\"}). ", "The introduction of such harmonization guidelines has led to significant improvement in response detection across laboratories ([@B27]) and decreased the overall variability in results between laboratories. ", "Further investigations of specific recommendations have led to even more detailed guidance in the harmonization process, for example by investigating the use of serum-free freezing and assay media in ELISPOT ([@B28], [@B29]), the implementation of a dump channel and viability marker in MHC-peptide multimer staining ([@B26]) and obtaining gating recommendations for flow-based experiments ([@B30], [@B31]). ", "Such assay harmonization activities, consisting of: (i) a mechanism for regular external proficiency testing with fast feed-back loops to participants, (ii) dynamic harmonization guidelines and (iii) benchmarks for assay performance, can support investigators to improve and maintain quality of their assays at any stage of development (Figure [1](#F1){ref-type=\"fig\"}).", "\n\n{#F2}\n\nWhile this assay harmonization process is ongoing and an increasing number of labs apply its results, there exists a discrepancy between what is being done in laboratories, and what is reported when publishing results from T cell assays. ", "To address the lack of transparency often observed in publications that hinders the accurate interpretation and replication of results, as well as the comparison of results from different laboratories, the Minimal Information about T cell assays (MIATA) project was introduced ([@B32]). ", "A 3-year extensive public consensus process involving more than 100 scientists from the different fields of translational immunology and regulatory agencies as well as editors from scientific journals resulted in a final reporting framework for results of T cell assays ([@B33]) that summarizes the minimal information to report about assay conduct. ", "Easy implementation tools are available online ([miataproject.org](miataproject.org)), and MIATA-compliant papers are listed with a link to the original publication.", "\n\nThese activities, together with available harmonization guidelines, if followed, elevate the T cell immune monitoring field to a level that allows the creation of high quality data that support immunotherapeutic developments and advances, and hence deserve the embracement by the translational science community at large.", "\n\nImmune Assays in Multi-Center Clinical Trials {#S3}\n=============================================\n\nA further complicating factor for performing T cell immunomonitoring is the complexity and fragility of the analyte. ", "In most cases, analysis is focused on T cells obtained from peripheral blood; less often (as more invasive sampling is required) T cells infiltrating other tissues such as bone marrow or skin are analyzed.", "\n\nImportantly, functional T cells assays are sensitive to the time passed since the sample has been taken on a typical scale of hours ([@B18], [@B19], [@B34]). ", "In terms of assay validation language, the sample stability is low. ", "This can be both influenced by the inherent instability of the T cells and by the instability of the sample matrix such as granulocytes that become activated over time ([@B35]). ", "For some assay parameters, this time window may be prolonged by adding stabilizers or by isolating the T cells without cryopreservation prior to shipping the sample ([@B36]). ", "More generally, there are two known solutions to this logistical challenge: (i) all measurements are being performed within short time using fresh samples, or (ii) all T cells are isolated from the biological samples and cryopreserved before the assay.", "\n\nThe first solution may be especially attractive in the case of monocentric studies. ", "A major drawback of such a scenario is that no retrospective analyses will be possible, longitudinal samples of a patient cannot be analyzed within the same assay, and in the case of multi-centric clinical trials this requires all immune assay parameters to be fully standardized at each site where patients are recruited. ", "Therefore, this solution that has been termed as \"peripheral analysis\" ([@B37], [@B38]) poses high demands on assay standardization, which should be completed before a trial is initiated. ", "Nevertheless, using fresh samples does not control inter-assay variability, and hence can introduce variability in measurements of samples obtained from different time points from a patient, which can confound the response determination between time points. ", "Determining the precision between measurements of samples obtained from different time points is logistically challenging, hence the introduced degree of variability by testing fresh samples cannot be easily defined.", "\n\nThe second solution requires isolation and cryopreservation of the T cells shortly after the sample has been taken. ", "Once the cells are frozen and kept at cryogenic temperatures, they are stable for very long time periods and can be shipped over great distances to enable batch-wise analysis within one central lab, thereby reducing assay variation. ", "This approach does control variability by allowing the simultaneous testing of samples obtained from different time points in one assay. ", "However, isolating and cryopreservation of T cells from biological samples is a relatively laborious process and is not performed as part of the tests for clinical routine. ", "Therefore, if it has to be implemented within a multi-centric clinical trial, all aspects of blood collection, transport to the laboratory isolating T cells, conduct of the isolation and cryopreservation process at the lab and shipping of the frozen sample should be standardized between labs using fully comparable processes and materials ([@B39]). ", "This solution has been termed as \"central analysis\" ([@B37], [@B38]) and poses high demands on standardized sample collection, while allowing more flexibility on the assay that are later being performed with the collected samples. ", "Recent harmonization efforts have addressed cryopreservation challenges, and provide some guidance ([@B28]), while others are still ongoing. ", "The performance of cell isolation and cryopreservation may be monitored by counting viable cell numbers at the time of isolation and after thawing the samples and in the case of blood samples the yield can be additionally monitored by comparing the numbers of isolated cells to the numbers of lymphocytes and monocytes from a routine hematology assessment.", "\n\nTo demonstrate the reproducible performance of immunoassays over time in one lab during the conduct of a clinical trial, and between labs as in the case of peripheral analysis, a stable source of reference samples that can be repeatedly analyzed is of central importance. ", "For T cell assays, the generation of a stable reference sample is a challenging task compared to chemical assays, for example, where a small molecule can be spiked into a sample matrix at pre-defined concentrations. ", "In the past, labs have often prepared local reference samples by aliquoting and cryopreserving cells from one large blood draw that contained T cells of a known reactivity. ", "Such reference samples are limited in size, not comparable between different batches, and do not contain pre-defined \"known\" numbers of T cells. ", "Recently, a first generation of reference samples that contain a defined number of functional antigen-specific T cells have been developed by CIP ([@B40]). ", "The technology is based on transfer of antigen-specific T cell receptors (TCRs) into primary lymphocytes using viral gene transfer. ", "Second generations of reference samples that are based on the use of *in vitro* translated RNA for TCR gene transfer are under development and has been shown to be simple to manufacture, robust, and sensitive, stable of at least 1 year and shown to be suitable for ELISPOT assays, HLA-peptide multimer staining as well as cytokine flow cytometry applications (unpublished data). ", "A completed proficiency panel with 12 labs in Europe and the USA showed that the technology is easily transferable to other labs and across protocols. ", "Given the currently available data on T cell reactivity against the AAV capsid, a set of reference samples engineered with capsid-specific TCRs for the most prevalent HLA-restrictions may become a useful tool for the gene therapy community and help to control assay performance and increase comparability across different studies using AAV gene transfer. ", "Thus RNA-based TCR-engineered reference samples may become a standard tool to control immune assay performance over time and help destigmatizing T cell assay use in clinical trials an become yet another component of immune assay harmonization.", "\n\nConclusion/Summary {#S4}\n==================\n\nSystematic immune assessments in gene therapy trials using quality controlled immune assays will help to understand the immunological interactions between AAV-based therapies and the adaptive immune system. ", "Associating immunological biomarker data with data on clinical safety and efficacy will enable the field to use immunomonitoring data for clinical decision making to improve gene therapy approaches. ", "Prior to use of immune assays investigators need to know and control those assay variables that determine the quality of sample specimens and assay results and should provide structured reporting on the assay setup in publications and reports. ", "By providing a fast feedback of assay performance over time or across institutions, assay harmonization can support immune assay development and use and thus may be considered as a tool to enhance biomarker research and development of new immune- and gene-therapies.", "\n\nConflict of Interest Statement {#S5}\n==============================\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.", "\n\nCedrik Michael Britten was supported by a grant from the Wallace Coulter Foundation (Miami, FL, USA).", "\n\n[^1]: Edited by: Federico Mingozzi, Université Pierre et Marie Curie/Genethon, France\n\n[^2]: Reviewed by: Valerie Ferreira, uniQure, Netherlands; Oumeya Adjali, Institut National de la Santé et de la Recherche Médicale, France\n\n[^3]: This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology.", "\n" ]

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[ "​Banned from marching in uniform in this year's Pride parade, a group of about 100 Toronto police and union representatives travelled to New York City this weekend to participate, in uniform, in that city's festivities.", "\n\nBut the force's own LGBT liaison officer admits that many here see the move as a \"slap in the face\" to those who supported the exclusion of uniformed officers from the Toronto parade.", "\n\n\"I've had conversations with community members, and I know a lot of them are not happy with our contingent down there,\" said Const. ", "Danielle Bottineau.", "\n\nThe invite was put out by the Gay Officers Action League (GOAL) New York, which bills itself as a non-profit human rights organization. ", "Toronto police Chief Mark Saunders lent his support to officers who wanted to attend and the union representing Toronto police encouraged members to make the trip.", "\n\nToronto Police Association president Mike McCormack has been a vocal critic of the decision to ban uniformed officers from marching in this year's parade.", "\n\n\"It's a bittersweet thing. ", "Isn't it great the New York Pride parade can be exclusive and includes us but that we can't even do that in our own city?\" ", "he asked.", "\n\nOfficers who took the trip donned these T-shirts while gathering at the airport. ", "While TPA president Mike McCormac said all officers paid their own way, at least one other officer interview said the TPA helped out financially. (", "CBC)\n\nChief Saunders announced in February that the Toronto police would not be participating in Pride events this year. ", "That move came after Pride Toronto voted in January to uphold a ban on uniformed officers first proposed by Black Lives Matter activists during a protest that stalled the 2016 parade for about an hour.", "\n\nToronto police will still be offering security and emergency services throughout the weekend. ", "And officers are still allowed to participate in the parade, but only in civilian dress.", "\n\nBottineau has marched alongside her partner, in uniform, for about the last eight years. ", "She says the last year has been an \"emotional roller coaster.\"", "\n\n\"I think we move forward from this, and I think there will tough conversations to be had after Pride is done,\" she said.", "\n\nBottineau added that the decision to go to New York City was left up to individual officers.", "\n\nConst. ", "Danielle Bottineau, left, said she understands that some community members are upset about how the trip 'looks optically.' (", "Twitter/@PsdboyV)\n\n\"I can't speak on behalf of the officers because I don't know what they were thinking or why they wanted to go,\" she said.", "\n\nMembers of the city's LGBT community have reached out to her \"voicing their concern\" about the optics of Toronto police officers marching in the New York parade when there is turmoil at home.", "\n\n\"They don't like the fact that, to them, we didn't get our way here so officers went down there ... So it's like a slap in the face. ", "Not for all, but for some,\" Bottineau said." ]

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[ "Join us for these classes where we create projects that foster a sense of self care, self expression, or well being. ", "Classes are small in nature to allow for individual attention as well as connecting with other participants.", "\n\nPlease note: Any of these classes can be custom scheduled for you and a small group of your choice. ", "Custom events are great for gifts, celebration, or a creative \"friends night out\". ", "Call Bonnie for more info at (207) 604-4146." ]

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[ "National survey of telemedicine education and training in medical schools in France.", "\nTelemedicine is a remote medical practice using information communication technology (ICT), and has been increasing in France since 2009. ", "With all new forms of medical practice, education and training (ET) is required for quality and safety. ", "To date, implementation of telemedicine ET has not been assessed in France. ", "The objective of this study was to describe the implementation of telemedicine ET and evaluate the knowledge, attitudes and practices (KAP) of deans and associate deans from all medical schools in France. ", "A cross-sectional non-mandatory, descriptive online survey with a self-administered questionnaire was performed from 15 November to 6 December, 2017. ", "Respondents were accessed through the ' Conférence des doyens des Facultés de médecine'. ", "There were 48 respondents with a 47.4% response rate among deans. ", "Telemedicine ET was limited in France; 10.4% in 1st year medicine (PACES); 4% in the final 3 years of medical school (D.F.A.S.M.) and 18.8% in medical residency. ", "Emergency medicine, dermatology, radiology, neurology and geriatrics were specialties with implemented telemedicine training during residency. ", "Of all respondents, 90% expressed a need to increase telemedicine ET, among which 75% accepted external support. ", "A highly positive attitude towards telemedicine practice was reflected by 60.4% of respondents, and 56.2% practiced telemedicine at least once. ", "This study was the first to assess national telemedicine ET implementation in France. ", "Telemedicine was integrated into initial medical education; however, telemedicine ET remains limited despite the positive attitudes of deans and associate deans. ", "Further research would need to be conducted on telemedicine ET implementation and KAP of medical students and residents." ]

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[ "Pokkiri\n\nPokkiri () is a 2007 Indian Tamil-language action thriller film directed by Prabhu Deva. ", "An official remake of the 2006 Telugu-language film Pokiri, it stars Vijay and Asin in the lead roles with Prakash Raj, Nassar, Vadivelu, Sriman and Napoleon playing supporting roles. ", "Mumaith Khan and Prabhu Deva make guest appearances. ", "Nirav Shah handled cinematography while Kola Bhaskar was the film's editor. ", "Filming took place in India and Australia. ", "\n\nSet in Chennai, the film revolves around a thug prepared to do anything for the sake of money, even if that means killing. ", "His killer instincts help him win the attention of two rival gangs, out of which he joins one and helps its members finish off their rivals. ", "On the other hand, he also attempts to save his girlfriend, who disapproves of his violent behavior, from a corrupt cop hellbent on marrying her against her will. ", "\n\nThe film was released theatrically on 12 January 2007 and received praise for its action sequences, humor and songs. ", "It became a commercial success, running for more than 200 days at the box office. ", "The film also had a Blu-ray release in United Kingdom on 21 June 2009. ", "In 2019, the film also had a limited re-release on the occasion of Vijay's birthday.", "\n\nPlot\nThe city of Chennai is rife with the nefarious activities of land mafia. ", "There are two rival gangs: one under Ali Bhai (Prakash Raj), who resides in Dubai and controls his India operations through his brothers Guru (Vincent Asokan) and Korattur Logu (Subbaraju) as well as his girlfriend Mona (Brinda Parekh); and another operated by a local goon named Narasimhan (Anandaraj). ", "They threaten builders and landowners into giving them protection money or property through force, extortion, or murder. ", "Mohammed Maideen Khan (Napoleon) takes charge as the new Police Commissioner of Chennai and starts cracking down on crime.", "\n\nTamizh (Vijay), a thug, is abducted by Logu and his henchmen. ", "Tamizh has taken a contract from Narasimhan to beat up Logu, which he does. ", "However, Guru and Mona invite Tamizh to join their gang. ", "Tamizh declines stating that he does not work for any gang, but is ready to do anything given enough money. ", "Meanwhile, Tamizh falls in love with Shruthi (Asin), when he visits his friend Saravanan's (Sriman) aerobics class, but she mistakes him for a thug. ", "Shruthi, a college student, lives with her widowed mother Lakshmi (Sriranjani) and younger brother Pappu (Master Bharath). ", "Body Soda (Vadivelu), a bogus kung fu master, lives above Shruthi's house and frequently, albeit comically and unsuccessfully, tries to convince her to marry him. ", "Inspector Govindan (Mukesh Tiwari) is a corrupt police inspector in the colony where Tamizh and Shruthi live and is on Ali Bhai's payroll. ", "He lusts for Shruthi and decides to make her his mistress, even after she rejects him multiple times.", "\n\nTamizh's first assignment with Ali Bhai's gang is to kill a member of Narasimhan's gang. ", "However, police show up at the spot where Tamizh and the other gangsters are waiting. ", "Tamizh engages the cops long enough for the others to finish the task and flee. ", "He also helps Shruthi escape from Govindan. ", "She is impressed by his kindness, and a friendship soon blossoms between the two, leading to the development of unspoken romantic feelings for each other. ", "When Shruthi tries to express her feelings to Tamizh, they are attacked by members of Narasimhan's gang, whom Tamizh finishes off. ", "Shruthi is shocked to learn that Tamizh is a gangster with no qualms about killing people. ", "Later, Govindan arranges for some thugs to pretend to rape Shruthi so that no decent family will want to take her as their daughter-in-law, as a result of which with no other option, Shruthi and Lakshmi will accept his demands. ", "Tamizh learns of this and thrashes Govindan incognito. ", "After much ado and mental anguish, Shruthi accepts Tamizh's love.", "\n\nSoon, Guru is found dead, presumably killed by Narasimhan in retaliation against the death of his gang members at the hands of Tamizh earlier, which forces Ali Bhai to come to Chennai from Dubai and kill Narasimhan. ", "He also meets Tamizh to discuss the killing of a minister by blowing up a school. ", "Tamizh disagrees with Ali Bhai's method as it would involve killing innocents including women and children. ", "In the middle of their argument, the police raids the club and arrests Ali Bhai. ", "His gang members retaliate by kidnapping Mohammed's daughter, drugging her, and creating a lewd video of her which they threaten to release to the media if Ali Bhai is not released, forcing the embattled commissioner to release Ali Bhai. ", "However, in her drugged state, Mohammed's daughter reveals that her father had placed a mole in Ali Bhai's gang.", "\n\nThe gang members find out that an IPS police officer by the name of Satyamoorthy, the son of a retired police inspector Shanmugavel (Nassar), has gone undercover to finish off the underworld mafia gangs and is now a part of their gang. ", "Ali Bhai kills Satyamoorthy in front of Shanmugavel. ", "However, it is revealed that the person who died was actually Saravanan, who was Shanmugavel's adopted son. ", "Ali Bhai then kills Shanmugavel, hoping that the real Satyamoorthy would come to see his father's body and avenge his death. ", "When the real Satyamoorthy actually turns up, everyone, especially Shruthi and Govindan, are shocked to see that he is none other than Tamizh. ", "Satyamoorthy (Tamizh) had gone undercover by posing himself as a criminal. ", "It is further revealed that Satyamoorthy was the one who killed Guru and not Narasimhan. ", "He killed Guru under the Commissioner's direction.", "\n\nAfter Shanmugavel and Saravanan's funerals, Satyamoorthy forces Govindan to call Ali Bhai to find out his location, which is Binny Mills. ", "He goes there and starts to eliminate Ali Bhai's gang members one by one, rescuing the commissioner's daughter in the process. ", "In a final confrontation, Satyamoorthy kills Ali Bhai by slashing his throat with a broken glass window, following which he kills Govindan as well.", "\n\nCast\n\n Vijay as ACP Satyamoorthy IPS (Tamizh) . ", "He is Shanmugavel's biological son and an undercover police officer.", "\n Asin as Shruthi, Tamizh's love interest\n Vadivelu as Body Soda / Sangi-Mangi\n Prakash Raj as Ali Bhai \n Mukesh Tiwari as Inspector Govindan\n Napoleon as Mohammed Maideen Khan IPS , Commissioner of Chennai city\n Nassar as Shanmugavel Tamizh biological father and Saravana's adopted father\n Sriman as Saravana Shanmugavel adopted son and Tamizh's friend\n Anandaraj as Narasimman\n Vincent Asokan as Guru\n Subbaraju as Korattur Logu\n Master Bharath as Pappu\n Sriranjini as Lakshmi\n Ajay Rathnam as Assistant commissioner \n Brinda Parekh as Mona\n G. V. Sudhakar Naidu as Das\n Dhamu as Juice Shop Owner\n Vaiyapuri as Tamizh's friend\n Karate Raja as Tamizh's friend\n Rekha as Mrs. Mohammed Maideen Khan\n Pandu as Elevator Operator\n King Kong as Lorry Driver\n Scissor Manohar as Colony Member\n Besant Ravi as Ali Bhai's henchman\n Soundhar as Veluchamy\n Sampath Ram as Narasimman's henchman\n Japan Kumar as Kannayiram\n G. K. as Vishwanath\n Bobby as Thamba\n Mumaith Khan (special appearance in the song \"En Chella Peru Apple\")\n Sridhar (special appearance in the song \"En Chella Peru Apple\")\n Ashok Raja (special appearance in the song \"Aadungada Yennai Suththi\")\n Prabhu Deva (special appearance in the song \"Aadungada Yennai Suththi\")\n\nProduction\nAfter his film Aathi in January 2006, for nearly six months Vijay was listening to stories, but none had appealed; he was supposed to do a Tamil version of Dharani's Bangaram, until that film's failure made him look at other options. ", "That's when he got to watch the Telugu Pokiri – he felt that it would work. ", "After difficulty in finding directors, Prabhudeva was selected as director, directing his first film in Tamil after the failure of his Telugu film Pournami. ", "The movie was launched on 6 July 2006. ", "Vijay's father SAC conducted special puja at the Sri Arunachaleswarar Temple in Tiruvannamalai. ", "On Saturday night, which was the full moon day, an auspicious occasion for the presiding deity there, he spent a full hour before the Lord seeking his blessings. ", "He also prayed at the Sacred Church at Velankanni. ", "Asin was selected, pairing with Vijay for the second time after Sivakasi.", "\n\nThe first day of shoot for the film was held at the new Pillayar Kovil at AVM studios, with various dignitaries gracing the occasion. ", "Vijay's mother Shobha Chandrasekhar gave the clap for the first shot. ", "The first scene shot was with Asin and Vijay, the lead pair in the film, in an elevator that was specially designed for the film.", "\n\nSoundtrack\nThe soundtrack has 8 songs composed by Mani Sharma. ", "Two of the songs from the original Telugu version were retained and remade in Tamil. ", "The soundtrack also features a remix of the song \"Vasantha Mullai\" from Sarangadhara (1958).", "\n\nRelease\nThe satellite rights of the film were sold to Sun TV. ", "The film was given a \"U/A\" certificate by the Indian Censor Board and released on 2007 at the festival of Pongal, alongside Ajith's Aalwar and Vishal's Thaamirabharani. ", "The film grossed 6.1 crore in Tamil Nadu in opening week from 142 screens.", "\n\nCritical reception\nPokkiri opened to positive Reviews.", "Sify said that the film was \"enjoyable while it lasts\". ", "Indiaglitz stated that Vijay stole the show with his \"typical 'Vijayisms' (action, humor and punch dialogues)\" and that the show was \"action-packed entertainer\". ", "Behindwoods review felt that Vadivelu and Prakash Raj’s performances were lackluster, and stated that Raj \" might do well to sit back and analyze the roles that he accepts,\" but concluded that the movie overall \"packs a punch.\" ", "Rediff.com gave the movie two stars, stating \"there's nothing more tedious than a badly made remake.\" ", "Nowrunning.com stated that \"Pokkiri''' is attractively packaged and presented\". ", "Oneindia.in stated that \"Pokkiri is a full length action movie of Vijay.\"", "\n\nBox office\nThe film was commercial success and ran over 200 days in Tamil Nadu, and 100 days in Kerala.", "\n\nAwards\n\n Remakes \nThe original Telugu film Pokiri, directed by Puri Jagannadh, was remade in several other languages and still found success in the respective regional cinemas. ", "Pokkiri is the first remake. ", "The second one was Wanted, the Hindi version in 2009. ", "Both Pokkiri and Wanted were directed by Prabhu Deva. ", "Prakash Raj reprises his role as the villain in both the remakes. ", "After that, a Kannada version, Porki, directed by M. D. Sridhar, was released on 14 January 2010. ", "Below is an actor map of the lead actors in the story of Pokiri and its remakes.", "\n\nDespite the Hindi remake, the original Telugu film Pokiri, its Tamil remake Pokkiri and Kannada remake Porki were dubbed in Hindi as Tapori Wanted, Wanted Baghi (2013) and Main Hoon Wanted (2012) respectively.", "\n\nLegacy\nA dialogue spoken by Vadivelu in the film, \"Vada Poche\" became very popular. ", "The dialogue inspired a comedy show in Sun Music with same name. ", "The dialogue also inspired a song sung by Velmurugan and Powerstar Srinivasan in Arya Surya'' (2013). ", "Vadivelu's dialogue \"Plan Panni Pannanum\" inspired a film of the same name.", "\n\nReferences\n\nExternal links\n \n\nCategory:Tamil-language films\nCategory:Indian films\nCategory:2007 films\nCategory:2000s action thriller films\nCategory:Tamil remakes of Telugu films\nCategory:Films featuring an item number\nCategory:Films directed by Prabhu Deva\nCategory:2000s Tamil-language films\nCategory:Indian action thriller films\nCategory:Tamil film scores by Mani Sharma\nCategory:Fictional portrayals of the Tamil Nadu Police" ]

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[ "Q:\n\nsublime text 2 setting custom code highlight\n\nI was using notpad++ till now and now using sublime text 2.", "\nSublime Text 2 has curly bracket matches with just underline beneath them which is not clearly visible to me and I want to change it to either bold or highlighted with a background color.", "\nAre there possibilities to define it in its preference or settings ?", "\n\nA:\n\nI think I know what you're looking for.", "\nYou need to install the BracketHighlighter package.", "\nI'd suggest you install the Package Control for ST2 first to make your installation smooth.", "\nI hope this will help you.", "\nEDIT\nYou don't have to download the package, just install the Package control and install BracketHighlighter from the Package Control.", "\nRegards,\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "1. ", "Introduction {#sec0005}\n===============\n\nIntra-neural microstimulation (INMS) is a technique by which sensory nerve fibres can be stimulated electrically by delivering microamperes of current through an electrode inserted into a peripheral nerve during microneurography ([@bib0045]; [@bib0075]). ", "It is typically performed in conscious human participants to evoke synthetic percepts, and *single unit* INMS can be used to stimulate individual afferents ([@bib0040]; [@bib0070]; [@bib0095]; [@bib0090]). ", "Here, a single mechanoreceptive afferent can be explored and characterised physiologically, and then stimulated electrically. ", "Currents of ∼1--3 μA produce a clear tactile sensation (e.g. a vibration sensation from a fast-adapting type 1 (FAI) afferent and a pushing sensation from a slowly-adapting type 1 (SAI) afferent) and this synthetic *sensory projected field* corresponds well to the physiological receptive field ([@bib0090]). ", "Since perceptually distinct, conscious sensations can be elicited from individual mechanoreceptive neurones in isolation (single unit), the contribution of the different mechanoreceptor classes to tactile sensation can be studied independently in a 'quantal' manner. ", "It is possible to combine single unit INMS with neuroimaging to explore and contrast these quantal signals. ", "The approach first involves microneurography, the recording of impulse traffic in a single primary afferent, resulting from mechanical stimuli applied to its receptive field. ", "This is followed by INMS, to selectively activate the same afferent. ", "A variety of electrical input patterns can then be used to probe subsequent central nervous system responses during neuroimaging.", "\n\nSingle unit INMS is in stark contrast to transcutaneous electrical stimulation of peripheral nerves, during which large numbers of different afferent types are non-selectively recruited, thus producing the sensation of paraesthesia ([@bib0005]; [@bib0015]). ", "Combining single unit INMS with neuroimaging allows the precise assessment of the brain's response to tactile stimulation in a very controlled manner. ", "We have previously used INMS to stimulate single units in conjunction with fMRI ([@bib0055], [@bib0080]) and in combination with electroencephalography (EEG) ([@bib0020]) to assess functional central nervous system responses. [", "@bib0055] performed INMS during 7 T fMRI, but no study to date has progressed to using more complex or patterned stimuli, nor have they presented a sufficient sample size for separate analysis by receptor class.", "\n\nThe approach of INMS with neuroimaging presents several technical problems in terms of compatibility, the ability to collect sufficiently low noise recordings from neurones, and participant safety. ", "In fMRI recordings, the switching of magnetic field gradients may be sufficient to generate currents in the long cables required to connect the participant to non-MR-compatible stimulation equipment ([@bib0030], [@bib0055], [@bib0080]). ", "Our previous research used a commercially-available stimulator system (AD Instruments, Castle Hill, Australia) for INMS in the MR scanner. ", "However, since this system was not designed specifically for this purpose, it provided limited functionality in the both the level of stimulation precision which could be presented (steps of 1 μA, rather than the required 0.1 μA precision) and in the pulses which could be generated (only pre-programmed, simple pulse trains can be delivered). ", "Additionally, manual switching between microneurography recording and INMS introduced problems, including long wait times when switching back to unit recordings (due to amplifier overload after stimulation), and additional preventative changes to the equipment were required to ensure that no extraneous currents were passed through the electrode to the participant ([@bib0055]). ", "In EEG and MEG recordings, reed-relays employed to deliver stimulation in conventional INMS equipment, produce stimulation artefacts which limits their use (personal observations). ", "To date, no study has demonstrated the use of MEG to study INMS induced responses.", "\n\nHere, we designed an INMS system that would be compatible for use in a range of neuroimaging methods, specifically including 7 T fMRI and MEG. ", "This system overcomes previous issues by allowing ease in switching between recording and stimulating, prevents extraneous electrical current discharge, and allows the delivery of customisable patterns of stimulation.", "\n\n2. ", "Methods {#sec0010}\n==========\n\nThis section is divided into two parts. ", "First, we describe the design specification of the INMS system, and follow this with the detailed design.", "\n\n2.1. ", "Design specification {#sec0015}\n-------------------------\n\nThe primary specification for an INMS system was that it should provide a safe connection to human participants whilst in use within the scanners. ", "It must conform to, or exceed, specifications for an Internally Powered Medical Equipment, Applied Part (AP) classified, type BF (floating patient connection) as outlined in IEC 60101-1 (Medical electrical equipment − Part 1: General requirements for basic safety and essential performance). ", "In addition, particular and collateral requirements for safe operation of Medical Equipment is pertinent to the design of the INMS system such as IEC 60101-2-33 (Magnetic Resonance Equipment), IEC 60101-2-26 (EEG) and IEC 60101-2-10 (Nerve and Muscle Stimulators). ", "The INMS system was not required to be suitable for use with any other equipment requiring electrical connection, such as EMG, electrocardiography, or other stimulus devices.", "\n\nThe INMS system was designed to be capable of operating safely in the presence of high static magnetic fields (7 T MRI), large switched magnetic fields, and high radio frequency (RF) fields within the magnet bore. ", "Conversely, the system required that INMS should have no detrimental effect on the quality of the image and functional data recorded by MRI and MEG scanners. ", "For both MRI and MEG there was a requirement that there should be no 'magnetic signature', whilst related, this requires different design features for the two neuroimaging modalities. ", "In addition, although the MEG environment imposes no particular safety conditions on the INMS system, the MR scanner has the potential for severe electrical interference effects, which should be addressed.", "\n\nConsidering MR safety, the INMS system was designed for use primarily within the Philips 7 T Achieva MR scanner (Best, Netherlands) equipped with a Nova Medical head volume transmit coil (Wilmington, MA). ", "This set-up reduces the levels of RF present compared to a conventional 3 T MR scanner, as the head-stage amplifier unit is mounted on the forearm, which is not within the RF coil at 7 T, unlike a 3 T MR scanner which has a built-in body RF coil. ", "The head-stage amplifier requires standard components with minimal ferrous content (i.e. using surface mount devices), so that there is no effect on scan quality. ", "If those parts of the system in proximity to the bore are not considered magnetic when subjected to the standard deflection test, the INMS system can be designated as MR-compatible.", "\n\nConnection of the amplifier to the patient via the electrodes creates a circuital loop, which can generate an electromotive force (EMF) in the presence of switched magnetic fields (audio or radio-frequencies). ", "Low frequency magnetic fields are used in the imaging process should not induce voltages in the loop which disturb the stimulator, potentially producing false stimuli or shocks. ", "RF (300 MHz at 7 T) could generate local heating due to antenna effects of the electrodes and leads. ", "Local Specific Absorption Rate (SAR) levels in the limb should not be exceeded with the device connected. ", "In addition there should be protection against local heating of the tissue round the electrode in the presence of high RF power.", "\n\nFor the MEG environment, there are no further participant- or equipment-related safety issues not already covered in the design for MRI compatibility. ", "The INMS system was tested in a CTF 275 channel MEG scanner equipped with DSQ3500 acquisition electronics (Coquitlam, BC, Canada). ", "In the MEG environment, there is a requirement for no participant movement, and care is taken to support the arm to ensure any is minimised. ", "Therefore, any minimal ferrous content of the amplifier head-stage circuit board is not an issue for MEG recordings. ", "It is desirable that the current loop generated by the INMS stimulus currents (\\<10 μA) entering the wrist through the electrodes does not generate a magnetic dipole of sufficient intensity to either be detected by the MEG system or cancelled by gradiometers and localisation methods.", "\n\nThere were two principal functional design objectives for the INMS system: (1) to perform microneurography, enabling placement of the electrodes in the median nerve and recording of unitary neuronal activity in the 'Amplify' mode; (2) to deliver a programmed sequence of pulse stimuli synchronous with the scanner acquisition when in the 'Stimulate' mode. ", "In addition, a specific requirement was the ability to switch between these two modes of operation simply and quickly during mechanoreceptive afferent testing. ", "It was essential that the switch-over should not produce any electrical shocks and could be controlled remotely by the operator even when the participant is within the scanner. ", "Previous attempts at this experiment with commercial equipment required the use of mechanical switches, which in combination with large cable capacitances could cause a discharge when inside the nerve, producing an unpleasant sensation for the participant (personal observations). ", "Furthermore, the amplifier in the commercial system was overloaded by the switching process, thus the experiment was delayed when switching back to 'Amplify' mode. ", "The key functions of the equipment were that it should be controllable by the operator via a remote MR compatible box for ease and speed of operation during an experiment.", "\n\nThe amplifier head-stage was designed to have high impedance and low-noise when connected to the electrodes (having resistive and capacitive impedances of 100--500 kΩ). ", "The nerve signals needed to be recordable and be fed back to the operator, both via an audio channel and visually on a screen. ", "The system was designed to allow a basic level of spike analysis in order to assist in identifying afferent fibre types (e.g. fast- or slowly-adapting). ", "The head-stage was designed to be small and light enough to mount on a body site near the electrode recording site, in order to make connections and cables to the electrodes as short as possible. ", "The electronics were screened from RF and other electromagnetic interference, with the screen not causing any movement of the head-stage electronics due to induced currents caused by gradient switching, as movement could dislodge the electrode, resulting in the recording from the afferent being lost.", "\n\nThe stimulator was designed to be an analogue current amplifier in order to deliver a completely flexible pattern of stimuli pulses. ", "The pulses were unipolar (switchable polarity), bipolar or D.C. balanced. ", "The stimulus pulse was typically 200 μs duration with peak currents of up to 200 μA and 0.1 μA resolution. ", "The maximum compliance was set to be of order 30 V in order to drive high impedance electrodes. ", "In practice, less than 10 μA of current was used, with a voltage of the order of 1--2 V. The system was designed to monitor the current and voltage delivered to the electrodes for both test purposes and for impedance estimation.", "\n\n2.2. ", "Design in detail {#sec0020}\n---------------------\n\n[Fig. ", "1](#fig0005){ref-type=\"fig\"} shows the functional blocks of the INMS system developed to achieve the design objectives. ", "The first block comprises the computer controller devices: scanner computers (for MEG or fMRI); a computer to generate synchronisation pulses from the scanner and provide a trigger to the INMS system to initiate its stimulation sequence (using Presentation software; Neurobehavioral Systems, Berkeley, CA); and a host computer for the INMS control and signal recording. ", "These devices are all positioned outside of the screened room of the MRI or MEG scanner, have a common ground, and are not isolated.", "Fig. ", "1INMS system diagram.", "All equipment within the screened room is optically isolated for participant safety. ", "Only the stimulator and head-stage units are approved for use within the bore of the 7 T magnet. ", "The piezo loudspeaker and remote control unit are non-magnetic and can be used near the magnet during participant preparation. ", "The interface unit and battery, whilst not projectile hazards, are not designed to work in high magnetic fields, and are situated at the edge of the screened room area. ", "A similar set-up is employed within the MEG suite. ", "The audio channel may, if preferred, be taken from the host control computer and played through speakers placed at the doors of the scan room.", "Fig. ", "1\n\nOptical fibres pass through to the scan rooms and all pieces of equipment are isolated from ground. ", "These provide the participant isolation and all equipment inside the scan room runs off rechargeable batteries. ", "The USB isolation is provided by a Corning (Hickory, NC) USB3.0 optical cable, which was modified to remove the cable \"phantom\" power supply to the isolated end, such that the power to the USB receiver electronics was replaced by a battery derived supply. ", "This provided \\>10 GΩ isolation at a tested 500 V for all isolated units. ", "The interface unit resided inside the MR screened room as far from the magnet as possible.", "\n\nWithin the interface unit a USB hub (TS-HUB3 K, Transcend Information Inc., Taipei, Taiwan) provides communications for a number of devices: a National Instruments (Austin, TX) USB 6216 provides all analogue and digital input and output functions; a PIC32 USB Audio interface (Microchip technology Inc., Chandler, AZ); and an Arduino Uno R3 ([www.arduino.cc](http://www.arduino.cc){#intr0005}) dedicated to the control of the remote display. ", "A 10 m cable runs from the interface box to the scanner bed (length defined by the layout of the MRI scan room), with an in-line stimulator unit 2 m before the unit containing the head-stage amplifier. ", "As the stimulator unit contains no magnetic or electromechanical parts it can be placed near the MRI magnet or MEG. ", "This location allows the reduction of the cable length between stimulator and electrodes to a minimum, and thus preserves pulse shape and minimises likelihood of any residual charge. ", "Only the stimulator and head-stage units are defined as MRI-compatible within the bore of the magnet. ", "The remote control box and piezo loudspeaker are nominally non-magnetic and can be used outside the bore of the magnet during microneurography. ", "These are placed for the ease of use of the operator.", "\n\nThe key design objectives and novelty of this work are realised with the design of the amplifier and stimulator units. ", "The success of the system relies on the ability to switch between recording and stimulation functions safely and quickly, without compromising the performance of either. ", "The switching function relies on the adoption of opto-isolated FET analogue switches (H11F1 M, Fairchild Semiconductor Corp., Phoenix, AZ). ", "These devices have a low on-resistance (200 Ω) and a high off-resistance ( \\> 100 MΩ), which result in a smooth transition between the two with the appropriately shaped LED current drive. ", "This ensured any residual currents were dissipated slowly during switch over between functions. ", "For safety, the current carrying capacity was limited to 500 μA, still well above the maximum value required for the INMS application.", "\n\n[Fig. ", "2](#fig0010){ref-type=\"fig\"} shows a simplified circuit diagram of the amplifier and stimulator units. ", "The opto-FET switches are shown without their LED drives for simplicity. ", "The switches were arranged in three groups: amplifier switch (AS) which connects the amplifier front-end to the electrodes; stimulator switch (SS) which connects the stimulator drive to the electrodes; and short switches (SH) which short circuit the stimulator. ", "AS and SS switches are never on at the same time and the SH switches are on in amplify mode to reduce potential noise being injected into the front end. ", "Note that the 'ground' electrode is only connected through R~G~ to the 'ground' of the electronics at time of amplification. ", "This key feature ensures that return currents during stimulus drive all pass through the reference electrode, and thus allows a differential drive stimulus to be used. ", "Hence, a 30 V compliance can be achieved with only 15 V power rails.", "Fig. ", "2Amplifier and stimulator circuit elements showing switching.", "The amplifier switch (AS), stimulator switch (SS), and short switch (SH) are opto-coupled FET analogue switches. ", "The head-stage, stimulator and interface blocks are shown in one diagram here for simplicity, but are in separate physical units, as described in [Fig. ", "1](#fig0005){ref-type=\"fig\"}.Fig. ", "2\n\nThe front-end of the amplifier uses low-noise (6.5 nV/√Hz and 0.8 fA/√Hz at f = 1 kHz) JFET operational amplifiers (OPA2141, Texas Instruments, Dallas, TX) arranged as a differential amplifier. ", "The inputs are D.C. coupled with an integrator feedback stage (time constant = 0.1 s) arranged to give a fast return to zero mean output. ", "The gain of subsequent stages is arranged to give an overall head-stage amplifier gain of 200 with a bandwidth from 10 Hz to 10 kHz. ", "The analogue output of the amplifier unit is sampled directly by the USB 6216 at a rate of 40 kHz. ", "The power supply rails to the amplifier front-end are switched on only when the system is in amplify mode.", "\n\nThe stimulator electronics use standard operational amplifier devices which are capable of driving 200 μA outputs into a wide range of impedances. ", "The driver amplifier employs a current sense resistor (R~S~) and positive feedback to the positive terminal of a differential amplifier to achieve a trans-conductance amplifier function. ", "The drive potential across the electrodes is differential and this is achieved by an inverting voltage follower with a series impedance of R~S~. A useable bandwidth of 50 kHz into typical electrode impedances is obtained with the amplifier being unconditionally stable under all load conditions. ", "The SH switch is used to test the current drive before connections are routed to the participant. ", "The current and voltage applied to the electrodes are monitored and sampled for test purposes. ", "Whilst it would be ideal to monitor these as close as possible to the electrodes they are monitored on the stimulator driver board. ", "In INMS, the actual current used is determined by the threshold of induced sensation, and these measurements are only used as a guide so absolute precision is not required. ", "The impedance of the electrodes is calculated and displayed as a guide to the operator as required. ", "The power supply to the stimulator unit can be switched into high or low voltages depending on selection of high or low compliance modes, or off when not required. ", "Switching the front-end circuits off when not required reduces the chance of instability or oscillations, plus saves battery lifetime. ", "Power for the amplifier and stimulator units is derived from four 9 V 300 mAh PP3 NiMH rechargeable batteries arranged to give up to ±18 V supplies. ", "These give at least two days intensive use of the INMS system.", "\n\nTo ensure compatibility with the MRI scanner, the amplifier and stimulator units have suitable screening and RF protection. ", "5 kΩ resistors are placed in-line with the electrode connections internal to the head-stage in order to reduce the magnitude of RF induced currents circulating through the electrodes, participant, and amplifier. ", "In addition 100 pF RF traps are present on the connections to the board in order to prevent RF signals from affecting the operation of the stimulator. ", "Hence, the 5 kΩ resistors and capacitors form a low-pass filter as seen by any RF pickup on the electrode wires. ", "The additional capacitance does compromise the delivery of current to the electrode slightly but could be removed if MRI usage was not required. ", "RF traps are used at the interface end of the cables to reduce the likelihood of common-mode RF signals passing down the cable. ", "The internal shielding of the PVC amplifier and stimulator housings is achieved by using a copper coated non-woven polymer fabric. ", "This gives good RF performance but has a relatively low conductance at low-frequencies. ", "Eddy currents induced by magnetic field switching or movements are substantially reduced compared to use of copper film screens. ", "In addition the ground plane of the amplifier board is carefully designed to minimise eddy current effects, which could lead to vibrations.", "\n\nAll devices are connected through the isolated USB and are controlled by software custom-written in MATLAB 2015a (The Mathworks, Natick, MA), specifically using the Data Acquisition Toolbox for control of the 6216 NiDAQ. ", "A graphical user interface based front-end ([Fig. ", "3](#fig0015){ref-type=\"fig\"}) allows control of all functions, automatically ensuring the correct sequence of power supply and opto-switch switching. ", "Acquisition data is sampled at 40 kHz, filtered within a selected band (usually 300--5000 Hz), recorded (if required), buffered to a rolling chart display, and streamed to the host computer's audio device. ", "The latter is useful, as the operator can then route the audio feed to either the PC's own internal audio, external speakers or back through the USB connection to the PIC32 audio driver in the interface unit and onwards to piezo speaker (or operator earpiece) as required.", "Fig. ", "3Software front panel.", "Function control buttons are on the left. ", "Stimulus control and functions are at the top, and amplifier functions are in the lower half of the panel. ", "A scrolling display shows the latest 2 s of acquired signal which can be directed to the audio channel and/or buffered to a recording file. ", "The data shown illustrates low-noise recordings from typical electrodes in saline within the bottle phantom. ", "In this graphic the display is set to auto-scale whereas the scale is usually fixed to ±50 μV during experiments. ", "A slider controls the set peak current value which can be updated from the computer or controlled by a rotary encoder on the remote control unit. ", "Other functions and panels are described in the text.", "Fig. ", "3\n\nA spike analysis module can be built into the acquisition data stream if required or applied to recorded data retrospectively. ", "The PC used (L540 Lenovo, China) takes 10 ms to acquire, filter, record and display the equivalent of 50 ms of data, so any further analysis should fit easily within the remaining time-frame.", "\n\nIn 'Stimulate' mode power is applied to the stimulator driver with the electrode amplifier powered down. ", "The opto-FETs SS are closed with SH and AS switches left open. ", "Hence stimulus current is routed to connect the driver to the electrodes. ", "Software-generated pulse sequences are produced at 50 kHz sampling rate, from a data file which defines the overall protocol. ", "There is complete flexibility in the waveforms generated and this opens the possibility of applying any pattern of INMS (e.g. one that mimics the natural firing of mechanoreceptive afferents). ", "The remote-control box allows the operator to control the important functions of the software, such as the Amplify/Stimulate switching function, controlling applied current, and initiating bursts of pulses for determining the current threshold for a perceived sensation. ", "To assist the operator, a visual display of the screen of the INMS control computer is projected into the scan room (a standard feature of most MEG and fMRI laboratories), as well as an alphanumeric display on the remote control box giving information including the electrical current level and impedance. ", "The latter display is achieved using the SPI port of the Arduino board. ", "Software is written for the Arduino to interpret a string of text sent to an attached COM port from MATLAB, and to put it on the screen.", "\n\nTwo 15 mm tungsten electrodes (one insulated and one uninsulated) (FHC, Bowdoin, ME, USA) were inserted through and glued to the cap of a polythene bottle (200 ml, 50 mm diameter). ", "A silver plated 'ground' electrode wire was also attached to the cap. ", "The bottle was filled with saline (0.5% by weight NaCl) such that the electrodes were covered. ", "Leads were attached in order to plug into the amplifier head-stage. ", "This bottle phantom was used for amplifier noise and stimulator tests prior to experiments taking place. ", "In addition the 'ground' electrode was connected to copper tape contacts on the outside of the bottle. ", "Hence for test purposes only an operator could hold the bottle phantom as a reliable test for electromagnetic interference in the scanner environments. ", "In addition, these test scans also allowed the assessment of signal-to-noise measures when inside and outside of the scanner.", "\n\n3. ", "Experimental {#sec0025}\n===============\n\nEthics for experiments on human participants using this equipment and associated imaging protocols was granted by The University of Nottingham Medical School Ethics Committee (E09022012, Experimental Protocol, Participant Information Sheet, informed Consent Form and MRI safety questionnaire). ", "All participants were given detailed information about the procedure and signed a written consent form. ", "All procedures were conducted in line with the Declaration of Helsinki.", "\n\nFour subjects participated in sessions involving characterisation of a single mechanoreceptive unit followed by INMS of this unit during either 7 T fMRI or MEG acquisition. ", "For the fMRI experiment, the participant lay on the scanner bed outside the bore of the magnet, while for the MEG experiment the participant was seated just below the level of the sensor helmet and wore a custom-fitted head-cast (Chalk Studios, London, UK) to prevent head movement ([@bib0025], [@bib0035]), as shown in [Fig. ", "4](#fig0020){ref-type=\"fig\"}. ", "In our MEG system, there was an interference signal conducted through the MEG earth which does elevate the noise floor as measured by the INMS. ", "By setting up the subject with their head removed from the MEG helmet and switching off the power to the bed and gantry controller, this noise was reduced to an acceptable level.", "Fig. ", "4Detection of units in MEG.(A) The subject is seated in the chair slightly lowered below the normal MEG scan position. ", "This is for their comfort during set-up of the electrodes and characterisation of the units found. (", "B) The amplifier head-stage is shown taped to the forearm with the electrodes visible. ", "The upper electrode (red terminal) is the median nerve electrode with the reference (current return) underneath placed subcutaneously. ", "The black wire is attached to the unseen 'ground' electrode. ", "The stimulator box is not shown in these photographs but is positioned on the floor close to the subject's feet. ", "The operator is locating the afferent by stroking or touching the skin with a monofilament whilst listening to the audio and observing the traces, as shown in [Fig. ", "5](#fig0025){ref-type=\"fig\"}. ", "The subject is wearing their individual head-cast. ", "The wires into the head cast are actively driven location markers for head registration. ", "For fMRI the cables going to the amplifier box are routed such that they cannot touch the subject and create an RF antenna loop which couples to the body.", "Fig. ", "4\n\nAn insulated tungsten electrode (FHC, Bowdoin, ME; length: 15 mm) was inserted percutaneously into the median nerve, approximately 3 cm proximal from the wrist fold, to stimulate and record from single mechanoreceptive afferent units. ", "A similar, un-insulated electrode was inserted just under the skin 4 cm away. ", "Once a single unit recording was identified in amplifier mode, it was characterised based upon its response characteristics to stimulation with a monofilament as fast-adapting type 1 (FAI) or type 2 (FAII), or as slowly-adapting type 1 (SAI) or type 2 (SAII) ([@bib0085]). ", "Unitary data were band pass filtered (0.3-4.5 kHz) for visualisation online and recorded, using custom software written in MATLAB. ", "Nerve data were only registered when the subject was positioned outside the bore of the 7T scanner or just below the sensor helmet in the MEG. ", "Offline, the data were processed with a band pass smoothing filter in MATLAB (0.16-2.5 kHz) to remove high frequency artefacts from MEG recordings, and exported to Spike 2 software (CED, Cambridge, UK) for identification of spikes based on a combination of amplitude and spike shape. ", "The INMS system was then switched to 'Stimulate' mode and positive current pulse trains of 60 Hz for 1 s were manually delivered by the operator, incrementing the current until a sensation was reported by the participant, or until 8 μA. If the perceived location of the electrically elicited sensation exactly matched the location where mechanical stimulation of the skin generated a response ([@bib0075]), the stimulation protocol was performed. ", "At this point the participant was moved either into the bore of the MR scanner, or into the MEG sensor helmet. ", "After moving the participant, INMS was re-evaluated to ensure that the perceptual response had not changed or was lost, and the stimulation current was adjusted if necessary.", "\n\n7 T fMRI scanning protocols and INMS pulse definitions are identical to those reported in [@bib0055], except from the spatial resolution which was here increased to 1.25 mm isotropic. ", "A burst of 60 Hz 200 μs current pulses of 1 s (0.5 s on and 0.5 s off) were repeated 8 times in a sequence, followed by a rest period of 23 s. This was repeated for a total of 8 cycles. ", "The MEG protocol consisted of a 1 s burst of 60 Hz 200 μs current pulses followed by a 10--10.5 (a randomly selected delay period) second rest period, repeated for 80 cycles in blocks of 10 cycles. ", "MEG data were recorded at 1200 Hz using a 275 channel MEG system (CTF, Coquitlam, BC), with the reference array set to a synthetic 3rd order configuration.", "\n\nAfter completing an fMRI stimulation cycle, or one block of MEG stimulation, the sensation was checked by asking the participant if the sensation had changed in intensity or quality. ", "If the sensation had faded during stimulation due to minute dislodgements of the electrode, the stimulation current was adjusted to give a comparable intensity of stimulation, with the same quality ([@bib0075]).", "\n\nfMRI image data were analysed using a General Linear Model in mrTools (<http://www.cns.nyu.edu/heegerlab>). ", "Statistical maps were formed by thresholding (Z \\> 3.08) after false discovery rate correction and projected onto a flattened representation of the contralateral central sulcus to compare the spatial localisation with previously acquired finger somatotopy in primary somatosensory cortex (for more details, see ([@bib0055])).", "\n\nMEG data were visually inspected for artefacts, such as SQUID resets, and magnetomyographic or magnetooculargraphic contamination, where trials containing excessive artefacts were removed. ", "To allow for the reconstruction of sensor data at the source level, three head position indicators (placed on the nasion, and left and right pre-auricular regions of the participant's face) were periodically energised to locate the participant's head within the dome. ", "The coils' positions relative to the brain were determined during the manufacture of the head casts. ", "Data were frequency filtered into the beta band (13--30 Hz) and reconstructed in source space using a beamformer ([@bib0050]; [@bib0100]), lead fields were computed using a dipole approximation ([@bib0065]) in conjunction with a multiple local sphere head model ([@bib0010]). ", "Dipole orientation was determined using a non-linear search for optimum signal to noise ratio (SNR). ", "To locate the source, a pseudo-T-statistical image was generated across a 2 mm isotopic grid spanning the right hemisphere's pre- and post-central gyri (active window: 0--1 s after stimulus onset; control window: 8--9 s after stimulus onset). ", "After determining the source location by finding the maximum absolute pseudo-T score, 1--150 Hz filtered sensor data were source reconstructed at the target location and a time-frequency spectrogram (TFS) generated.", "\n\n4. ", "Results {#sec0030}\n==========\n\nA number of experiments and measurements were made to ensure and demonstrate the safe working of the equipment before use with humans. ", "The results in detail, methods and discussion can be found in the Data in Brief document accompanying this paper. ", "In summary, during fMRI sequences, no temperature rise local to the electrodes due to SAR heating effects was discerned (±0.1 K). ", "In addition, measurements showed a level of current injection due to magnetic field gradient switching was less than 10 nA, well below the level which would influence applied stimulation patterns or cause pain.", "\n\nTest recordings from electrodes with known impedances demonstrated an acceptable low-level of noise, with no undue noise attributable to the extra series impedances of the switches and RF protection. ", "A low-noise recording from the bottle phantom is shown in [Fig. ", "3](#fig0015){ref-type=\"fig\"}. ", "This noise recording has an RMS amplitude of 3.3 μV, equivalent to 48 nV/√Hz, which is in-line with an expected value of 41 nV/√Hz for a 100 kΩ resistor at room temperature. ", "The latter value assumes an ideal filter and a frequency invariant source impedance − neither of which are true for this type of electrode. ", "However, similar baseline noise levels are observed in practice.", "\n\n[Fig. ", "3](#fig0015){ref-type=\"fig\"} shows a 4 μA current pulse being delivered to the bottle phantom electrodes, which is of negative polarity with respect to the reference electrode. ", "The pulse has an equalisation reverse polarity of 1/10 peak amplitude with 10 times duration. ", "The associated electrode voltage (top right) and impedance as a function of frequency (middle right graph) can be seen, with the measured impedance at 1 kHz (printed as 118.7, −59.22 j kΩ). ", "Periodic measurement of electrode impedance gives the operator an insight into the condition of the electrode.", "\n\n[Fig. ", "4](#fig0020){ref-type=\"fig\"} shows the process of setting up the subject in the MEG system. ", "The amplifier head-stage and electrode arrangement can be seen. ", "The operator is finding the nerve signals at this point by lightly touching the hand and fingers. ", "When a unit has been found it can be characterised by its response to touch or pressure. ", "The setup phase for fMRI is similar except the subject is lying down and no head-cast is used. [", "Fig. ", "5](#fig0025){ref-type=\"fig\"} shows example recordings from both the 7 T fMRI ([Fig. ", "5](#fig0025){ref-type=\"fig\"}A and 5D) and MEG ([Fig. ", "5](#fig0025){ref-type=\"fig\"} B and 5C) environments. ", "Physiological single unit recordings are shown from each type of mechanoreceptive afferent found in the glabrous hand skin. ", "Hence, this demonstrates that it is possible to obtain clear recordings from all mechanoreceptor types in both MRI and MEG environments. ", "The recordings have a low noise-floor, with very little external interference and easily distinguishable neuronal spikes.", "Fig. ", "5Examples of recordings from individual mechanoreceptive afferents in the 7 T fMRI and MEG environments.", "Recordings from individual SAI (A) and FAII (D) mechanoreceptive afferents in the 7 T fMRI environment. ", "The SAI recording shows the response to long-lasting indentation with a 2 g monofilament and the FAII recording shows the response to lightly blowing onto its receptive field. ", "The recordings are made while the participant is lying on the 7 T scanner bed, with the head-stage positioned on the participant's arm at the bore-end of the scanner. ", "The magnetic field experienced by the amplifier head-stage is ∼ 0.5 T. (B) Recordings from individual FAI (C) and SAI (B) mechanoreceptive afferents in the MEG environment. ", "The FAI recording shows its response to repeatedly moving a wooden stick across its receptive field and the SAII shows its response to a sustained indentation with a blunt wooden stick. ", "The MEG recordings are made with the participant positioned just outside of the helmet in the MEG scanner. ", "In all recordings, the bar above the trace indicates the timing of the respective receptive field stimulation. ", "In both environments, amplifier noise was less than 5 μV RMS with a 300--5000 Hz filter bandwidth. ", "Note the higher noise floor in the MEG recordings.", "Fig. ", "5\n\n[Fig. ", "6](#fig0030){ref-type=\"fig\"} shows an example of fMRI activation from the stimulation of a single FAI unit at the base of the index finger, using 60 Hz pulses. ", "The fMRI data show statistical activation maps (Z \\> 3.08, FDR-corrected) to INMS of the unit overlaid onto a surface reconstruction of the contralateral (right) hemisphere and on a flattened patch of the central sulcus. ", "INMS activation patterns in contralateral primary somatosensory cortex (S1) area are consistent with the expected spatial localisation from finger somatotopy derived from a travelling wave vibrotactile paradigm ([@bib0060], [@bib0055]). ", "No difference in image SNR was demonstrated on phantom data, and no significant difference in the temporal signal-to-noise ratio (tSNR) of the fMRI data was found between the INMS stimulation ON period (tSNR grey matter: 46 ± 4) and OFF period (tSNR grey matter: 44 ± 5) or tSNR with no INMS system in place (tSNR grey matter: 43 ± 4), demonstrating that the INMS system does not alter MR image quality.", "Fig. ", "6Example 7 T fMRI activation in response to INMS stimulation (60 Hz) of an FAI unit located on the base of the index finger. ", "Data is shown on an inflated brain and activity can be seen to localise within contralateral S1 (note that the activation posterior of the thumb region −red outline- is due to a large draining vein). ", "On the expanded map the INMS-induced activity is shown in detail along with coloured lines indicating the borders of each finger representation obtained from a previous travelling wave somatotopy experiment in the same participant.", "Fig. ", "6\n\n[Fig. ", "7](#fig0035){ref-type=\"fig\"}A demonstrates localisation of the neuronal activity for single unit INMS of an SAI afferent in MEG located in the palm of the hand. ", "Here, to aid visualisation of the source location, the pseudo-T statistical image has been projected onto an inflated cortical surface of the participant using the Freesurfer analysis suite (<http://freesurfer.net>). ", "The source image shows that the maximal change in beta power during the stimulation was located within the dorsolateral postcentral gyrus. ", "The time-frequency spectrum plot in [Fig. ", "7](#fig0035){ref-type=\"fig\"}B shows the average change in spectral power across the 80 trials. ", "Within the 15--30 Hz band, the characteristic event-related cortical desynchronisation during the time of the stimulus (0--1 s) and resynchronisation after cessation of the INMS is seen. ", "Note, at 60 Hz no clear power modulation specific to the trial is seen, suggesting that with the applications of appropriate environmental noise cancellation and spatial filtering methods, artefacts from passing current from the INMS system into the nerve are negligible.", "Fig. ", "7Results from a single INMS experiment in MEG, in which stimulation of an SAI unit located on palm of the hand occurred. (", "A) The localisation of task-induced changes in power, projected onto an inflated cortical surface, showing the location of the source to be within the dorsolateral postcentral gyrus. ", "The image is threshold at 80% of the maximum value for clarity. (", "B) Trial-averaged time frequency spectrogram (TFS) of a virtual electrode placed at the source location, derived from the maximum absolute pseudo-T score.", "Fig. ", "7\n\n5. ", "Discussion {#sec0035}\n=============\n\nThese results demonstrate the superior level of measurement using this specially-designed INMS system, and show that its performance is comparable to equipment used in a dedicated microneurography laboratory. ", "Further, the system provides overall ease of use in setting up, switching of function, and workflow, meeting all of the requirements in terms of safety and usage. ", "Specifically, low-noise recordings from individual mechanoreceptive afferents were recorded in both the 7 T MR and MEG scanners. ", "This made it possible to search for, identify, and record from single units, which were then subject to INMS. ", "The system allowed precise electrical pulses to be sent back down the electrode, to excite a single afferent and produce a quantal sensation (cf. [", "@bib0075]; [@bib0090]). ", "This clear perceived sensation continued to be artificially-induced on re-stimulation once the participant had entered the 7 T magnet bore or MEG sensor helmet, allowing the combination of single unit INMS with concurrent neuroimaging.", "\n\nFrom a safety point of view, no incidental electrical micro-shocks were produced (cf. ", "the previous commercially-available system used in Sanchez Panchuelo et al. (", "2016)) and the present system provides complete user control, with a dedicated control box near the microneurographer, as well as full computer control outside the scanner. ", "Our results show the potential in combining single unit INMS with 7 T fMRI and MEG. ", "Although not shown here, it is likely that such a system can be combined with other neuroimaging methods, such as EEG, electrocorticography, and functional near-infrared spectroscopy, as well as other neurophysiological monitoring (e.g. electrocardiography, eye movements).", "\n\nThe present system can be used to perform INMS during neuroimaging, which greatly facilitates the study of, primarily cortical, responses to controlled input from somatosensory afferent nerves. ", "We provide the first demonstration of such an application in MEG. ", "This system will allow the contribution of different afferent classes to the processing of somatosensory information throughout the brain to be evaluated. ", "Using high spatial resolution 7 T fMRI, it is hoped that the activity within- and between cortical layers in primary somatosensory cortex can be visualised. ", "Similarly, using high temporal resolution MEG, the precise cortical dynamics over time in response to INMS of different afferent types can be assessed. ", "The compatibility of the system with multiple neuroimaging techniques will potentially allow for the combination of data across methodologies, to further elucidate the spatio-temporal dynamics of cortical somatosensory responses. ", "Results from separate experiments in the same subject in MEG and 7T fMRI, may be combined to aid in the understanding of the relationship between locations of the neurovascular response (fMRI) and MEG inverse localisation. ", "Using the precise signal generated during single unit INMS should aid in elucidating localisation accuracy between techniques, as well as understanding detailed cortical signals. ", "Presumed compatibility with additional neuroimaging techniques will allow simultaneous acquisition of neuroimaging data such as EEG/fMRI, EEG/MEG, or EEG/functional near infra-red spectroscopy. ", "Furthermore, the INMS system allows unconstrained electrical patterns to be delivered; hence a variety of different frequencies can be tested, with the possibility of delivering other more variable patterns, such as those derived from the natural firing of mechanoreceptors. ", "These studies will aid in understanding the fundamental workings and connectivity in somatosensory circuits.", "\n\n6. ", "Conclusions {#sec0040}\n==============\n\nWe show the implementation and application of a dedicated system for single unit INMS of mechanoreceptive afferents, during combined 7 T fMRI or combined MEG acquisition. ", "This is the first demonstration of the feasibility of performing single unit INMS measures while recording MEG signals. ", "The INMS system goes beyond previous systems, where it provides safe and effective operation, and provides comparable neuronal recording and stimulation to equivalent procedures in dedicated microneurography laboratories. ", "Using this system will enable the smooth and efficient collection of high spatial and temporal resolution data from single unit INMS during neuroimaging. ", "Due to the unconstrained stimulation capabilities of the system, further experiments will probe a variety of artificial input INMS patterns and examine the detailed and precise central responses generated.", "\n\nAppendix A. Supplementary data {#sec0050}\n==============================\n\nThe following is Supplementary data to this article:\n\nThis work was supported by the Medical Research Council \\[grant number MR/M022722/1\\]. ", "This work was also supported by a Royal Society International Exchange Programme award. ", "We acknowledge the valuable assistance of Andrew Stuart and Alan Dorkes in the University of Nottingham electronics and mechanical workshops.", "\n\nSupplementary data associated with this article can be found, in the online version, at [http://dx.doi.org/10.1016/j.jneumeth.2017.07.016](10.1016/j.jneumeth.2017.07.016){#intr0020}.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "tag:blogger.com,1999:blog-8945911681330301542.post6916904526558002383..comments2020-06-05T15:44:53.104+01:00Comments on Interactive Dreams: Kingdom: The Far Reaches - Full Motion Video Adventure on CD-iUnknownnoreply@blogger.comBlogger1125tag:blogger.com,1999:blog-8945911681330301542.post-62038569558618112782007-07-06T11:17:00.000+01:002007-07-06T11:17:00.000+01:00never liked these games either. ", "beautfiful to watc...never liked these games either. ", "beautfiful to watch the cartoon, but it's so damn hard and frustrating. ", "All these 'cartoon FMV's' I think are frustrating, not the best CD-i had.Anonymousnoreply@blogger.com" ]

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[ "Histamine is a compound possessing significant biological activity mediated by pharmacological receptors. ", "Histamine has long been contemplated as a molecule having primarily negative biological effects. ", "Recently, however, new uses for histamine as a powerful pharmaceutical agent have come to light. ", "For example, histamine has been used in conjunction with interferon-alpha to activate NK cells in the presence of monocytes. ", "See U.S. Pat. ", "No. ", "5,728,378. ", "To take full advantage of the therapeutic properties of histamine, it is necessary to obtain large quantities of the compound in a pharmaceutical grade.", "\nHistamine occurs widely in nature as a result of putrefactive processes and a derivative, histamine dihydrochloride, is sold commercially for use as a standard in assays and as a component in certain allergy diagnostic kits. ", "The source of this histamine is often a natural one and as such contains a variety of contaminants that render it unsuitable for pharmaceutical use. ", "There are also synthetic protocols for the synthesis of histamine dihydrochloride known in the art.", "\nHistamine dihydrochloride can be conveniently synthesized by exploiting the decarboxylation of histidine. ", "Using this synthesis pathway, histidine is decarboxylated and subsequently treated to form the dihydrochloride salt form of the molecule. ", "For example, Hashimoto et al., ", "discussed the preparation of histamine using cyclohexenone as a catalyst for the decarboxylation of histidine. (", "Hashimoto, M., et al., ", "Chemistry Letters, 893-896 (1986)). ", "The Hashimoto, et al., ", "paper reported the isolation of histamine dihydrochloride at a 95% yield, using 2-cyclohexen-1-one as the catalyst, from the reaction involving histidine and 1% v/v of 2-cyclohexen-1-one in 10 parts of refluxing cyclohexanol (26 hours). ", "The Hashimoto method also teaches the use of toluene and HCl gas bubbled through the resulting decarboxylated solution to precipitate out and harvest the final histamine dihydrochloride product.", "\nAttempts to reproduce the Hashimoto procedure to generate pharmaceutically pure amounts of histamine failed. ", "Additional amounts of the catalyst were required to make the procedure operative and a substantial number of impurities were present in the final product. ", "Moreover, those impurities were difficult to remove. ", "In view of these results, it was found that the Hashimoto procedure is an unsuitable method for generating large quantities of pharmaceutically acceptable histamine.", "\nThe use of acetophenone as a catalyst for the decarboxylation of histamine has also been reported. ", "We recreated the method described in the Japanese patent to Akimasa, et al., ", "patent, Japanese Patent No. ", "05,255,204 (1983), and used 0.26 equivalents of acetophenone and 10 parts of diethylene glycol as the solvent for the decarboxylation reaction. ", "Although the Akimasa et al. ", "method was far more efficient in converting histidine to histamine, it failed to consistently yield a pharmaceutical grade product. ", "Like the final product using the Hashimoto method, impurities were observed in the final product made using the Akimasa method during the HPLC analysis.", "\nAlthough the conditions with acetophenone and diethylene glycol looked promising, there existed a problem related to the work-up. ", "Both histamine free base and the dihydrochloride salt are readily soluble in water, therefore, it was difficult to utilize any extraction technique to separate the product from the diethylene glycol solvent, which was usually removed by a water extraction. ", "Furthermore, the histamine dihydrochloride was also readily soluble in diethylene glycol, thus the direct isolation by filtration was also impossible.", "\nThe reaction conditions of Takano et al., ", "involving pentan-3-one were also recreated. (", "Heterocycles, 6:1167 (1977)). ", "The results from these experiments showed no improvement over the acetophenone conditions described above.", "\nA consistent source of pharmaceutical grade histamine is required, especially in view of the new-found pharmaceutical applications for histamine. ", "The standard methods used by the art wherein histamine is purified from natural sources, fail to yield histamine of a sufficiently high grade for pharmaceutical uses. ", "Moreover, the synthetic methods practiced in the art also fail to yield histamine of a sufficiently high grade. ", "Accordingly, there is a need in the art for an improved method by which to produce pharmaceutical grade histamine dihydrochloride.", "\nThe invention disclosed herein relates to the preparation of pharmaceutical grades of histamine dihydrochloride using a two step non-enzymatic synthetic method. ", "One embodiment of the invention is a method for the synthesis of histamine dihydrochloride comprising: decarboxylating a L-histidine containing solution, whereby a histamine containing solution is formed in the absence of a decarboxylating enzyme; forming a histamine monohydrochloride containing solution from the histamine containing solution; and forming a histamine dihydrochloride containing solution from the histamine monohydrochloride containing solution.", "\nOne aspect of this embodiment further comprises triturating the histamine containing solution, for example, the histamine containing solution can be triturated with a methylene chloride solution. ", "In another aspect of this embodiment, the histamine monohydrochloride containing solution is formed by addition of an effective amount of hydrochloric acid in an isopropanol solution. ", "For example, the effective amount of hydrochloric acid is about 0.1 to 0.9 molar equivalents of hydrochloric acid to histamine free base. ", "In another example, the effective amount of hydrochloric acid is about 0.6 molar equivalents of hydrochloric acid to histamine free base. ", "Still another aspect of this embodiment further comprises the step of isolating a pharmaceutical grade of histamine dihydrochloride from the histamine dihydrochloride containing solution.", "\nAnother embodiment of the invention disclosed herein is a method for synthesizing a pharmaceutical grade of histamine dihydrochloride comprising: decarboxylating a L-histidine containing solution, whereby a histamine containing solution is formed in the absence of a decarboxylating enzyme; forming a histamine monohydrochloride containing solution from the histamine containing solution; forming a histamine dihydrochloride containing solution from the histamine monohydrochloride containing solution; and isolating the histamine dihydrochloride from the histamine dihydrochloride containing solution.", "\nIn one aspect of this embodiment, the histamine dihydrochloride contains equal to or less than each of the following: 0.8% L-histidine HCl monohydrate, 0.1% individual chromatographic impurities, and 2% total impurities." ]

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[ "This invention relates generally to improvements in mechanical face seals of the type designed to prevent or minimize fluid leakage between assembled structural components, such as assembled housing components of a fluid flow control valve or fluid flow conduits or the like. ", "More particularly, this invention relates to an improved yet relatively simple face seal assembly adapted for economical production and reliable, reusable service in relatively high pressure environments of operation.", "\nMechanical face seals are well known in the art for use in preventing or minimizing fluid leakage between assembled mechanical structures, particularly such as assembled housing components of a fluid control or regulator valve or the like. ", "In one common form, face seals are defined by standard elastomer O-rings or other nonmetallic packing materials which are compressively retained between mechanical structures to prevent or limit undesired fluid leakage. ", "Such nonmetallic face seal devices are relatively economical and provide satisfactory sealing function throughout a relatively non-hostile range of operating conditions, such as operation at relatively low pressures, moderate temperature extremes, and/or exposure to non-corrosive fluids and the like. ", "However, in some environments of use, improved face seals of a more sophisticated design and/or engineered material are required to accommodate adverse operating conditions.", "\nMore specifically, a variety of improved and relatively complex face seals have been designed for specialized use in relatively high pressure, extreme temperature environments, or other adverse operating conditions. ", "Such specialized face seals commonly include one or more deflectable seal legs adapted for compression engagement with assembled structural components to prevent fluid leakage therebetween. ", "Face seal configurations of generally U-shaped, V-shaped and K-shaped geometries are known in the art. ", "To accommodate adverse operating conditions, such as relatively high pressures of several hundred to several thousand psi, such face seals are normally constructed from relatively hard metals which are coated with a seal film, typically such as a Teflon coating or a soft metal coating or the like. ", "However, such coatings are difficult to apply in precision thicknesses which may be necessary to conform with close tolerances, resulting in face seals which are relatively costly to manufacture. ", "Moreover, such coatings tend to deform and/or wear away during use, resulting in mandatory seal replacement whenever the related structures are disassembled, for example, for repair and maintenance purposes. ", "In some instances, the seal coating can encounter sufficient wear to result in seal failure and/or brinnelling damage of seal surfaces caused by direct contact of the hard metal seal with adjacent structural surfaces.", "\nThere exists, therefore, a significant need for improvements in mechanical face seals, particularly with respect to the provision of a relatively simple and economical face seal designed to prevent or minimize fluid leakage in high temperature or high pressure or other adverse operating environments. ", "Moreover, there exists a need for an improved face seal which can be reused following disassembly of associated housing structures. ", "The present invention fulfills these needs and provides further related advantages." ]

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[ "Gisdar Aga\n\nGisdar Aga or Albanes Gisdar (d. 1500) was an Ottoman commander of Albanian Epirote origin defending the Castle of St. George during the Siege of the Castle of Saint George on the island of Kefalonia against the Spanish and Venetians led by Benedetto Pesaro and Gonzalo Fernández de Córdoba in 1500. ", "Gisdar had 700 jannisaries under his command. ", "When he was required to surrender he allegedly responded “I return you thanks, Christians. ", "I return you thanks for being the cause of so much glory, as well as for apportioning us, whether alive or nobly slain, such a laurel meed for our fidelity to Bajazet our emperor. ", "Your menaces do not intimidate us, for destiny hath stamped upon the brow of each the term of his career. ", "Go, tell your general, that every one of my soldiers posesseth seven bows, and seven thousand arrows, with which we will at least avenge our fall, even though we fail to resist your power, or your better fortune\". ", "He was killed during the siege with 300 others.", "\n\nReferences \n\nCategory:People of the Ottoman Empire of Albanian descent\nCategory:15th-century Albanian people\nCategory:Ottoman military personnel killed in action" ]

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[ "Focal leptomeningeal metastasis following curative surgery for lung cancer: case report.", "\nA 58-year-old woman presented with 4 lesions of pulmonary adenocarcinoma which were curatively resected. ", "No adjuvant therapy was needed because the lesions were all in the early stage. ", "Magnetic resonance (MR) imaging of the brain, taken 10 months after the curative surgery, disclosed focal enhancement along the right central sulcus. ", "Cerebrospinal fluid examination was normal. ", "The lesion remained stable for 16 months, then began to spread out. ", "She underwent open biopsy and the histological diagnosis was leptomeningeal metastasis from adenocarcinoma. ", "She was treated with gefitinib at first because the lesion expressed epidermal growth factor receptor domain mutation. ", "However, the lesion continued to enlarge, so she underwent whole cranial irradiation which was not effective. ", "She died 2 years 10 months after the first detection of the metastasis. ", "Early histological diagnosis is important even though the MR imaging lesion is not likely to be metastasis after curative surgery of the primary lesions." ]

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[ "Chris Graythen/Getty Images\n\nWhen the New Orleans Saints put 41 points on Tampa Bay Sunday and kept the Buccaneers from scoring, it did more than just give a small taste of how good it’s been over recent years. ", "The Saints’ first shutout since a 12-0 win over the New York Jets in 1995 showed the football world that it couldn’t count New Orleans out for very long.", "\n\nHeck, it’s still mathematically possible for the Saints to make the playoffs. ", "It’s not a very good shot—in fact, Lloyd Christmas might have had better odds—but, I am telling you there’s a chance.", "\n\nThe first thing that has to happen is New Orleans has to win every game left on its schedule and finish the year 8-8. ", "Then, the Saints needs lots of help.", "\n\nThere are four teams—the Minnesota Vikings, the Chicago Bears, the Dallas Cowboys and the New York Giants—sitting at 8-6 that all have to lose both their remaining games to finish at 8-8.", "\n\nThe Saints also need the St. Louis Rams to lose once (twice would be fine, too) pushing their record to 7-8-1.", "\n\nThe Rams would then be out because they’d finish a half-game behind the Saints in the win column. ", "That’s the easy one to cross off the list.", "\n\nNow we have to find out how to whittle down five teams to one.", "\n\nThe first step is to narrow things down to three by picking only one of the two NFC East teams to stick around, and one of the two NFC North teams.", "\n\nThe Cowboys and the Giants split their season series, so on to the next step. ", "Since the Cowboys would have a 3-3 division record and the Giants a 2-4 record, New York is eliminated. ", "This is an important step because the Giants have the best conference record of the bunch. ", "But since only one team per division can be considered in a multi-team wild-card tiebreaker scenario, the Giants get axed first.", "\n\nThe Vikings and Bears also split this season. ", "But the Vikings are going to end up one game better in the division which means the Bears are forced out.", "\n\nThe next step in the tiebreaker scenario is head-to-head, but only if one or more teams has won or lost to every team still around. ", "Since that’s not applicable, we have to move on.", "\n\nThe third tiebreaker scenario is win-loss record within the conference. ", "Since the Saints and Vikings would be 6-6 and the Cowboys would be 5-7, Dallas would be eliminated. ", "Remember how good it was that the Giants got eliminated a few steps back. ", "Their conference record would have been 7-5 and they would have secured the final playoff spot here. ", "Since they’re already gone, that point is moot.", "\n\nNew Orleans and Minnesota are the only two teams left. ", "Since they did not face off head-to-head, we’ll move down the tiebreaker scenario checklist.", "\n\nThe next determining factor is win-loss record versus common opponents, using a minimum of four games. ", "Each team had four common opponents, but there are five games, since New Orleans played Tampa Bay twice and Minnesota played Green Bay twice.", "\n\nThe Saints’ record would be 2-3 in those five common games, and the Vikings’ record would be 1-4. ", "This is where New Orleans would slide into the No. ", "6 spot of the NFC playoffs.", "\n\nUnless otherwise noted, all quotes and statements were obtained firsthand.", "\n\nKnox Bardeen is the NFC South lead writer for Bleacher Report and the author of “100 Things Falcons Fans Should Know & Do Before they Die.” ", "Be sure to follow Knox on Twitter." ]

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[ "\n\nList of paradoxes - wqfeng\nhttp://en.wikipedia.org/wiki/List_of_paradoxes\n\n======\ndamian2000\nThe Blub Paradox is by far the most interesting ... ;-)\n<http://en.wikipedia.org/wiki/Blub_paradox#Blub>\n\n(its to do with programmers' views of other languages)\n\n" ]

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[ "Occupational exposures to respirable crystalline silica during hydraulic fracturing.", "\nThis report describes a previously uncharacterized occupational health hazard: work crew exposures to respirable crystalline silica during hydraulic fracturing. ", "Hydraulic fracturing involves high pressure injection of large volumes of water and sand, and smaller quantities of well treatment chemicals, into a gas or oil well to fracture shale or other rock formations, allowing more efficient recovery of hydrocarbons from a petroleum-bearing reservoir. ", "Crystalline silica (\"frac sand\") is commonly used as a proppant to hold open cracks and fissures created by hydraulic pressure. ", "Each stage of the process requires hundreds of thousands of pounds of quartz-containing sand; millions of pounds may be needed for all zones of a well. ", "Mechanical handling of frac sand creates respirable crystalline silica dust, a potential exposure hazard for workers. ", "Researchers at the National Institute for Occupational Safety and Health collected 111 personal breathing zone samples at 11 sites in five states to evaluate worker exposures to respirable crystalline silica during hydraulic fracturing. ", "At each of the 11 sites, full-shift samples exceeded occupational health criteria (e.g., the Occupational Safety and Health Administration calculated permissible exposure limit, the NIOSH recommended exposure limit, or the ACGIH threshold limit value), in some cases, by 10 or more times the occupational health criteria. ", "Based on these evaluations, an occupational health hazard was determined to exist for workplace exposures to crystalline silica. ", "Seven points of dust generation were identified, including sand handling machinery and dust generated from the work site itself. ", "Recommendations to control exposures include product substitution (when feasible), engineering controls or modifications to sand handling machinery, administrative controls, and use of personal protective equipment. ", "To our knowledge, this represents the first systematic study of work crew exposures to crystalline silica during hydraulic fracturing. ", "Companies that conduct hydraulic fracturing using silica sand should evaluate their operations to determine the potential for worker exposure to respirable crystalline silica and implement controls as necessary to protect workers." ]

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[ "Q:\n\nCross-database foreign keys vs. database design best practice\n\nMySQL allows to create cross-database foreign keys - but is it a good method of ensuring data integrity? ", "Is it possible to give a general answer or is it project-dependent? ", "What are the advantages and what threat does it pose?", "\nLet's say there are two databases, A and B, that in general store different information for different purposes and with different means of uploading data, however some part of the data may appear in both databases. ", "Now let's assume that one wants to make sure that everything out of this small intersection that ends up in B has been previously uploaded to A. Is a foreign key a good idea in this case?", "\n\nA:\n\nMySQL allows to create cross-database foreign keys - but is it a good method of ensuring data integrity? ", "Is it possible to give a general answer or is it project-dependent? ", "What are the advantages and what threat does it pose?", "\n\nMySQL doesn't really have a concept of \"database\". ", "This is because MySQL \"evolved\" confusing \"database\" for \"schema\" and never really fixed it. ", "If you're talking to a real DBA, this is not a cross-database foreign key. ", "So for MySQL, this is perfectly fine and acceptable.", "\nEven in version 8.0 of MySQL,\n\nCREATE SCHEMA is a synonym for CREATE DATABASE.", "\n\nIn PostgreSQL, for instance, we have \"schema\" and \"databases\". ", "And cross-schema foreign keys are perfectly fine, but you can't do cross-database fkeys.", "\npsql (9.6.3, server 9.5.6)\nYou are now connected to database \"foobar\" as user \"ecarroll\".", "\nfoobar=# CREATE TABLE foo ( id int primary key );\nCREATE TABLE\nfoobar=# INSERT INTO foo SELECT * FROM generate_series(1,10);\nINSERT 0 10\nfoobar=# \\connect test;\npsql (9.6.3, server 9.5.6)\nYou are now connected to database \"test\" as user \"ecarroll\".", "\ntest=# CREATE TABLE foo ( id int references foobar.foo.id, name text );\nERROR: cross-database references are not implemented: \"foobar.foo.id\"\n\nThat's what a cross-db fkey would look like. ", "Notice it would require explicit schema specification and I'm not aware of any database that implements schema's and databases that permits it.", "\nThe downside of the MySQL confusing databases and foreign keys is pretty clear. ", "If you have full access to a single specific database, you do not have the ability to organize your own content. ", "Whereas in PostgreSQL, if you full access to a single database you can create any amount of arbitrary schemas. ", "You don't need SUPER USER nor the ability to CREATE DATABASE\n\n" ]

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[ "Screw Compressors for Dual-fuel LNG Carrier\n\nKobe Steel, Ltd. said it has received an order to supply the first two screw compressors for use with marine dual fuel engines.", "\n\nThe compressors will be installed in an LNG carrier to be owned by a 50/50 joint venture between Mitsui O.S.K. Lines Co., Ltd. (or MOL) and Itochu Corporation for Uniper Global Commodities SE, a subsidiary of Uniper SE, Europe’s one of largest power and gas companies. ", "Uniper Global Commodities will charter the new carrier for 20 years. ", "Plans call for Kobe Steel to deliver the compressors in August 2017 to South Korea’s Daewoo Shipbuilding & Marine Engineering Co., Ltd., which is constructing the vessel.", "\n\nThe market size of nonstandard compressors for marine dual fuel engines is forecast to total over 20 billion yen for the coming five years, according to Kobe Steel. ", "Kobe Steel aims to gain over 50 percent of the market by 2020.", "\n\nNonstandard compressors for marine dual fuel engines are generally used to compress vaporized LNG, namely boil-off gas (BOG), which is then sent to the engines. ", "To date, marine dual fuel engines have been of the middle speed, four-stroke type and driven predominantly by low gas pressure, and the compressors for these engines have only been centrifugal compressors, which excel at low-pressure compression.", "\n\nHowever, in recent years due to the need to save energy in ship operation and comply with stricter environmental regulations, dual fuel, low speed, two stroke engines that offer high efficiency with a 10-percent improvement in fuel consumption have entered the market. ", "In the future, this type of engine will become the mainstream as its adoption is being considered for nearly all new vessels.", "\n\nAs marine dual fuel, low speed, two-stroke engines require relatively high gas pressure, centrifugal compressors are less efficient. ", "These engines need to have their fuel gas (FG) pressure controlled within the allowable level of the load percentage of the engines. ", "Screw compressors are highly suitable for these engines as they can keep pace with load fluctuations and operate most efficiently in the medium- to high-pressure range. ", "Owing to this feature, screw compressors have been adopted for use with marine dual fuel engines for the first time.", "\n\nKobe Steel has received an additional order for one reciprocating compressor for BOG reliquefaction, which will be installed in the same vessel.", "\n\nMore than 100 LNG carriers have been constructed in the three years from 2013 to 2015. ", "Although the shipbuilding boom has settled slightly due to the fall in raw material prices and the downturn in the world economy, demand remains high for LNG and the market for this clean fuel is expected to grow in the future." ]

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[ "51918 Emerald\n\nProduct Type\n\nProduct Line\n\nColor/Look\n\nInformation\n\nArmstrong's most popular tile visual. ", "Imperial Series has been proven in tens of thousands of commercial applications oover the past years. ", "The key to Imperial Series popularity is unbeatable quality and performance at an economical price.", "We've refreshed the visual and the colours over the years to keep current with design trends,but still have the tried and tested true colors and patterns that have made Imperial Series the standard of VCT industry.", "\n\nColor and design are \"through-pattern\" to last the lifetime of the floor.", "\n\nEasy installation and low installed price with excellent durability.", "\n\nSuperior edging and squareness offers near seamless visual.", "\n\nAvailable in three gauges to meet a range of performance and budget needs." ]

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[ "NMR solution structure of viscotoxin C1 from Viscum album species Coloratum ohwi: toward a structure-function analysis of viscotoxins.", "\nThe high resolution three-dimensional structure of the newly discovered plant viscotoxin C1, from the Asiatic Viscum album ssp. ", "Coloratum ohwi, has been determined in solution by (1)H NMR spectroscopy at pH 3.6 and 285 K. The viscotoxin C1-fold, consisting of a helix-turn-helix motif and a short stretch of an antiparralel beta-sheet is very similar to that found for the highly similar viscotoxins A2 and A3 and for other related thionins. ", "Different functional properties of members of the thionin family are discussed here in light of the structural and electrostatic properties. ", "Among the very homologous family of alpha- and beta-thionins, known for their antimicrobial activity, the viscotoxin subfamily differs from the other members because of its high toxicity against tumoral cells. ", "Key residues for the modulation of viscotoxin cytotoxicity have been identified on the basis of sequence and structural alignment." ]

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[ "Q:\n\nBuilding a linear Power supply\n\nBeing a poor student and a hobbyist, I've decided to build a power supply. ", "For simplicity's sake, I've chosen a linear supply, build around 2 variable independent channels with 3 commonly used taps - 3.3, 5 and 12 volts. ", "The taps are fairly straight forward, but I want to implement current limiting on my 2 independent channels. ", "While scrolling through the datasheet for the LM317, I noticed they had exactly what I needed.", "\nhttp://www.ti.com/lit/ds/symlink/lm117.pdf - The circuit is on page 21. ", "\nThe MJ4502 transistor is seriously outdated and thus, expensive. (", "~5\n on ebay, e/a!) ", "I understand I want to pick something with similar\n specs, but am coming up empty. ", "The closest I've found so far is the\n TIP147, which is rated for around half the current (10A continuous).", "\n I could parallel them with ballast resistors, but the only problem\n is they're darlington, where as I need a single transistor.", "\nOr I could use a MOSFET. ", "I only know the absolute basics of getting\n them to work for me, but I'd love to use one - an IRF3205, 10 for $2?", "\n that would be a dream budget-wise.", "\nAm I better of paying extra for the originally spec'd part, or should I go with a MOSFET or substitute transistor?", "\nThanks for the help.", "\n\nA:\n\nThe NTE180 appears to be very similar to the MJ4502.", "\nWhether these can be found cheap enough is another matter.", "\nBut, you can probably use a much lower spec transistor for the circuit in question: -\n\nIf you use Farnell, mouser or digikey's search engines and look for a PNP transistor that has a minimum voltage rating of (say) 60 volts (100V for MJ4503), a current of (say) 10 amps (MJE4502 is 30 A) and an Ft greater than 2 MHz, then pretty much all PNPs you find are going to be suitable.", "\nCome back when you find one.", "\n\n" ]

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[ "Flynas expand their frequencies between Abu Dhabi and Saudi Arabia\n\nThe Saudi-based national airline, flynas, is increasing capacity between their home country and the UAE with new flights linking Abu Dhabi with Riyadh and Jeddah.", "\n\nEffective on 23 June, flynas will add a second\ndaily service between Riyadh and Abu Dhabi, increasing its combined offer with\nEtihad Airways to four daily services. ", "Also on 23 June, flynas will enter the\nJeddah – Abu Dhabi market with a daily flight which will complement Etihad\nAirways’ existing thrice daily services. ", "Together, both carriers will offer\nfour daily services linking Jeddah and the capital of the UAE.", "\n\nThese services will provide guests with\ngreater choice and flexibility when travelling between the two countries and\nbeyond over Etihad Airways’ worldwide network.", "\n\nIn addition to Riyadh and Jeddah, Etihad\nAirways currently serves Dammam and Madinah, offering a total of 63 weekly flights\nto the Kingdom of Saudi Arabia. ", "Whilst flynas new services will offer 14 weekly\nflights from Riyadh to Abu Dhabi and seven weekly flights from Jeddah to Abu\nDhabi.", "\n\nThe additional flights from flynas will be\noperated by a two-class Airbus A320 aircraft, offering an additional 3,416 seats\nper week, and ensuring maximum connectivity through Etihad Airways’ Abu Dhabi\nhub to key destinations in North America, Europe, the Indian Subcontinent, and\nSoutheast Asia.", "\n\nThis comes as part of an expanded codeshare\nagreement between the two airlines signed in October 2012. ", "The codeshare agreement\nallows flynas to place its ‘XY’ code on multiple Etihad Airways’ flights between\nAbu Dhabi and 20 destinations on its global network.", "\n\n“The new flynas\nservices will offer business and leisure travellers greater choice and better\nflight connection in their travel to Riyadh, Jeddah and Abu Dhabi to Etihad\nAirways’ worldwide network.”", "\n\nBander Al Mohanna, CEO of\nNAS Holding, said. “", "Since its launch in\nDecember 2015, we have seen a significant increase in traffic on our daily\nRiyadh to Abu Dhabi route, owing to the strong demand for travel between the\ntwo capitals.", "\n\n“By\ndoubling the frequency of flights between these two strategically important\ndestinations, we are pleased to offer our guests increased flexibility, more\nchoice and greater convenience.", "\n\n“The\nlaunch of the additional flights is also a true testament to the success of our\ncodeshare partnership with the UAE’s national airline, Etihad Airways, with\nwhom we look forward to continue expanding our services in the future, most\nimmediately with the introduction of daily flights between Jeddah and Abu Dhabi\nfrom 23 June, which will further widen the choice available to guests traveling\nin both directions for business or leisure.”", "\n\nFlynas Riyadh, Jeddah and Abu Dhabi schedule effective\n23 June 2016 - all times local" ]

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[ "Gaya Map and plan route and access road Kano-State\n\nSelect Map or Satellite\nof Gaya\nin the región or District Kano-State in the plane\nMove the map with your mouse from your computer\nSee photos and landscapes of Gaya Join the Gaya group G+ 1\nWith the arrows at the top left corner, you can use the mouse to zoom the Gaya map plane. ", "Also with the mouse can drag the map to search areas and parts of the Gaya environment.", "\nIf you click on the top right of the satellite map, you can see the street names with images.", "\nIn some countries and cities, if the puppet on the left is in yellow, dump the doll with the mouse to the area searched and you can view photos and watch the city, landscapes, monuments and people men and women as if in person live on street Gaya\n\n&Copy; Viewphotos.org | 2018 | World Images |Gaya Contacto: flmartinro(arroba)gmail.com Condiciones de uso - Aviso Legal - Fotos wikipedia -\nSee Photos, pictures and images of the environment Gaya en Kano-State Kano State. ", "Photographs are uploaded to Panoramio.com for tourists on their trips to these places reflect their history, customs of the people with pictures of monuments, landscapes, men girls and women. ", "You'll also find the number of inhabitants and the flat coordinates map to get to that population. ", "Pics of Gaya . ", "The most beautiful photos and pictures of old from all countries and cities. ", "Earth Google map de Gaya Panoramic view street view.--- Viewphotos.org is not sponsored by or affiliated with Google. ", "Gaya Maps and routes." ]

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[ "Q:\n\nC++ Ubuntu not releasing lock on lock file when terminated\n\nI have a C++ script, which checks whether any action has to be done and if so it starts the right processor C++ script. ", "However, since it runs every x minutes it also checks whether the processor isn't still running using lock files.", "\nI use the following function to acquire the lock:\nint LockFile(string FileNameToLock) {\n FileNameToLock += \".lock\";\n int fd = open(FileNameToLock.c_str(), O_RDWR | O_CREAT, 0666);\n int rc = flock(fd, LOCK_EX | LOCK_NB);\n if (rc || rc == -1) {\n cout << errno << endl;\n cout << strerror(errno) << endl;\n return -1;\n }\n return fd;\n }\n\nThe code that is being executed:\n[...]\nif (LockFile(ExecuteFileName, Extra) == -1) {\n cout << \"Already running!\" ", "<< endl; //MAIN IS ALREADY RUNNING\n //RETURNS ME Resource temporarily unavailable when processor is running from an earlier run\n exit(EXIT_SUCCESS);\n }\nif (StartProcessor) { //PSEUDO\n int LockFileProcessor = LockFile(\"Processor\");\n if (LockFileProcessor !", "= -1) {\n string Command = \"nohup setsid ./Processor\"; //NOHUP CREATES ZOMBIE?", "\n Command += IntToString(result->getInt(\"Klantnummer\"));\n Command += \" > /dev/null 2>&1 &\"; //DISCARD OUTPUT\n system(Command.c_str());\n //STARTS PROCESSOR (AS ZOMBIE?)", "\n }\n }\n\nThe first run works well, however when the main script runs again, the lock file returns -1, which means an error occurred (only when the processor is still running). ", "The errno is 11 which results in the error message: Resource temporarily unavailable. ", "Note that this only happens when the (zombie) processor is still running. (", "However, the main script has already terminated, which should close the file handle?)", "\nFor some reason, the zombie keeps the file handle to the lock file of the main script open???", "\nI have no idea where to look for this problem.", "\nSOLVED:\nsee my answer\n\nA:\n\nI solved this issue, since the system and fork commands seem to pass on the flock, by saving the command to execute in a vector. ", "Unlock the lock file right before looping the Commands vector and execute each command. ", "This leaves the main with a very tiny gap of running while not locked, but for now it seems to work great. ", "This also supports ungraceful terminations.", "\n[...]\nif (LockFile(ExecuteFileName, Extra) == -1) {\n cout << \"Already running!\" ", "<< endl; //MAIN IS ALREADY RUNNING\n //RETURNS ME Resource temporarily unavailable when processor is running from an earlier run\n exit(EXIT_SUCCESS);\n }\nvector<string> Commands;\nif (StartProcessor) { //PSEUDO\n int LockFileProcessor = LockFile(\"Processor\");\n if (LockFileProcessor !", "= -1) {\n string Command = \"nohup setsid ./Processor\"; //NOHUP CREATES ZOMBIE\n Command += IntToString(result->getInt(\"Klantnummer\"));\n Command += \" > /dev/null 2>&1 &\"; //DISCARD OUTPUT\n Commands.push_back(Command);\n }\n }\n//UNLOCK MAIN\nif (UnlockFile(LockFileMain)) {\n for(auto const& Command: Commands) {\n system(Command.c_str());\n }\n }\n\n" ]

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[ "Keeping An Office Clean\n\nBusy Bee: How To Keep An Office Clean\n\nUnfortunately, with today’s busy schedules, keeping one’s home and vehicle clean and tidy is becoming more and more difficult. ", "This is true even more so when it comes to an office or workspace, where papers, files, and other pieces of equipment can rapidly accumulate. ", "Individuals who are serious about keeping a clean office are often encouraged to understand its importance, develop a paper management system, limit pictures, and organize books. ", "Finally, individuals who attempt these techniques and still experience difficulty with keeping a clean office may want to consider hiring an office cleaning service. ", "Individuals who are considering hiring office cleaners should remember that depending on the particular region or country, an office building cleaning service can vary quite dramatically in price.", "\n\nUnderstand the Importance of Maintaining a Clean Office\n\nUnderstanding the importance of maintaining a clean office is essential for both new and experienced business men and women. ", "Keeping an office clean can not only be an effective way to save time, but can portray an image of professionalism to potential clients. ", "For individuals with multiple offices, cleaning can seem especially intimidating. ", "As described above, those who are new to the process may want to consider hiring an office building cleaning service.", "\n\nDevelop a Paper Management System\n\nThe task of office cleaning is an unpopular task for many busy employees. ", "Unfortunately, by the time that the need for a good office cleaning is recognized, the mess has become so large that it is almost unmanageable. ", "One of the easiest ways to prevent stress and decrease hours of work when it comes to office cleaning is to implement an effective paper management system. ", "In general, a good paper management system features an inbox, which contains items that have not yet been reviewed, a current projects rack, which holds items that are currently “in the works,” and an incubation box, which may feature items that are “on hold.” ", "Individuals who are serious about office building cleaning may also want to include a filing cabinet, dump boxes, and a variety of other materials. ", "While an effective a paper management system may take time to develop, it is essential when it comes to the process of streamlining office building cleaning.", "\n\nLimit Pictures\n\nTo ensure a clean office, pictures should also be kept in check. ", "In most cases, this is one of the most unpopular parts of office building cleaning, as many individuals will be unwilling to part with photos of family and/or friends. ", "According to some researchers, however, more than three or four photos on ones’ desk can prove to be a distraction. ", "To enhance offices cleaning, workers should remove all unnecessary pictures, paintings, or photos. ", "These items can be instead put in a place of prominence at home.", "\n\nOrganize Books\n\nAn important part of cleaning office buildings involves the organization of text and reference books. ", "Depending on the particular industry, these books may become outdated—and therefore useless—in a relatively short period of time. ", "When cleaning office buildings, employees should be sure to evaluate the usefulness of books on a regular basis. ", "Those that have not been used within the last year may be eligible for donation or disposal. ", "While this task may be an unpopular part of cleaning office buildings, it is essential to ensure optimal results.", "\n\nHire an Office Cleaning Service\n\nFinally, individuals who simply do not have enough hours in the day to maintain a clean office may want to consider hiring an office cleaning service. ", "Office cleaning services can often be hired on a daily, weekly, or monthly basis, and may charge by the hour, day, or work on a salaried basis. ", "Individuals who are interested in hiring office cleaning services may want to speak with colleagues in the field to obtain references or recommendations. ", "Busy business men or women may also be able to hire office cleaning services based on Internet referral systems and message boards. ", "When hiring for multiple offices, cleaning services may be able to offer a group or reduced rate.", "\n\nIn some cases, smaller businesses or organizations may not be able to afford an office building cleaning service. ", "For these businesses, the job of office cleaner may need to be assigned to a particular employee, volunteer, or intern. ", "While the position of office cleaner may not be a popular one, it should still be treated with respect. ", "The assigned office cleaner should still be allowed an adequate amount of time to perform his or her other tasks. ", "Employers may also want to recognize assigned office cleaners at the end of the year with a special gift or bonus.", "\n\nTo ensure optimal results when it comes to hiring cleaning services, office managers may want to evaluate their effectiveness from time to time. ", "Employees within the cleaning services, office managers, and other leaders within the organization should set expectations and ensure they are being met. ", "In the event that assigned tasks are not being completed, cleaning services office contracts may need to be terminated. ", "Office cleaners should always be provided with an appropriate explanation for the termination, to ensure all legal requirements have been met.", "\n\nDispose of Food Storage Containers\n\nThe regular disposal of food storage containers should be a no-brainer for business men and women of all levels. ", "Fast food or ziplock bags, plastic utensils, and storage containers are not only unsightly, but in many cases can be unsanitary. ", "Unfortunately, in some cases, especially busy workers may not have time to perform this task themselves—and instead, it often becomes a responsibility of office cleaners. ", "For optimal results, employers should always remember to treat office cleaners with respect and dignity." ]

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[ "UPDATE:Our latest information still indicates that Toledo Supplier Park (TSP) will shut down in April 2018 to retool for the 2020 JT Scrambler Pickup (See also: JL/JT Toledo plant schedule).", "\n\nIn the FCA 2017 first quarter results conference call held on Wednesday, April 26, 2017, FCA chief Sergio Marchionne reiterated that in the “first half of 2018” the company would be “decommissioning the old Wrangler and begin work on the introduction of the pickup truck which is coming up next.”", "\n\nWe expect that the plant will be shut down for an estimated 6 months and begin production in late 2018 (as early as October).", "\n\nAs the JT truck has been officially approved by FCA management, the production timing has shifted back so that the truck is now a 2020 model year vehicle. ", "According to sources, the 3.0-liter diesel which is scheduled for the JT and JL Wrangler will be built starting in late 2019 which should coincide with the pickup truck’s debut.", "\n\nRegarding the timing for the pickup, Manley said at the recent Jeep Compass press event: “The key thing for me is to make sure the new Wrangler is fully up and running.” ", "The new (JL) Wrangler begins production this November, so there will be approximately 2 years between the start of production for the JL Wrangler and the JT pickup.", "\n\nThis delay may affect the retooling schedule for Toledo South as that’s where the JT pickup will be produced. ", "The plant currently builds the JK Wrangler and is scheduled to do so until March 2018.", "\n\nManley also said last week he expects the bulk of sales for the Wrangler pickup to be in North America and the Middle East." ]

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[ "---\nabstract: 'We study resonant tunneling through a single-level quantum dot in the presence of strong Coulomb repulsion beyond the perturbative regime. ", "The level is either spin-degenerate or can be split by a magnetic field. ", "We, furthermore, discuss the influence of a bosonic environment. ", "Using a real-time diagrammatic formulation we calculate transition rates, the spectral density and the nonlinear $I-V$ characteristic. ", "The spectral density shows a multiplet of Kondo peaks split by the transport voltage and the boson frequencies, and shifted by the magnetic field. ", "This leads to zero-bias anomalies in the differential conductance, which agree well with recent experimental results for the electron transport through single-charge traps. ", "Furthermore, we predict that the sign of the zero-bias anomaly depends on the level position relative to the Fermi level of the leads.'", "\naddress: |\n $^1$ Institut für Theoretische Festkörperphysik, Universität Karlsruhe, 76128 Karlsruhe, Germany\\\n $^2$ Department of Technical Physics, Helsinki University of Technology, 02150 Espoo, Finland\nauthor:\n- 'Jürgen König$^1$, Jörg Schmid$^1$, Herbert Schoeller$^1$, and Gerd Schön$^{1,2}$'\ntitle: 'Resonant tunneling through ultrasmall quantum dots: zero-bias anomalies, magnetic field dependence, and boson-assisted transport'\n---\n\npsfig\n\nIntroduction\n============\n\nThe experimental study of tunneling through zero-dimensional states in quantum dots with high charging energies has received recently considerable interest [@Kou-rev; @Gol-Cun; @Gue-etal; @Joh-etal; @Fox-etal; @Weiss; @Ral-Bla-Tin]. ", "Theoretical studies cover the classical regime (high temperatures) [@Ave-Kor-Lik; @Bee; @Wei; @Bru-HS; @Gla-Mat] as well as the quantum-mechanical regime (low temperatures) [@Her-Dav-Wil; @Mei-Win-Lee; @Koe-HS-Sch2; @Gro1; @Ng-Lee; @Gla-Rai; @Kaw; @Ng1; @YMF; @Het-HS; @Bru-Faz-HS]. ", "In the latter case, Coulomb blockade and resonant-tunneling phenomena together with nonequilibrium generalizations of the Kondo effect are expected to occur. ", "This leads to zero-bias anomalies in the differential conductance, which recently have been observed by Ralph & Buhrman [@Ral-Buh1]. ", "In this article, we present a new real-time diagrammatic approach to describe resonant tunneling at low temperatures and compare our results to the latter experiment.", "\n\nThe experiments for Coulomb blockade phenomena in zero-dimensional systems are usually performed in double-barrier resonant-tunneling structures [@Gol-Cun; @Gue-etal], split-gate quantum-dot devices [@Joh-etal; @Fox-etal; @Weiss], quantum point-contacts with single-charge trap states [@Ral-Buh1] and quite recently also in ultrasmall metallic tunnel junctions [@Ral-Bla-Tin] with Al particles of diameter below $10nm$. In the latter experiment, the level spacing is of order $0.5meV$ which is comparable to the Coulomb charging energy in usual quantum dots. ", "Therefore, the quantum dot is described by the nonequilibrium Anderson model where the energy level $\\epsilon_\\sigma$ (with spin label $\\sigma$) is coupled via tunneling barriers to two electron reservoirs with different electrochemical potentials $\\mu_L$ and $\\mu_R$. The charging energy is described by a strong on-site Coulomb repulsion $U$ which suppresses double occupancy of the dot level. ", "In equilibrium, it is well known from the theory of strongly correlated fermions [@Bic] that the spectral density of the dot can exhibit a Kondo resonance at the Fermi level. ", "It occurs for a low lying level $\\epsilon_\\sigma -\\mu_{L,R} < -\\Gamma$ and weak Zeeman splitting $|\\epsilon_\\sigma-\\epsilon_{\\bar{\\sigma}}| < \\Gamma$, where $\\Gamma/2$ is the level width in the noninteracting case, and provided that temperature is lower than the Kondo temperature [@Bic; @Hal] $T_K=1/2(U\\Gamma)^{1/2}\\exp{[\\pi\\epsilon (\\epsilon+U)/(\\Gamma U)]}$. Since the weight of the equilibrium spectral density at the Fermi level is proportional to the linear conductance, an enhancement of the latter due to Kondo-assisted tunneling was predicted [@Ng-Lee; @Gla-Rai]. ", "Typical values for quantum dots are $U\\sim 1meV$ and $\\Gamma\\sim 50\\mu eV$ which, for $\\epsilon\\sim -\\Gamma$, yield a Kondo temperature of the order $T_K\\sim 50mK$. Due to heating effects such temperatures are still hard to realize in realistic dots. ", "A more pronounced feature was found for the nonlinear conductance which shows a zero-bias maximum even for temperatures above the Kondo temperature [@Her-Dav-Wil; @Mei-Win-Lee]. ", "At zero magnetic field the spectral density of each spin channel exhibits a Kondo resonance at each of the chemical potentials. ", "An applied magnetic field causes the Kondo peaks to shift from the chemical potential by the Zeeman energy, in opposite directions for the different spin channels. ", "As a consequence, Kondo-assisted tunneling can only occur if the bias voltage exceeds the Zeeman energy. ", "Therefore, the zero-bias anomaly is split by an applied magnetic field [@Mei-Win-Lee]. ", "These features have been observed experimentally by Ralph & Buhrman [@Ral-Buh1]. ", "They measured the differential conductance through single-charge traps in a metallic quantum point-contact. ", "Although this system does not allow a controlled variation of the level position, the appearance of a zero-bias maximum with a peak height varying logarithmically with temperature clearly demonstrates the mechanism of Kondo-assisted tunneling. ", "However, the detailed comparison of the line shape in the experiment and the existing theory showed significant deviations.", "\n\nIn this paper, we will describe a new approach to calculate nonequilibrium properties of strongly correlated mesoscopic systems coupled to fermionic or bosonic baths via particle and energy exchange. ", "It consists in a real-time diagrammatic approach closely related to path-integral methods formulated in connection with dissipation [@Fey-Ver; @Leg-etal; @Wei-Buch] or tunneling in metallic junctions [@Eck-Sch-Amb; @Sch-Zai; @Sch-Uebersicht]. ", "One of the difficulties of the present problem lies in the fact that we have to account for the Coulomb interaction in a nonperturbative way. ", "Therefore, the standard many-body diagrammatic approaches are not sufficient (since Wick’s theorem cannot be applied naively). ", "We circumvent the problem by keeping track explicitly of the time evolution of the density matrix of the dot and tracing out only the bath degrees of freedom, which are assumed to be in equilibrium. ", "The final diagrammatic language is set up by an expansion in the coupling to the fermionic reservoirs whereas the strong correlations on the local system are exactly taken into account. ", "The basic step is the calculation of transition and current rates between different states of the dot. ", "We present an exact expression for these rates as the sum over all irreducible diagrams. ", "The transition rate is used to set up a formally exact Master equation from which the time-dependent probability distribution for the dot can be calculated. ", "The current rate is generally not identical to the transition rate since it contains also the number of particles transferred to the reservoir where the current is calculated. ", "This number can take arbitrary values if one considers all higher order processes. ", "The occupation probabilities multiplied with the current rates are used to calculate the current flowing through the system. ", "In earlier publications, we have presented this technique in connection with tunneling through a metallic island with a continuum of states [@HS-Sch] and demonstrated the equivalence to path-integral methods [@Koe-HS-Sch1]. ", "There we used an approximation for the rate to sum up “inelastic resonant tunneling” processes to arbitrary order where different electrons tunnel coherently back and forth between the island and the reservoirs. ", "Here, we apply an equivalent approximation to describe resonant tunneling between metallic leads through an ultrasmall quantum dot with a single level. ", "An important advantage of our approach is that we can solve the noninteracting limit exactly and can control systematically if this limit is contained within a given approximation for the correlated case. ", "The theory is current conserving and can be used for the calculation of correlation functions or Green’s functions as well.", "\n\nFor the case where the dot level is $M$-fold degenerate we recover for $M\\ge 2$ and a low lying dot level a Kondo peak in the spectral function. ", "An applied transport voltage leads to a splitting of the Kondo peak (at $\\mu_\\alpha$ where $\\alpha$ denotes the lead), which results in a zero-bias anomaly in the differential conductance, such that the conductance has a maximum at $V=0$. On the other hand, if the dot level lies above the Fermi levels of the leads $\\mu_\\alpha$ we predict [@Koe-HS-Sch2] a zero-bias anomaly in the conductance which has a minimum at $V=0$.\n\nSeveral extensions will be considered. ", "We study the case where the (spin-) degeneracy of the dot level is lifted, e.g., by an applied magnetic field. ", "In this case the Kondo peaks of both spin channels move apart from each other by the level spacing $\\epsilon_{\\sigma}-\\epsilon_{\\bar{\\sigma}}$, and Kondo-assisted tunneling sets in only at transport voltages $eV$ exceeding this splitting. ", "The calculated conductance agrees well with the experimental results of Ref.", " .", "\n\nWe, furthermore, account for inelastic interactions with bosonic modes coupled to the dot. ", "They describe applied time-dependent fields, interaction with phonons, or the fluctuations in the electrodynamic environment. ", "The investigation of this field has started only recently in connection with transport through interacting quantum dots. ", "The classical regime ($\\Gamma \\gg T$) has been analyzed for time-dependent fields [@Bru-HS] and bosonic environments [@Sta]. ", "Photon- and boson-assisted tunneling leads here to resonant side peaks in the Coulomb oscillations which can be used to analyze the complete excitation spectrum of the dot. ", "The results agree well with experiments [@Delft-Diplom]. ", "In the Kondo regime it has been found [@Het-HS] that time-dependent perturbations split the Kondo resonances which leads to satellite anomalies in the differential conductance and offers the possibility to realize pump effects which are purely based on the presence of Kondo resonances. ", "The linear AC-conductance has been analyzed in Ref.", " . ", "In this paper, we will investigate the influence of an external bosonic field on transport phenomena through ultrasmall quantum dots at low temperatures and small boson frequencies (compared to $\\Gamma$). ", "The emission and absorption of bosons causes additional Kondo singularities, for a one-mode field at $\\mu_\\alpha+n\\omega_B$, where $n=\\pm 1,\\pm 2,\\ldots$. Again, these resonances lead to corresponding anomalies in the differential conductance, which are inverted if the level position of the dot is moved through the Fermi energy.", "\n\nHamiltonian\n===========\n\nWe concentrate here on a dot containing only one energy level $\\epsilon_\\sigma^{(0)}$ with degeneracy $M$. In a magnetic field, due to the Zeeman energy the level position is spin dependent. ", "The dot is connected via high tunneling barriers to two large noninteracting reservoirs and coupled capacitively to an external gate voltage. ", "The model Hamiltonian of this “single-electron transistor” (see Fig.", " \\[Fig.transistor\\]) is $$H=H_0+H_T=H_D+\\sum_{\\alpha=L,R}H_{\\alpha}+H_T \\, .", "\n\\label{HH}$$ Here, $H_D$ is the Hamiltonian for the dot. ", "It includes the Coulomb interaction of the dot electrons, which is described within the capacitance model of a single-electron transistor by the capacitances $C_L$ and $C_R$ for the left and right tunnel junction and $C_G$ for the gate. ", "Furthermore, the dot electrons are coupled to bosonic modes $\\omega_q$ with electron-boson coupling $g_q$. Thus, $H_D$ reads $$H_D=\\sum_{\\sigma}\\epsilon_\\sigma^{(0)} n_{\\sigma}+\n E_C\\left( \\hat{N} - n_G \\right) ^2+\\sum_q \\omega_q d_q^\\dagger d_q\n +\\hat{N}\\sum_q g_q (d_q + d_q^\\dagger)\\;. ", "\n\\label{HDot}$$ (Throughout this work, we set $\\hbar=k=1$ and use the convention $e>0$.) The particle number on the dot with spin $\\sigma$ is $n_\\sigma=c^\\dagger_\\sigma c_\\sigma$, and $\\hat{N} =\\sum_{\\sigma} n_{\\sigma}$. The scale of the charging energy is provided by $E_C\\equiv e^2/ 2C$, where $C=C_L+C_R+C_G$ is the total capacitance of the system. ", "The transistor can be tuned by the gate voltage $V_G$ via $e n_G= C_LV_L+C_RV_R+C_GV_G$. We remark here, that $H$ is invariant under a global shift of all energies. ", "Therefore, we can always choose symmetric bias, $V_L=-V_R=V/2$.\n\nThe next term in Eq.", " (\\[HH\\]), $H_{\\alpha}=\\sum_{k\\sigma}\\epsilon_{k\\alpha}a^\\dagger_{k\\sigma\\alpha}\na_{k\\sigma\\alpha}$, describes the reservoir $\\alpha$ of noninteracting electrons in the leads. ", "Finally, the dot is coupled via tunnel barriers to the left and right lead. ", "This coupling is described by the tunnel Hamiltonian $$H_T=\\sum_{k\\sigma\\alpha}(T^\\alpha_{k} a^\\dagger_{k\\sigma\\alpha}\n c_\\sigma + h.c.).$$\n\nThe bosonic modes can represent interaction with phonons [@Win-Jac-Wil; @Gla-She; @Jon] or fluctuations of the electrodynamic environment [@Devoret-etal; @Odi-etal; @Flens-etal; @Ima-Pon-Ave] very similar to the Caldeira-Leggett model[@Cal-Leg]. ", "For our theory no assumption is needed for the specific kind of the modes $\\omega_q$ and the couplings $g_q$. In this way we are able to present a general result for the current which shows the influence of inelastic interactions for an arbitrary environment.", "\n\nThe capacitive model is equivalent to the Anderson Hamiltonian, which we obtain by defining the interaction $U_0=2E_C$ and shifting the level position $\\epsilon_\\sigma^{(0)}+2E_C- eV_G C_G/C -a_ceV/2 \\rightarrow \n\\epsilon^{(0)}_\\sigma(V,V_G)$. The asymmetry factor $a_c=(C_L-C_R)/C$ accounts for a different capacitive coupling of the left and right lead. ", "We see here, that the effective level position in the Anderson model depends on the gate voltage, as well as, due to $a_c$, on the transport voltage. ", "The dot is then described by $$H_D=\\sum_{\\sigma}\\epsilon_\\sigma^{(0)}(V,V_G) \\, n_{\\sigma}+\n U_0\\sum_{\\sigma < \\sigma'} n_\\sigma n_{\\sigma'}\n +\\sum_q \\omega_q d_q^\\dagger d_q\n +\\hat{N}\\sum_q g_q (d_q + d_q^\\dagger) \\; .$$\n\nAn unitary transformation [@Mah] with $V=\\exp(-i\\hat{N}\\varphi)$ and $\\varphi=i\\sum_q (g_q/\\omega_q)(d_q^\\dagger-d_q)$ yields $\\bar{H}=VHV^{-1}=\\bar{H}_0+\\bar{H}_T$, where $\\bar{H}_0=H_R+\\bar{H}_D$, $$\\label{dot}\n \\bar{H}_D=\\sum_{\\sigma}\\epsilon_{\\sigma}n_{\\sigma}\n +U\\sum_{\\sigma<\\sigma'}n_\\sigma n_{\\sigma'}+\\sum_q \\omega_q \n d^\\dagger_q d_q$$ and $$\\label{tunnel}\n \\bar{H}_T=\\sum_{k\\sigma\\alpha}(T^\\alpha_{k} \n a^\\dagger_{k\\sigma\\alpha}c_\\sigma e^{i\\varphi}+h.c.)\\, .$$ The electron-boson interaction renormalizes the level position and the Coulomb repulsion, $\\epsilon_{\\sigma}=\\epsilon_\\sigma^{(0)}-\\sum_q {g_q^2/\\omega_q}$ and $U=U_0-2\\sum_q{g_q^2/\\omega_q}$, and the tunneling term acquires phase factors $e^{\\pm i\\varphi}$.\n\nFor strong Coulomb repulsion $U$ we restrict ourselves to states with $N=0,1$. In lowest order perturbation theory the rates for tunneling in and out of the dot to reservoir $\\alpha$ are $$\\label{gamma}\n 2\\pi \\gamma_\\alpha^\\pm(E)=2 \\pi \\int dE' \\bar{\\gamma}^\\pm_\\alpha (E')\n P^\\pm (E-E') \\, ,$$ where $2\\pi \\bar{\\gamma}_\\alpha^\\pm(E)= \\Gamma_\\alpha(E)f^\\pm_\\alpha(E)$ is the classical rate without bosons, $\\Gamma_\\alpha (E)=2\\pi\\sum_k |T^\\alpha_k|^2 \\delta (E-\\epsilon_{k\\alpha})$, and $f_\\alpha^+(E)$ is the Fermi distribution of reservoir $\\alpha$ with electrochemical potential $\\mu_\\alpha$, while $f_\\alpha^-(E)=1-f^+_\\alpha (E)$. Finally, $$\\label{Ppm}\n P^\\pm (E)={1\\over 2\\pi}\\int dt \\, e^{iEt} <e^{i\\varphi (0)}\n e^{-i\\varphi (\\pm t)}>_0$$ describes the probability that an electron absorbs ($P^+$) or emits ($P^-$) the boson energy $E$.[@Devoret-etal; @Odi-etal; @Flens-etal] The expectation value is taken with the free boson Hamiltonian. ", "These probabilities satisfy the condition of detailed balance [@Ing-Naz] $$\\label{detailed balance}\n P^-(E) = P^+(-E) = e^{\\beta E} P^+(E)$$ The classical rates combined with a master equation are sufficient in the perturbative regime $\\Gamma = \\sum_{\\alpha} \\Gamma_{\\alpha} \\ll T$.[@Sta]\n\nIn order to go beyond the perturbative regime, we need a nonperturbative treatment of the tunneling, where quantum fluctuations yield finite life-time broadening and renormalization effects of the dot levels. ", "As an illustration we first assume that (for $B=0$) the broadening is given by the sum of the classical transition rates, Eq.", " (\\[gamma\\]). ", "Using Kramers-Kronig we deduce the renormalization and obtain for the self-energy $$\\label{sigma}\n \\sigma(E)=\\int dE' \\, {M \\gamma^+ (E')\n +\\gamma^-(E')\\over E-E'+i0^+}.$$ where $\\gamma^\\pm=\\sum_\\alpha\\gamma_\\alpha^\\pm$. The aim of the present letter is to test and extend this simple physical picture within a systematic and conserving theory for all Green’s functions and the current. ", "To achieve this we use a real-time technique developed in Ref.", "  which provides a natural generalization of the classical and cotunneling theory to the physics of resonant tunneling.", "\n\nDiagrammatic technique\n======================\n\nA quantum-statistical expectation value of an operator $A$ at time $t$ is given by $$\\langle A(t)\\rangle = \\mbox{tr}[\\rho_0 A(t)_{\\bar{H}}],$$ where $A(t)_{\\bar{H}}=\\exp [i\\bar{H}(t-t_0)] A\\exp [-i\\bar{H}(t-t_0)]$ is the operator in Heisenberg picture with respect to the initial time $t_0$. Permutation under the trace yields $\\langle A(t)\\rangle = \\mbox{tr}[\\rho(t)A]$ with $A$ in Schrödinger picture. ", "The density matrix $\\rho (t)$ evolves in time via $\\rho (t) = e^{-i\\bar{H}(t-t_0)}\\rho(t_0)e^{i\\bar{H}(t-t_0)}$. We assume that the initial density matrix $\\rho_0=\\rho (t_0)$ factorizes into parts for the dot electrons, the bosons, and the leads: $$\\rho_0=\\rho_0^D\\rho_0^B\\prod_{\\alpha}\\rho_0^{\\alpha}.$$ The leads are treated as large equilibrium reservoirs with fixed electrochemical potentials $\\mu_{\\alpha}=-eV_{\\alpha}$. Therefore, we describe the electrons in the leads by Fermi functions $f_{\\alpha}(E)$ and the density matrix reads $$\\rho^{\\alpha}_0={1\\over Z^{\\alpha}_0}\n \\exp \\left[- \\beta(H_{\\alpha}-\\mu_{\\alpha}{N_{\\alpha}}) \\right]$$ where $\\beta=1/T$ and $N_{\\alpha}=\\sum_{k\\sigma} a^{\\dagger}_{k\\sigma{\\alpha}}\na_{k\\sigma{\\alpha}}$ the number of electrons in the lead $\\alpha$. The normalization factor $Z^{\\alpha}_0$ is determined by $\\mbox{tr} \\, \\rho_0^{\\alpha}=1$. The boson part reads $$\\rho_0^B={1\\over Z^B_0} \\exp\n \\left[-\\beta_B \\sum_q \\omega_q d_q^{\\dagger}d_q\\right]\\, .$$ The temperature of the boson bath, $T_B=1/\\beta_B$, may differ in real experiments from the electron temperature $T$.\n\nFor the initial distribution of the dot we assume that it is diagonal in the many-body [*dot*]{} states, $|\\chi \\rangle$, which include the strong correlations within the quantum dot but are assumed to have fixed occupation numbers, $$\\rho^D_0=\\sum_{\\chi} P^0_{\\chi} |\\chi \\rangle \\langle \\chi | \\, ,$$ with $\\sum_{\\chi} P^0_{\\chi}=1$. We will see later, that in the stationary limit, i.e., when $t_0$ is shifted to minus infinity, all the physical quantities are independent of the choice of $P^0_{\\chi}$.\n\nIn the following, it is convenient to change to the interaction picture with respect to $\\bar{H}_0$. This implies $A(t)_{\\bar{H}}=\\tilde{T}\\exp \\left(-i\\int_t^{t_0} dt' \\, \n\\bar{H}_T(t')_I \\right) A(t)_I \\,T\\exp \\left( -i\\int_{t_0}^t dt' \\, \n\\bar{H}_T(t')_I \\right)$ in which $T$ is the time-ordering and $\\tilde{T}$ denotes the anti-time-ordering operator. ", "We write the integrals as one contour integral $\\int_K dt'\\ldots$ over the [*Keldysh contour*]{}. ", "It is parameterized by the “time” $t'$ which first runs forward from $t_0$ to $t$ and then backward from $t$ to $t_0$. In the diagrammatic language, the Keldysh contour is represented by horizontal lines running from the left to the right and then back to the left (see Fig.", " \\[fig1\\]). ", "We find $$\\label{general}\n \\langle A(t)\\rangle = \\mbox{tr} \\left[ \\rho_0 \\, T_K \\exp \\left(-\n i\\int_K dt' \\bar{H}_T(t')_I \\right) A(t)_I \\right].$$ Here, we have introduced the Keldysh time-ordering operator $T_K$, which orders all following operators along the Keldysh contour such that the one with the later “time” along the Keldysh contour appears at a more left position (without any sign change for an exchange of Fermi operators).", "\n\nIn the following we will encounter also higher order correlation functions of the type $\\langle T_K A_1(t_1)_I A_2(t_2)_I\\ldots A_n(t_n)_I \\rangle$. The final time $t$ of the Keldysh contour is then given by $\\mbox{max}\\{t_1, \\ldots , t_n\\}$.\n\nFor a diagrammatic description we expand the exponential with respect to the tunneling Hamiltonian and obtain $$\\label{expansion}\n \\displaystyle \\langle T_K \\prod_{i=1}^n A_i(t_i)\\rangle = \\mbox{tr} \\,\n \\left[ \\rho_0\n \\sum_{m=0}^{\\infty} (-i)^m\n \\int_Kdt_1'\\int_Kdt_2'\\ldots\\int_Kdt_m'\\,\n T_K \\left\\{ {\\bar{H}_T(t_1')}_I{\\bar{H}_T(t_2')}_I\\ldots\n {\\bar{H}_T(t_m')}_I \\prod_{i=1}^n A_i(t_i)_I \\right\\} \\right]\n \\atop \n \\scriptstyle t_1'\\, >\\, t_2'\\, >\\, \\ldots\\, >\\, t_m' \n \\qquad\\qquad\\qquad$$ in which the relation $t_1'>t_2'>\\ldots >t_m'$ has to be understood with respect to the Keldysh contour. ", "The time-ordering operator $T_K$ acts also on the operators $A_i(t_i)_I$ and puts them on the right place between the tunneling Hamiltonians.", "\n\nThe next task is to perform the trace of each term of the expansion. ", "We insert the tunnel Hamiltonian (\\[tunnel\\]) and notice that the Hamiltonian $\\bar{H}_0$ is bilinear in the lead electron operators. ", "For this reason, Wick’s theorem holds for these degrees of freedom, i.e., the lead electron operators are contracted in pairs. ", "This includes contractions between pairs of field operators from $\\bar{H}_T$ as well as contractions to lead electron operators which can be present in the operators $A_i$. These contractions are given by equilibrium distribution functions. ", "For the dot electrons, the situation is different. ", "The Coulomb interaction is expressed by a quartic term of dot electron operators. ", "Therefore, Wick’s theorem does not hold for this part of the system. ", "A product of dot electron operators can not be contracted into pairs, but has to be treated explicitly. ", "The trace over the bosonic part, however, poses no problem. ", "Each tunneling term contains an exponential $e^{\\pm i\\varphi}$ of the bosonic operators $\\varphi$. The trace over the product of such exponentials can be performed easily (see Eq.", " (\\[bosontrace\\])) provided that the operator $A$ also contains only such exponentials.", "\n\nThe rules\n---------\n\nWith regard to the applications discussed in section \\[master and probability\\] and \\[the current\\], we assume here that the operators $A_i$ (representing “external vertices”) depend on the lead and boson degrees of freedom only in the form $$\\label{special Ai}\n A_i = A_i\\left( \n \\sum_k T^\\alpha_k a_{k\\sigma\\alpha}^\\dagger c_\\sigma e^{i\\varphi}\n \\, , \\,\n \\sum_k {T^\\alpha_k}^* c^\\dagger_\\sigma a_{k\\sigma\\alpha} e^{-i\\varphi}\n \\, , \\,\n c_\\sigma e^{i\\varphi}\n \\, , \\,\n c^\\dagger_\\sigma e^{-i\\varphi}\\right)\\; .$$\n\nEach term of the expansion Eq.", " (\\[expansion\\]) is visualized by a diagram (see Fig.", " \\[fig1\\]). ", "There is a forward and a backward propagator symbolized by the upper and lower horizontal line, running from $t_0$ to $t$ and back from $t$ to $t_0$, respectively. ", "Along this time path, we arrange internal and external vertices according to their time-ordering. ", "The internal vertices emerge from the insertion of the tunneling Hamiltonian (\\[tunnel\\]) into the expansion (\\[expansion\\]). ", "Each of them corresponds to a product of a lead and a dot electron operator and a phase factor $e^{\\pm i \\varphi}$. After integrating out the lead degrees of freedom, all vertices (either internal or external) containing a lead electron operator are connected in pairs by directed tunneling lines (dashed lines) $\\bar{\\gamma}_{\\alpha}^K(t,t')$ from $t'$ to $t$, with $\\bar{\\gamma}_{\\alpha}^K(t,t')=\\bar{\\gamma}_{\\alpha}^+(t-t')$ for $t<t'$ and $\\bar{\\gamma}_{\\alpha}^K(t,t')=\\bar{\\gamma}_{\\alpha}^-(t-t')$ for $t>t'$ with respect to the Keldysh contour with $\\bar{\\gamma}_{\\alpha}^{\\pm}(t)=\\int {dE}e^{-iE t}\n\\bar{\\gamma}_{\\alpha}^{\\pm}(E)$. These tunneling lines represent contractions of lead electron operators.", "\n\nThere are vertices from which a tunneling line leaves (representing $a_{k\\sigma\\alpha}^\\dagger (t) c_\\sigma (t) e^{i\\varphi (t)}$ which removes a dot electron with spin $\\sigma$) and others to which a tunneling line enters (visualizing $c_\\sigma^\\dagger (t) a_{k\\sigma\\alpha}(t) e^{-i\\varphi (t)}$ which adds a dot electron with spin $\\sigma$). ", "Fermi statistics, furthermore, yield a minus sign for each crossing of tunneling lines.", "\n\nIn the interaction picture the dot electron operators get exponential factors which contain the energies $\\epsilon_{\\chi}$ of the many-body dot states $\\chi$ given by $\\epsilon_{\\chi}|\\chi\\rangle=\\bar{H}_D|\\chi\\rangle$. The order of the electron operators may induce furthermore a minus sign due to Fermi statistics.", "\n\nThe trace over the boson operators gives rise to a factor of the form $$C_B(t_1,t_2,\\ldots,t_m,t_1',t_2',\\ldots,t'_{m'})\n =\\langle T_K \\left[\n e^{-i\\varphi(t_1)}e^{-i\\varphi(t_2)}\\ldots e^{-i\\varphi(t_m)}\n e^{i\\varphi(t_1')}e^{i\\varphi(t_2')}\\ldots e^{i\\varphi(t'_{m'})}\n \\right] \\rangle$$ Since $\\varphi$ is linear in the boson operators, we get $$\\label{bosontrace}\n C_B(t_1,t_2,\\ldots,t_m,t_1',t_2',\\ldots,t'_{m'})=\n \\prod_{i<j}P^K(t_i,t_j)^{-1}\n \\prod_{i<j}P^K(t_i',t_j')^{-1}\n \\prod_{i,j}P^K(t_i,t_j')\\, .$$ We write $P^K(t,t')=P^+ (t,t')$ for $t<t'$ and $P^K(t,t')=P^- (t,t')$ for $t>t'$ on the Keldysh contour with $P^{\\pm}(t)=\\int dE e^{-iE t}P^{\\pm}(E)$. In the diagrammatic language, we represent the factors $P^K$ by boson lines connecting each vertex with each other.", "\n\nA summary of these rules are given in Appendix \\[append rules in time\\].", "\n\nIn order to calculate stationary transport properties it is convenient to change to an energy representation. ", "Without loss of generality we assume that the times $t_1,\\ldots,t_n$ of the correlation function (\\[expansion\\]) are ordered on the real axis according to $t_n<t_{n-1}<\\ldots <t_1=t$. This may be different to the ordering on the Keldysh contour which depends on whether the times lie on the upper or lower branch. ", "In the stationary limit we can set $t_0=-\\infty$ and $t = t_1 = 0$.\n\nWe consider the Laplace transform $$\\label{correlation}\n G(E_2,E_3,\\ldots,E_n)=(-i)^{n-1}\n \\int^0_{-\\infty}dt_2\\int^{t_2}_{-\\infty}dt_3\\ldots\n \\int^{t_{n-1}}_{-\\infty}dt_n\\, \n e^{iE_2 t_2}e^{iE_3 t_3}\\ldots e^{iE_n t_n}\n \\langle T_K A_1(0) A_2(t_2) \\ldots A_n(t_n) \\rangle\\;.$$ We will account for the exponential factors $\\exp (iE_i t_i)$ ($i=2,\\ldots,n$) by drawing directed virtual lines from the external vertices with time $t_i$ to the last vertex with time $t_1=0$ and assigning the energy $E_i$ to this virtual line.", "\n\nPerforming the time integrals we end up with diagrammatic rules in energy representation. ", "These rules are summarized in Appendix \\[append rules in energy\\].", "\n\nMaster equation and stationary probabilities {#master and probability}\n--------------------------------------------\n\nIn this section we will derive a formally exact expression for the central object of this paper: the quantum-mechanical transition rate $\\Sigma_{\\chi',\\chi}(t',t)$ for the reduced system (the dot) to go from a state $\\chi'$ at time $t'$ to a state $\\chi$ at time $t$. This rate will serve as an input for a formally exact and time-dependent Master equation which, in principle, could be used to calculate all occupation probabilities of the dot as a function of time for an arbitrary initial state. ", "Similar Master equations are well-known and successfully applied in connection with macroscopic quantum coherence phenomena in spin bose models [@Leg-etal; @Wei-Buch; @Gri-Sas-Wei]. ", "The connection to these path-integral approaches will be described in Ref.", " .", "\n\nA matrix element of the reduced density matrix of the dot at time $t$, $P^{\\chi_1}_{\\chi_2}(t)$, is given by the quantum-statistical expectation value of the projector $(|\\chi_2 \\rangle \\langle \\chi_1 |) (t)$ $$P^{\\chi_1}_{\\chi_2}(t)=\\langle(|\\chi_2\\rangle\\langle \\chi_1|)(t)\n \\rangle \\, ,$$ i.e., we have to set $n=1$ and $A_1=|\\chi_2\\rangle\\langle\\chi_1 |$ in Eq.", " (\\[expansion\\]). ", "The reduced density matrix commutes with the particle number on the dot. ", "Thus, the operator $|\\chi_2\\rangle\\langle\\chi_1 |$ is unaffected by the unitary transformation and no tunneling and boson line emerges from this external vertex. ", "The matrix element $P^{\\chi_1}_{\\chi_2}(t)$ can be expressed by the reduced propagator $\\Pi^{\\chi'_1,\\chi_1}_{\\chi'_2,\\chi_2}(t',t)$ from $\\chi'_1$ at time $t'$ forward to $\\chi_1$ at time $t$ and then from $\\chi_2$ at time $t$ backward to $\\chi'_2$ at time $t'$ $$\\label{propagation}\n P^{\\chi_1}_{\\chi_2}(t)=\\sum_{\\chi'_1,\\chi'_2}P^{\\chi'_1}_{\\chi'_2}(t')\n \\Pi^{\\chi'_1,\\chi_1}_{\\chi'_2,\\chi_2}(t',t) \\;.$$ The propagator is the sum of all diagrams with the given states at the ends and can be expressed by an irreducible self-energy part $\\Sigma^{\\chi'_1,\\chi_1}_{\\chi'_2,\\chi_2}(t',t)$, defined as the sum of all diagrams in which any vertical line cutting through them crosses at least one tunneling or boson line. ", "The propagators for the four lines attached to the self-energy are not included in $\\Sigma^{\\chi'_1,\\chi_1}_{\\chi'_2,\\chi_2}(t',t)$. We obtain an iteration in the style of a Dyson equation (see Fig.", " \\[Fig.dyson1\\]), $$\\label{Dyson}\n \\Pi^{\\chi'_1,\\chi_1}_{\\chi'_2,\\chi_2}(t',t) = \n {\\Pi^{(0)}}^{\\chi_1}_{\\chi_2}(t',t) \\delta_{\\chi_1,\\chi_1'} \n \\delta_{\\chi_2,\\chi_2'} + \n \\sum_{\\chi''_1,\\chi''_2}\\int_{t'}^t dt_2 \\int^{t_2}_{t'} dt_1 \\, \n \\Pi^{\\chi'_1,\\chi''_1}_{\\chi'_2,\\chi''_2}(t',t_1)\\, \n \\Sigma^{\\chi''_1,\\chi_1}_{\\chi''_2,\\chi_2}(t_1,t_2) \\, \n {\\Pi^{(0)}}^{\\chi_1}_{\\chi_2}(t_2,t) \\; ,$$ where ${\\Pi^{(0)}}^{\\chi_1}_{\\chi_2}(t',t)=\\exp \\left[-i(\\epsilon_{\\chi_1}-\n\\epsilon_{\\chi_2})(t-t')\\right]$ is the propagator of the isolated quantum dot. ", "Multiplying this equation with $P^{\\chi'_1}_{\\chi'_2}(t')$, summing over the states $\\chi'_1,\\chi'_2$ and differentiating with respect to $t$, we obtain together with Eq.", " (\\[propagation\\]) and setting $t'=t_0$ $$\\label{master-nondiagonal}\n \\frac{d}{dt}P^{\\chi_1}_{\\chi_2}(t)+\n i(\\epsilon_{\\chi_1}-\\epsilon_{\\chi_2}) P^{\\chi_1}_{\\chi_2}(t) = \n \\sum_{\\chi'_1,\\chi'_2}\\int_{t_0}^t dt'\\, P^{\\chi'_1}_{\\chi'_2}(t') \n \\Sigma^{\\chi'_1,\\chi_1}_{\\chi'_2,\\chi_2}(t',t)\\;.$$ This formally exact equation is the most general kinetic equation for the reduced density matrix of the dot. ", "No assumption is necessary for the initial state and the integral kernel $\\Sigma$ on the r.h.s. ", "shows that memory effects are fully taken into account.", "\n\nThe equation simplifies considerably if we assume that the initial density matrix is diagonal. ", "In the general case, this does not imply that the reduced density matrix stays diagonal for all times. ", "However, for the special case of the Anderson model considered here, spin conservation implies that the reduced density matrix will be diagonal for all times $t>t_0$. Hence, we consider $\\Sigma_{\\chi',\\chi}\\equiv\\Sigma^{\\chi',\\chi}_{\\chi',\\chi}$ and obtain from (\\[master-nondiagonal\\]) $$\\label{master}\n \\frac{d}{dt}P_{\\chi}(t) = \\sum_{\\chi'}\\int_{t_0}^t dt'\\,\n P_{\\chi'}(t') \\Sigma_{\\chi',\\chi}(t',t)\\;,$$ where $P_{\\chi}(t)\\equiv P^{\\chi}_{\\chi}(t)$ denotes the probability to be in the state $\\chi$ at time $t$. For a time-translational invariant system, the time-dependent rates $\\Sigma_{\\chi',\\chi}(t',t)$ depend only on the time difference $\\Sigma_{\\chi',\\chi}(t'-t)$. Performing the Laplace transform of Eq.", " (\\[master\\]) one can then study the time evolution of arbitrary initial probability distributions into the stationary state.", "\n\nBy attaching the rightmost vertex of each diagram $\\Sigma$ to the upper and lower propagator the minus sign for each vertex on the backward propagator yields $\\sum_{\\chi}\\Sigma_{\\chi',\\chi}(t',t)=0$, which allows us to rewrite Eq.", " (\\[master\\]) in the form $$\\label{time master}\n \\frac{d}{dt}P_{\\chi}(t) = \\sum_{\\chi'\\ne\\chi}\\int_{t_0}^t dt'\\,\n \\left[ P_{\\chi'}(t') \\Sigma_{\\chi',\\chi}(t',t)\n -P_{\\chi}(t') \\Sigma_{\\chi,\\chi'}(t',t)\\right]\\;,$$ We obtain the structure of a master equation with transition rates given by $\\Sigma_{\\chi',\\chi}(t',t)$.\n\nThe stationary distribution is given by $$P_{\\chi}^{st}=\\lim_{t\\rightarrow\\infty}P_{\\chi}(t)\n =\\lim_{t_0\\rightarrow -\\infty}P_{\\chi}(0)$$ and is [*not*]{} the equilibrium one if the electrochemical potentials of the leads are different. ", "From (\\[master\\]) and (\\[time master\\]) we obtain $$\\label{stationary master}\n 0=\\sum_{\\chi'}P^{st}_{\\chi'} {\\Sigma}_{\\chi',\\chi} = \n \\sum_{\\chi'\\ne\\chi} [ P^{st}_{\\chi'} \\Sigma_{\\chi',\\chi} \n - P^{st}_{\\chi} \\Sigma_{\\chi,\\chi'}] \\; ,$$ where $$\\label{self-energy}\n \\Sigma_{\\chi',\\chi}=i\\int_{-\\infty}^0 dt'\\,\\Sigma_{\\chi',\\chi}(t',0)$$ can be calculated directly by using our diagrammatic rules in energy space. ", "The prefactor $i$ in (\\[self-energy\\]) together with the $m-1$ time integrations over the internal vertices in $\\Sigma$ gives a factor $i^m$ in (\\[integral\\]) which cancels the factor $(-i)^m$ from rule 5.", "\n\nThe self-energy part $\\Sigma_{\\chi',\\chi}$ is purely imaginary. ", "This can be seen by changing the vertical positions of all vertices on the Keldysh contour (without changing their horizontal position) and reversing the direction of all tunneling and boson lines. ", "Consequently, only the energy differences $\\Delta E_j$ from rule 2’ will change sign. ", "Since the number of vertices is even (all tunneling vertices are coupled in pairs by tunneling lines), there is no sign change due to rule 5’ and the number of resolvents is odd. ", "Thus, the whole diagram has been changed to its conjugate complex up to a sign.", "\n\nThe tunneling current {#the current}\n---------------------\n\nThe tunneling current flowing into reservoir $\\alpha$ is defined by $I_{\\alpha}(t)=e{d\\over dt}{\\langle N_{\\alpha} (t)\\rangle}\n=ie \\langle [\\bar{H},N_{\\alpha}](t)\\rangle$, which is equivalent to $$\\label{current}\n I_\\alpha(t)=-ie \\sum_{k\\sigma}\\left\\{\n T^{\\alpha}_{k}{\\langle(a^\\dagger_{k\\sigma\\alpha}\n c_{\\sigma}e^{i\\varphi})(t)\\rangle}\\,-\\,\n {T^{\\alpha}_{k}}^*{\\langle(c^\\dagger_{\\sigma}\n a_{k\\sigma\\alpha}e^{-i\\varphi})(t)\\rangle}\\right\\}\\, .$$\n\nThe tunneling current is an expectation value of a product of a dot, boson and reservoir electron operator (see Fig.", " \\[currentdot\\]). ", "We obtain $$\\label{current-sigma}\n I_\\alpha (t)=e\\sum_{\\chi,\\chi'}\\int_{t_0}^t dt' P_{\\chi'}(t')\n \\Sigma^{\\alpha+}_{\\chi',\\chi}(t',t)\n = -e\\sum_{\\chi,\\chi'}\\int_{t_0}^t dt' P_{\\chi'}(t')\n \\Sigma^{\\alpha-}_{\\chi',\\chi}(t',t)$$ where the partial self-energies $\\Sigma^{\\alpha \\pm}_{\\chi',\\chi}(t',t)$ are parts of the total self-energy $$\\label{rate-partial rate}\n \\Sigma_{\\chi',\\chi}(t',t)=\n \\sum_{\\alpha} \\left\\{ \\Sigma^{\\alpha+}_{\\chi',\\chi}(t',t) +\n \\Sigma^{\\alpha-}_{\\chi',\\chi}(t',t) \\right\\} \\, .$$ They describe processes in which the rightmost tunneling line corresponds to reservoir $\\alpha$ and is an outgoing (incoming) line if the rightmost vertex lies on the upper propagator or an incoming (outgoing) line if the rightmost vertex lies on the lower propagator. ", "Their physical meaning is displayed by the current formula (\\[current-sigma\\]) which shows that they give the total contribution to the current rate. ", "We can relate them to an intuitively more physical object, namely the rate $\\Sigma_{\\chi',\\chi}^{\\alpha p}(t',t)$, $p=0,\\pm 1,\\pm 2,\\ldots$, which describes the transition rate where $p$ particles are transferred to reservoir $\\alpha$. Within our graphical language $\\Sigma_{\\chi',\\chi}^{\\alpha p}(t',t)$ is given by all diagrams where the number of tunneling lines with reservoir index $\\alpha$ running from the forward to the backward propagator minus the number of tunneling lines with reservoir index $\\alpha$ running from the backward to the forward propagator is given by $p$. We obtain $$\\label{rate relation}\n \\sum_{\\chi}\\Sigma^{\\alpha\\pm}_{\\chi',\\chi}(t',t)=\\pm\n \\sum_{\\chi}\\sum_p p\\,\\Sigma^{\\alpha p}_{\\chi',\\chi}(t',t).$$ This relation together with current conservation is proven in Appendix \\[append proof\\]. ", "The factor $p$ shows clearly that $\\Sigma^{\\alpha\\pm}$ describes the contribution to the current rate. ", "In contrast to lowest order processes, i.e., the golden rule rate, where $p$ can only take the values $\\pm 1$, $p$ can be arbitrary for higher order processes. ", "Nevertheless, Eq.", " (\\[rate-partial rate\\]) shows that the current rate can be calculated as a partial selection of diagrams already contained in the total transition rate $\\Sigma_{\\chi',\\chi}$.\n\nWe emphasize that the current formula (\\[current-sigma\\]) together with the Master equation (\\[master\\]) constitutes a complete theory to describe time-dependent phenomena starting from an arbitrary diagonal initial state. ", "The original problem has now been shifted to the evaluation of the various self-energy diagrams which correspond to transition and current rates. ", "The self-energies are defined by a set of irreducible diagrams and thus their corresponding perturbation expansion in the number of tunneling lines is a well-defined series and contains no divergent time-integrals.", "\n\nFor time-translational invariant systems the current rates $\\Sigma^{\\alpha\\pm}_{\\chi',\\chi}(t',t)$ depend only on the time difference $t'-t$. To calculate the stationary current we define in analogy to (\\[self-energy\\]) $$\\label{current-rates}\n \\Sigma^{\\alpha\\pm}_{\\chi',\\chi}=\n i\\int_{-\\infty}^0 dt' \\Sigma^{\\alpha\\pm}_{\\chi',\\chi}(t',0)$$ which again can be calculated directly with our diagrammatic rules in energy space. ", "The stationary current is then given by $$\\label{stationary current}\n I_\\alpha^{st}=-ie\\sum_{\\chi,\\chi'} P^{st}_{\\chi'} \n \\Sigma_{\\chi',\\chi}^{\\alpha +}\n =ie\\sum_{\\chi,\\chi'} P^{st}_{\\chi'} \\Sigma_{\\chi',\\chi}^{\\alpha -}\\, .$$\n\nGreen’s functions\n-----------------\n\nAfter the unitary transformation the Green’s functions of the dot electrons read $$\\begin{aligned}\n G^>_{\\sigma}(t,t')&=&-i \\langle (c_{\\sigma}e^{i\\varphi})(t)\n (c^{\\dagger}_{\\sigma}e^{-i\\varphi})(t')\\rangle\n \\\\\n G^<_{\\sigma}(t,t')&=&i \\langle (c^{\\dagger}_{\\sigma}\n e^{-i\\varphi})(t') (c_{\\sigma}e^{i\\varphi})(t) \\rangle \\, .\\end{aligned}$$ Here $G^>_{\\sigma}$ and $G^<_{\\sigma}$ are independent quantities since we do not assume equilibrium. ", "For time-translational invariant systems, the Green’s functions depend only on the time difference $G(t,t')=G(t-t')$. The Fourier transform $G(E)=\\int dt e^{i E t} G(t)$ can be written in the form $$\\begin{aligned}\n G^>_{\\sigma}(E)&=&2i \\, \\mbox{Im} \\, (-i) \\int_{-\\infty}^0 dt \n e^{-iE t}\\langle \n T_K(c_{\\sigma}e^{i\\varphi})(0)(c^{\\dagger}_{\\sigma}e^{-i\\varphi})(t^+)\n \\rangle \n \\\\\n G^<_{\\sigma}(E)&=&-2i \\, \\mbox{Im} \\, (-i) \\int_{-\\infty}^0 dt \n e^{-iE t}\\langle \n T_K(c_{\\sigma}e^{i\\varphi})(0)(c^{\\dagger}_{\\sigma}e^{-i\\varphi})(t^-)\n \\rangle \\, ,\\end{aligned}$$ where $t^{\\pm}$ means that the the time $t$ lies on the upper (lower) branch of the Keldysh contour. ", "Note that the time ordering is defined here by a pure ordering along the Keldysh contour without any sign change if we interchange fermion operators. ", "The integrals can be calculated like Eq.", " (\\[correlation\\]) whereby instead of assigning the energy $-E$ to the virtual line connecting the external vertices one can change the direction of the line and assign the energy $E$.\n\nIn order to relate the current to the Green’s functions of the dot we consider the first diagram on the r.h.s. ", "of Fig.", " \\[currentdot\\] (the second one is just the conjugate complex). ", "The external vertex can be either contracted by a tunneling line to the upper or lower propagator and we recover immediately the structure of the Green’s functions $G^>$ and $G^<$, respectively (see Fig.", " \\[currentcorr\\]). ", "We recover for the stationary current the relation [@Car-etal; @Her-Dav-Wil; @Mei-Win-Lee] $$I^{st}_\\alpha=-ie \\sum_\\sigma \\int dE \\left\\{ \n \\gamma^+_\\alpha(E)G_\\sigma^>(E)+\n \\gamma^-_\\alpha(E)G_\\sigma^<(E)\\right\\}.$$\n\nIn the case that the couplings to the leads have the same energy dependence, $\\Gamma_{\\alpha}(E) / \\Gamma_{\\alpha'}(E)=\\lambda_{\\alpha,\\alpha'}$, this can be written in the form (which was already derived in Ref.", " ), $$\\label{strom}\n I^{st}_{\\alpha}=e\\sum_{\\alpha'}\\sum_{\\sigma}\\int dE \\,\n {\\Gamma_{\\alpha}(E) \\Gamma_{\\alpha'}(E) \\over \n \\sum_{\\alpha''}\\Gamma_{\\alpha''}(E)} \\rho_{\\sigma} (E) \n [f^+_{\\alpha'} (E)-f^+_{\\alpha} (E)] \\;.$$ Here, we used the relation between the Green’s functions $G^<_{\\sigma}, G^>_{\\sigma}$ and spectral density $\\rho_{\\sigma} \\equiv {G^<_{\\sigma} - G^>_{\\sigma}\\over 2\\pi i}$.\n\nResults\n=======\n\nWhat we have done so far is to derive a diagrammatic language which allows a systematic description of transport processes. ", "We have, furthermore, shown how the physical quantities of interest, the stationary probability distribution and the current, can be obtained if we know the value of special diagrams. ", "In this section, now, we will explicitly calculate the value of the corresponding diagrams.", "\n\nWe consider here the case of strong Coulomb repulsion $U$, i.e., we restrict ourselves to the states with $N=0,1$. Diagrams in which a higher occupancy occurs do not contribute since they have resolvents of the order $1/U$.\n\nIn the following, the index $\\sigma$ labels the singly occupied state with spin $\\sigma=1,\\ldots M$. The label $\\chi$ additionally allows an empty dot, $\\chi=0,1,\\ldots M$.\n\nIn general, we can not sum up [*all*]{} possible diagrams. ", "Therefore, we have to find a systematic criterion which diagrams should be retained and summed.", "\n\nThe simplest approximation is to neglect all diagrams where two or more tunneling lines overlap in time (see the leftmost diagram parts in Fig.", " \\[fig1\\]). ", "This means we include those processes which are also described by the master equation with rates obtained in lowest order perturbation theory (sequential tunneling), which is a good description at high temperature, $\\Gamma \\ll T$.\n\nIn situations when sequential tunneling is suppressed by Coulomb blockade, the lowest order contribution to the current arises due to cotunneling. ", "The rates for a process in which an electron enters the dot from the left lead and leaves to right one is described by diagrams with two overlapping lines (see the diagram part in the middle of Fig.", " \\[fig1\\]).", "\n\nAt lower temperature the perturbative approach is not sufficient. ", "Higher-order processes become important. ", "In generalization to cotunneling we have to take into account irreducible diagrams with an arbitrary number of correlated tunneling processes, i.e., we include resonant tunneling.", "\n\nSimilar to the case of metallic islands [@HS-Sch; @Koe-HS-Sch1] we proceed in a conserving approximation, taking into account non-diagonal matrix elements of the total density matrix up to the difference of one electron-hole pair excitation in the leads. ", "The graphical representation of this constriction is that only diagrams in which any vertical line will cut at most two tunneling lines are taken into account.", "\n\nWe give two arguments why this class of diagrams is the most important one. ", "Firstly, since we treat the leads as large equilibrium reservoirs there should be a tendency of the system to stay close to diagonal states. ", "Secondly, our approximation contains the exact solution for the noninteracting limit $U=0$: if there is no electron-electron interaction in the dot, electrons with different spin do not influence each other, so that this limit is described within our model by choosing $M=1$. In this case, the selected diagrams are the only contributing ones. ", "The sum of all other, more complicated, diagrams is zero.", "\n\nFurthermore, we include only boson lines between vertices which are already connected by tunneling lines, i.e., $$C_B(t_1,t_2,\\ldots,t_m,t_1',t_2',\\ldots,t_m') \\approx\n \\prod_{i=1}^m P^K(t_i,t_i')\\, .$$ where the pairs $t_i,t'_i$ are already coupled by tunneling lines running from $t'_i$ to $t_i$. This amounts to a dressing of the tunneling lines $\\bar{\\gamma} \\rightarrow \n\\gamma$. This approximation, while neglecting many diagrams, describes well the spectral density of the dot at resonance points. ", "The reason is that position and value of the peaks of the spectral density are determined by a self-energy $\\sigma$ (see Eq.", " (\\[sigma2\\])) which is calculated here in lowest order perturbation theory in $\\Gamma$ including the bosons. ", "Higher orders are small for high tunnel barriers.", "\n\nFirst, we relate the rate $\\Sigma_{\\chi',\\chi}$ to an irreducible diagram labeled by $\\phi^{\\chi'_1,\\chi_1}_{\\chi'_2,\\chi_2}(\\alpha,\\sigma,E)$ (see Fig.", " \\[Fig.phi\\]). ", "It has an open tunneling line associated with tunneling of an electron with spin $\\sigma$ in the junction $\\alpha$ carrying the energy $E$. The line is directed from the right to the left and its value together with the corresponding resolvent is included in $\\phi$. The self-energy is then constructed by attaching the open tunneling line of these diagrams to the upper and lower propagator (see Fig.", " \\[sigmaphi\\]) with the result $$\\begin{aligned}\n\\label{partial rates}\n \\Sigma_{\\chi',\\chi} &=& 2i \\, \\mbox{Im} \\int dE \\sum_{\\sigma,\\alpha}\n \\sum_{\\chi_1} \\left\\{ \\langle \\chi | c_\\sigma | \\chi_1 \\rangle \n \\phi^{\\chi',\\chi_1}_{\\chi',\\chi} (\\alpha,\\sigma,E) -\n \\langle \\chi_1 | c_\\sigma | \\chi \\rangle\n \\phi^{\\chi',\\chi}_{\\chi',\\chi_1} (\\alpha,\\sigma,E) \\right\\}\n \\nonumber \\\\\n &=& \\sum_{\\alpha} \\left\\{ \\Sigma^{\\alpha+}_{\\chi',\\chi} +\n \\Sigma^{\\alpha-}_{\\chi',\\chi} \\right\\} \\, .\\end{aligned}$$ where the current rates $\\Sigma^{\\alpha\\pm}_{\\chi',\\chi}$ correspond to the first and second term, respectively. ", "Again we have made use of the fact that a diagram becomes the conjugate complex if we change the vertical position of all vertices and the direction of all tunneling and boson lines. ", "As pointed out in Appendix \\[append proof\\], any approximation for $\\phi$ will lead to a current conserving theory.", "\n\nWe construct the diagram $\\phi$ by iteration (see Figs.", " \\[phidot1\\] and \\[phidot2\\]). ", "To do so, we need the diagram $\\pi (E)$ which is the propagator $\\pi (E)$ while a tunneling line with energy $E$ is running in parallel from the right to the left. ", "This diagram can also be expressed as an iteration in the style of a Dyson equation (see Fig.", " \\[Fig.dyson2\\]) $$\\label{pi-dyson}\n \\pi^{\\chi'_1,\\chi_1}_{\\chi'_2,\\chi_2} (E)= \n {\\pi^{(0)}}^{\\chi'_1}_{\\chi'_2} (E) \\delta_{\\chi'_1,\\chi_1} \n \\delta_{\\chi'_2,\\chi_2} + \\sum_{\\chi''_1,\\chi''_2}\n \\pi^{\\chi'_1,\\chi''_1}_{\\chi'_2,\\chi''_2}(E)\\, \n \\sigma^{\\chi''_1,\\chi_1}_{\\chi''_2,\\chi_2}(E) \\, \n {\\pi^{(0)}}^{\\chi_1}_{\\chi_2} (E)\\; .", "\n\\label{dyson2}$$\n\nIn analogy to $\\Sigma$, the self-energy $\\sigma(E)$ denotes the sum of all irreducible diagrams with a tunneling line going backward in time. ", "Here, the free propagator in energy space is given by $${\\pi^{(0)}}^{\\chi_1}_{\\chi_2}(E)= \n {1\\over E - (\\epsilon_{\\chi_1} - \\epsilon_{\\chi_2})+i0^+}$$ Hence, we can solve Eq.", " (\\[pi-dyson\\]) and find in matrix notation the general relation $$\\label{pi}\n \\pi(E)=[[\\pi^{(0)}(E)]^{-1} - \\sigma(E)]^{-1} \\, .$$\n\nBecause of the restriction to two charge states, only the matrix elements $\\pi^\\sigma(E)\\equiv\\pi^{\\sigma,\\sigma}_{0,0}(E)$ of $\\pi(E)$ and $\\sigma^\\sigma(E)\\equiv\\sigma^{\\sigma,\\sigma}_{0,0}(E)$ of $\\sigma(E)$ are involved, and we deduce from Eq.", " (\\[pi\\]) $$\\label{pi2}\n \\pi^\\sigma(E)=\n {1\\over E-\\epsilon_\\sigma-\\sigma^\\sigma(E)} \\, .$$ Since at most two tunneling lines are allowed at once, the irreducible self-energy $\\sigma^\\sigma(E)$ consists of only one tunneling line. ", "We calculate all contributions, which are depicted in Fig.", " \\[somegadot\\], and get $$\\label{sigma2}\n \\sigma^\\sigma(E)=\\int dE'{\\gamma^-(E')\\over\n E-E'+i0^+} +\n \\sum_{\\sigma'}\\int dE'{\\gamma^+(E')\\over\n E-E'+\\epsilon_{\\sigma'}-\\epsilon_\\sigma+i0^+}\\, .$$ In the spin degenerate case, this is exactly the relation (\\[sigma\\]) which we found from intuitive arguments.", "\n\nAccording to our rules, Figs.", " \\[phidot1\\] and \\[phidot2\\] lead to the self-consistent equation for the diagram $\\phi(\\alpha,\\sigma,E)$ $$\\begin{aligned}\n \\phi_{0,0}^{0,\\sigma}(\\alpha,\\sigma,E)=\n \\pi^{\\sigma}(E)\\left[\\gamma^+_\\alpha(E)\n - \\gamma^-_\\alpha(E)\\sum_{\\alpha'}\\int dE'\n {1\\over E-E'+i0^+}\n \\,{\\phi^*}_{0,0}^{0,\\sigma}(\\alpha',\\sigma,E')\\right.", "\n \\nonumber \\\\\n - \\left. ", "\\gamma^+_\\alpha(E)\\sum_{\\sigma'}\\sum_{\\alpha'} \n \\int dE' \n {1\\over E-E'+\\epsilon_{\\sigma'}-\\epsilon_\\sigma+i0^+}\n \\,{\\phi^*}_{0,0}^{0,\\sigma'}(\\alpha',\\sigma',E')\\right]\\end{aligned}$$ and $$\\begin{aligned}\n \\phi_{\\sigma',0}^{\\sigma',\\sigma}(\\alpha,\\sigma,E)=\n \\pi^{\\sigma}(E)\n \\left[-\\gamma^-_\\alpha(E)\\delta_{\\sigma \\sigma'}\n - \\gamma^-_\\alpha(E)\\sum_{\\alpha'}\\int dE'\n {1\\over E-E'+i0^+}\n \\,{\\phi^*}_{\\sigma',0}^{\\sigma',\\sigma}(\\alpha',\\sigma,E')\\right.", "\n \\!\\!\\!\\!\\!\\!\\!\\!\\! ", "\\nonumber \\\\\n - \\left. ", "\\gamma^+_\\alpha(E)\\sum_{\\sigma''}\\sum_{\\alpha'} \n \\int dE'\n {1\\over E-E'+\\epsilon_{\\sigma'}-\\epsilon_\\sigma+i0^+}\\,\n {\\phi^*}_{\\sigma',0}^{\\sigma',\\sigma''}(\\alpha',\\sigma'',E')\n \\right]\\,\\,\\end{aligned}$$\n\nThe stationary probabilities and the current are derived from Eqs.", " (\\[stationary master\\]) and (\\[stationary current\\]). ", "To calculate the rates we specify Eq.", " (\\[partial rates\\]) and obtain $$\\begin{aligned}\n\\label{rates-special}\n \\Sigma_{\\chi',0}^{\\alpha+}&=&2i\\,\\mbox{Im} \\sum_{\\sigma} \\int dE \\,\n \\phi^{\\chi',\\sigma}_{\\chi',0}(\\alpha,\\sigma,E) \\, , \\\\\n \\Sigma_{\\chi',\\sigma}^{\\alpha-}&=&-2i\\,\\mbox{Im} \\int dE \\,\n \\phi^{\\chi',\\sigma}_{\\chi',0}(\\alpha,\\sigma,E) \\, ,\\end{aligned}$$ whereas all other rates are zero.", "\n\nThe correlation functions can be calculated from the diagrams shown in Figs.", " \\[Cdotgr\\] and \\[Cdotkl\\]. ", "We have to consider only the latest (i.e. rightmost) correlated part of the diagram. ", "The processes before end up with probability $P^{st}_{\\chi}$ in a diagonal state $\\chi$. We have used the same criterion as for the calculation of the density matrix with one exception. ", "If a vertical line lies between the external vertices we allow a cut through at most one tunneling line. ", "Here we have used the fact that such a vertical line will in addition always cut the virtual line connecting the external vertices. ", "The sum of all these diagrams gives (where we can combine always two diagrams to the imaginary part of one of them) $$\\begin{aligned}\n G_\\sigma^>(E)&=& \\int dE'\\, \\bar{G}_\\sigma^>(E') P^+(E'-E)\n \\\\\n G_\\sigma^<(E)&=& \\int dE'\\, \\bar{G}_\\sigma^<(E') P^-(E'-E)\\end{aligned}$$ with $$\\begin{aligned}\n\\label{correlation function1}\n \\bar{G}_\\sigma^>(E)&=&2i\\,\\mbox{Im}\\left\\{\\pi^\\sigma(E) \\left[\n P_0^{st} - \n \\sum_\\alpha \\sum_{\\sigma'} \\int \\, dE'{P_0^{st}\n {{\\phi^*}^{0,\\sigma'}_{0,0}(\\alpha,\\sigma',E')}\n +\\sum_{\\sigma''}P_{\\sigma''}^{st}\n {{\\phi^*}^{\\sigma'',\\sigma'}_{\\sigma'',0}(\\alpha,\\sigma',E')}\n \\over E-E'+\\epsilon_{\\sigma'}-\\epsilon_\\sigma+i0^+} \\right]\\right\\}\n \\\\\n \\label{correlation function2}\n \\bar{G}_\\sigma^<(E)&=&-2i\\,\\mbox{Im}\\left\\{\\pi^\\sigma (E) \\left[\n P_{\\sigma}^{st} +\n \\sum_\\alpha \\int \\, dE'{P_0^{st}{\\phi^*}^{0,\\sigma}_{0,0}\n (\\alpha,\\sigma,E')\n +\\sum_{\\sigma'}P_{\\sigma'}^{st}{\\phi^*}^{\\sigma',\\sigma}_{\\sigma',0}\n (\\alpha,\\sigma,E')\n \\over E-E'+i0^+} \\right] \\right\\}\\, .\\end{aligned}$$\n\nIn the following, we discuss for transparency the effect of the coupling to bosons and the presence of a magnetic field separately.", "\n\nBoson-assisted tunneling\n------------------------\n\nFor zero magnetic field, i.e. $\\epsilon_{\\sigma}=\\epsilon$ for all $\\sigma$, we can perform the resummation of the corresponding diagrams for the rates and the Green’s functions analytically (details are given in Appendix \\[append boson\\]) and find $$\\label{current boson}\n I^{st}_\\alpha = 2\\pi e M \\sum_{\\alpha'}\\int dE \\,\n [\\gamma_\\alpha^-(E)\\gamma_{\\alpha'}^+(E) - \\gamma_{\\alpha'}^-(E)\n \\gamma_\\alpha^+(E)]\\,|\\pi (E)|^2\\,$$ with $\\pi (E)=\\pi^\\sigma (E)$. We can write this equation in a more intuitive way by inserting the definition (\\[gamma\\]) for $\\gamma^\\pm_\\alpha$ $$\\label{transmission formula}\n I_\\alpha^{st}=\\frac{e}{h}\\sum_{\\alpha'}\\int dE \\int dE'\n \\left\\{ T_{\\alpha',\\alpha}(E',E) f_{\\alpha'}(E')(1-f_\\alpha (E))-\n T_{\\alpha,\\alpha'}(E,E') f_\\alpha (E) (1-f_{\\alpha'}(E'))\\right\\}\\,,$$ where $$\\label{transmission probability}\n T_{\\alpha,\\alpha'}(E,E')=M\\Gamma_\\alpha (E)\\Gamma_{\\alpha'}(E')\n \\int dE_1 P^+(E_1-E)P^-(E_1-E') |\\pi(E_1)|^2$$ can be interpreted as a transmission probability for an electron to start from reservoir $\\alpha$ with energy $E$ and end in reservoir $\\alpha'$ with energy $E'$. From the detailed balance condition (\\[detailed balance\\]) we get $$\\label{trans detailed balance}\n T_{\\alpha',\\alpha}(E',E) = e^{\\beta (E'-E)}\n T_{\\alpha,\\alpha'}(E,E')\\,.$$ This guarantees that the current is zero if all chemical potentials of the reservoirs are identical.", "\n\nHowever, the interpretation of $T_{\\alpha,\\alpha'}$ as a one-particle transmission probability in analogy to a generalization of the Landauer-Büttiker formula to inelastic interactions [@Hek-Naz-Sch] is not correct. ", "We see that the transmission probability still depends on the Fermi distribution functions via the self-energy $\\sigma (E)$ in the denominator of the propagator $\\pi (E)$. This reflects the many-particle aspect of the electron-electron and electron-boson interaction in our model.", "\n\nComparing our result for $T_{\\alpha,\\alpha'}$ with other approaches in the case $M=1$ [@Win-Jac-Wil; @Gla-She; @Jon; @Ima-Pon-Ave], we see that the energy dependence of $\\sigma(E)$ has been neglected in all previous treatments. ", "We find that even in the $M=1$ case, the energy dependence of $\\sigma(E)$ cannot been neglected if the temperature $T$ and the typical frequency $\\omega_B$ of the bosons are smaller than $\\Gamma$.\n\nWithout bosons, the current formula is exact up to order $O(\\Gamma^2)$, i.e., sequential and electron cotunneling are fully taken into account. ", "With bosons, cotunneling is not described correctly since we have treated the bosons only by a dressing of the tunneling lines. ", "This means that our approximation is not valid in regions where the current is very small. ", "However, at resonance we believe our treatment to be correct since there we expect that sequential tunneling will be just modified by a renormalization and broadening of the local state of the dot which is described by the self-energy $\\sigma (E)$ which is calculated in lowest order in $\\Gamma$ here. ", "Higher orders will be small for high tunneling barriers.", "\n\nFinally, we calculate the Green’s functions and find $$\\begin{aligned}\n G^>(E)&=&-2\\pi i \\int dE'\\,\\gamma^-(E')P^+(E'-E)\\,|\\pi(E')|^2\\\\\n G^<(E)&=&2\\pi i \\int dE'\\,\\gamma^+(E')P^-(E'-E)\\,|\\pi(E')|^2\\,.\\end{aligned}$$ In equilibrium, i.e. $\\mu_\\alpha = 0$ for all $\\alpha$, we obtain the correct sum rule $G^>(E)=-\\exp{(\\beta E)}G^<(E)$. Furthermore, for the $M=1$ case, particle-hole symmetry is satisfied. ", "The spectral density has the form $$\\rho(E)=\\int dE' \\left[ \\gamma^+(E') P^-(E'-E) +\n \\gamma^-(E') P^+(E'-E) \\right] |\\pi(E')|^2\\, .", "\n\\label{spec}$$ The effect of the resonant-tunneling processes is described by the resolvent $\\pi(E)$ containing the self-energy $\\sigma(E)$, Eq.", " (\\[sigma2\\]). ", "The real and imaginary part of the self-energy express energy renormalization and broadening and determine, therefore, the position and the width of the maxima in the spectral density.", "\n\nTo proceed we consider from now on a one-mode environment (Einstein model) with boson frequency $\\omega_q=\\omega_B$. Experimentally realizations of this model are optical phonons [@Win-Jac-Wil; @Gla-She; @Jon] or by fluctuations of an external $LC$-circuit with frequency [@Devoret-etal; @Odi-etal; @Flens-etal; @Ima-Pon-Ave] $\\omega_B=(LC)^{-1/2}$. The results for a general environment can be anticipated approximately from the one-mode case by a superposition. ", "Furthermore, we choose the special case of two reservoirs $\\alpha=L/R$ and constant level broadening $\\Gamma/2=\\Gamma_L=\\Gamma_R$.\n\nDefining $g=\\sum_q {g_q^2 / \\omega_B^2}$ we obtain $P^\\pm(E)=\\sum_n p_n \\delta(E\\pm n\\omega_B)$, where $p_n=e^{-g(1+2N_0(\\omega_B))}e^{n\\omega_B/2T_B} I_n(2gN_0(\\omega_B) \ne^{\\omega_B/2T_B})$ is the probability for the emission of $n$ bosons with frequency $\\omega_B$. Here, $N_0(\\omega_B)$ is the Bose function and $I_n$ the modified Bessel function. ", "Using Eq.", " (\\[sigma2\\]) we obtain [@Koe-HS-Sch2] $$\\mbox{Re}\\,\\sigma(E)=\\sum_{n,\\alpha} (M p_n - p_{-n}){\\Gamma_{\\alpha}\n \\over 2\\pi}\n \\Big{[} \\ln \\left( {E_C\\over 2\\pi T} \\right)\n -\\mbox{Re}\\,\\Psi \\left({1\\over 2}\n +i{E+n\\omega_B-\\mu_\\alpha \\over 2\\pi T} \\right) \\Big{]}\n\\label{Resigma}$$ $$\\mbox{Im}\\, \\sigma(E)=-\\pi\\sum_n p_n[M \\bar{\\gamma}^+(E+n\\omega_B)+ \n \\bar{\\gamma}^-(E-n\\omega_B)] \\, .$$ Here $\\Psi$ denotes the digamma function, and we have chosen in the energy integrals a Lorentzian cut-off at $E_C$.\n\nThe real part of $\\sigma(E)$ renormalizes the level position to higher energies. ", "Furthermore, it depends logarithmically on energy, temperature, voltage and frequency. ", "These logarithmic terms are typical for the occurrence of Kondo peaks. ", "Hence, we anticipate logarithmic singularities either for $M\\ge 2$ or for $p_n\\neq p_{-n}$. This includes not only the degenerate case but also the case of a single dot level without spin ($M=1$) since the probabilities for absorption and emission of bosons are different. ", "It is important to remark here, that for systems coupled to classical time-dependent fields[@Het-HS] the situation is different since then both probabilities are equal. ", "At low enough temperatures we obtain logarithmic peaks in $\\sigma(E)$ at $E=\\mu_\\alpha + n\\omega_B$ ($n\\neq 0$ for $M=1$). ", "They lead to maxima of the resolvent $\\pi(E)$ at $E=\\mu_\\alpha + n\\omega_B$ ($n>0$ for $M=1$, $n\\geq 0$ for $M>1$) for $\\epsilon<0$ and at $E=\\mu_\\alpha + n\\omega_B$ ($n<0$) for $\\epsilon>0$. The spectral density (\\[spec\\]) shows resonances at the same points but, due to the additional $P^\\pm$ functions in the integrand, they are shifted by multiples of $\\omega_B$. This boson-assisted tunneling is completely independent from the influence of the bosons on the self-energy $\\sigma(E)$.\n\nThe spectral density at different voltages for a low lying level $\\epsilon < 0$ is depicted in Fig.", " \\[fig2\\]. ", "Without an applied bias voltage, we obtain (for $M=2$) the usual Kondo peak near the Fermi level (which we choose as zero energy). ", "The emission of bosons leads to additional resonances at multiples of $\\omega_B$. For $M=1$ and $\\epsilon<0$, resonances occur for negative energies and in the case $\\epsilon>0$ we find resonances at positive energies. ", "In these cases, the effects are less pronounced and are only visible for very low temperatures. ", "At finite bias voltages all peaks split and decrease in magnitude.", "\n\nThe resonances in the spectral density can be probed by the nonlinear differential conductance as function of the bias voltage $V$, as shown in Fig.", " \\[fig3\\] for the case $\\epsilon < 0$. The splitting of the Kondo peak leads to an overall decrease of the spectral density in the energy range $|E|<eV$ (see inset of Fig.", " \\[fig3\\]). ", "For this reason, the conductance shows the well-known [@Mei-Win-Lee; @Het-HS; @Ral-Buh1] maximum at zero bias. ", "The emission of bosons produces a set of symmetric satellite maxima. ", "They can be traced back to the fact that pairs of Kondo peaks can merge if the bias voltage is a multiple of the boson frequency (see Fig.", " \\[fig2\\]). ", "This gives rise to pronounced Kondo peaks at $E=\\pm eV/2$ and thus to an increase of the spectral density with bias voltage near these points.", "\n\nFig.", " \\[fig4\\] shows the differential conductance for $\\epsilon \\ge 0$ with and without bosons. ", "A striking result is that the whole structure is inverted compared to the case $\\epsilon<0$, and we find a zero-bias anomaly although the Kondo peak at zero energy is absent. ", "The coupling to bosons yields satellite steps at $|eV|=n\\omega_B$. The contributions of sequential and cotunneling lead, compared to resonant tunneling, only to a weak bias voltage dependence of the differential conductance. ", "This shows clearly that the influence of the logarithmic terms in $\\sigma(E)$ are still important. ", "The logarithmic peaks in $\\mbox{Re}\\, \\sigma(E)$ decrease with increasing bias voltage and approach the value of $E-\\epsilon$ if $\\epsilon$ is large enough. ", "Thus the value of $E-\\epsilon-\\mbox{Re}\\, \\sigma(E)$ decreases which in turn leads to an overall increase of the resolvent $\\pi(E)$ and the spectral density $\\rho(E)$ near zero energy (see the inset of Fig.", " \\[fig4\\]).", "\n\nZero-bias minima are known from Kondo scattering from magnetic impurities. [", "@Jan-etal] They have been observed in recent experiments [@Ral-Buh2] and have been interpreted as 2-channel Kondo scattering from atomic tunneling systems [@Ral-Lud-Del-Buh; @Het-Kro-Her] or by tunneling into a disordered metal. [", "@Win-Alt-Mei] Here we have shown that zero-bias minima can also arise due to resonant tunneling via local impurities if the level position is high enough such that we are in the mixed valence regime.", "\n\nFinally, we have investigated the differential conductance at fixed bias voltage as function of the position of the dot level, which experimentally can be varied by a gate voltage coupled capacitively to the dot (see Fig.", " \\[fig5\\]). ", "The result shows a (classical) pair of peaks at $|\\epsilon|=eV/2$ together with satellites (due to emission and absorption of bosons) and peaks for $|\\epsilon|>eV/2$ (only due to absorption). ", "The energy dependence of $\\mbox{Im}\\, \\sigma(E)$ gives rise to an asymmetry of the peak heights. ", "The peak at $\\epsilon=eV/2$ is higher than the one at $\\epsilon=-eV/2$ since $|\\mbox{Im}\\, \\sigma(E)|=\\pi |M\\gamma^+(E)+\\gamma^-(E)|$ is smaller for higher energies (except for $M=1$ when particle-hole symmetry holds). ", "This significant effect is due to the broadening of the spectral density by quantum fluctuations.", "\n\nMagnetic field dependence\n-------------------------\n\nIn this section we discuss the effect of an applied magnetic field and do not take into account the coupling to bosons. ", "Again we consider the case of two reservoirs and constant level broadenings. ", "Since the energy levels $\\epsilon_{\\sigma}$ are now spin dependent, we can no longer solve the self-consistent equations analytically but have to solve them numerically.", "\n\nWe find Kondo resonances in the spectral density $\\rho_{\\sigma}(E)$ at energies $E=\\mu_{\\alpha}+\\epsilon_{\\sigma'}-\\epsilon_{\\sigma}$ with $\\sigma' \\neq \\sigma$. This is due to the fact, that the correlation functions $G^<_\\sigma(E)$ and $G^>_\\sigma(E)$ are mainly determined by the resolvent $\\pi^\\sigma(E)$ (see Eqs.", " (\\[correlation function1\\]) and (\\[correlation function2\\])) which contains via the self-energy $\\sigma^\\sigma(E)$ logarithmic singularities at the corresponding energies, $$\\begin{aligned}\n \\mbox{Re}\\,\\sigma^\\sigma(E)&=&\\sum_{\\alpha}{\\Gamma_{\\alpha}\\over 2\\pi}\n \\sum_{\\sigma' \\neq \\sigma} \\Big{[} \\ln \\left( {E_C\\over 2\\pi T} \n \\right) -\\mbox{Re}\\,\\Psi \\left({1\\over 2}\n +i{E+\\epsilon_{\\sigma'}-\\epsilon_\\sigma-\\mu_\\alpha \\over 2\\pi T} \n \\right) \\Big{]}\n \\\\\n \\mbox{Im}\\, \\sigma^\\sigma(E)&=&-\\pi \\left[ \\bar{\\gamma}^-(E)\n + \\sum_{\\sigma'} \\bar{\\gamma}^+(E+\\epsilon_{\\sigma'}-\\epsilon_\\sigma)\n \\right] \\, .\\end{aligned}$$\n\nFrom Eq.", " (\\[strom\\]) we see that only energies within the window defined by the difference of the Fermi functions contribute to the current. ", "For this reason, there is no Kondo-assisted tunneling at low transport voltage but sets on if transport voltage and level splitting are equal. ", "Therefore, for low lying levels the conductance peak at zero bias found in the previous section now splits up into two peaks separated by the twice the level splitting [@Mei-Win-Lee] (see Fig.", " \\[Fig.experiment\\]).", "\n\nRalph and Buhrman recently measured Kondo-assisted tunneling via a single charge trap of a point contact tunnel barrier.[@Ral-Buh1] We follow the model proposed by the authors interpretating the experiment as a realization of the Anderson model with strong Coulomb repulsion such that double occupancy does not occur. ", "However we think that the interaction energy $U$ and not the conduction band width is the relevant cut-off in this situation.", "\n\nA comparison of the experiment and our theory is given in Fig.", " \\[Fig.experiment\\], Fig.", " \\[Fig.expgross\\] and Fig.", " \\[Fig.exptemp\\]. ", "We find a good agreement for the peaks induced by Kondo-assisted tunneling processes if we set the cut-off $U=30meV$. The authors suspect the single-charge trap to be a dangling bond, for which they expect $U=100meV$. Our result agrees in the order of magnitude, it gives a hint however, that the state may have a larger extension than an ordinary dangling bond or that there is screening due to the copper electrodes or both. ", "The peaks for larger magnetic fields show, however, a stronger broadening than predicted from our calculation. ", "Nevertheless, our theory reproduces the experimental curves much better than the fits given in Ref.", "  using perturbation theory since we have taken into account nonperturbative effects which are obviously important here.", "\n\nThe model proposed by the authors of Ref.", "  explains the broad peaks at large voltages by the matching of the energies of the empty and the singly occupied dot. ", "Our calculations for this case, however, lead to a broader and lower peak for positive voltages in comparison with experiment (see Fig.", " \\[Fig.expgross\\]). ", "We think, therefore, that due to the capacitance asymmetry the system becomes doubly occupied before the empty state is energetically favorable. ", "The capacitance asymmetry $a_c$ makes then the corresponding resonance peak sharper. ", "An energy dependent transparency of the barriers could then explain the different heights. ", "A generalization of our theory to situations, where multiple occupancy of the dot is important, is currently under way and will be presented elsewhere.", "\n\nFinally, we consider the case when the energy level is above the Fermi energies of the leads. ", "The zero-bias minimum found in the previous section splits for finite magnetic field into two minima separated by twice the level splitting (see Fig.", " \\[Fig.minimum\\]).", "\n\nConclusions\n===========\n\nIn conclusion, we have studied low-temperature transport in the nonequilibrium Anderson model with bosonic interactions. ", "The latter yield new Kondo resonances in the spectral density which can be probed by the measurement of the nonlinear differential conductance. ", "Both the gate and bias voltage dependence are important. ", "Quantum fluctuations due to resonant tunneling yield zero-bias anomalies as function of the bias voltage, [*which can be changed from maxima to minima by varying the gate voltage*]{}. ", "We, furthermore, discussed the splitting of the zero-bias anomaly by an external magnetic field and found good agreement with recent experiments.", "\n\nWe have presented a real-time approach which is based on a nonperturbative calculation of transition rates between different states of a local strongly correlated system coupled to fermionic or bosonic baths. ", "We present systematic rules of how to set up well defined perturbation expansions for the rates in terms of the tunneling matrix elements between dot and leads. ", "The formally exact rates are used to calculate occupation probabilities and the current from Master equations and current formulas which are intuitively obvious. ", "The method has a wide applicability, ranging from the study of arbitrary dot level structures up to the investigation of macroscopic quantum coherence phenomena. ", "The latter can arise from the time evolution of non-stationary initial states or by the application of explicitly time-dependent fields.", "\n\nThe usage of real-time methods to understand low-temperature behavior of strongly correlated fermions either in equilibrium or non-equilibrium situations is a rather new field and has not yet been applied extensively. ", "Compared with the conventional methods in imaginary time [@Kei-Mor] they offer the possibility to set up new approximation schemes. ", "In this paper we have performed a nonperturbative resummation of higher order coherent tunneling processes to calculate transition and current rates analytically for temperatures smaller than the intrinsic broadening $\\Gamma$. Although the criterium for considering certain diagrams is yet not motivated by the usage of a “small” parameter, the diagrams are selected in a systematic way. ", "We have chosen all diagrams which keep the total density matrix as close as possible to the diagonal state up to one electron-hole pair excitation in the reservoirs. ", "This reminds of techniques applied within variational wave function ansatzes [@Sch-etal] but here formulated on the basis of density matrices for nonequilibrium systems at finite temperatures. ", "Furthermore, there are many possibilities to improve our approximation by considering more diagrams by analytical or numerical methods. ", "Simple limiting cases as e.g. the noninteracting case are already exactly incorporated within our approximation. ", "Since the strongly interacting case gives also at least qualitatively good results, our method may be a good candidate to cover the whole range from weak to strong interaction within the same approximation scheme.", "\n\nWe like to thank D. Averin, J. von Delft and M. Hettler for useful discussions. ", "The support by the Deutsche Forschungsgemeinschaft, through SFB 195, by the Swiss National Science Foundation (H.S.), and by the A.v.", "Humboldt award of the Academy of Finland (G.S.) is gratefully acknowledged.", "\n\nThe rules in time space {#append rules in time}\n=======================\n\nEach term of the expansion Eq.", " (\\[expansion\\]) with operators $A_i$ of the form Eq.", " (\\[special Ai\\]) can be calculated according to the following rules:\n\n 1. ", "\n\n: Draw all topological different diagrams with directed tunneling lines connecting pairs of internal or external vertices containing lead electron operators. ", "Assign a reservoir index $\\alpha$ and a spin index $\\sigma$ to each of these lines. ", "Connect all vertices containing boson operators in all possible ways by boson lines. ", "Assign states $\\chi$ and the corresponding energy $\\epsilon_{\\chi}$ to each element of the Keldysh contour connecting two vertices.", "\n\n 2. ", "\n\n: The propagation from $t'$ to $t$ with $t'<t$ on the Keldysh contour implies a factor $\\exp[- i \\epsilon_{\\chi}(t-t')]$.\n\n 3. ", "\n\n: The state $\\chi$ which is assigned to the left most part of the diagram implies a factor $P_\\chi^0$ from the initial density matrix. ", "Each vertex containing a dot operator $B$ gives rise to a matrix element $\\langle \\chi '| B |\\chi\\rangle$ where $\\chi$ ($\\chi '$) is the dot state entering (leaving) the vertex with respect to the Keldysh contour.", "\n\n 4. ", "\n\n: Each directed tunneling line with index $\\alpha$ running from $t'$ to $t$ implies $(-1)^v\\bar{\\gamma}^K_{\\alpha}(t,t')$ with $v$ being the number of electron operators (due to external vertices) on the part of the Keldysh contour from $t'$ to $t$. The line corresponds to a tunneling process in reservoir $\\alpha$. Each boson line connecting vertices at times $t$ and $t'$ implies $P^K(t,t')$ if the phase factors at these vertices have different sign. ", "Otherwise, the boson line has the value $P^K (t,t')^{-1}$.\n\n 5. ", "\n\n: Each diagram carries a prefactor $(-i)^m(-1)^c$, where $m$ is the total number of internal vertices and $c$ the number of crossings of tunneling lines. ", "There may be a further minus sign due to the order of dot electron operators which emerges from the matrix elements $\\langle \\chi '| B | \\chi\\rangle$ discussed in rule 3.", "\n\n 6. ", "\n\n: Integrate over the internal times along the Keldysh contour without changing their ordering and sum over the reservoir and spin indices.", "\n\nWe emphasize that these diagrammatic rules hold for arbitrary dot Hamiltonians $\\bar{H}_D = \\sum_\\chi \\epsilon_\\chi |\\chi\\rangle\\langle \\chi|$, i.e., the states $\\chi$ can be many-body eigenfunctions of $\\bar{H}_D$ containing complicated correlations due to Coulomb interaction, magnetic fields, geometric setups, etc. . ", "Such eigenfunctions have been calculated for special situations [@Pfa-etal; @Hae-etal] and can be used as an input for our diagrammatic language. ", "In this paper, however, we will concentrate ourselves on the dot Hamiltonian (\\[dot\\]) where the states $\\chi$ are trivially known. ", "For this special case, the matrix elements $\\langle \\chi '| B |\\chi\\rangle$ from rule 3 can only give rise to minus signs whereas they can have a more pronounced influence in more general situations [@Pfa-etal; @Hae-etal].", "\n\nFurthermore, we note that the same diagrammatic rules even hold for arbitrary time-dependent dot Hamiltonians $\\bar{H}_D(t)$ which are not diagonal in the states $\\chi$. In this case one has to assign two states $\\chi'$ and $\\chi$ to the beginning and the end of each element of the Keldysh contour, respectively. ", "The factor $\\exp[- i \\epsilon_{\\chi}(t-t')]$ from rule 2 is then replaced by the matrix element $\\langle \\chi | U_D(t,t')|\\chi '\\rangle$ where $U_D$ denotes the time evolution operator of $\\bar{H}_D$ and $t$ ($t'$) are the times at the end (beginning) of the element of the Keldysh contour.", "\n\nThe rules in energy space {#append rules in energy}\n=========================\n\nWe obtain the diagrammatic rules in energy space by expanding the expectation value in Eq.", " (\\[correlation\\]) and then performing the time integrals. ", "We order the times of all internal ($m$) and external vertices ($n$) from left to right and label them by $\\tau_j$ with $j=1,2,\\ldots,m+n$ (with $\\tau_{m+n}=0$), irrespective on which branch they are. ", "The Keldysh contour integrals are now written as ordinary integrals. ", "This includes a minus sign for each internal vertex on the backward propagator. ", "If the initial density matrix is diagonal we then encounter expressions of the type $$\\begin{aligned}\n\\label{integral}\n \\int^0_{-\\infty} d\\tau_1 \\int^0_{\\tau_1} d\\tau_2\n \\ldots \\int^0_{\\tau_{m+n-2}} d\\tau_{m+n-1} \\, e^{0^+ \\tau_1}\n e^{-i \\Delta E_1(\\tau_1-\\tau_2)} \n e^{-i \\Delta E_2(\\tau_2-\\tau_3)} \\cdots\n e^{-i \\Delta E_{m+n-1}\\tau_{m+n-1}}\n \\nonumber \\\\\n =\\, i^{m+n-1} \\frac{1}{\\Delta E_1+i0^+}\\, \\cdot \\, \n \\frac{1}{\\Delta E_2+i0^+}\n \\cdots \\frac{1}{\\Delta E_{m+n-1}+i0^+} \\; .\\end{aligned}$$ Here $\\Delta E_j$ is the difference of all energies going to the left minus all energies going to the right in each segment limited by $\\tau_j$ and $\\tau_{j+1}$. This includes the energies of the propagators and – if present – the energies of the tunneling, boson and virtual lines. ", "The convergence factor $e^{0^+ \\tau_1}$ is related to an adiabatic switching on of the tunneling term $\\bar{H}_T$. The factor $i^{m+n-1}$ cancels with the factor $(-i)^m$ from rule 4 above together with the prefactor $(-i)^{n-1}$ from the definition Eq.", " (\\[integral\\]). ", "Therefore, the corresponding rules in energy representation read:\n\n 1’. ", "\n\n: Draw all topologically different diagrams with fixed ordering of the vertices along the real axis, i.e., irrespective on which branch they are. ", "The vertices are connected by tunneling and boson lines as in time space. ", "In addition to the energy $\\epsilon_{\\chi}$ assigned to the propagators we assign an energy $E$ to each tunneling line. ", "For each boson line choose a direction (arbitrarily) and assign also an energy $E$. The external vertices are connected by virtual lines with energies $E_i$ ($i=2,\\ldots,n$) as described above.", "\n\n 2’. ", "\n\n: For each segment derived from $\\tau_j \\le \\tau \\le \\tau_{j+1}$ with $j=1,2,\\ldots,m+n-1$ assign a resolvent ${1\\over \\Delta E_j +i0^+}$ where $\\Delta E_j$ is the difference of the leftgoing minus the rightgoing energies (including the energies of the tunneling, boson and virtual lines).", "\n\n 3’. ", "\n\n: See rule 3 in time space.", "\n\n 4.’ ", "\n\n: For each coupling of vertices write $(-1)^v \\bar{\\gamma}^+_{\\alpha}(E)$, if the tunneling line of reservoir $\\alpha$ is going backward and $(-1)^v \\bar{\\gamma}^-_{\\alpha}(E)$, if it is going forward with respect to the closed time path (definition of $v$ see rule 4 in time space). ", "For each boson line write $P^+(E)$, if it is going backward and $P^-(E)$, if it is going forward with respect to the closed time path.", "\n\n 5’. ", "\n\n: The prefactor is given by $(-1)^b(-1)^c$, where $b$ is the total number of internal vertices on the backward propagator and $c$ the number of crossings of tunneling lines. ", "There may be a further minus sign due to the order of dot electron operators which emerges from the matrix elements $\\langle \\chi'| B | \\chi\\rangle$ discussed in rule 3.", "\n\n 6’. ", "\n\n: Integrate over the energies of tunneling and boson lines and sum over the reservoir and spin indices.", "\n\nCurrent conservation {#append proof}\n====================\n\nIn this appendix we prove Eq.", " (\\[rate relation\\]) and current conservation. ", "Let us consider any diagram $\\Sigma^{\\alpha p}_{\\chi',\\chi}(t',t)$ in the expression $$\\label{append rate}\n \\sum_{\\chi}\\sum_p p\\,\\Sigma^{\\alpha p}_{\\chi',\\chi}(t',t) \\, .$$ By changing the vertical position of the rightmost vertex we get a new diagram which has up to a minus sign the same value as the old diagram from which the new one was constructed. ", "If the rightmost tunneling of the old diagram line has a reservoir index different from $\\alpha$, then the new diagram is of the form $\\Sigma^{\\alpha p}_{\\chi',\\chi''}$, so that the sum of all these contributions in Eq.", " (\\[append rate\\]) is zero. ", "The other diagrams are divided into two classes: in the one (the other) class, the rightmost tunneling line of each diagram enters (leaves) the forward propagator or leaves (enters) the backward propagator. ", "The change of the vertical position of the rightmost vertex, then, increases (decreases) the value of $p$ by one, so that the new diagram is of the form $\\Sigma^{\\alpha p\\pm 1}_{\\chi',\\chi''}$. Furthermore, the old and the new diagram belong to different classes. ", "After changing the position of the rightmost vertex of only one class and then shifting the summation index $p$ in Eq.", " (\\[append rate\\]), we obtain exactly all diagrams of $\\sum_{\\chi}\\Sigma^{\\alpha +}_{\\chi',\\chi}$ which proves Eq.", " (\\[rate relation\\]).", "\n\nThe conservation of probability follows directly from the master equation (\\[master\\]). ", "Summation over $\\chi$ together with $\\sum_{\\chi}\\Sigma_{\\chi',\\chi}(t',t)=0$ yields $$\\label{probability conservation}\n \\sum_{\\chi} \\frac{d}{dt} P_\\chi (t) = 0\\,.$$\n\nTo prove current or charge conservation we first recognize that $$\\label{conserving condition}\n \\sum_{{\\chi\\atop N(\\chi)=p}}\\Sigma^{\\alpha+}_{\\chi',\\chi}=\n -\\sum_{{\\chi\\atop N(\\chi)=p+1}}\\Sigma^{\\alpha-}_{\\chi',\\chi}$$ where $N(\\chi)$ is the particle number on the dot for state $\\chi$. This relation follows directly by changing the vertical position of the rightmost vertex.", "\n\nAfter multiplication of the master equation (\\[master\\]) with $-e$ and $N(\\chi)$ and summation over $\\chi$, we use Eqs.", " (\\[rate-partial rate\\]) and (\\[conserving condition\\]), insert the current formula (\\[current-sigma\\]) and find the conservation law for the total charge flowing into the dot $$\\label{current conservation}\n \\sum_\\alpha I_\\alpha (t) = \\frac{d}{dt} Q(t)$$ where $Q=-eN=-e \\sum_{\\chi} N(\\chi) P_\\chi$ is the charge on the dot.", "\n\nIn the stationary and time-independent case Eq.", " (\\[current conservation\\]) reduces to the conservation of the tunneling current $$\\sum_\\alpha I^{st}_\\alpha = 0$$ whereas for the general case the r.h.s. ", "of Eq.", " (\\[current conservation\\]) is minus the sum over all displacement currents flowing in the reservoirs.", "\n\nAn important result of this appendix is that any approximation for the rates is current conserving provided that the condition Eq.", " (\\[conserving condition\\]) is satisfied. ", "This means that we always have to consider both vertical positions of the rightmost vertex.", "\n\nAnalytic solution for zero magnetic field {#append boson}\n=========================================\n\nFor zero magnetic field, i.e. $\\epsilon_{\\sigma}=\\epsilon$ for all $\\sigma$, we define the quantities $\\pi(E)\\equiv\\pi^\\sigma(E)$, $\\sigma(E)\\equiv\n\\sigma^\\sigma(E)$, and $$\\phi^+_\\alpha(E)=\\phi_{0,0}^{0,\\sigma}(\\alpha,\\sigma,E)\n \\qquad \\mbox{and} \\qquad\n \\phi^-_\\alpha(E)= \\sum_{\\sigma'} \n \\phi_{\\sigma,0}^{\\sigma,\\sigma'}(\\alpha,\\sigma',E)$$ which are independent of $\\sigma$. We get the integral equations $$\\label{integral equation}\n [E-\\epsilon -\\sigma(E)]\\phi^{\\pm}_\\alpha(E)=\n \\pm\\gamma^{\\pm}_\\alpha(E)-\\gamma_\\alpha(E)\\int dE'\n {1\\over E-E'+i0^+}\\,{\\phi^*}^{\\pm}(E')$$ where $\\gamma_\\alpha (E)=\\gamma^-_\\alpha (E) + M\\gamma^+_\\alpha (E)$ and $\\phi^\\pm (E)=\\sum_\\alpha\\phi^\\pm_\\alpha (E)$. Summing over $\\alpha$ and taking the imaginary part we obtain the solution $$\\label{ImPhi}\n \\mbox{Im}\\,\\phi^{\\pm}(E)=\\mp\\pi{\\lambda^{\\pm}\\over\\lambda}\n \\gamma(E)|\\pi(E)|^2$$ where we used the definitions $\\gamma^\\pm (E) = \\sum_\\alpha \\gamma^\\pm_\\alpha (E)$, $\\gamma (E) = \\gamma^- (E) + M\\gamma^+ (E)$, $$\\lambda^{\\pm}=\\int dE \\, \\gamma^{\\pm}(E)|\\pi(E)|^2\n \\qquad \\mbox{and} \\qquad\n \\lambda=\\int dE \\, |\\pi(E)|^2 \\, .$$ Furthermore, we obtain directly from (\\[integral equation\\]) a relation between $\\phi_\\alpha$ and $\\phi$ $$\\label{phi-alpha}\n \\gamma (E)\\phi^{\\pm}_\\alpha (E)=\\gamma_\\alpha (E)\n \\phi^{\\pm}(E)\\pm \\pi (E)[\\gamma (E) \\gamma^\\pm_\\alpha (E) -\n \\gamma^\\pm (E) \\gamma_\\alpha (E)]$$ Using (\\[rates-special\\]), the current rates follow from $\\Sigma^{\\alpha +}_{0,0}=2iM\\int dE \\, \\mbox{Im}\\, \\phi^+_\\alpha (E)$ and $\\Sigma^{\\alpha +}_{\\sigma,0}=2i\\int dE \\, \\mbox{Im}\\, \\phi^-_\\alpha (E)\\,$. With Eqs.", " (\\[ImPhi\\]) and (\\[phi-alpha\\]), the result is $$\\begin{aligned}\n\\label{current rate solution}\n \\Sigma^{\\alpha+}_{0,0}&=&-2\\pi i M \\left [\\frac{\\lambda^+}{\\lambda}\n \\lambda_\\alpha + \\int dE \\, |\\pi(E)|^2 [\\gamma^-(E)\\gamma^+_\\alpha (E)\n -\\gamma^+(E)\\gamma_\\alpha^-(E)]\\right ]\\\\\n \\Sigma^{\\alpha+}_{\\sigma,0}&=&2\\pi i \\left [\\frac{\\lambda^-}{\\lambda}\n \\lambda_\\alpha - M \\int dE\\, |\\pi(E)|^2[\\gamma^-(E)\\gamma^+_\\alpha (E)\n -\\gamma^+(E) \\gamma_\\alpha^-(E)]\\right ]\\,,\\end{aligned}$$ where $\\lambda_\\alpha = \\int dE \\gamma_\\alpha (E) |\\pi (E)|^2$.\n\nSumming the current rates over $\\alpha$ and using $\\sum_\\alpha \\lambda_\\alpha \n= \\lambda^- + M\\lambda^+ =1$, we get the total transition rates (note that $\\Sigma^{\\alpha-}_{\\chi',0}=0$) $$\\label{transition rate solution}\n \\Sigma_{0,0}=-2\\pi iM{\\lambda^+\\over\\lambda}\\qquad\\mbox{and}\\qquad\n \\Sigma_{\\sigma,0}=2\\pi i{\\lambda^-\\over\\lambda}$$ and the solution of the stationary Master equation (\\[stationary master\\]) reads $$\\label{P}\n P^{st}_0=\\lambda^- \\qquad \\mbox{and} \\qquad P^{st}_{\\sigma}=\\lambda^+ \n \\qquad \\mbox{with} \\qquad \\lambda^-+M\\lambda^+=1 \\, .$$ The stationary current follows from (\\[stationary current\\]) $I^{st}_\\alpha = -ie [P_0^{st}\\Sigma^{\\alpha+}_{0,0}+M P^{st}_\\sigma\n\\Sigma^{\\alpha +}_{\\sigma,0}]\\,$ (note that $\\Sigma^{\\alpha+}_{\\chi',\\sigma}=0$), which gives as the final result Eq.(\\[current boson\\]).", "\n\nP.L. 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{ "pile_set_name": "ArXiv" }

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[ "The bushido code essay\n\nBushido: the soul of japan is, along with the classic text hagakure by tsunetomo yamamoto (1659–1719), a study of the way of the samurai a best- seller in its. ", "Disclaimer: free essays on culture and mythology posted on this site were donated the bushido, the warrior code, became an expression of national morality. ", "Explore the ancient japanese code of chivalry used by the famous samurai warriors and test your understanding of feudal japan, samurai culture and. ", "Free samurai papers, essays, and research papers the samurai and the bushido code - the samurai were élite warriors in japan during the 1200's to the . ", "Learn about the role bushido, or the code of the samurai, play in modern business, politics, sports, and other aspects of japanese life.", "\n\nFree essay: the samurai were élite warriors in japan during the 1200's to the early 1700's fifth century japan saw conflicts with korea and china, but japan. ", "Posted in: essay, writing tagged: bushido code of loyalty, fallopian tubes, maverick, race, samurai, the last samurai, tom cruise, top ramen, vampires . ", "Bushido code essay free essay: when the samurai were about to engage in battle, most of them would state their rank, family name, and. ", "The popular view holds that bushido was a centuries-old code of behavior rooted in this essay provides an insight into why, despite his prolific writing and.", "\n\n2016 film essays in turn, wuxia's zen base influenced japan's bushido code, both in history and in storytelling samurai had similar codes of. ", "Literary works, as well as the media has shown us many elements of the bushido code such as honor, justice, loyalty, and bravery which have greatly imp.", "\n\nAmazoncom: bushido, the soul of japan ebook: inazo nitobe: kindle store like many reviews already published about bushido and its code of virtues, i also . ", "Knights in europe followed a code called chivalry and japanese samurais bushido stresses loyalty and self-sacrifice for one's superior while code of chivalry is set to protect the vulnerable samurais were interested in world essay. (", "1615–1868), the cult of the warrior, bushido, became formalized and an idealized code of behavior, focusing on fidelity to one's lord and honor, developed. ", "The samurai and the bushido code essay 1016 words | 5 pages the samurai were élite warriors in japan during the 1200's to the early 1700's fifth century.", "\n\nThis essay will present why i believe bushido is a paramount being principal areas of bushido code, have heavily influenced the japanese. ", "The japanese fighting spirit was based on the way of the samurai an the bushido code it was the spirit behind the kamikazee in the final year. ", "Bushido contrary to popular belief in both japan and the west, bushido--the way of the samurai--was not a universal, stratified code passed down as law,.", "\n\nThe bushido code outlines seven attributes of the samurai: one of the wonderful things about the obeyance of this code by the characters is it.", "\n\nIn this unit will be shintoism, buddhism, samurai and the bushido code lesson 4: make your own anime/manga character and 5 paragraph essay.", "\n\nNitobe describes bushido as the code of moral principles that the knights previous presentations: earlier versions of this essay were. ", "Literature essays, quiz questions, major themes, characters, and a full it was originally just for the samurai as part of their bushido code, but. ", "Bushido is the moral code that has provid 410 words 1 page an essay on the controversial topic of the atomic bomb the atomic bomb is the subject of much ." ]

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[ "An official website of the United States government, Department of Justice.", "\n\nHere's how you know\n\nThe .gov means it’s official.", "\nFederal government websites always use a .gov or .mil domain. ", "Before sharing sensitive information online, make sure you’re on a .gov or .mil site by inspecting your browser’s address (or “location”) bar.", "\n\nThe site is secure.", "\nThe https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.", "\n\n50 Years of Building Solutions, Supporting Communities and Advancing Justice\n\n1986 DNA Technology\n\nNIJ begins support for development of DNA technology applicable to criminal justice. ", "In 1998, NIJ establishes the National Commission on the Future of DNA Evidence, which provides recommendations on enhanced use of DNA from crime scene to the courtroom. ", "President George W. Bush in 2003 launches his DNA initiative to ensure accuracy and fairness in criminal justice. ", "OJP helps laboratories reduce their backlogs, provides training on solving cold cases, works to prevent wrongful convictions and reviews potential cases of post-conviction innocence. ", "Federal funding helps state and local DNA laboratories increase their capacity almost four-fold between 2005 and 2010." ]

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[ "Have you noticed that all modern Java web frameworks support Lambda-based implementation of RESTful services? ", "In general, it looks like this:\n\nget(\"/foo\", (req, resp) -> { application logic }); post(\"/bar\", (req, resp) -> { application logic });\n\nWhat's wrong with this style? ", "The style is fine, but we can do much better.", "\n\nNaive Implementation of a RESTful API With Rapidoid\n\nI will use the powerful Rapidoid web framework to implement a very simple RESTful service, which calculates the sum of the x and y parameter values:\n\npackage com.example; import org.rapidoid.setup.", "On; public class Main { public static void main(String[] args) { On.get(\"/sum\").json(req -> { int x = Integer.parseInt(req.param(\"x\")); // ugly! ", "int y = Integer.parseInt(req.param(\"y\")); // ugly! ", "return x + y; }); } }\n\nThis explicit parameter handling is verbose and ugly. ", "Who cares about the sweet Lambda syntax if retrieving a simple parameter needs so much code?", "\n\nRunning the application will start the Rapidoid server, and by navigating to http://localhost:8888/sum?x=3&y=7, we should see 10 .", "\n\nBeautiful Implementation of a RESTful API With Rapidoid\n\nLet's simply declare x and y as Lambda parameters.", "\n\npackage com.example; import org.rapidoid.annotation.", "Required; import org.rapidoid.setup.", "On; public class Main { public static void main(String[] args) { On.get(\"/sum\").json((@Required Integer x, @Required Integer y) -> x + y); } }\n\nThe Rapidoid web framework will retrieve the names, types, and annotations of the Lambda parameters and it will initialize them from the request parameters with automatic type conversion and validation.", "\n\nPOJO-Style Lambda Parameters\n\nOf course, we can wrap the x and y parameters inside a POJO ( SumParams ) and Rapidoid will do its magic (automatic instantiation, initialization, validation, etc.):", "\n\npackage com.example; import org.rapidoid.setup.", "On; class SumParams { public int x; // x is required public Integer y; // y is optional, can be null } public class Main { public static void main(String[] args) { On.get(\"/sum\").json((SumParams p) -> p.x + p.y); } }\n\nThis approach separates the structure of the parameters from the application logic and it scales well as the number of parameter grows, giving more space for annotations and maybe some extra logic.", "\n\nConclusion\n\nThe Java 8 Lambdas are great, but they can be used in either a beautiful or an ugly way. ", "The Rapidoid web framework embraces their ultimate power, empowering the developers to implement their APIs or applications in a clean, robust, and elegant way.", "\n\nI discussed the different coding styles through a trivial API implementation. ", "The hardest aspects of the web and API development haven't been covered (yet)." ]

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[ "In 2008, “Jane,” an engineer living in an apartment on Beacon Hill, saw her rent go up to $1,200 a month. ", "While only 24, she thought she might as well buy a place for that money, rather than see it “continuing to go down the drain.”", "\n\nShe started looking in Seattle, but found prices too high. ", "So she explored Renton, where she worked. ", "There she found a two-bedroom condominium for $175,000. ", "It was nothing fancy, but it had big windows and was near a slick new retail complex called The Landing. ", "She assumed she got a pretty good deal since housing prices had dipped since the height of the bubble. ", "When her boyfriend, also an engineer, became her husband, he moved in.", "\n\nWhat they didn’t know is that prices would not only continue to drop, but would go into free fall in south King County’s condo market—one that real-estate lawyer Craig Blackmon observes “has been absolutely hammered.”", "\n\nThe couple watched the value of their condo plummet to $80,000, then $70,000, then even lower. ", "A one-bedroom in their 120-unit complex is currently listed at $40,000. ", "In other south King County complexes, some condos are selling for under $30,000.", "\n\n“It kept me up at nights,” Jane wrote on a blog she started to chronicle the decision she was on the verge of making. “", "It would depress me at the most random times.” (", "Wary of provoking her bank, she uses pseudonyms for herself and her husband. “", "Cory,” on the blog—schrodingershouse.blogspot.com—and asked to be identified that way in this story.)", "\n\nUnlike millions of Americans caught by disastrous subprime mortgages and their own desire to live above their means, Jane and Cory can easily afford their mortgage, which with taxes runs roughly the same as the rent for her old Beacon Hill apartment. ", "Earning more than $100,000 between them, they could afford at least twice that. ", "The problem is they don’t want to stay in what Jane has taken to calling their “sad little condo”—and if they attempt to sell it, they’re looking at a huge loss.", "\n\nIn February they consulted a lawyer, who asked not to be identified for this article. “", "Walk away, right now!” ", "the couple recalls the lawyer saying. ", "The attorney indicated that the couple should simply stop making mortgage payments and let the bank foreclose on the property—a course of action, among relatively affluent homeowners, known as a strategic default. ", "In fact, the attorney said that if they were a business, they would be obligated to default. “", "It would be the right choice for our stockholders,” Cory relates.", "\n\nEven two or three years ago, they might have received different advice. ", "A 2010 study by Fannie Mae found that 88 percent of respondents believed it was morally wrong to default on one’s mortgage. ", "The business community was solidly behind this moral code, which served their interests. ", "The national conversation then centered on how to keep people in their homes.", "\n\nBut today no one paradigm governs the housing bust, which has given rise to market trends never before seen, unpredictable behavior by banks, and a new morality on the part of homeowners and the professionals who advise them. ", "While local figures on strategic defaults aren’t available, statistics for this state from the Mortgage Bankers Association show that defaults as a whole are at a record high. ", "Washington now has the fifth highest rate of mortgage payments that are more than 90 days past due—remarkable given that in 2007, Washington ranked almost dead last among states. ", "Just a year ago, it placed 20th.", "\n\n“Why is Washington state going in this direction?” ", "asks Scott Jarvis, director of the state Department of Financial Institutions. “", "Boeing is going great guns. ", "The last time I checked, Microsoft is still in business. ", "It’s not like we’re in the middle of the Arizona desert.”", "\n\nOne possibility, Jarvis acknowledges, is that a growing number of homeowners can pay their mortgage, but are choosing not to.", "\n\nBlackmon says such people now constitute “the vast majority” of his clients. ", "Likewise, fellow attorney David Leen says he gets “dozens of calls a day” from people wanting to leave their homes—and mortgages—behind them. ", "He says the calls come from “doctors, lawyers, people with means.”", "\n\n“Most of the cases I see are not economic hardship,” echoes Lars Neste, another attorney who frequently represents underwater homeowners. “", "A lot of them have done the math, and realize that the market isn’t going up anytime soon.”", "\n\nOr if it does go up—and the past few months have seen an uptick in Seattle—they believe it won’t be enough to justify all the money they’ll spend during the life of their mortgages. ", "Says Blackmon: “People might as well be burying money in their backyard.”", "\n\nAs in Jane and Cory’s case, the situation usually sparks tremendous anxiety—which is not to say it doesn’t have an upside. ", "As Blackmon points out, defaulters effectively get to squat in their homes “with zero housing costs.” ", "And because banks have gotten slower and slower at carrying out foreclosures—often because they don’t want the properties either—people are sometimes staying for years in homes they’ve stopped paying for. ", "The rules of the game have changed, if not been thrown out entirely.", "\n\nFor the past two years, Tami and Ron have been living in a stunning $1.4 million house in Shoreline. ", "Their housing costs during that time: zero. ", "That’s not what they intended, though.", "\n\nThe couple tells their convoluted tale one morning while their two children, who know nothing about the situation, are at school. (", "The desire to protect their kids, as well as anxiety about prompting the bank into further action, leads them to request that they be identified by their first names only.) ", "Their story, Tami admits, highlights the excesses of the bubble as much as the resulting chaos.", "\n\nUntil the bust, Tami and Ron were making a lot of money—particularly Tami, a chatty 42-year-old realtor. ", "Ron, 48, is a lawyer who until recently worked for the federal government. “", "Our best year, we probably made $300,000,” Tami says, about 70 percent of which came from her income selling houses.", "\n\nConsequently, they splashed out when, expecting a second child, they decided to tear down their small house and build a bigger one that stretched above a neighboring property to offer sweeping views of Puget Sound. ", "In 2007, they took out a $1.4 million “construction loan” to build the house, which was supposed to roll over into a conventional mortgage after they moved in. ", "They had so much money—and so much faith in the market—that they then bought, for $550,000, another house a few blocks away to live in during the construction.", "\n\nIn July 2009, almost done with construction, they moved into what Ron calls their “forever house,” with the Sound glimmering into almost every room, lots of room for the kids, an expansive kitchen, his-and-hers offices, and a second-floor hallway like a bridge floating through space, connecting the children’s bedrooms on one side with their parents’ on the other.", "\n\nIn December, they let the bank know they were wrapping up construction and ready for the loan to roll over. ", "But by then the bust had kicked in, and banks were being much tighter with mortgage requirements. ", "Still, the couple maintains, the rollover was part of the deal they’d signed in 2007. ", "The bank, according to Tami, told her it should only take a couple of weeks to process. ", "All they had to do was fill in a few more forms to update their income and other information.", "\n\nThe rollover never came through. ", "The couple continued to receive bills for their construction loan. ", "Then, in June 2010, according to bank documents reviewed by Seattle Weekly, they received a jaw-dropping invoice for nearly $1.4 million—the entire balance of their loan.", "\n\n“Oh, how weird. ", "I better call the bank,” Tami says, characterizing her initial reaction to the whopping bill. ", "At that point, she and Ron stress, they had paid every bill except the one before, an omission they attribute to their concern over why the loan hadn’t yet rolled over.", "\n\nShe says she was told that the bill was no mistake, but was given no explanation. ", "They simply had to pay $1.4 million, plus the $5,000 owed from the month before, within two weeks or they would be in default.", "\n\nPaying $1.4 million wasn’t an option. ", "They didn’t make that much money. ", "In fact, Tami’s income had dramatically dropped due to the housing crisis as well as the three-month hiatus she’d taken from work while undergoing treatment for thyroid cancer. ", "As for paying the back amount, she says there was no point, given that they would be in default anyway. “", "Screw you,” she says she thought. “", "I’m going to keep my $5,000.”", "\n\nA month later, the couple received a terse e-mail from a loan administrator containing several bullet-pointed reasons why they no longer qualified for a conventional mortgage. “", "Unacceptable payment history with us” is one, a charge the couple denies except for the one unpaid bill. “", "Misreps [sic] in file—co- borrower’s employment” is another. ", "The alleged misrepresentations are apparently a reference to the discrepancy between Tami’s income at the time she applied for the construction/rollover loan and her 2010 income, which she says dropped by about half.", "\n\nThe final reason: “Rental property in foreclosure.” ", "This appears to be a reference to the house they bought while building their dream home. ", "And here’s where the bust pulled a double whammy on them: “The market was super-hot,” Tami says, explaining the decision to buy rather than rent a temporary home. “", "I thought I’d sell it and make $150,000.” ", "Instead, when it came time to sell and move back into house #1, house #2 had lost $75,000.", "\n\nThey ended up doing a short sale, wherein banks agree to let houses sell for less than the mortgages and, in many cases, forgive the difference. ", "Before that, they’d missed close to a dozen payments, cognizant that banks are reluctant to approve short sales if they’re still getting money from homeowners. ", "Tami says the house fleetingly went into foreclosure during that time.", "\n\nNow Tami and Ron faced a foreclosure on their forever house. ", "They considered walking away, but this was the house they never wanted to leave. ", "So they hired an attorney, Leen, and decided to fight. ", "And they’ve kept living there. “", "A lot of people would think, ‘Good for you, you’re living rent-free,’ ” Tami says. ", "In reality, she says, “It’s not that cool.”", "\n\nThey went into bankruptcy to put off a foreclosure auction. ", "They achieved a delay, but shot their credit. ", "Ron found the stress “was affecting the quality of my work. ", "I made a decision to leave before anything got worse.” ", "He is now looking for work. ", "Tami also lost her zeal for work, and gained 30 pounds. ", "They’ve largely kept what’s going on a secret, which hasn’t always been easy—like the time a client stopped by just as a bank representative was nailing a foreclosure notice onto the house.", "\n\nTheir castle has more than a few chinks in it, since they hadn’t put the finishing touches on the house when they went into default, and don’t want to put any more money into it until they know they’re keeping it. ", "As they give a tour, they point out the paintings that are covering holes in the walls, the missing range hood that frequently results in a smoke-filled kitchen, the blackened cedar shingles, and the raggedy yard in desperate need of retaining walls—which prompts Tami to describe their home as the “big-ass house with a crappy yard.”", "\n\nTheir predicament has dragged on. ", "A second foreclosure auction was scheduled and then canceled after the state last year passed a law requiring banks to agree to mediation if requested by homeowners. ", "A mediation session was scheduled, delayed, then scheduled again for this past February. ", "A few days before it was to take place, the couple says, the bank called to request another postponement.", "\n\nSince February, they have heard nothing from the bank. ", "Leen figures they will. ", "The bank, he says, is not going to give Tami and Ron “a free house.”", "\n\n“We’re in limbo,” Tami says.", "\n\nBrian Heberling was a Bellevue-based real-estate investor, buying properties and fixing them up or renting them out, when the market started to collapse. ", "As his holdings suddenly lost value, he sensed a new business opportunity. ", "In 2009, he started Nest Financial, with the idea of helping others caught by the downturn. ", "Initially, one line of the business was devoted to securing loan modifications for homeowners—or trying to.", "\n\n“It was a maddening experience,” Heberling says of dealing with banks. “", "They wouldn’t modify.” ", "As a stalling tactic, he claims, lenders “would lie and say they didn’t have the paperwork” from homeowners.", "\n\nEventually, Heberling devoted himself to the other side of his business: helping people shed their homes. ", "He does this specifically through short sales, and says his five-person operation has now done several hundred.", "\n\nHe markets his business with populist rhetoric. “", "The banks are not on your side,” his website proclaims, adding that homeowners need a “take-no-prisoners team” to handle these financial sharks. ", "Wearing jeans and an untucked shirt one afternoon as he talks about his business, he evinces the chic/scruffy air of someone who enjoys wrestling with the suits of the financial world. ", "His rhetoric is even sharper in person: He talks about banks “raping the system” and participating in “fraud squared.”", "\n\nHeberling says he’s spent a lot of time researching the subject. ", "He traveled to the mountains of North Carolina, for instance, to take part in a multiday “boot camp” given by an attorney there named Max Gardner, who over fine meals and single-malt Scotch teaches colleagues how to challenge foreclosures by calling attention to errors by banks, who are often in the process of selling the mortgages to investors. ", "Inside Job, the scathing 2010 documentary that looks at this flawed process of mortgage “securitization”—which entails selling mortgages in investment bundles—is a touchstone for Heberling.", "\n\nHe talks tough about his tactics with banks, saying he’ll tell them to “take it or leave it” when presented with an offer. ", "But part of his strategy has to do with keeping some things to himself. ", "All banks require proof of a homeowner’s “hardship”—backed up by bank statements—before they will sign off on a short sale.", "\n\n“I don’t lie,” he says. “", "But I certainly don’t tell them what they don’t need to know.” ", "For instance, he elaborates, “What is the definition of a ‘bank statement’? ", "If a person’s got $250,000 in a retirement account and a bank’s not asking for it, I’m not necessarily going to disclose that.”", "\n\nHeberling says he’s proudest, however, not of his tangles with banks, but of his role as a kind of morality coach. ", "His clients, he says, have included a “high Microsoft wage earner” and a “prominent Seattle businessman,” who inevitably come to him “shocked and embarrassed.” ", "He tells them “they’ve done nothing wrong,” that a mortgage is “nothing more than a financial contract,” and that “there’s nothing wrong with a homeowner seeking a financial renegotiation.”", "\n\nBefore he gets to that, though, he insists that all his clients buy Underwater Home, a book by University of Arizona law professor Brent White.", "\n\nIn 2008, White was an untenured faculty member who specialized in “social psychology”—in essence, the ways groups of people make decisions. ", "The housing crisis hit Arizona early and hard, and as he watched, he wondered why, given the dramatic loss in value of homes, more people weren’t intentionally defaulting.", "\n\n“At that point, the default rate was quite low,” White recalls. ", "The statistics he gathered by late 2009 showed that as many as a third of American homeowners were underwater. ", "In Arizona, nearly half of homeowners had homes worth less than they owed; in parts of California, that figure reached 85 percent. (", "The Seattle area hit the one-third mark in 2011, according to a Zillow.com estimate.) ", "Negative equity sometimes reached into the hundreds of thousands of dollars.", "\n\nYet the rate of homeowners defaulting or going into foreclosure was only about 14 percent in 2009, according to Mortgage Bankers Association data. ", "One estimate, published that year in a joint report by consulting firms Experian and Oliver Wyman, suggested that strategic defaults accounted for just a quarter of the 14 percent.", "\n\nHomeowners’ reluctance to stiff their banks struck White as running counter to economic theory, which holds that people operate in their financial self-interest. ", "He wrote a paper in late 2009 about this disconnect, because, as he puts it now, “that’s what academics do,” especially in their publish-or-perish world.", "\n\n“Homeowners should be walking away in droves,” he wrote. “", "But they aren’t.” ", "He argued that people’s “shame and guilt” caused this “irrational” behavior. ", "They were indoctrinated in the deeply held belief that paying one’s mortgage is the right thing to do. ", "They also had an “exaggerated” idea of the consequences of not doing so. “", "A few years of poor credit need not seriously impact one’s life.”", "\n\n“I thought a few hundred people might look at it,” White says of his paper. ", "Instead, it set off a national debate. ", "He says he was not intending to present a moral argument, merely a societal analysis. ", "But the moral questions the paper raised by implication were central to its reception. ", "University of Chicago economist Luigi Zingales, in the policy magazine City Journal, warned that the erosion of the social stigma associated with not paying one’s mortgage, which White advised, would lead to “catastrophic results.” ", "Housing prices would fall even further into negative territory. ", "Zingales’ piece was entitled “The Menace of Strategic Default.”", "\n\n“There’s a moral dimension to this, as homeowners who simply abandon their homes contribute to the destabilization of their neighborhood and community,” echoed Fannie Mae spokesperson Brian Faith in a Washington Post piece about what author Kenneth Harney termed White’s “incendiary core message.”", "\n\nSo White tackled the morality questions head-on in further papers and then, in 2010, Underwater Home. ", "He argued that defaulting on one’s mortgage may in fact be the moral choice—even if one can technically afford it “according to some arbitrary debt-to-income ratio established by the banking industry”—when faced with a home that is no longer an investment but a threat to the “financial security” of one’s family. ", "To seal this argument in the public’s mind, he noted that corporations had no scruples about defaulting themselves: Witness Morgan Stanley’s 2009 default, despite record profits, on a $1.5 billion mortgage in San Francisco.", "\n\nWhite’s message no longer seems so incendiary. ", "He’s been quoted approvingly in such publications as The New Yorker and The New York Times. ", "And White notes that Suze Orman, the queen of financial responsibility, has taken to advising homeowners to default if they’re underwater by 20 percent or more and the bank refuses to negotiate a short sale. ", "Again and again, you can hear his thinking show up in the rhetoric of what The New Yorker‘s James Surowiecki sees as the beginnings of a “De-Occupy Your House Movement.”", "\n\nIn 2010, a Vancouver, Wash., man—who asks to be identified by his online name, “Izzle”—started to think about walking away from a house on which he owed $300,000, but which was then worth only about $225,000. ", "Researching the matter online, he stumbled across a website called LoanSafe.org, which offers a forum for underwater homeowners to discuss their plight.", "\n\nStrategic default was a popular discussion thread for posters from California, Nevada, Arizona, and Florida. ", "But Izzle says he was one of the first from Washington to post on the subject. ", "The housing crisis’ delayed local timetable, he figures, made strategic default a rare phenomenon in Washington. “", "A year later there are a lot of people from Washington [posting on the site],” Izzle says.", "\n\nOne LoanSafe member, “KentWalk”—she’s from Kent and walked away from her home—decided to invite local posters to get together in person to share their stories. ", "In January, about 20 met for lunch at Bellevue’s Rock Bottom Brewery, according to Izzle, who attended. ", "In late March, Izzle arranged another such lunch in Vancouver, and there is talk of yet another in Olympia.", "\n\nIzzle declined Seattle Weekly‘s request to attend the Vancouver lunch because, he says, his cohorts wanted to talk freely. ", "Judging by LoanSafe’s webpage, the conversation could have turned to some tactics that might raise eyebrows among the general public.", "\n\nConsider, for instance, the “HAMPSTER wheel game” described on the site—so named after the federal Home Affordable Modification Program, which facilitates loan modifications for people within certain income ranges. “", "Here’s how a homeowner plays,” the website declares. “", "The homeowner has already decided to walk, but wants to stay rent/mortgage free for as long as possible. ", "So the homeowner, even knowingly not qualified, submits the . . . [", "HAMP application process] to the loan servicer.” ", "When the homeowner is inevitably denied, the homeowner can simply reapply or perhaps try for a short sale, thereby dragging out the process even longer—perhaps “for a couple years. ", "This would indeed be a game well played!”", "\n\n“And for bonus points,” the website continues, “here’s an added strategy. ", "When the foreclosure sale appears imminent, the homeowner moves into new living accommodations, rents their home, and collects rent.”", "\n\nThis strategy isn’t entirely acceptable to lawyers in the field. ", "Blackmon, for instance, says he thinks “acting in bad faith” through bogus applications to HAMP “is a bad idea.” ", "Seattle real-estate attorney Lynn Arends says she warns homeowners against offering long-term leases for properties they’re about to default on. “", "That could be fraud,” she says.", "\n\nBut if defaulting homeowners rent out their places month-to-month, that’s a different story, Arends and others suggest. ", "After all, somebody should live in the home to make sure it’s kept up. ", "Defaulting or not, homeowners are responsible for their properties until the titles are transferred.", "For that reason, lawyers have no problem with homeowners staying put. “", "I tell clients to live there until the bitter end,” says Arends.", "\n\nAnd bankers apparently prefer it that way. “", "It’s better to have people in the home,” says Jim Pishue, president and CEO of the Washington Bankers Association. “", "Vacant homes lose value.” ", "Transients move in or homes fall into disrepair, dragging property values down throughout the neighborhood. ", "In fact, he says that’s partly why banks are so slow to foreclose: They don’t want a whole lot of homes that are just going to sit vacant.", "\n\nThe banks’ unhurried pace furthers the opportunities to game the system, which is exactly what some of Jane’s Facebook friends thought she was doing. ", "They called her a “freeloader” and a “squatter.” ", "Jane’s mom, too, questioned her and Cory about the ethics of their decision.", "\n\nOver coffee, the couple says they aren’t trying to pull one over on anyone. “", "My feeling is we’re on a sinking ship and we have to jump off,” Jane says.", "\n\nShe and her husband are quick to resort to numbers and technical specifications. “", "We’re engineers,” Cory says repeatedly. ", "They hand over a chart they created which shows, assuming modest market growth, that they wouldn’t break even on their condo until 2029.", "\n\nCory, initially unsure about defaulting, says he became convinced after scrutinizing the mortgage contract itself, which he stresses has written into it the possibility and the consequences of defaulting. “", "We’re putting up collateral—our house—and if we don’t pay you back, you have the right to take the collateral,” he says.", "\n\nHe felt himself on even firmer ground when he looked up the state’s foreclosure laws. ", "He found out that in Washington, unlike in some states, most foreclosures occur outside of court. ", "These “non-judicial” foreclosures generally leave homeowners owing nothing, even if a property sells for far less than what is owed. ", "That’s why some homeowners, in contrast to Heberling’s approach, favor foreclosures over short sales, which offer no such protection unless you’re crafty enough to negotiate it.", "\n\nThere are a few exceptions to these rules. ", "If you have a second mortgage, that debt lingers after a foreclosure. ", "More pertinent for Jane and Cory, a bank can decide to sue you for your full debt through a judicial foreclosure. ", "The couple’s lawyer, however, thinks this is unlikely to happen.", "\n\nThe more likely legal pitfall is that they could be sued by their homeowners’ association should they default on their $300-a-month dues in addition to their mortgage. ", "Attorney Dean Pody, who specializes in representing condo associations, says he’s frequently tasked with going after deadbeat residents. ", "Associations have little choice but to sue, he says, because they’re struggling to raise money for necessary repairs at a time when significant portions of their complexes are in default.", "\n\nPody recalls one suit against a “professional athlete”—he won’t say who—who stopped paying dues after he left town for another team and walked away from his condo. ", "The athlete, Pody says, was making more than $4 million a year, yet refused to pay $20,000 in back dues.", "\n\nThe problem, Pody says, is compounded by the recent trend of banks to be even slower to foreclose on condos; he says it can take up to three years. ", "Many speculate that this is because banks are on the hook for association dues once they assume ownership.", "\n\nJane and Cory say they understand this issue, and have therefore decided to continue to pay their dues. “", "We didn’t feel like stiffing our neighbors,” she says. ", "They have no such concern, however, about their bank—an institution Jane associates with public bailouts, excessive bonuses, and “heartless” behavior.", "\n\nDay 1 of their adventures in defaulting began on March 1. ", "The calls from the bank started coming immediately, and daily.", "\n\n“You have no obligation to even be polite,” their lawyer advised. “", "Just hang up.” ", "The attorney was concerned that the bank might find out the couple has money, and decide to exercise the rare option of a judicial foreclosure. ", "Jane and Cory do one better and don’t answer their home line at all. “", "That’s what cell phones are for,” Jane says.", "\n\nJane also plans to close her current bank account and move her money to a credit union. ", "That way, she figures, the bank that holds her mortgage (which at one time got automatic payments from her account at another bank) won’t be able to track her money. ", "It’s a move that corresponds nicely to her new anti- banking credo. “", "Part of this economic adventure has been realizing that I don’t want to be with a bank anymore,” Jane writes on her blog.", "\n\nShe also outlines her “next plan of action”: improving her credit score as much as possible before the looming tumble. ", "She went to a website called Credit Karma and found that her score would improve if she had more credit cards. ", "So she applied for a new one, also from a credit union.", "\n\n“My credit score went up one point!” ", "she says laughingly. ", "It’s not much compared to the hundreds of points it will soon fall. ", "But then again, she figures, so many people have foreclosures on their records that standards are a lot lower than they used to be.", "\n\nAt least for landlords, that definitely seems to be the case. “", "It’s not a big problem getting a rental if you’ve gone through a foreclosure,” says Tim Seth, president of the Washington Landlord Association. ", "In fact, he says that some landlords see a past foreclosure in favorable terms, reasoning that the prospective tenant “had the get-up-and-go to buy the house in the first place.”", "\n\nThe decreasing stigma attached to foreclosures would seem to foretell even more strategic defaults down the road. ", "But Glenn Crellin, associate research director for the University of Washington’s Runstad Center for Real Estate Studies, doesn’t think so. ", "He ventures that more homeowners may instead choose to refinance, because, for the first time, the feds are rolling out a program that may actually work.", "\n\nKnown as HARP 2.0 (the Home Affordable Refinance Program, a revamped version of the original), this program is designed specifically for underwater homeowners. ", "And it doesn’t matter whether you’re financially strapped or not, making it a good fit for potential strategic defaulters. ", "In fact, HARP 2.0 requires participants to be current on their mortgages, which Crellin says may give people incentive not to default.", "\n\nMatthew Gardner, a Seattle real-estate consultant catering to corporations and public entities, also hazards that the exodus of people from their homes may be slowing. ", "Exhibit A: King County currently has the lowest inventory of houses for sale it’s had in years. ", "In March, just over 5,000 single-family homes were on offer—less than half the number on the market in 2008.", "\n\n“A lot of people are waiting,” Gardner speculates. “", "They’re seeing signs of stability and hoping for modest price increases.”", "\n\nBut there’s another possibility, Gardner acknowledges: The sparse inventory might reflect, at least to some extent, the number of houses that are in a kind of netherworld, their owners defaulting and waiting for the banks to foreclose—a theory bolstered by the recent high default figures. ", "There’s even a name for this reservoir of forfeited homes: “the shadow inventory.”", "\n\nJust how many Tamis, Rons, Janes, and Corys are out there, though, is a question that escapes even the best real-estate economists. ", "Says Gardner, “That’s the great unknown.”", "\n\nnshapiro@seattleweekly.com\n\n\n\n\n\n" ]

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[ "Posted By RVBusiness On February 13, 2013 @ 1:16 pm In Breaking News | No Comments\n\nFollowing a huge fire at a former Mishawaka, Ind., foundry on Monday (Feb. 13), people who kept vehicles inside the building for storage are beginning to assess the damage to their property, including RVs and boats.", "\n\nWSBT TV, South Bend, reported that the RMG Foundry has been closed for a number of years.", "\n\nStarboard Choice Marine, located on Division Street in Mishawaka, is one of about a half-dozen businesses that stored high-ticket items such as RVs, in the warehouse.", "\n\n“Some of the boats were big boats with living quarters in them, some cabins, a lot of motorhomes,” said firefighter Jim Cocquyt, who also lost property in the blaze. “", "They all had LP tanks in them, various sizes, 30 pounds and above.”", "\n\nFire investigators believe it may have been those propane tanks exploding that people heard Monday night as firefighters battled the blaze.", "\n\nCocquyt says sections of the 200,000-plus square-foot foundry are 100-years-old, and a good portion of it is still standing.", "\n\nHowever, one section on the south side of the building is completely wiped out, where the losses could run into the millions.", "\n\n“Unfortunately, this was an occupied section, and there’s people that had a lot of valuable things. ", "You know, mostly toys, but those can be replaced,” added Cocquyt. “", "That’s why we have insurance. ", "None of the important things were really lost.”", "\n\nWSBT News did hear from a woman who lost a $40,000 pontoon boat in the fire. ", "She stores her boat through Starboard Choice Marine and says they told her they lost 121 boats in Monday’s fire.", "\n\nFire investigators expect it will take days before they can actually get into the building and start looking for an origin or a cause." ]

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[ "Q:\n\nRunning my work webapp locally but cant access the correct site\n\nI have been trying to get a Django webapp run in local. ", "What I have done was set my debug = True and basically carried my settings.py file over from my test server. ", "I finally got my python manage.py runserver [::]:8000 to run smoothly without errors. ", "The problem that I am now having is that I cant access the correct idea.", "\nSorry for any incorrect terms but lets say my application is at three links www.webapp.com, www.buying.webapp.com and www.selling.webapp.com where the SITE_IDs are 1,2,3. ", "I have learned to use localhost:8000 to access webapps before but that was with my simpler webapps.", "\nAny help would be appreciated! ", "Thank you.", "\nEDIT:\nI followed DOMAINS_URLCONF and found this \nclass SubdomainMiddleware:\n \"\"\" Make the subdomain publicly available to classes \"\"\"\n\n def process_request(self, request):\n domain_parts = request.get_host().split('.')", "\n if (len(domain_parts) > 2):\n subdomain = domain_parts[0]\n if (subdomain.lower() == 'www'):\n subdomain = None\n domain = '.'.join(domain_parts[1:])\n else:\n subdomain = None\n domain = request.get_host()\n# if subdomain in settings.", "DOMAINS_URLCONF:\n# request.__setattr__('urlconf',settings.", "DOMAINS_URLCONF[subdomain])\n try:\n current_site = Site.objects.get(domain=request.get_host())\n except Site.", "DoesNotExist:\n current_site = Site.objects.get(id=settings.", "SITE_ID)\n\n request.current_site = current_site\n #settings.", "SITE_ID = current_site.id\n request.subdomain = subdomain\n request.domain = domain\n\nA:\n\nFor that to work, you simply need different domains on your local machine. ", "That can be simply achieved by editing your local /etc/hosts file (on windows it is C:\\Windows\\System32\\drivers\\etc\\hosts). ", "Simply add this line in it:\n127.0.0.1 buying.x.localhost selling.x.localhost\n\nUpdate:\nAfter seeing your middleware code, there is one more caveat: local domains for buying and selling should have at least 3 parts. ", "I've just added .x in the middle of domains above, so it should be parsed correctly by this middleware. ", "You can structure those urls as you wish, but they have to have at least 3 parts and the first part has to match one of the subdomains of your project.", "\nAfter doing this, if you type just localhost:8000 in the address bar of your browser, you should see the main page, by entering buying.x.localhost:8000 you will see the content of buying. ", "subdomain and by entering selling.x.localhost:8000 you will see content of selling. ", "subdomain.", "\n\n" ]

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[ "\nAI Crowd Anonymization for Black Lives Matter – Stanford ML Group - manderchar\nhttp://blm.stanford.edu\n======\nmanderchar\nCrowd anonymization AI to fight police use of face recognition. ", "Detects faces\namong huge crowds of BLM protesters and shields their faces with a BLM fist.", "\n[http://blm.stanford.edu](http://blm.stanford.edu)\n\n" ]

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[ "Koloonella hasta\n\nKoloonella hasta is a species of sea snail, a marine gastropod mollusk in the family Murchisonellidae, the pyrams and their allies.", "\n\nDistribution\nThis marine species occurs off Eastern Australia and New South Wales.", "\n\nReferences\n\n Iredale, T. & McMichael, D.F. (1962). ", "A reference list of the marine Mollusca of New South Wales. ", "Memoirs of the Australian Museum. ", "11 : 1-109\n\nExternal links\n To World Register of Marine Species\n\nCategory:Murchisonellidae\nCategory:Gastropods described in 1951" ]

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[ "Can you guess which hair color gets the most attention when it comes to online dating? ", "According to the new data, blonde Russian girls are on the top of the searching list. ", "Russian girls with brown hair are on the second place. ", "The third place is being shared between Russian girls with red hair and black haired ladies.", "\n\nOf course we don't think that someone would date only girls with a certain hair color, but it’s great to know your preferences. ", "We can help you find any type of a girl 33-80 years whether it’s a beautiful blonde Russian woman or a pretty girl with black hair." ]

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[ "1. ", "Introduction\n===============\n\nThe *Arenaviridae* is a diverse and growing family of viruses, presently containing 24 recognized species \\[[@B1-viruses-05-00528]\\] and several other proposed species \\[[@B2-viruses-05-00528],[@B3-viruses-05-00528],[@B4-viruses-05-00528],[@B5-viruses-05-00528],[@B6-viruses-05-00528],[@B7-viruses-05-00528],[@B8-viruses-05-00528],[@B9-viruses-05-00528],[@B10-viruses-05-00528],[@B11-viruses-05-00528],[@B12-viruses-05-00528],[@B13-viruses-05-00528],[@B14-viruses-05-00528]\\], including many of considerable significance to human health ([Table 1](#viruses-05-00528-t001){ref-type=\"table\"}). ", "Based on their antigenicity and phylogenetic analysis, and underscored by their geographical distribution, arenaviruses can be taxonomically divided into the Old World arenavirus (OWAV) and the New World arenavirus (NWAV) serocomplexes \\[[@B2-viruses-05-00528]\\].", "\n\nAmong the OWAVs, both Lassa virus (LASV) and the recently identified Lujo virus (LUJV) are capable of causing hemorrhagic fever (HF) \\[[@B7-viruses-05-00528],[@B15-viruses-05-00528]\\]. ", "While the number of Lujo cases thus far reported has been minimal, LASV represents a major public health problem in Western Africa, where it has been estimated to cause 300,000--500,000 cases annually, resulting in 3,000--5,000 deaths \\[[@B16-viruses-05-00528]\\]. ", "In addition, while lymphocytic choriomeningitis virus (LCMV) usually causes asymptomatic illness in healthy individuals, in some cases it is known to cause aseptic meningitis, and while fatalities are rare, vertical transmission during pregnancy can have severe deleterious effects on the fetus. ", "Further, severe infection has been reported in a few cases involving transplant patients \\[[@B17-viruses-05-00528]\\], indicating that in immunocompromised individuals LCMV infection may pose additional risks. ", "The remaining members of this serocomplex do not appear to be significant human pathogens.", "\n\nIn the case of the NWAV serocomplex, viruses can be further divided into three clades (A, B and C) based on phylogenetic relationships \\[[@B18-viruses-05-00528]\\], although recombination events between these clades are also possible. ", "This is the case with Whitewater Arroyo virus (WWAV) as well as other North American arenaviruses, which are clade A/B recombinants \\[[@B19-viruses-05-00528]\\]. ", "Interestingly, this separation into distinct clades also corresponds to differences in receptor usage and disease phenotype \\[[@B2-viruses-05-00528]\\]. ", "The NWAVs are responsible for at least five distinct HFs \\[[@B8-viruses-05-00528],[@B18-viruses-05-00528]\\], collectively referred to as South American Hemorrhagic Fevers (SAHFs), which are caused by Junìn (JUNV), Machupo (MACV), Chapare (CHPV), Guanarito (GTOV) and Sabiá (SABV) viruses. ", "All of these viruses are members of the Clade B NWAVs and have been shown to use the Transferrin alpha receptor (TfR1) for entry into target cells \\[[@B20-viruses-05-00528],[@B21-viruses-05-00528]\\]. ", "While non-pathogenic Clade B members use the TfR1 orthologs of various other mammalian species \\[[@B22-viruses-05-00528]\\], some evidence also exists that they can infect cells efficiently in a completely TfR1-independent manner \\[[@B23-viruses-05-00528]\\]. ", "NWAVs of Clade C have been shown to use α-dystroglycan as a receptor \\[[@B24-viruses-05-00528]\\], similar to OWAVs \\[[@B25-viruses-05-00528]\\].", "\n\nIn total arenaviruses cause at least seven distinct hemorrhagic fevers, making them the largest family of HF-causing viruses currently known. ", "In addition, both the NWAVs and OWAVs contain a number of human apathogenic strains, which are in some cases quite closely related to the agents of HF disease. ", "The basis for these marked differences in virulence among genetically closely related viruses remains unknown. ", "Similarly, despite their significance for public health, many details of the arenavirus lifecycle, including the pathways used for virus morphogenesis and budding, remain poorly understood. ", "However, in recent years significant progress has been made in this area and has revealed interesting commonalities in the mechanisms used by the various arenaviruses but also striking differences that remain to be fully explained from a mechanistic stand-point. ", "Here we attempt to summarize the current state of our knowledge, including recent findings, in the field of arenavirus morphogenesis and budding.", "\n\nviruses-05-00528-t001_Table 1\n\n###### \n\nViruses of the family *Arenaviridae*, their geographic distribution, reservoirs andassociated human diseases.", "\n\n -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n Virus Distribution Reservoir Human Disease\n ---------------------------------------- -------------------------- ------------------------------------ ----------------------------------------------------- ----------------------------------------------------------\n **Old World Arenviruses** **Dandenong virus\\*** Yugoslavia (?)\\ ", " Unknown Febrile illness with encephalopathy (transplant-related)\n Australia (?) ", " \n\n **Gbagroube virus\\*** Côte d\\'Ivoire Mus (Nannomys) setulosus None known \n\n **Ippy virus** Central African Republic *Arvicanthus spp.* ", " None known \n\n **Lassa virus** Western Africa *Mastomys natalensis* Febrile illness, hemorrhagic fever in severe cases \n\n **Lymphocytic Choriomeningitis virus** Worldwide Mus musculus Febrile illness, aseptic meningitis in severe cases \n\n **Lujo virus** Zambia Unknown Hemorrhagic fever \n\n **Luna virus\\*** Zambia *Mastomys natalensis* None known \n\n **Kodoko virus** **\\*** Guinea Mus (Nannomys) minutoides None known \n\n **Menekre virus\\*** Côte d\\'Ivoire Hylomyscus *spp.* ", " None known \n\n **Merino Walk virus** **\\*** South Africa *Myotomis unisulcatus* None known \n\n **Mobala virus** Central African Republic *Praomys jacksoni* None known \n\n **Mopeia virus** Mozambique *Mastomys natalensis* None known \n\n **Morogoro virus** **\\*** Tanzania *Mastomys spp.* ", " None known \n\n **New World Arenaviruses** **Allpahuayo virus** Peru *Oecomys spp.* ", " None known\n\n **Amapari virus** Brazil *Oryzomys gaeldi Neacomys guianae* None known \n\n **Bear Canyon virus** USA Peromyscus californicus None known \n\n **Big Brushy Tank virus\\*** USA *Neotoma albigula* None known \n\n **Catarina virus** **\\*** USA *Neotoma micropus* None known \n\n **Chapare virus** Bolivia Unknown Hemorrhagic fever \n\n **Cupixi virus** Brazil *Oryzomys spp.* ", " None known \n\n **Flexal virus** Brazil *Oryzomys spp.* ", " Febrile illness(Lab-acquired) \n\n **Guanarito virus** Venezuela *Zygodontomys brevicauda* Hemorrhagic fever \n\n **Junín virus** Argentina *Calomys musculinus* Hemorrhagic fever \n\n **Latino virus** Bolivia *Calomys callosus* None known \n\n **Machupo virus** Bolivia *Calomys callosus* Hemorrhagic fever \n\n **Oliveros virus** Argentina *Bolomys spp.* ", " None known \n\n **Paraná virus** Paraguay *Oryzomys buccinatus* None known \n\n **Pichinde virus** Columbia *Oryzomys albigularis* None known \n\n **Pinhal virus** Brazil *Calomys tener* None known \n\n **Pirital virus** Venezuela *Sigmodon alstoni* None known \n\n **Real de Catorce virus** **\\*** Mexico *Neotoma leucodon* None known \n\n **Sabiá virus** Brazil Unknown Hemorrhagic fever \n\n **Skinner Tank virus** **\\*** USA *Neotoma mexicana* None known \n\n **Tacaribe virus** Trinidad *Artibeus spp.* (", "bat) Possible febrile illness (Lab-acquired) \n\n **Tamiami virus** USA *Sigmodon hispidus* None known \n\n **Tonto Creek virus** USA *Neotoma albigula* None known \n\n **Whitewater Arroyo virus** USA *Neotoma albigula* Possible hemorrhagic fever \n -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n\n**\\***proposed species not yet classified by the ICTV\n\n2. ", "Arenavirus Biology\n=====================\n\nArenavirus particles are enveloped and highly pleomorphic, having a diameter of 50-300 nm ([Figure 1](#viruses-05-00528-f001){ref-type=\"fig\"}). ", "They contain a bi-segmented negative strand RNA genome that encodes for four viral proteins. ", "The small genome segment (S segment, \\~3.5 kb) contains genes for the surface glycoproteins (GP1 and GP2) and nucleoprotein (NP), while the large genome segment (L segment, \\~7.5 kb) encodes the RNA-dependent RNA polymerase (L) and a multifunctional protein known as the small RING-finger protein (Z).", "\n\n{#viruses-05-00528-f001}\n\nTogether with NP and L the two ambisense genome segments are assembled into ribonucleoprotein complexes (RNPs), which serve as the templates for transcription and replication by the RNA-dependent RNA polymerase, L. Indeed, studies have shown that together NP and L represent the minimal protein requirements for transcription and replication of both NWAVs and OWAVs \\[[@B26-viruses-05-00528],[@B27-viruses-05-00528],[@B28-viruses-05-00528],[@B29-viruses-05-00528],[@B30-viruses-05-00528]\\]. ", "In addition to its role in viral transcription and replication, NP also functions as an interferon (IFN) antagonist \\[[@B31-viruses-05-00528]\\]. ", "NP interferes with interferon regulatory factor 3 (IRF3) activation, thereby inhibiting the induction of IRF3-dependent promoters, a process that is likely to be fundamental in the ability of arenaviruses to overcome the host innate immune response \\[[@B32-viruses-05-00528]\\]. ", "The glycoprotein GP is the only arenaviral surface protein and is synthesized as a precursor, GPC. ", "It is first cleaved by signal peptidase to yield a stable signal peptide (SSP), which remains non-covalently bound to the glycoprotein \\[[@B33-viruses-05-00528],[@B34-viruses-05-00528],[@B35-viruses-05-00528]\\]. ", "Association with SSP is necessary for further cleavage of the glycoprotein into the receptor-binding ectodomain subunit, GP1, and transmembrane-spanning fusion competent subunit, GP2, by the proprotein convertase site 1 protease/subtilisin kexin isozyme-1 (S1P/SKI-1) during its transport through the secretory pathway \\[[@B36-viruses-05-00528],[@B37-viruses-05-00528],[@B38-viruses-05-00528]\\]. ", "This mature GP complex, consisting of GP1, GP2 and the SSP is located on the surface of virus particles \\[[@B39-viruses-05-00528]\\].", "\n\nDespite being the smallest of the arenavirus proteins, with a size of only 89 to 103 amino acids, Z has been demonstrated to take part in a number of processes and interactions central to the viral lifecycle ([Figure 2](#viruses-05-00528-f002){ref-type=\"fig\"}). ", "Consistent with its numerous and varied biological roles, Z has been shown to participate in multiple interactions including directly interacting with the polymerase as well as with NP and GP, in addition to forming homo-oligomers \\[[@B40-viruses-05-00528],[@B41-viruses-05-00528],[@B42-viruses-05-00528]\\]. ", "The Z protein was first identified as a zinc-binding RING protein and found to be a negative regulator of genome transcription and replication \\[[@B28-viruses-05-00528],[@B43-viruses-05-00528]\\]. ", "However, since then it has also been shown to interact with several cellular factors, including the ribosomal P0 protein and the promyelocytic leukaemia protein (PML), which is redistributed to the cytoplasm after binding to Z \\[[@B44-viruses-05-00528],[@B45-viruses-05-00528],[@B46-viruses-05-00528]\\]. ", "Further, an interaction of Z with the eukaryotic translation initiation factor 4E (eIF4E), which is accompanied by repression of eIF4E-dependent translation in the host cell, was identified \\[[@B47-viruses-05-00528]\\]. ", "Additional studies have recently revealed an IFN regulating function for the Z protein of NWAVs (i.e. GTOV, JUNV, MACV and SABV), but not OWAVs (i.e. LASV and LCMV). ", "This occurs as a result of its ability to bind to retinoic acid-inducible gene 1 (RIG-I) and thereby inhibit Type I IFN induction via the RIG-I signalling pathway \\[[@B48-viruses-05-00528]\\], helping to overcome the innate immune response of the host cell. ", "In addition to these regulatory functions, the Z protein of arenaviruses has been shown for several species to function as a matrix protein \\[[@B49-viruses-05-00528],[@B50-viruses-05-00528],[@B51-viruses-05-00528],[@B52-viruses-05-00528],[@B53-viruses-05-00528]\\]. ", "Characteristic for such proteins is their ability to mediate their own release in the form of virus-like particles, which resemble authentic virus particles in their morphology but lack the viral genomic material \\[[@B54-viruses-05-00528]\\].", "\n\n{#viruses-05-00528-f002}\n\n3. ", "Virus Budding and Host Cell Sorting\n======================================\n\nThe host cell membrane represents a significant barrier to the egress of newly formed or forming viral particles. ", "In order to overcome this physical barrier many viruses have evolved to take advantage of host cell sorting pathways, in particular those directing vesicle formation into multi-vesicular bodies (MVBs). ", "Thus for many enveloped viruses, including arenaviruses, it has been shown that they recruit the endosomal sorting complex required for transport (ESCRT) machinery of the host cell to facilitate their release \\[[@B55-viruses-05-00528],[@B56-viruses-05-00528]\\]. ", "However, there are also viruses whose release appears to be completely independent of the cellular ESCRT complexes \\[[@B55-viruses-05-00528],[@B56-viruses-05-00528]\\]. ", "The ability of viruses to subvert the cellular ESCRT machinery to drive viral budding likely derives from the fact that both of these processes involve budding being directed away from the cytoplasm, either into MVBs, in the case of vesicular budding, or into the extracellular space, in the case of virus budding.", "\n\nIn the uninfected host cell the ESCRT-system is involved in MVB vesicle formation and cytokinesis. ", "It consists of six complexes (ESCRT-0, -I, -II, -III, Alix/AIP1 and Vps4) that are recruited sequentially to the sites of membrane remodelling and fission. ", "While ESCRT-0 binds to and accumulates ubiquitinated cargo for delivery into the MVBs, the ESCRT-I and ESCRT-II complexes are recruited and co-assemble on the membrane to drive bud formation. ", "ESCRT-III, which is responsible for final membrane scission, is recruited by binding to ESCRT-I and/or Alix/AIP1, which connects these complexes. ", "Finally the AAA-type ATPase Vps4 mediates disassembly of the complex and its subsequent recycling \\[[@B57-viruses-05-00528]\\]. ", "During virus infection some of these ESCRT-complexes are targeted by the viral matrix protein, and in some cases also other viral proteins, to the sites of viral budding where they mediate the budding process of membrane enveloped particles using an analogous mechanism.", "\n\nFor many enveloped viruses it has been shown that the self-budding activity of their matrix protein is functionally dependent on the presence of late domain motifs within their sequences (reviewed in \\[[@B56-viruses-05-00528],[@B57-viruses-05-00528],[@B58-viruses-05-00528]\\]). ", "To date several late domain sequences have been reported ([Table 2](#viruses-05-00528-t002){ref-type=\"table\"}), with the tetrapeptide motifs PPxY, PT/SAP, and YxxL (x = any amino acid) appearing to be the most prevalent \\[[@B55-viruses-05-00528]\\]. ", "However, more recently θPxV (θ = hydrophobic amino acid) was identified as the functional late-domain sequence in simian virus 5 (SV5) \\[[@B59-viruses-05-00528]\\] and although its interaction partner remains unknown, its identification serves to reinforce the possibility that other as yet unidentified late-domain motifs may also exist.", "\n\nviruses-05-00528-t002_Table 2\n\n###### \n\nLate-domain motif usage among different virus families.", "\n\n -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n Motif Virus families using this motif (interacting proteins) References\n -------- -------------------------------------------------------- -----------------------------------------------------------------------------------------------------------------------------\n YxxL *Arenaviridae* (NP, Z)\\ \\[[@B60-viruses-05-00528],[@B61-viruses-05-00528],[@B62-viruses-05-00528],[@B63-viruses-05-00528],[@B64-viruses-05-00528]\\]\n *Retroviridae* (Gag)\\ \n *Paramyxoviridae* (C, M) \n\n PPxY *Arenaviridae* (Z)\\ \\[[@B52-viruses-05-00528],[@B65-viruses-05-00528],[@B66-viruses-05-00528],[@B67-viruses-05-00528]\\]\n *Filoviridae* (VP40)\\ \n *Retroviridae* (Gag)\\ \n *Rhabdoviridae* (M) \n\n PT/SAP *Arenaviridae* (Z)\\ \\[[@B52-viruses-05-00528],[@B66-viruses-05-00528],[@B68-viruses-05-00528],[@B69-viruses-05-00528],[@B70-viruses-05-00528]\\]\n *Filoviridae* (NP, VP40)\\ \n *Retroviridae* (Gag)\\ \n *Rhabdoviridae* (M)\\* \n\n θ\\ *Paramyxoviridae* (M) \\[[@B59-viruses-05-00528]\\]\n PxV \n -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n\nX indicates any amino acid, while θ indicates hydrophobic amino acids.", "\n\n\\* not important for budding\n\nLate-domain motifs promote viral budding by mediating the interaction of viral proteins with components of the cellular ESCRT-machinery or ESCRT-associated ubiquitin ligases, an observation that appears to hold true for a variety of virus families with which these studies have been conducted. ", "The viral PT/SAP motif has been shown to recruit the ubiquitin-binding ESCRT-I-component tumor susceptibility gene 101 (Tsg101) to initiate viral budding \\[[@B51-viruses-05-00528],[@B66-viruses-05-00528],[@B68-viruses-05-00528],[@B69-viruses-05-00528],[@B71-viruses-05-00528]\\]. ", "This interaction occurs through an N-terminal ubiquitin E2 variant (UEV) domain, which is normally responsible for interaction of the ESCRT-I complex with ESCRT-0 and ubiquitinated cargo \\[[@B72-viruses-05-00528]\\] ([Figure 3](#viruses-05-00528-f003){ref-type=\"fig\"}). ", "A C-terminally located PTAP motif in Tsg101 is also capable of binding to the UEV domain and in doing so blocks access of additional molecules, thus serving an auto-regulatory function \\[[@B72-viruses-05-00528]\\]. ", "For the PPxY motif, Nedd4-like ubiquitin ligases have been identified as an interaction partner \\[[@B66-viruses-05-00528],[@B73-viruses-05-00528],[@B74-viruses-05-00528]\\] with interaction taking place between the PPxY tetrapeptide and a series of WW-domains in Nedd4-like proteins ([Figure 3](#viruses-05-00528-f003){ref-type=\"fig\"}). ", "Finally the MVB component Alix/AIP1 can also be recruited by viral matrix proteins and this occurs through binding of the YxxL motif to the V domain \\[[@B61-viruses-05-00528],[@B64-viruses-05-00528],[@B75-viruses-05-00528],[@B76-viruses-05-00528]\\] ([Figure 3](#viruses-05-00528-f003){ref-type=\"fig\"}). ", "In addition Alix/A1P1 contains a C-terminal PSAP, which mediates its interaction with Tsg101, again through the UEV domain of Tsg101, and a Bro1 domain, which is responsible for interaction with CHMP4, an important ESCRT-III component \\[[@B76-viruses-05-00528]\\].", "\n\n{#viruses-05-00528-f003}\n\n4. ", "Requirements for Arenavirus Budding\n======================================\n\nThe Z protein has been shown for several arenaviruses to serve as the viral matrix protein providing the principle driving force for the budding of virus particles, and as such it is capable of forming virus like particles (VLPs) when expressed alone \\[[@B54-viruses-05-00528]\\]. ", "During budding, Z forms an inner layer beneath the viral envelope and is also able to interact with NP and GPC and to recruit them independently into viral particles. ", "This NP-Z interaction is likely critical for incorporation of RNPs into progeny virions during the budding process. ", "It has been directly shown for several arenaviruses that the budding activity of Z is linked to the presence of late domains and/or depends on the ESCRT pathway \\[[@B49-viruses-05-00528],[@B51-viruses-05-00528],[@B53-viruses-05-00528],[@B71-viruses-05-00528]\\]. ", "However, while one or more proline-rich late-domain (PT/SAP and/or PPxY) in the C-terminus and/or a YxxL motif located in the RING domain appear to be important for assembly and budding, the number and combination of the late domains within Z varies between different arenavirus species ([Figure 4](#viruses-05-00528-f004){ref-type=\"fig\"}).", "\n\n{#viruses-05-00528-f004}\n\nSequence analysis of OWAVs shows that they generally contain either a PPxY motif alone or both a PPxY and a PT/SAP motif at their C-terminus. ", "In addition, several of the OWAVs contain an additional YxxL motif in the RING domain. ", "The exceptions to this are Merino Walk virus, which based on the available sequencing data does not appear to have any known late-domain motifs, and LUJV, which displays an unusual late domain motif arrangement more closely related to that of the NWAVs. ", "This may reflect the fact that while LUJV is classified as belonging to the OWAVs, it is only distantly related to all other known OWAVs \\[[@B7-viruses-05-00528]\\], which might explain its distinct late domain arrangement. ", "In contrast to the OWAVs, nearly all NWAVs contain a single PT/SAP motif in the C-terminus, in addition to a YxxL in the RING domain. ", "The only exception is TCRV, in which the canonical PT/SAP motif is replaced with an ASAP motif, which is not known to be functional in budding.", "\n\nInterestingly, despite the presence of multiple late domain motifs in some arenaviruses, the extent to which virus budding is dependent on each of these motifs seems to vary between viruses ([Table 3](#viruses-05-00528-t003){ref-type=\"table\"}). ", "For OWAVs the proline-rich late-domains (PPxY and PT/SAP) have so far been shown to play the more significant role in Z-induced virus budding. ", "However, while LCMV contains only a single PPxY motif in Z, which was identified as the major determinant responsible for budding \\[[@B51-viruses-05-00528]\\], LASV Z contains both a PTAP and PPxY motif. ", "In this case, while both motifs contribute to LASV particle release, PPxY has been reported to play the dominant role \\[[@B52-viruses-05-00528]\\]. ", "Interestingly, additional studies using siRNAs have revealed that LASV budding depends on the ESCRT-components Tsg101 and Vps4A/B but not Nedd4 or Alix/AIP1 \\[[@B71-viruses-05-00528]\\]. ", "This is despite the presence of a YxxL motif in the LASV Z protein, as well as the important role in LASV budding of the PPxY motif. ", "Thus, this observation leaves the role, if any, of the YxxL late domain, as well as the identity of the ESCRT pathway interaction partner for the PPxY motif, unclear. ", "For Mopeia virus (MOPV) it was also shown that the YxxL motif in Z does not contribute to its budding activity, but rather that it plays an important role in NP incorporation into Z-induced VLPs \\[[@B60-viruses-05-00528]\\].", "\n\nviruses-05-00528-t003_Table 3\n\n###### \n\nContributions of various matrix protein (Z) motifs and nucleoprotein(NP) to arenavirus budding.", "\n\n Influence on Budding Ref. ", " \n ---------------------------- ---------------------- ------ ----- ----- ----- ----------------------------------------------------- -----------------------------------------------------\n **Old World Arenaviruses** **LCMV** +++ +++ N/A N/A ? ", " \\[[@B51-viruses-05-00528],[@B77-viruses-05-00528]\\]\n **LASV** +++ +++ \\+ ?\\* ", " ? ", " \\[[@B52-viruses-05-00528],[@B78-viruses-05-00528]\\] \n **MOPV** +++ ? ", " ? ", " \\- \\- \\[[@B60-viruses-05-00528],[@B79-viruses-05-00528]\\] \n **New World Arenaviruses** **JUNV** +++ N/A +++ ? ", " \\- \\[[@B49-viruses-05-00528],[@B80-viruses-05-00528]\\]\n **TCRV** +++ N/A N/A \\- +++ \\[[@B53-viruses-05-00528],[@B80-viruses-05-00528]\\] \n\n\\*LASV budding does not depend on Alix/AIP1\n\nN/A, not applicable\n\nFor the NWAV JUNV, the release of chimeric VLP was shown to be heavily dependent on the PTAP motif \\[[@B49-viruses-05-00528]\\], but the role of the YxxL motif in JUNV Z has so far not been analysed. ", "Intriguingly, despite containing no canonical proline-rich late domains (the PSAP motif is replaced with an ASAP motif at the corresponding position), TCRV Z still functions as a matrix protein and initiates the release of VLPs in the absence of other viral proteins. ", "However, both the ASAP and the YxxL motifs in TCRV Z appear to be expendable for the budding activity of Z \\[[@B53-viruses-05-00528],[@B80-viruses-05-00528]\\], which is surprising given that TCRV Z can be shown by co-immunoprecipitation to bind to Alix/AIP1 ([Figure 5](#viruses-05-00528-f005){ref-type=\"fig\"}A). ", "Further, the release of TCRV VLPs is still dependant on the ESCRT pathway and has been shown to require Vps4A/B but not Tsg101 activity \\[[@B53-viruses-05-00528]\\]. ", "This finding also supports the lack of functional activity of the TCRV ASAP motif to mediate Z-Tsg101 interaction. ", "Finally, recent studies have also revealed an essential role for NP in promoting TCRV budding, thereby providing further evidence that TCRV uses a budding mechanism distinct from that of other known arenaviruses, whose budding does not appear to be significantly influenced by NP \\[[@B80-viruses-05-00528]\\].", "\n\n5. ", "Role of NP in Arenavirus Budding and RNP incorporation\n=========================================================\n\nNP has been described as an accessory factor for the budding of members of several virus families, including the paramyxoviruses \\[[@B81-viruses-05-00528],[@B82-viruses-05-00528]\\], retroviruses \\[[@B83-viruses-05-00528]\\] and filoviruses \\[[@B69-viruses-05-00528],[@B84-viruses-05-00528]\\]. ", "While the nucleocapsid (NC) domain of retroviruses interacts with Alix/AIP1 and is essential for Alix-mediated HIV release \\[[@B85-viruses-05-00528]\\], Ebola virus VLP formation is driven by the major matrix protein VP40 but is significantly enhanced by the presence of NP \\[[@B84-viruses-05-00528]\\]. ", "For Marburg virus, NP was found to increase VP40-induced VLP release by recruiting Tsg101 via its PSAP motif \\[[@B69-viruses-05-00528]\\], possibly in order to compensate for the absence of a PT/SAP motif in VP40 itself.", "\n\nAll evidence to date has clearly demonstrated that Z is the key determinant without which arenavirus budding cannot proceed. ", "However, for TCRV Z, budding is considerably enhanced by the presence of NP \\[[@B80-viruses-05-00528]\\], an effect not so far reported for other arenaviruses. ", "This raises the possibility that, as for filoviruses, TCRV NP may be acting to recruit additional ESCRT complex components to the sites of budding. ", "Indeed, sequence analysis shows that the NP of TCRV contains putative late domains of both the YxxL and the θPxV-type ([Figure 5](#viruses-05-00528-f005){ref-type=\"fig\"}B), and that mutation of the YxxL motif at amino acid position 298 blocks enhancement of Z-mediated VLP release by NP ([Figure 5](#viruses-05-00528-f005){ref-type=\"fig\"}C). ", "Given that TCRV NP is able to functionally bind Alix-AIP1 (Fig 5A), this observation then suggests that NP may support virus budding by recruiting Alix/AIP1 to the sites of budding. ", "This apparent difference in the mechanism of TCRV budding seems to correlate with its lack of any proline-rich late- domains in Z and the independence of budding on the Z protein YxxL late-domain motif \\[[@B53-viruses-05-00528],[@B80-viruses-05-00528]\\]. ", "This makes it interesting to speculate that other arenavirus Z proteins that lack known late domains, such as that of Merino Walk virus, might be similarly dependent on additional viral proteins to help promote budding.", "\n\n![", "Role of NP late-domain motifs in the enhancement of TCRV Z-induced budding. **(", "A)** TCRV NP and Z both interact with the ESCRT-binding component Alix/AIP1. ", "Co-immunoprecipitation studies using HA-agarose were performed 48 h after transfection of 293T cells with pCAGGS Alix-flag alone or in combination with pCAGGS TCRV NP-HA or TCRV Z-HA. **(", "B)** Schematic representation of TCRV NP and its putative late-domains. ", "Mutants in which individual late domains are knocked-out (NP_1AxxA, NP_2AxxA, NP_θAxxA) by exchanges to alanine at the indicated positions are also shown. **(", "C)** TCRV Z-directed budding and the incorporation of NP late-domain mutants. ", "VLPs were generated as previously described \\[[@B80-viruses-05-00528]\\]. ", "The release of Z in combination with NP was set at 100% and the relative budding efficiencies of Z alone or together with the various NP mutants shown in (B) were calculated. ", "Release of Z in VLPs is shown in black while release of NP is shown in grey. ", "Data represent the mean value and standard deviation of three independent experiments. ", "The statistical significance was determined using Student's t test. ", "Asterisks indicate statistically significant differences (\\*p\\<0.05, \\*\\*p\\<0.01, \\*\\*\\*p\\<0.001).](viruses-05-00528-g005){#viruses-05-00528-f005}\n\nInteraction of NP with Alix/AIP1, via its Bro-1 domain, has also been described for MOPV where, rather than enhancing budding, it was shown to mediate the incorporation of NP into Z-induced VLPs \\[[@B60-viruses-05-00528]\\], suggesting that this interaction may be similarly responsible for the incorporation of RNPs into viral particles in the context of an infection. ", "In MOPV the incorporation of NP into VLPs was shown to be facilitated by mutual interaction of Alix/AIP1 with both NP and Z, thus functioning as a \"bridge\" between these two viral proteins, which otherwise only weakly interact \\[[@B60-viruses-05-00528]\\]. ", "Since co-immunoprecipitation studies with TCRV also reveal an interaction of both NP and Z with Alix/AIP1 ([Figure 5](#viruses-05-00528-f005){ref-type=\"fig\"}A) it is likely that an analogous interaction to that described for MOPV is also taking place between TCRV Z and NP. ", "Indeed, such a mechanism would explain data indicating that mutational knock-out of the YxxL motif in TCRV Z blocks NP incorporation into VLPs \\[[@B80-viruses-05-00528]\\]. ", "However, it is interesting to note that while YxxL motifs in the RING domain are widely conserved among the NWAVs, MOPV is one of only a few OWAVs that possess a YxxL domain in Z ([Figure 4](#viruses-05-00528-f004){ref-type=\"fig\"}). ", "Thus it seems likely that alternative mechanisms to recruit RNPs, an essential step in virus infection, must also exist.", "\n\n6. ", "The Budding Pathway as a Potential Target for Therapeutics\n=============================================================\n\nArenaviruses are serious public health concerns in many parts of the world and thus the development of vaccines and anti-viral therapies remains an important priority. ", "An understanding of the exact mechanisms used for virus morphogenesis and release will help to offer new possibilities to combat viral infection by targeting these pathways. ", "Such targets could include both the interactions among viral proteins (i.e. Z-NP interactions) and interactions between viral and host cell components. ", "Emphasizing this potential, tetherin has recently been identified as a novel antiviral factor that is able to inhibit Z-mediated release of arenaviruses \\[[@B86-viruses-05-00528],[@B87-viruses-05-00528]\\]. ", "Tetherin or BST-2 (bone marrow stromal antigen 2) is an IFN-inducible membrane protein that was first shown to inhibit the release of HIV-1 \\[[@B88-viruses-05-00528],[@B89-viruses-05-00528]\\]. ", "For arenaviruses it was shown that the overexpression of tetherin reduced MOPV and LASV VLP production, as well as production of LASV virions \\[[@B86-viruses-05-00528]\\]. ", "Even if the exact mechanism by which tetherin antagonizes arenavirus budding remains unclear, the identification of this protein as an inhibitor of LASV Z-mediated budding \\[[@B87-viruses-05-00528]\\] reinforces the importance of the budding pathway as a potential target for novel therapeutics.", "\n\nIn addition to the proline-rich and YxxL-type late-domains found within the matrix protein, N-terminal myristoylation also plays a decisive role in viral budding. ", "This post-translational modification takes place at a glycine residue at position 2 (G2) in the Z protein sequence and is universally conserved among all arenaviruses ([Figure 4](#viruses-05-00528-f004){ref-type=\"fig\"}). ", "The myristoylation of Z is necessary for its binding to the plasma membrane, which is the site of arenavirus budding, and thus is also required for efficient viral release. ", "For the OWAVs LASV, LCMV and MOPV, as well as for the NWAVs JUNV and TCRV it was shown that inhibition of myristoylation, either by mutation of the G2 residue or the use of an inhibitor, clearly represses Z-mediated budding \\[[@B49-viruses-05-00528],[@B53-viruses-05-00528],[@B60-viruses-05-00528],[@B77-viruses-05-00528],[@B78-viruses-05-00528]\\], thus presenting another cellular pathway that could potentially be exploited by intervention strategies.", "\n\nFinally, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is involved in a variety of cellular processes \\[[@B90-viruses-05-00528]\\], has also been shown to be important in the lifecycle of diverse viruses, including arenaviruses \\[[@B91-viruses-05-00528],[@B92-viruses-05-00528],[@B93-viruses-05-00528],[@B94-viruses-05-00528]\\]. ", "In the case of LCMV it was shown that inhibition of PI3K/Akt signalling, while not having an influence on viral entry, resulted in reduced viral RNA synthesis and the inhibition of viral budding \\[[@B94-viruses-05-00528]\\]. ", "As the PI3K/Akt pathway is involved in cellular vesicular trafficking, it has been suggested that the associated signalling might be needed for assembly of the ESCRT-complexes and, therefore, that an inhibition of this pathway might disrupt the budding process \\[[@B94-viruses-05-00528]\\]. ", "It has also been further speculated that the PI3K/Akt pathway might be involved in phosphorylation of LCMV and LASV Z \\[[@B94-viruses-05-00528]\\]. ", "However, despite these intriguing suggestions the exact mechanism by which the PI3K/Akt pathway contributes to arenavirus budding remains to be determined.", "\n\n7. ", "Conclusions\n==============\n\nThe formation of progeny virus particles and their release is an essential step in the lifecycle of a virus. ", "In recent years significant progress has been made in the field of arenavirus morphogenesis and budding. ", "The findings have revealed many commonalities in the budding mechanisms used by different arenaviruses, but also striking differences.", "\n\nThe matrix protein Z of arenaviruses has been shown to provide the driving force for budding, an activity that depends on various distinct motifs that have been identified within the protein. ", "Among these are an N-terminal myristoylation at glycine 2 (G2) of Z, which mediates binding of Z to the host cell plasma membrane, and various late domains (YxxL, PPxY and/or PT/SAP). ", "These late domains are responsible for the recruitment of different components of the cellular ESCRT-machinery, normally involved in vesicle formation, to the budding-site where they initiate the release of membrane enveloped virions from the infected host cell ([Figure 6](#viruses-05-00528-f006){ref-type=\"fig\"}). ", "While the arrangement of late-domains in Z differs between the individual arenavirus species, interaction with components within the ESCRT-dependent budding pathway appears to be universal. ", "While NWAVs mostly contain a single PT/SAP motif, OWAVs generally contain either a PPxY motif alone or both a PPxY and a PT/SAP motif at the C-terminus of the Z protein. ", "The PT/SAP motif has been shown to mediate interaction with and recruitment of the ESCRT-I component Tsg101, however, an interaction partner for the PPxY motif of Z has yet to be identified. ", "While interaction of the PPxY motif with a Nedd4-like ubiquitin ligase is likely, in the case of LASV, interaction with Nedd4 itself has been shown not to occur. ", "TCRV Z appears to present a unique case in that it does not contain any proline-rich late domain at all. ", "However, it still functions as a matrix protein. ", "Perhaps due to this lack of any proline-rich late domains the ESCRT-dependent release of TCRV Z-induced particles is strongly enhanced by the presence of NP, raising the question of whether the recruitment of additional ESCRT-components might be assisted by late domains within NP ([Figure 6](#viruses-05-00528-f006){ref-type=\"fig\"}). ", "Such a mechanism appears, thus far, to be unique among the arenaviruses. ", "Finally, recent studies of MOPV have revealed that the ESCRT-machinery might also facilitate recruitment of the viral nucleocapsid to the site of budding and its subsequent incorporation into particles through an interaction between Alix/AIP1 and both Z and NP. ", "A similar mechanism also seems likely for TCRV; however, it remains unclear how OWAVs that lack a YxxL domain, and thus likely the ability to recruit Alix-AIP1, are able to incorporate their RNPs.", "\n\nIn summary, the current data reveal a budding mechanism for arenaviruses that is ESCRT-dependent, but involves a variety of different players depending on the virus species examined. ", "Clearly there are also a number of unknowns and issues that need to be further investigated, especially given the significance of arenaviruses for public health, as a better understanding of the mechanisms and pathways used for virus morphogenesis might offer new possibilities for the development of antiviral therapies to combat arenavirus infection.", "\n\n{#viruses-05-00528-f006}\n\nThe authors are very grateful to Stephen Becker (Philipps Universität Marburg) for helpful discussion and Olga Dolnik (Philipps Universität Marburg) for conceptual assistance with some of the figures. ", "This work was funded by grants of the Jürgen Manchot Stiftung (S.W.) and the Canadian Institutes of Health Research (A.G.) as well being funded in part by the Philipps Universität Marburg and the Division of Intramural Research, NIAID, NIH.", "\n\nOpinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the NIH or the Philipps Universität Marburg.", "\n\nThe authors declare no conflict of interest.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Thursday, November 22, 2007\n\nLong Steps\n\nDo not take very long steps. ", "Taking very long steps dims one five-hundredth part of the vision of one's eyes. ", "The meaning is that a person must ascend to higher spiritual levels gradually, not by big steps, because if he takes too big steps to come to the top he may lose his vision." ]

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[ "The Science Is Settled.", "\n\nNine days ago, the CDC reported on its website that you could catch Ebola from droplets that are coughed or sneezed from an infected person three feet away from you.", "\n\n\n\nFrom the CDC website on October 24:\n\nDroplet spread happens when germs travelling inside droplets that are coughed or sneezed from a sick person enter the eyes, nose, or mouth of another person. ", "Droplets travel short distances, less that 3 feet (1 meter) from one person to another.", "\n\nTwo days ago, on Friday October 31, 2014, the CDC website changed the language to say you could catch Ebola from droplets that are coughed or sneezed from an infected person six feet away from you.", "\n\n\n\nThe CDC changed it’s warning on Friday, October 31, 2014. ", "They revision stated that a person within 6 feet of an Ebola victim may potentially become infected:\n\nA person might also get infected by touching a surface or object that has germs on it and then touching their eyes, mouth or nose. ", "Droplets generally travel shorter distances, less that about 6 feet from a source patient. ", "Germs like plague, meningitis and Ebola can be spread through large droplets.", "\n\nTRENDING: BREAKING: Omaha Bar Owner Charged For Killing Rioter Who Attacked Him and His Business Has Committed Suicide\n\nBut that was Friday.", "\n\nNow the CDC has removed its coughing-sneezing warning altogether-\n\n“There is no evidence that Ebola is spread by coughing or sneezing.”", "\n\n\n\nFrom the current CDC website:\n\nThere is no evidence that Ebola is spread by coughing or sneezing. ", "Ebola is transmitted through direct contact with the blood or body fluids of a person who is sick with Ebola; the virus is not transmitted through the air (like measles virus). ", "However, large droplets (splashes or sprays) of respiratory or other secretions from a person who is sick with Ebola could be infectious, and therefore certain precautions (called standard, contact, and droplet precautions) are recommended for use in healthcare settings to prevent the transmission of Ebola from patients to healthcare personnel and other patients or family members.", "\n\nIn Africa Ebola is called “The Nurse Killer.” ", "Over 230 medical professionals including doctors, nurses and aides have died from the disease so far. ", "Obviously, there is much more to learn about this deadly disease." ]

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[ "College football on TV: What to watch on Saturday\n\nThe morning begins with a Big Ten matchup between No. ", "19 Nebraska and No. ", "12 Penn State, which will play without legendary coach Joe Paterno, who was fired Wednesday.", "\n\nJoe Paterno, left, will not be on the sideline Saturday when Penn State plays… (Carolyn Kaster / Associated…)\n\nBreak out the chips and cold drinks, but let Chris Dufresne handle the remote. ", "Each Friday, the Times' national college football writer handicaps what's worth watching, and skipping, on Saturday's menu of games:\n\nMORNING\n\nNo. ", "19 Nebraska (7-2) at No.12 Penn State (8-1)\n\n9 a.m., ESPN\n\nYou thought nothing could top the drama surrounding last week's buildup to No. ", "1 Louisiana State at No. ", "2. ", "Alabama? ", "Well, try this one. ", "Penn State plays the game without legendary coach Joe Paterno, who was fired Wednesday night in the aftermath of a child sex-abuse case scandal that has engulfed his program. ", "Students took to the streets in protest and now interim Coach Tom Bradley must try to somehow get his team focused. ", "Penn State has a two-game lead in the Big Ten Leaders division with road games left at Ohio State and Wisconsin.", "\n\nPennsylvania (5-3) at Harvard (7-1)\n\n9 a.m., Versus\n\nTake a break from the 24-7 news coverage of kids overturning news trucks in State College and watch a Pennsylvania team not under national scrutiny. ", "Football doesn't get any more pure than the Ivy League, which does not even allow its champion to compete in the postseason.", "\n\nFamilies of players on both teams anxiously await this battle of 1-6 vs. 0-6 in Pac-12 play. ", "This is no doubt Colorado's best shot to pick up its first win in league history. \"", "It means a lot to the kids,\" Colorado Coach Jon Embree said this week. \"", "We're running out of opportunities for these seniors.\"", "\n\nNo. ", "24 Auburn (6-3) at No. ", "14 Georgia (7-2)\n\n12:30 p.m., Channel 2\n\nIt's back to the 12:30 slot for Verne and Gary as they take an announcing team step down from LSU vs. Alabama. ", "The story line here is Georgia has won seven straight since opening losses to Boise State and South Carolina and controls its destiny in the Southeastern Conference East Division. ", "Georgia winning the East could help Boise State's national title hopes.", "\n\nTexas Christian (7-2) at No. ", "5 Boise State (8-0)\n\n12:30 p.m., Versus\n\nBoise State's shocking loss at Nevada last year allowed TCU to qualify for the Rose Bowl and defeat Wisconsin. ", "Boise hasn't lost a home conference game since 1998 but needs to keep it that way to stay in contention for a spot in the national title game. ", "This game was switched from TCU to Boise after the Horned Frogs announced they were bolting the Mountain West.", "\n\nArkansas is the third wheel behind LSU and Alabama in the SEC West but can't be counted out of the BCS national hunt. ", "The Razorbacks can clinch the division if they win out — which would include a victory over LSU on Nov. 25 — and Alabama loses at least one more time.", "\n\nNo. ", "4 Alabama (8-1) at Mississippi State (5-4)\n\n4:45 p.m., ESPN\n\nDoes this game ring a cowbell? ", "It will be shocking if Alabama doesn't come out flat after last week's heartbreaking overtime loss to LSU. ", "Mississippi State started the season ranked but has been one of this year's most underachieving teams.", "\n\n3:30 p.m.: UCLA at Utah, Prime.", "\n\n4 p.m.: Western Kentucky at Louisiana State, ESPNU.", "\n\n4:30 p.m.: Maryland at Notre Dame, Channel 4.", "\n\nEVENING\n\nNo. ", "6 Oregon (8-1) at No. ", "3 Stanford (9-0)\n\n5 p.m., Channel 7\n\nLet's hope this is as good as USC vs. Stanford in Saturday night prime time. ", "Stanford handed Oregon its only conference loss two years ago at Palo Alto but got smoked in Eugene last year after blowing an early 21-3 lead. ", "The winner stays in the national title hunt and the loser could earn a BCS at-large bid to the Fiesta Bowl.", "\n\nArizona State (6-3) at Washington State (3-6)\n\n7:30 p.m., Versus\n\nArizona State is in a three-way tie with USC and UCLA in the Pac-12 South, but the Sun Devils are still in decent shape to claim the crown. ", "USC is ineligible this season and UCLA still has USC left to play. ", "Washington State has lost five straight after a 3-1 start." ]

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[ "Novel superalkali superhalogen compounds (Li3)+(SH)- (SH=LiF2, BeF3, and BF4) with aromaticity: new electrides and alkalides.", "\nOptimized structures, with all real frequencies, of superalkali superhalides (Li(3))(+)(SH)(-) (SH=LiF(2), BeF(3), and BF(4)), are obtained, for the first time, at the B3LYP/aug-cc-pVDZ and MP2/aug-cc-pVDZ computational levels. ", "These superalkali superhalides possess three characteristics that are significantly different from normal alkali halides. ", "1) They have a variety of structures, which come from five bonding mode types: edge-face, edge-edge, face-face, face-edge, and staggered face-edge. ", "We find that the bonding mode type closely correlates with the Li(3)-SH bond energy. ", "2) The valence electrons on the Li(3) ring are pushed out by the (SH)(-) anion, and become excess electrons, conferring alkalide or electride characteristics on these Li(3)-SH species, depending on the bonding mode type. ", "3) The highest occupied molecular orbital of each Li(3)-SH species is a doubly occupied delocalized sigma bonding orbital on the Li(3) ring, which indicates its aromaticity. ", "It is noticeable that the maximum negative nucleus-independent chemical shift value (about -10 ppm) moves out from the center of the Li(3) ring, owing to repulsion by the SH(-) anion. ", "We find that these superalkali superhalides are not only complicated \"supermolecules\", but are also a new type of alkalide or electride, with aromaticity." ]

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[ "1. ", "Field of the Invention\nThe present invention relates to a thin film transistor (TFT) substrate used for a liquid crystal display apparatus, and more particularly, to a TFT substrate that may prevent faulty pixels from occurring due to permeation of cleaning liquid.", "\n2. ", "Discussion of the Background\nGenerally, a liquid crystal display (LCD) displays images using electrical and optical properties of liquid crystals that are injected into a liquid crystal panel. ", "LCD displays have several advantages such as they may be made thin, lightweight, and they have relatively low power consumption as compared to electronic products having a cathode ray tube (CRT). ", "Therefore, LCDs are extensively used in a variety of applications, including display devices such as laptop and desktop computers, HD imaging systems, and the like.", "\nAn LCD generally includes a liquid crystal panel assembly and a backlight assembly. ", "The liquid crystal panel assembly may include a liquid crystal panel, a driving integrated circuit (IC), and a flexible printed circuit board. ", "The liquid crystal panel may be formed by injecting liquid crystal material having an anisotropic dielectric constant between a TFT substrate and a color filter substrate. ", "The driving IC applies a driving signal to a gate line and a data line formed on the liquid crystal panel. ", "The flexible printed circuit board connects the driving IC with a printed circuit board, which transmits predetermined data and control signals to the driving IC. ", "The liquid crystal panel assembly is combined with the backlight assembly, which includes a lamp assembly and various optical sheets, thereby forming the LCD.", "\nGenerally, the TFT substrate includes gate wiring, data wiring, and a pixel electrode. ", "The gate wiring includes a gate line end portion, a gate line, a gate electrode, and a storage electrode line. ", "The data wiring includes a data line end portion, a source electrode, a drain electrode, and a data line. ", "The pixel electrode transmits a signal received through the data line to a pixel area to form an electric field in a liquid crystal layer.", "\nThe drain electrode overlaps a portion of the storage electrode line. ", "The overlapped portion of the storage electrode line and the drain electrode forms a storage capacitor that stores a signal applied to the pixel electrode until a subsequent signal is applied.", "\nA passivation layer may be formed on the gate wiring and the data wiring to protect them. ", "A contact hole may be formed in the passivation layer so that a predetermined region of the drain electrode may be electrically connected with the pixel electrode. ", "The contact hole may expose a step of the storage electrode line.", "\nWhen depositing a metal material for forming the data wiring, the metal material may not be deposited on the step, thereby resulting in a crevice since the step is not favorable to the formation of a layer thereon. ", "In particular, the step is more unfavorable to layer formation when the gate wiring and the data wiring have a multilayer structure than when they have a single-layer structure. ", "If a crevice forms at the step, cleaning liquid may collect at the crevice when performing various cleaning processes, which may cause the data and gate wirings to erode.", "\nSuch erosion of the data wiring or the gate wiring causes a faulty pixel to occur. ", "Accordingly, it is desired to prevent faulty pixels from occurring due to the permeation of a cleaning liquid to increase yield." ]

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[ "Q:\n\nHow to make better jQuery search box with resize from right to left then mine?", "\n\nIm trying about same search box like here in top right side of page: Search Box\nI have this, but it doesn't work correctly:\n\n$(document).ready(function(){\r\n $(\"#search\").mouseenter(function(){\r\n $(this).stop().animate({marginLeft:'-40',width:\"181\"},300) \r\n /*function(){\r\n $(this).animate({marginLeft:'0',width:\"141\"},300)\r\n });*/\r\n });\r\n $(\"#search\").mouseleave(function(){\r\n $(this).animate({marginLeft:'0',width:\"141\"},300);\r\n });\r\n});\n<script src=\"https://ajax.googleapis.com/ajax/libs/jquery/2.1.1/jquery.min.js\"></script>\r\n<!", "DOCTYPE html>\r\n<html lang=\"cs-cz\">\r\n<head>\r\n <meta charset=\"UTF-8\">\r\n <title>Document</title>\r\n <meta name=\"viewport\" content=\"width=device-width\" />\r\n <link rel=\"stylesheet\" href=\"index.css\">\r\n <script src=\"https://ajax.googleapis.com/ajax/libs/jquery/2.1.3/jquery.min.js\"></script>\r\n <script src=\"script.js\" type=\"text/javascript\"></script>\r\n</head>\r\n<body>\r\n <form id=\"searchbox\" action=\"\">\r\n <input id=\"search\" type=\"text\" placeholder=\"Type here\">\r\n <input id=\"submit\" type=\"submit\" value=\"Search\">\r\n</form>\r\n</body>\r\n</html>\n\nA:\n\nGive a float: right or text-align: right:\n\n$(document).ready(function() {\r\n $(\"#search\").css({\r\n marginLeft: 0,\r\n width: 141\r\n });\r\n $(\"#search\").mouseenter(function() {\r\n $(this).stop().animate({\r\n marginLeft: '-40',\r\n width: \"181\"\r\n }, 300);\r\n });\r\n $(\"#search\").mouseleave(function() {\r\n $(this).animate({\r\n marginLeft: 0,\r\n width: \"141\"\r\n }, 300);\r\n });\r\n});\n#searchbox {\r\n text-align: right;\r\n}\n<script src=\"https://ajax.googleapis.com/ajax/libs/jquery/2.1.1/jquery.min.js\"></script>\r\n<form id=\"searchbox\" action=\"\">\r\n <input id=\"search\" type=\"text\" placeholder=\"Type here\">\r\n <input id=\"submit\" type=\"submit\" value=\"Search\">\r\n</form>\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "The crew of a horror web series travels to an abandoned asylum for a live broadcast. ", "It soon encounters much more than expected as it moves deeper inside the nightmarish old building." ]

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[ "Dundalk\n\nLong known as an urban centre, Dundalk stands on the Castletown River near the border of Northern Ireland. ", "It is the famed home of the Irish demi-God Cú Chulainn, as well as his death place at the standing stone where he is said to have tie himself to.", "\n\nBig Acts in Dundalk Soon\n\nNever miss great events\n\nDiscover Dundalk\n\nLong known as an urban centre, Dundalk stands on the Castletown River near the border of Northern Ireland. ", "It is the famed home of the Irish demi-God Cú Chulainn, as well as his death place at the standing stone where he is said to have tie himself to. ", "Dundalk also houses Proleek Dolmen, a 5000-year-old mushroom shaped collection of stacked rocks which is still shrouded in mystery as no one knows how it’s Stone Age creators built it. ", "Besides Dundalk’s vast history and legends, it also has a variety of exciting venues, like the Spirit Store and their array of comedy, music and gigs!" ]

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[ "1. ", "Field of the Invention\nThe present invention relates to a communications receiver for receiving messages, such as a radiopager. ", "In the present specification the term radiopager refers to a communications receiver for receiving only an address codeword or an address codeword together with concatenated data message codewords. ", "Normally such receivers are not able to transmit signals, although what is termed answer-back radiopagers are becoming available. ", "For convenience of description, the invention will be described in terms of its use in a POCSAG or CCIR Radiopaging Code No. ", "1 system the details of which system are described in \"The Book of the CCIR Radiopaging Code No. ", "1,\" available from Secretary RCSG, British Telecom, Radiopaging, 23 Howland Street, London, W1P 6HQ, United Kingdom. ", "However the teachings of the invention are not system dependent and could readily be applied to radiopagers operating in accordance with the Golay or ERMES radiopaging protocols.", "\n2. ", "Description of the Related Art\nIn the United Kingdom, POCSAG digital radiopaging services are provided by several network providers. ", "However the service providers also supply radiopaging receivers to the end user and bill the customer at periodic intervals, such as every 3 months. ", "When supplying a radiopager, a service provider writes a radio identity code (RIC) or address in a non-volatile store included therein. ", "The RIC uniquely links that radiopager with the particular user. ", "Thus, in operation, if the radiopager detects its RIC in the relevant predetermined frame of a transmitted batch, it remains energised to provide an audio, visual and/or tactile alert indication to the user, and when appropriate will store message data which is concatenated with the RIC address codeword. ", "The service provider will also adjust the receiver to receive signals in the relevant frequency channel, the bit rate being already predetermined by the POCSAG protocol. ", "The radiopager as delivered to the end customer is then able to operate within the receiving range of transmitters operated by a predetermined network provider.", "\nAt the present time many countries have their own national digital paging systems based on POCSAG. ", "However, because of the likelihood of the same RIC being issued to a different pager in each country, and each country operating its paging system on a different frequency or frequencies, it is not usually possible for a user to take a normal UK digital radiopager to another country which is also on the POCSAG system and use it there. ", "Furthermore, no arrangements currently exist for billing users who cross national boundaries.", "\nA number of PTTs and other network providers in Europe operate Euromessage, which is an attempt to provide a degree of international paging coverage within certain parts of Europe, primarily the major cities. ", "Euromessage operates on a single frequency at UHF, and requires a user to hire a radiopaging receiver from a service provider. ", "It also requires the user to indicate, several weeks in advance of his departure, those countries in which the user wishes to be paged. ", "Drawbacks to Euromessage are that it is relatively inflexible, is not comprehensive in its coverage of the respective countries, and requires a user to have to carry a second radiopaging receiver in addition to that usable in his home country." ]

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[ "A little background: I've been working on my jerk technique lately, and it has come along nicely. ", "My problem (one of many) used to be that I hardly put my front foot forward at all, resulting in all the weight being placed on that foot, with me of course recovering with my back foot first to chase the bar forward. ", "I've got that taken care of for the most part, and the weight is now distributed between my feet better, and I can recover with the front foot first.", "\n\nNow: The knee on my rear leg has started hurting after jerks. ", "Specifically right above the patella. ", "After a little research, it seems that knee pain above the patella can be attributed to an issue with the rectus femoris. ", "I'm guessing I'm keeping my rear leg too straight, putting a strain on the rectus femoris and my kneecap which it just so happens to be connected to.", "\n\nThis is all just a guess, everything I know about anatomy I learned from Google images. ", "hah! ", "But it actually hurts a good deal, so I'd appreciate some ideas, feedback on how to correct the problem and get things healed up.", "\n\nThat's a good possibility. ", "Start stretching it aggressively, foam rolling the quad, and bending that back knee more. ", "RF tightness will very consistently create pain right across the front of the knee cap." ]

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[ "Today, most personal computer systems operate with one instruction to produce one result. ", "Performance increases are achieved by increasing execution speed of instructions and the processor instruction complexity, and by performing multiple instructions in parallel; known as Complex Instruction Set Computer (CISC). ", "Such processors as the Intel 80386™ microprocessor, available from Intel Corp. of Santa Clara, Calif., belong to the CISC category of processor.", "\nPrevious computer system architecture has been optimized to take advantage of the CISC concept. ", "Such systems typically have data buses thirty-two bits wide. ", "However, applications targeted at computer supported cooperation (CSC—the integration of teleconferencing with mixed media data manipulation), 2D/3D graphics, image processing, video compression/decompression, recognition algorithms and audio manipulation increase the need for improved performance. ", "But, increasing the execution speed and complexity of instructions is only one solution.", "\nOne common aspect of these applications is that they often manipulate large amounts of data where only a few bits are important. ", "That is, data whose relevant bits are represented in much fewer bits than the size of the data bus. ", "For example, processors execute many operations on eight bit and sixteen bit data (e.g., pixel color components in a video image) but have much wider data busses and registers. ", "Thus, a processor having a thirty-two bit data bus and registers, and executing one of these algorithms, can waste up to seventy-five percent of its data processing, carrying and storage capacity because only the first eight bits of data are important.", "\nAs such, what is desired is a processor that increases performance by more efficiently using the difference between the number of bits required to represent the data to be manipulated and the actual data carrying and storage capacity of the processor." ]

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[ "Q:\n\nGet information out of Azure AD with curl and accestoken\n\nRepost-warning but struggling for hours now with curl (Ubuntu prompt and shell script), Azure Active Directory (AAD), Bearer tokens, passing parameters and quotes I can not figure it out with all the help found yet on the net.", "\nI got an accesToken = { a really long unworkable and frequently needs-to-be-refreshed string }\n1) When I execute: \n\nresponse=curl --location --request GET 'https://graph.microsoft.com/v1.0/users?$select=userPrincipalName' --header \"Authorization: Bearer { this long string from above }\"\n\nI receive a proper answer, a list of all userPrincipalNames of users I have in AAD.", "\n2) When I execute any of below mentioned commands:\n\nexport authentication=\"Authorization: Bearer \"$accessToken \nresponse=curl --location --request GET 'https://graph.microsoft.com/v1.0/users?$select=userPrincipalName' --header \"'\"$authentication\"'\"\nresponse=curl --location --request GET 'https://graph.microsoft.com/v1.0/users?$select=userPrincipalName' --header \"\"$authentication\"\"\nresponse=curl --location --request GET 'https://graph.microsoft.com/v1.0/users?$select=userPrincipalName' --header \"$authentication\"\nresponse=curl --location --request GET \"https://graph.microsoft.com/v1.0/users?$select=userPrincipalName\" --header $authentication\n\nI got a \"can not resolve host error\" or value like '}date\": \"2020-03-31T15:26:58\"40e8-a128-67f994881632\",' ...\n3) When I execute this command:\n\nresponse=curl --location --request GET \"https://graph.microsoft.com/v1.0/users?$select=userPrincipalName\" --header \"Authorization: Bearer $accessToken\"\n\nI receive all information of all users listed in AAD and not only userPrincipalName allthough mentioned in url.", "\nMy main and only 2 questions are: \n1) what exactly do I wrong regarding quotes and\n2) How can I get this userPrincipalName only, without typing this long accesToken in my command?", "\nThanks in advance for advice and thinking along and kind regards,\nAad Dijksman\n\nA:\n\n1) what exactly do I wrong regarding quotes \n\nI test in my site and it works with code as below:\nexport accessToken=\"eyJoexxxxxxxxxxxxxxxx\"\nexport authentication=\"Authorization: Bearer \"$accessToken\ncurl --location --request GET 'https://graph.microsoft.com/v1.0/users' --header \"$authentication\"\n\nThe whole command snapshot is as below:\n\n2) How can I get this userPrincipalName only, without typing this long accesToken in my command?", "\n\nNo, it's impossible. ", "When you want to access Graph API in Azure AD, you must contain your access token.", "\n\n" ]

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