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Ibrutinib has the following structure, with a chemical name of 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one Ibrutinib is the first in class of an oral Bruton's tyrosine kinase (BTK) inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and is one of the first medicines to file for FDA approval via the new Breakthrough Therapy Designation pathway. Ibrutinib forms a covalent bond with a cysteine residue (Cys-481), leading to irreversible inhibition of BTK, thus effectively blocking the transfer of cancer cell from B-cell to lymphoid tissue where is benefit for the growth of tumor. The intermediate compound having the following structure is employed to synthesize ibrutinib. The compound of formula VI can be used to produce ibrutinib according to the method disclosed in America U.S. Pat. No. 7,514,444, and its synthesis route is depicted as below: The current methods for preparing the compound of formula VI are confined to two routes published in America U.S. Pat. No. 7,514,444, which can be represented by the following two routes: Route 1: Route 2: Hence, it is necessary to develop new preparation methods for the industrial production.

Esophagectomy without thoracotomy. It should be understood that esophagectomy without thoracotomy is not a surgical procedure for the treatment of a particular esophageal lesion but is only a surgical aid. Therefore, it is extremely important to discuss the specific indications for using this technique to treat a particular esophageal disorder. The technique of esophagectomy without thoracotomy should not be used for malignant lesions of the thoracic esophagus except under particular circumstances, such as resection of a carcinoma in an extremely early stage or palliative resection of advanced carcinoma of the thoracic esophagus without local invasion. Esophagectomy without thoracotomy is extremely useful for the treatment of esophageal or esophagus-related lesions, such as hypopharyngeal carcinoma, benign stricture of the esophagus, or even some carcinomas of the lower esophagus and cardia of the stomach.

Association of the serotonin transporter promoter polymorphism with smoking behavior among adolescents. Serotonin transporter promoter polymorphism (5-HTTLPR) genotype was previously found associated with smoking behavior, difficulty in quitting smoking, and nicotine addiction; with non-replicated findings and contrasting results. Aim of the present study was to evaluate the possible association between 5-HTTLPR genotype and smoking behavior among adolescents, in relationship with psychological characteristics. Two hundred and ten Caucasian high school students (aged 14-19 years); 103 non-smokers, who have never smoked nicotine; and 107 tobacco smokers have been genotyped. Aggressiveness levels and temperamental traits were measured in both smokers and non-smokers, respectively, utilizing Buss-Durkee Hostility Inventory (BDHI) and Cloninger Three-Dimensional Personality Questionnaire (TPQ). Data about school performance have been also collected. The short-short (SS) genotype frequency was significantly higher among smokers compared with non-smokers (P = 0.023). The odds ratio for the SS genotype versus the long-long (LL) genotype frequency was 1.17 [95% CL (0.30-2.05)], when smokers were compared with non-smokers. The SS genotype frequency was significantly higher among heavy smokers with early onset, compared with moderate smokers with late onset (P = 0.042). BDHI irritability scores, NS scores at TPQ, and school failure frequency were significantly higher in smokers than in non-smokers. Multivariate model-fitting analysis evidenced a significantly greater relationship of genotype with irritability levels (BDHI scores) (0.34, P < 0.001) and temperament traits (NS scores) (0.36, P < 0.001), than with school performance (rate of school under-achievements) (0.18, P < 0.05) and nicotine smoking (number of cigarettes) (0.24, P < 0.01). Accordingly, factor-analysis showed that gene polymorphism contributes more directly to BDHI scores and NS scores (0.73; 0.71) than to smoking behavior and school under-achievement (0.54; 0.51). Our data suggest that a decreased expression of the gene encoding the 5-HTT transporter, due to "S" promoter polymorphism, may be associated with smoking behavior among adolescents and increased risk to develop nicotine dependence, possibly in relationship to personality traits, temperamental characteristics, and school under-achievements.

We continued biochemical studies of mammalian DNA replication proteins. cDNAs for rat and human beta-polymerase have been subcloned in expression vectors, and the proteins have been overproduced in E. coli, purified in mg quantities, and sequenced. Structure-function aspects and in vitro DNA repair activities of the recombinant enzymes are being studied. Genomic DNA spanning the gene for human beta-polymerase was further characterized. The promoter region was studied by detailed deletion and site-directed mutagenesis using a transient expression system for assay. In other work, we purified and characterized a transcription factor for the human beta-polymerase gene. In vitro transcription studies of the gene are under way, as well as physical biochemical studies of the sequence-specific binding between the promoter and the purified factor. Studies of cell lines carrying inducible beta-polymerase mRNA antisense transcripts revealed that down regulation of beta-polymerase expression is associated with a block in DNA repair after nitrogen mustard treatment of cells.

Q: \hrule\hskip stretchability This \documentclass[12pt]{report} \def\usrf{\leavevmode\leaders\hrule\hskip 0pt plus 1em minus 0pt\kern 0sp} \begin{document} \noindent A\usrf{}B C\linebreak DEFGH \end{document} results in that where the "underscore" between A and B is way longer than 1em. How can I limit the maximum length of the \hrule, and why does it not work with the glue "stretchability" as given? A: You are telling TeX to stretch a line to the line width, so it will obey your order. Let's see a simpler example (plain TeX): \hbox to\hsize{A\leaders\hrule\hskip 0pt plus 1em minus 0pt B C} \noindent\the\badness \bye You get The value printed by \the\badness is the badness of the last typeset box. Indeed, the terminal will also show Underfull \hbox (badness 10000) detected at line 1 \tenrm A B C As soon as a glue has nonzero stretchability, it will stretch as much as required, at the expense of badness. Just like it happens to the glue between B and C. If you change the first line to \setbox0=\hbox to\hsize{A\leaders\hrule\hskip 0pt plus 1em minus 0pt B C} \showbox0 you'll find, in the log file, \hbox(6.83331+0.0)x469.75499, glue set 38.11542 .\tenrm A .\leaders 0.0 plus 10.00002 ..\rule(0.4+0.0)x* .\tenrm B .\glue 3.33333 plus 1.66498 minus 1.11221 .\tenrm C so the glue stretch ratio is 38.11542; this means that the first glob of glue (from \leaders) will become 38.11542 * 10.00002 = 381.15496 point wide and the second glob will become 38.11542 * 1.66498 = 63.46141 point wide. Can I state “stretch at most X”? No, because of the rule above. With some computations it is of course possible.

Fast transient transistor simulation programs are important aids in computer aided design (CAD) of very large scale integrated (VLSI) circuits. A fast transient simulator differs from accurate circuit simulators like SPICE in its ability to simulate very large circuits at significantly higher speed, at the expense of some accuracy. Fast transient simulators provide the ability to simulate at transistor level circuits containing hundreds of thousands of transistors with high speed on the orders of hundreds time faster than accurate circuit simulators such as SPICE. The goal of fast transient simulators is to compute waveforms of voltages at circuit nodes and currents through circuit elements. Fast transient simulators are used when it is required to simulate circuits at an accuracy higher than that can be achieved by gate and switch level simulators, and with a speed higher than SPICE-like simulators. Fast transient simulation of a Metal Oxide Semiconductor (MOS) transistor circuit usually partitions the given circuit into D.C. connected components (DCCC). Each MOSFET model is cut across its transistor gate. The interaction between partitions is simplified by considering only the dependence of MOSFET channel current on its gate voltage. Each partition is simulated independently for a short time interval called the time step. During this time interval, it is assumed that all voltages at the boundary nodes of the partition are known. Usually they are computed through linear approximation, by interpolation and extrapolation. Based on such simplifications, the behavior of each partition is simulated independently for some short time interval called a time step. Time steps can be different for different partitions and they can vary during simulation for getting the desired trade-off between speed and accuracy. The partitions that do not change their state or change it slowly are evaluated with much longer time steps. This technique improves simulation speed as compared to traditional transistor level circuit simulators like SPICE. Because of the partition mechanism and the use of different time steps, the time points at which the simulator recomputes the states of the partitions are different for each partition. The simulator arranges reevaluation of partition states in an event driven manner. The simulator plans reevaluations of partition states according to its internal processes and changes of voltages at the partition boundary. For this purpose, it uses an event queue where it schedules partitions for reevaluation. From this queue, the simulator gets partitions for reevaluation according to their time schedule. The accurate behavior of each partition is described by a system of non-linear differential equations. One of the most accurate techniques to simulate the behavior of non-linear circuits is to use a modified nodal analysis for computing the system of equations, trapezoidal or backward Euler integration algorithm for their numerical integration, and Newton-Raphson iterations for computing voltage and current values at each time point. Such an approach is common for implementing accurate circuit simulators like SPICE. In order to get higher simulation speed, this technique is simplified in many ways. For example, the forward Euler integration algorithm can be applied, or the Newton-Raphson iterations can be substituted by approximate linearization of non-linear elements at each time point. Any type of simplification is at the cost of accuracy of the simulation results. Fast simulators differ among themselves in their selection of trade-off between speed and accuracy. For simulating partitions, fast circuit simulators similar to traditional SPICE-like circuit simulators require a model of MOS transistors. For SPICE simulators, an accurate transistor model is specified by very complex formulae for computing currents and charges of each transistor terminal as a function of terminal voltages. Computation of these complex formulae significantly slows down circuit simulation. In order to have high simulation speed, fast transient circuit simulators usually use a simplified transistor model. The simplified transistor model can be either analytical or table-based. Analytical models are usually not accurate enough for submicron short channel MOS transistors. Table models usually are able to provide much higher accuracy with higher computation speed. In the simplest straight forward approach, a table model is a collection of tables, each of which provides values of transistor terminal currents or charges as functions of terminal voltages. The tables are usually computed by using an accurate transistor level simulator like SPICE. The structure of a conventional bulk MOS transistor 10 is shown in FIG. 1. Transistor 10 has a substrate 12, a gate oxide 14, a gate 16, a drain 17 and a source 18. The electrical model 34 of transistor 10 is shown in FIG. 2 and has four terminals: a drain 37, a source 38, a gate 36 and a substrate 39. Therefore, a straight-forward model approach results in four charge tables and four current tables. Each of the tables has four arguments or inputs, viz. the four terminal voltages. Unfortunately, tables organized in such a manner are too large to use efficiently in any simulator. Therefore, fast transient simulators use different techniques to simplify their table models. The first simplification comes from the fact that transistor behavior does not change if we change all terminal voltages by the same value. In other words, transistor behavior is invariant to voltage shift. This simplification allows a reduction in the number of table arguments by one as one of the four terminals can be treated as a reference terminal. Other facts that are used for model simplification are charge and current conservation laws. The conservation laws make it sufficient to have models only for three terminal currents and charges and allow computation of the current and charge of the fourth terminal so that total charge and current ate zero. Unfortunately, these simplifications are not enough to make transistor models sufficiently efficient. Therefore, fast transient circuit simulators often use additional approximations for simplifying a transistor table model. For bulk MOS transistors, it is common to assume that transistor terminal capacitances are linear, meaning that they do not depend on transistor terminal voltages. This assumption permits using just average values of transistor terminal capacitances instead of a table of terminal charges as functions of terminal voltages. Currents of bulk MOS transistor table models can be simplified by ignoring substrate and gate currents as they are orders of magnitude less than transistor channel current and do not affect circuit behavior drastically. Simulators can simplify the model of bulk transistor channel current by considering the channel current as a function of two variables: (1) the voltage between drain and source and (2) the effective gate voltage. The effective gate voltage is defined as a difference between gate-to-source voltage and a threshold voltage, predetermined for each transistor. Threshold voltage is considered as a function of body voltage and may be modeled by a separate one-dimensional table. This approach follows from the simple analytical model of a bulk MOS transistor. Thus, instead of one three-dimension table for channel current, two smaller tables are used: one two-dimensional table and one single-dimensional table. Such table reduction costs some accuracy of the model. For pure digital MOS circuits, especially for CMOS circuits, the foresaid reduction still retains sufficient accuracy and allows the simulator to compute good approximation of circuit delays and power consumption. However, this model is not accurate enough for many circuits, for example circuits using many pass gates, circuits having very large D.C. connected components, and circuits that are very sensitive to accuracy, such as the PLL (Phase Locked Loop) circuits. Additional challenge and problem for fast circuit simulation are SOI circuits that are becoming more and more popular in high speed and low power VLSI designs. The structure of an SOI MOS transistor 20 is shown in FIG. 3. An SOI transistor is similar to a bulk transistor but it is manufactured on an insulator layer and completely isolated from one to another by the same insulator. SOI transistor 20 has a substrate (backgate) 22, a buried oxide 24, a body 26, a gate oxide 27, a gate 28, a source 29, a drain 30 and a shallow trench isolation 32 around the perimeter. Because of the SOI structure, transistor capacitances are much smaller than the ones in a comparable size bulk transistor. The reduced capacitances make an SOI transistor significantly faster and reduce power consumption. Thus SOI transistors are very attractive for high performance and low power circuits. SOI transistors also have other benefits like latch-up immunity, lower radiation susceptibility, etc. Unfortunately, designing VLSI circuits with SOI transistors is more difficult than with bulk transistors because SOI transistors have more complicated behavior than bulk transistors. In bulk transistors, the fourth terminal is a VLSI substrate that is permanently connected to ground or a supply voltage VDD. The counterpart terminal in an SOI transistor is a body that has very small capacitance and usually is not connected to any other circuit node. Because of that, the body potential (voltage) varies significantly during circuit operation due to such effects like capacitive coupling with other circuit nodes, leakage, and impact ionization currents. These effects significantly influence SOI transistor behavior by changing its threshold voltage. Another complication with the SOI transistor model arises due to its usage with different types of body connections. The most common case, and also the most difficult to simulate, is the floating body configuration wherein the transistor body is not connected to any other circuit node. The floating body type SOI transistor configuration provides the smallest transistor area but makes its behavior less predictable. The potential of a floating body can vary due to variation in the switching frequency, thus giving rise to an effect known as the history effect. This effect makes logic gate delay depend on gate switching history. Another type of SOI MOSFET configuration has its body and source connected together that makes its behavior similar to a bulk MOS transistor. An example of this configuration is illustrated in FIG. 4 wherein a structure 50 has an SOI transistor having an n+ drain 52, a gate 54, an n+ source 56 and a p+ tie 58 to tie the body with the source 56. The third type of SOI transistor configuration has a separate body contact that can be connected to any node of the circuit. An example of this configuration is illustrated in FIG. 5 wherein a structure 60 has an SOI transistor having an n+ drain 62, an n+ source 64, a gate 66 and a p+ body contact 68. Thus, transient simulators of SOI circuits should handle all these three types of transistors. The electrical model of an SOI transistor is shown in FIG. 6. SOI transistor 40 has five terminals as compared to four terminals of a bulk MOS transistor. Transistor 40 has a gate 42, a drain 44, a source 45, a body 46 and a backgate (substrate) 48. The additional terminal makes an SOI model significantly more complex and results in significant increase in model's table size. Simulation of SOI circuits is more sensitive to numerical errors because the history effect has a very large characteristic time constant as compared to logic gates' switching time. Even small numerical errors in body charge computation are accumulated resulting in prediction of wrong circuit delays. Because of that, accurate transient circuit simulators simulate SOI circuits much slower than bulk circuits that makes circuit design with SOI transistors even more difficult. Skilled artisans appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in the figures may be exaggerated relative to other elements to help improve the understanding of the embodiments of the present invention.

{#sp1 .51} {#sp2 .52}

[Carotenoids as components of dietary supplements recommended for smokers and persons passively exposed to cigarette smoke]. Smoking is a very common addiction and a reason of many serious diseases of cardiovascular, respiratory and digestive systems and also a cancer. Active and passive smokers are exposed to nicotine and many carcinogenic products of tobacco smoke. Carotenoids (e.g. beta-carotene, lycopene) as natural, plant-derived antioxidants may decrease a risk of diseases connected with smoking. In accordance with literature, low level of carotenoids in blood plasma of smokers was observed and diet supplementation by carotenoids may compensate their deficit. However there are some reports in the literature that supplementation by high doses of beta-carotene may be dangerous for smokers.

Trends in hepatitis B and hepatitis C virus among blood donors over 16 years in Turkey. We document in the present study the trends over the sixteen years in HBV and HCV seroprevalence among blood donors in Turkish populations. In this study, serologic test results of whole blood (n = 6.240.130) donors at 22 Red Crescent Centers between 1989 and 2004 were evaluated retrospectively. The overall prevalence was 4.19% for HBsAg and 0.38% for HCV antibody during the study period. The annual prevalence of HBsAg gradually increased from 4.92% in 1989 to 5.23% in 1991 (p=0.001, t=21.00, CI(95), 17237-22490) and gradually decreased from that to 2.10% in 2004 (p=0.001, t=17.27, CI(95), 12869-21342). The seroprevalence of HCV antibody gradually increased from 18 per 10.000 in 1996, to 56 per 10.000 in 1998 (p=0.073, t=3.81, CI(95), 459.62-5721.23), while that decreased to 34 per 10.000 in 2004 (p=0.021, t=7.49, CI(95), 743.98-3980.11). The seroprevalence of hepatitis B and C has decreased markedly between 1989 and 2004 in Turkey. This could be related to the significant increase in the number of volunteer blood donors that increased from 135,779 to 197,815.

Hyperlinks in GNOME terminal how to benefit from fancy hyperlinks in your terminal... Over the years I’ve learned about many of the advantages of using a modern terminal and shell. I’m talking about using bash with GNOME terminal on a modern GNU/Linux distribution. I particularly like switching between the terminal and GUI applications. It’s now even better. Automatic Hyperlinks Occasionally, some program running in your shell might output what looked like a link: gnome terminal and vte will automatically add links to text that looks like a web hyperlink or an email address They can be seen when you hover over them, and a right-click will display a useful context menu: the terminal detected this text sequence as an email address, and the dialog makes it easy to open your MUA This was always useful, but detection was always a heuristic. In many situations it might show a hyperlink unnecessarily or omit one that would have been useful. Integrating Hyperlinks With recent versions of VTE this is now done properly, without needing a heuristic! Here’s what it might look like: the ls program can automatically add relevant links All this magic works because programs can include magic “escape codes” which tell the shell to do special things. They have been traditionally used to add colours or underlining to shell output. In this case they’re been used to send a special message telling the shell that it might want to hyperlink something. The venerable ls program was updated to include a --hyperlink option, which, when active produces the above output. If you look closely, it puts a fine line of dots over any such link. I chose to make this automatic, so I’ve added an alias that includes this by default, and other options: $ alias ls alias ls = 'ls -FGh --color=auto --hyperlink=auto' When you right click on one of the above links, it now shows a helpful menu: this is some magic that opens things in the right program I suspect that it uses xdg-open to run the correct program. In my case it causes folders to open in nautilus , images in eog , and pdf’s in evince . This isn’t limited to ls . A bunch of other programs have started to add this feature in various ways. A recent release of systemd has even added support for this in the systemctl status output. Future Work It’s now time to add useful contextual information to more of the terminal apps out there. Imagine having a git log with clickable sha1 hashes, or pasted irssi links which shorten and ellipsize, but which are still clickable? All of these things are possible, so start getting those patches upstream! Advanced Use Cases I started to think about if some fancier use cases were possible. Imagine if running an ls command over ssh could have the hyperlink information modified by the local shell so that it knew it was a remote URL. In that case, the terminal might consider converting it to a gvfs link instead, giving you easy access to remote files. It might be fun thinking about if adding hyperlinks to vim could offer links to full screen help dialogs. An even fancier idea might be to include a link to a trusted execution agent which could open up a GTK+ dialog, and send the response back to some socket that the program is listening on. The emacs and mutt users could have an easier way to view graphical email attachments. As we blur the lines between working in graphical environments and the terminal, power users who aren’t afraid of the shell only get more proficient. Fancy $PS1 Some of you might remember my earlier, $PS1 , hacks. I’ve decided to add a little more magic on to it. In my ~/.bashrc , in my ps1_prompt function, that runs and sets the $PS1 as part of my PROMPT_COMMAND , I added a little snippet: # get the url encoded version of URI on each PS1 display local encoded = " $( urlencode 'file://' ) \h $( urlencode ` pwd ` ) " local W = '\[\033]8;;' " ${ encoded } " '\a\]''\w''\[\033]8;;\a\]' # thanks purpleidea! This builds a special hyperlink for the displayed path. I had to use the pwd hack to get the working directory, because the \w and \W variants both ellipsize the path, and include the tilde ( ~ ), which would disrupt the expected path format. The URI needs to be safely encoded, and the urlencode function that I used is: # urlencode <string> # TODO: suggestions and improved versions are welcome! function urlencode () { local length = " ${# 1 } " for (( i = 0 ; i < length; i++ )) ; do local c = " ${ 1:i:1 } " case $c in [ a-zA-Z0-9.~_- ]) printf " $c " ;; * ) printf '%s' " $c " | xxd -p -c1 | while read c; do printf '%%%s' " $c " ; done ;; esac done } My full $PS1 now looks like: # all on a single line w/o newline (this might wrap due to the space at the very end) PS1 = " ${ debian_chroot:+($debian_chroot) } [email protected] \h:\[\033[01;34m\] ${ W } \[\033[00m\] ${ ps1_git }${ ps1_status } " (Please note that some portions of this are not included here. See my earlier PS1 blog posts for more information.) here's a screenshot of what this looks like showing a tooltip on mouseover (the mouse pointer is hidden in this screenshot) Now I can click to cause the path to open in nautilus . I previously used the nautilus . command to cause this to happen, and while I probably still will to avoid the context switch-over to the mouse, it’s a nice little addition which I think is pretty neat. It also gives me some extra material for this article. Understanding The Escape Sequences If you’d like to understand why there are additional \[ and \] sequences in the above local W= , that’s because bash needs to know how to wrap the text in the shell output. It’s not smart enough to know which characters are visible (and that should take up space) and which ones aren’t, so in order to tell it, you must wrap the “non-printing” (invisible) characters with those special open and close sequences so that all the math works out as intended. If you don’t, you’ll see a weird mess of characters when you resize your terminal or use tab completion. Remove them and see for yourself! Inside each of those sequences of characters, you’ll first see a: \033]8;; followed by the encoded URL, and then a closing \a in quotes. That’s because \033 is the magic way to write ESC , and the start code is ESC ] . It all ends with a BELL character which is an \a . Inside of that we have the magic number 8 , which means that we want to use the hyperlink feature, and it includes a custom pattern which is that ;; part. This can include a URI to begin the location of a hyperlink, and omit it inside another magic 8 sequence to close it. Inside the ;; you can include some special params if needed. For more information on this, you can review the ANSI escape codes. Information about which other applications are tracking this feature is available here. Conclusion Hope you enjoyed this. Hopefully you can add some hyperlink integrations to your application today! Can you think of any other types of magic escape codes we should add? Thanks to xmby in #bash for helping me understand some of the shell escape code nuances. Happy Hacking, James You can follow James on Twitter for more frequent updates and other random thoughts. You can support James on Patreon if you'd like to help sustain this kind of content.

A. Harmsworth Glacier A. Harmsworth Glacier or Alfred Harmsworth Glacier () is a glacier in northern Greenland. Administratively it belongs to the Northeast Greenland National Park. The glacier was named by Robert Peary after British newspaper magnate Alfred Harmsworth, who had gifted him expedition ship "Windward" following a lecture on Polar exploration Peary gave at the Royal Geographical Society in 1897. Geography The A. Harmsworth Glacier is flowing roughly to the NW and has its terminus at the head of the Benedict Fjord. It fills most of the inner fjord. It has a velocity of per year. The peaks of the Roosevelt Range rise on both sides and at the head of the A. Harmsworth Glacier. To the east some peaks rise to heights above . The A. Harmsworth Glacier is one of the large glaciers in the area. See also List of glaciers in Greenland Peary Land References External links 83° 35' 56" N 36° 47' 32" W Fjord Gletcher. The northernmost calving glacier Category:Glaciers of Greenland

Q: Learning functional programming after other programming paradigms I have taught myself C, Python, Java and a few other procedural or object oriented languages to an intermediate degree from resouces on the internet (thanks SO :D) and in books. When I tried to learn Haskell, I couldn't wrap my head around what the code actually did. Is there a better functional language for someone coming from a background in procedural or object oriented programming to learn? Are there any resources meant for people in my situation? Thanks! A: It's probably varies with people (and this question is bound to get closed over that), but the way I see it: there isn't a stair you need to step on before you can be within reach to Haskell. So I'd say you're not driven temporarily off necessarily by the language, but by your sources of learning. For the only truly gentle introduction, I recommend LYAH. It keeps things within reasonable difficulty and it has some really entertaining points every now and then. However, if you still want to almost-soften your transition, you can check out F# which isn't a functional language but it will give you a good taste of FP, and it will be very familiar to you because you still live in an OO world. You can also check out basically any other functional language and it will give you some of the mindset (Scala, ML, etc.). Keep in mind that I say "almost-soften", because Haskell is very different (especially because of purity), and that gives you a very logical and mathematical mindset to things and that has been very different for me than any other language I learned. It's incredible. It was much beyond learning different syntax, it's a way to think about things and I can always find myself learning more and a truly amazing part of it is that (since it's so logical, mathematical, reasonable, etc.) the new ways of thinking I acquire with Haskell don't leave me both when I use other languages and even in my personal daily life. That being said, the only thing truly horrible with Haskell is that it ruined me for other languages. I used to like C#... :(

CREATE ACCOUNT FORGOT YOUR DETAILS? PakistanCriminalRecords.com is a free research resource being provided free of charge by managed by Background Check Pvt Ltd, one of the Asia's largest screening firms, to public for the awareness about the serious and organized crime in Pakistan. Quetta: 2 bodies found, man shot dead Quetta: 2 bodies found, man shot dead QUETTA: A man was killed on the provincial capital’s SariabRoad and twomutilatedbodies were found in Lasbeladistrict on Thursday. Police said armedmen on a motorbikeopenedfire on a man near Irrigation Colony in Quetta, leaving him injured. Identified as AhmedAli, the man was taken to hospital where he died. A case was registered against unidentifiedkillers. Two mutilated bodies were found in Bela tehsil of Lasbeladistrict. Levies Force sources identified the bodies as that of BahadurKhan, a resident of Kharandistrict, and Rashid of Quetta.

In the first of a series of guest editorials for Kayfabe News, self-described “sports entertainment superfan” Vance Kenneth MacManus explains why he believes WWE’s flagship program, Monday Night Raw, should be an hour longer. As a life-long member of the WWE Universe®, I cannot wait to watch WWE Raw every Monday night on the USA Network. Quite frankly, it is the highlight of my week! Like each and every one of you, I look forward to watching the WWE Superstars® and Superstarlets compete inside the squared circle. Anything can happen in WWE! Quite frankly, WWE brings smiles to people’s faces — including my own! When I’m watching WWE’s captivating weekly live events and biweekly pay-per-views — whether at home, sculpting my preposterous physique at the gym, or flying aboard my private jet — I can’t help but admire the creative genius and business savvy that has made WWE an international juggernaut. But, quite frankly, I have one complaint: I just wish Raw were longer! Three hours is just not enough time for WWE to put enough smiles on enough faces each Monday! As a superfan, I just need more time to watch my favorite Superstars®, like Roman Reigns, Seth Rollins, and Roman Reigns! If Raw were four hours long, it would give me the time I need to fully appreciate Raw, which is the longest running weekly episodic program in television history! Longer episodes of Raw would also give me more time to appreciate the valued sponsors that help WWE create such captivating programming, and would give me more more time to buy amazing fashions and other radical products on WWEShop.com®! So if you feel like I do, why not use the hashtags #FourHourRaw and #ThankYouVince on social media, and perhaps WWE executives will listen to us fans, the way they always do! Perhaps, if we’re lucky, SmackDown LIVE® will get longer too! Sure, I’m just a fan like each and every one of you, but make no mistake about it — together we can make our voices heard, quite frankly. – Vance Kenneth MacManus Quite frankly, you need to subscribe to our YouTube Channel, quite frankly

Mail piling up early in state legislative races AUGUSTA, Maine — Need a sign that the battle for control of the Maine Legislature is intensifying? Look to your mailbox. If you live in a select handful of state Senate and House districts, you’re probably seeing the result of nearly $375,000 the state’s Democratic and Republican parties have spent on political mailers since mid-August in an effort to win legislative seats that ultimately could decide which party controls the House and Senate chambers. In the last two weeks alone, the two major parties have pumped more than $220,000 into mail pieces — about $137,000 from Democrats and nearly $85,000 from Republicans — that expressly support or oppose the election of House and Senate candidates, according to expenditure reports filed with the Maine Ethics Commission. For the Senate, a half dozen races appear to have most consistently attracted the parties’ attention in recent weeks. The list of House races is considerably longer. By this point in 2010, the parties hadn’t even started spending their funds on mail pieces specifically supporting or opposing the election of legislative candidates. At this point in 2008, the state’s Democratic party had spent only $4,700 on a mail piece supporting a single Senate candidate, according to Ethics Commission records. Story continues below advertisement. “To me, the conclusion one can draw based on the level of spending so far is that everybody recognizes that control of both chambers is up for grabs and that it’s going to be a close election,” said Josh Tardy, a former House Republican leader who directed legislative campaigns. And while the parties together have recorded $375,000 in spending on legislative campaign mailers so far, that number doesn’t offer a complete picture of the total amount parties have spent on legislative campaign mail. That’s because if third-party campaign mailers don’t expressly advocate for or against a candidate’s election, political parties and outside groups aren’t required to report them to the Maine Ethics Commission within two days of making the expenditure until the final 35 days of the campaign. Quarterly campaign finance reports due next week will offer additional insight into what the parties have spent to mail out their messages. While the Maine Republican Party has spent nearly $85,000 on campaign mailers expressly supporting or opposing candidates since mid-September, the party also recently launched a mail campaign that encourages voters to call the Republican candidate in their district and “thank him for fighting for Maine working people and advocating for lower state taxes.” A Republican mailer in August compared the voting records of GOP legislators and their Democratic predecessors, saying, “What a difference one year can make.” By avoiding express advocacy, the party hasn’t had to publicly report spending for those mailings or which legislative districts they targeted. “It just depends on what kind of a message we want to send to which district,” said Maine GOP spokesman David Sorensen. “Sometimes an advertisement that doesn’t expressly say, ‘Vote for so and so,’ is a little more convincing. Other times, we see fit to expressly say, ‘Vote for so and so.’” The Senate race that’s most consistently attracted the parties’ attention so far is in Senate District 32, where Democrats have spent $23,000 on mailers so far in hopes of recapturing a seat they lost in 2010. First-term Republican Sen. Nichi Farnham of Bangor is facing a challenge from Democrat Geoffrey Gratwick in that district. Farnham said the mailers aren’t coming up in her conversations with voters. “I’m doing what I set out to do in my plan,” she said, “which was to go door to door and meet with as many voters as possible. Another district that has captured the attention of both parties is Senate District 20 in Lincoln and Knox counties, where Democrats are trying to defend their special election victory in February. That’s when Sen. Chris Johnson of Somerville won what was a Republican seat. Republicans, whose candidate is Rep. Les Fossel of Alna, are trying to recapture it. Johnson said outside mailers don’t seem to be making a difference at this point in the campaign. “I haven’t heard from anyone saying I’ve received a mailer and it changed my mind,” he said. The parties have targeted more than three dozen House districts in recent mailing campaigns. Reinholt said the Democratic Party is targeting a number of districts where Democrats lost seats in 2010, when Republicans took over control of both the House and Senate. In deciding on races to target, she said, Democrats also consider whether their candidates have built up strong volunteer and supporter networks and whether voters seem to be responding well when the candidates knock on doors. “There’s no denying our top priority is winning back the Legislature,” Reinholt said. Sorensen said Republicans take into account polling, whether their candidates are well known in their communities and a range of other factors in deciding which races to target. “We are incredibly confident with our slate of candidates,” he said. And campaign mail pieces, along with phone calls to voters, are a key part of what the political parties do to support their legislative candidates in key districts. “They’re cost-effective,” Sorensen said. “They’re eye-catching when you get a big, glossy mailer.” And they’re targeted precisely to voters in a particular district, said Reinholt. “When it comes to the size of our House districts, going up on radio and TV does cost a lot of money,” she said. “We have to use our resources really smartly, and you never know how many people you’re connecting with when you go on TV and radio.” In addition to heated competition, said Tardy, the former House Republican leader, legislative mailers are coming earlier this year than they have in the past as an increasing number of people cast their ballots early. But spending on mailers from both sides is likely to pick up in the final month of the campaign, he said. “That’s typically how the final month of the campaign goes,” Tardy said. “The mailboxes become targets.”

Hemodynamic and morphologic evaluation of sequelae of primary upper extremity deep venous thromboses treated with anticoagulation. This study was performed to describe venous function, residual morphologic abnormalities, and the occurrence of post-thrombotic syndrome in patients with conservatively treated primary upper-extremity deep venous thromboses (UEDVT). This was a retrospective follow-up study of 31 patients with previous primary UEDVT treated with anticoagulation only, identified by a search of medical records. The mean follow-up time was 5 years. The patients were evaluated by interview, clinical examination, computerized strain-gauge plethysmography, and color duplex ultrasound imaging. The grade of post-thrombotic syndrome was rated according to the Villalta score (0 to 3 on each of four subjective and five clinically assessed features). The rate of venous emptying was significantly lower in the arms with DVTs than in the contralateral arms (P < .001). Eleven of the patients (35%) had a remaining outflow obstruction in the affected arm (venous emptying <68 mL/100 mL per min). Eighteen (58%) had a residual thrombus according to color duplex ultrasound scans, with four remaining occluded subclavian veins. None of the patients had deep or superficial venous reflux. There was no statistically significant relationship between plethysmographic and duplex findings. Most (77%) of the patients reported remaining symptoms in the affected arm, and there was a significant side difference in upper arm circumference (P < .001). Approximately one third had developed a moderate grade of post-thrombotic syndrome according to the Villalta score (total, 5 to 9). No significant relation was evident between the post-thrombotic syndrome score and duplex findings. Patients with post-thrombotic syndrome had a lower venous emptying value than those without (69 vs 84 mL/100 mL per min), but this difference was not statistically significant. Patients with conservatively treated previous primary UEDVT had significantly reduced venous outflow capacity and a residual thrombus was common. Swelling of the arm was the most common symptom, and one third had a moderate grade of post-thrombotic syndrome. However, there was no clear relation between hemodynamic and morphologic factors and the development of post-thrombotic syndrome in these 31 patients, examined at a mean of 5 years after an acute DVT episode.

Salmonella excretion in adult cattle on the Maltese island of Gozo. A cross-sectional study was conducted, between June and November 1993, to determine the prevalence of Salmonella excretion in a representative sample (n = 300) of adult cattle, chosen by strict random sampling of the isolated bovine population in Gozo. Salmonellae were found in 41.3% of the cattle investigated, and seven animals yielded multiple Salmonella serovars. The total number of Salmonella isolates was 131. These included Salmonella Croft (55 isolates), S. Telaviv (29), S. Montevideo (17), S. Kpeme (7), S. Infantis (2) and S. Abadina (1). A seventh serovar (14 isolates) was found to have a novel antigenic structure: the name S. Gozo was proposed, and was accepted by the World Health Organisation Salmonella Reference Centre. All isolates were sensitive to four antibiotics, while 43% of the Salmonella strains were sensitive to nine antibiotics. No resistance was detected to cefuroxime, ciprofloxacin and gentamicin.

BlueFinity International supplies Microsoft-centric tools which allow MultiValue developers to create applications using the very latest technologies while retaining their valuable and often substantial investment in MultiValue software and knowledge. Today, BlueFinity International has extended its reach to enable applications running on any flavor of MultiValue database to be deployed across any of the wide range of today's interface devices – tablets, handhelds, phones and other mobile devices. "From our personal lives to how we do business, there is no doubt that modern technology has changed the way we do just about everything," explains Pete Loveless, CEO of BlueFinity International. "There is a rapidly growing trend, fuelled by the rapid uptake of smartphone and tablet devices, for IT strategy to be driven by end-user expectation. Ultimately, it's all about being able to deliver solutions that address the evolving needs and expectations of users and customers. Using mv.NET, it is possible to take your tried and trusted MultiValue applications to new heights by creating powerful mobile solutions that address these needs quickly and cost effectively." Many BlueFinity customers have already taken MultiValue on the move and are reaping the benefits today. The largest US distributor of aluminium sheet products is using mv.NET to deliver their MultiValue application on mobile phones to enable real time information access and updates for their sales and management teams while in the field. "Taking our application mobile greatly improves the productivity of our sales force as it enables them to retrieve and input information about their customers while the information is fresh in their minds rather than having to update the database at a later time," says Cliff Ponce, Systems Development Manager at Eastern Metal Supply. "Our general managers are able to access real-time reports and our IT team can diagnose and resolve problems - all from their phones. We were able to maximize on the investment we've already made in our MultiValue application to meet the needs of today's modern business, and mv.NET made the move to mobile easier than we even expected." UK-based applications provider to the office supplies industry, Calidore Computer Systems, has also given their MultiValue application wings and enhanced the sequence of their order delivery process to provide electronic, seamless proof of delivery to their back office MultiValue system on a Windows 7 Phone. "The idea of a proof of delivery application isn't new, but purchasing a new system of this type is extremely expensive," explains Richard Olds, Director at Calidore. "mv.NET allows us to record signatures and delivery information on a Windows 7 phone and automatically update the order history in the back office system with an image of the signature and even enables automatic emailing of the invoice and delivery note to the customer all by simply pressing a button on the phone." .NET developers don't even need MultiValue knowledge to produce applications. "The development cycle was very short – astonishingly short, actually! We were able to use our in house developers who had no knowledge of mv.NET or MultiValue. The application was developed entirely using industry standard technology in Visual Studio 2010," explains Olds. Because BlueFinity provides all of the 'plumbing' and framework to support the application creation process, developers can save valuable time and money as well as reduce the inherent risks of developing their own framework in getting the application implemented and ready to launch. "Using mv.NET's powerful, automatic web service generation capabilities, developers are able to create industry standard web services to populate user interfaces with MultiValue resident data in a fraction of the time normally taken to build this type of infrastructure," explains David Cooper, Lead Developer at BlueFinity. "This, combined with the fact that by using mv.NET you are not tying your solution to a particular MultiValue implementation makes mv.NET an attractive proposition for MultiValue developers needing to deliver modern user interfaces for their existing applications." Loveless concludes: "Over the past few years, the significant rise of mobile device usage and the huge advances in mobile technology have brought about a number of opportunities for businesses to connect with consumers and increase sales. BlueFinity's goal is to allow the MultiValue community to be in the forefront of this exciting opportunity. Enhancements to the product are continuing and some exciting announcements will be made as we approach the third quarter of this year. Watch this space!" BlueFinity International, part of the Mpower1 group of companies, supplies leading-edge software development tools and consultancy services to the MultiValue database and Microsoft developer communities. Its flagship product - mv.NET - is a comprehensive solution for developers wishing to access MultiValue databases from within Microsoft's .NET environment.

The Drama Of Being A Venture Capitalist Isn’t Really For Me - thankuz http://techcrunch.com/2011/04/26/gideon-yu-drama-venture-capitalist/ ====== phlux What is the TL;DR regarding his reputation, I haven't particularly followed his career... Would it be safe to assume that he tried to overly apply his CFO mentality to tech/eng? I have had way too many CFOs like that in my past...

172 Cal.App.2d 372 (1959) THE PEOPLE, Respondent, v. JUNIOR GRAYSON, Appellant. Crim. No. 2895. California Court of Appeals. Third Dist. July 27, 1959. Douglas C. Busath, under appointment by the District Court of Appeal, for Appellant. Stanley Mosk, Attorney General, Doris H. Maier and G. A. Strader, Deputy Attorneys General, for Respondent. SCHOTTKY, J. An information was filed charging appellant with six counts of violation of the Health and Safety Code, section 11500. Counts I, II, III, V, and VI charged the appellant with having sold a narcotic, marijuana, on October 10, October 13, October 24, October 9, and November 5, 1957, respectively. Count IV charged the appellant with possession of a narcotic, marijuana, on November 6, 1957. Appellant was found guilty by a jury on all six counts, and this appeal is from the judgment entered on the verdicts. At the trial Hector Reyna, a special investigator for the Bureau of Narcotic Enforcement of California, testified that he had purchased quantities of marijuana cigarettes from appellant on five occasions. The respective purchases were offered in evidence and were properly identified as marijuana. Appellant was arrested on November 5th, after Reyna had purchased five marijuana cigarettes from him. After the appellant *375 had been arrested, a search was made of his room by state narcotic inspector, Major McBee, in company with Vallejo police captain, Dan Horan. The arrest of the appellant occurred about 10 p.m. on November 5th, and the search of his room occurred in the early morning hours of November 6th. The officers went to the Manx Hotel, and after inspecting the register and determining that the appellant, Mr. Grayson, lived in room 12, requested and received permission of the landlady to enter the room and they did so after she opened the door for them. A search of the room resulted in the discovery by Captain Horan of 32 marijuana cigarettes hidden in an overstuffed chair in the middle of the room. Appellant does not argue that the judgment is not supported by sufficient evidence but does contend: (1) That the trial court erred in restricting certain cross-examination; (2) That the trial court erred in permitting one of the witnesses to consult notes during the course of the trial; (3) That the trial court erred in admitting hearsay evidence relating to appellant's occupancy of a room in which marijuana was found; (4) That certain evidence was obtained by illegal search and seizure; and (5) That the trial court erred in excluding certain hotel records. Appellant contends that the trial court unduly restricted counsel in his cross-examination of prosecution witnesses Hector Reyna and Major McBee. It is argued by the appellant that the cross-examination of Reyna was unduly restricted by the trial court in that counsel was not permitted to test the witness' recollection and credibility. [1] Mr. Reyna testified on direct examination that he was employed by the State Bureau of Narcotic Enforcement on September 28, 1957. He came to Vallejo for the purpose of making purchases of narcotics and was given a list of places where he could make a connection. He then testified as to the various purchases of marijuana cigarettes from appellant. On cross- examination Reyna was questioned concerning his employment, and in doing so, counsel attempted to bring out facts relating to the recent discharge of a state narcotics agent, Fred Braumoeller. The appellant contends that the restricting of cross-examination on this point was error. This contention is without merit. Whether Braumoeller had been "fired" by the state neither related to any fact testified to by Reyna on direct examination nor tended to impeach the witness or test his credibility or recollection of the facts concerning which he testified. *376 [2] A witness may not be cross-examined on matters which are irrelevant or outside the scope of direct examination for the purpose of testing the witness' credibility, nor may unrelated matters be brought out for the purpose of showing that the witness on other occasions made contradictory statements. (See People v. McCarthy, 88 Cal.App.2d 883 [200 P.2d 69]; and People v. Sims, 165 Cal.App.2d 108, at pp. 114-115 [331 P.2d 799].) [3] Appellant also contends that he was not permitted to cross- examine the witness Reyna in regard to Reyna's incarceration in the Alameda County jail, arguing that the fact of Reyna's incarceration impeached his testimony to the effect that he and his wife reside in Oakland. However, the record shows the following: "Q. [By appellant's counsel.] Isn't it a fact that you are presently serving time in the Alameda County Jail? A. That's right, sir. Q. Then you are not residing at the address? The Court: Now hold on. By virtue of an Alameda jail sentence for speeding, that is not a change of his residence. He is still a resident of the place of above, Mr. Raftery." We are unable to see how appellant was prejudiced in any way. The question was asked and answered, and there was no prejudicial error in the court's refusal to permit appellant to pursue the matter further. [4a] Appellant also contends that the court unduly restricted the cross-examination of the witness McBee. Appellant's counsel was cross- examining witness McBee, a state narcotic inspector, and attempted to elicit facts relating to the question of whether the witness Reyna's wife was addicted to the use of narcotics. No such issue had been brought out upon the direct examination of this witness and the questions were obviously outside the scope of the direct examination. The appellant asserted that the purpose of the questioning was to show a motive which might induce Mr. Reyna to perjure himself. However, not only was this testimony improperly sought to be elicited from Mr. McBee on cross-examination but, if admissible at all, it should have been brought out by the appellant's own witness. [5] It is, of course, true that evidence is admissible for the purpose of showing that a witness has a motive for testifying falsely. [4b] The alleged motive in the present case was Mr. Reyna's asserted desire to prevent prosecution of his wife for narcotic addiction or otherwise win favorable treatment from police or prosecuting officials. However, the proper method of showing such motive would have been to establish *377 that the witness had been promised a reward, or that an inducement or threat held out or made to him in return for testimony favorable to the prosecution motivated him to distort or falsify his testimony. There was not the slightest attempt by counsel for the appellant to introduce such testimony. He merely attempted to show on cross-examination of Mr. McBee that Mr. Reyna was a user of narcotics (the witness answered that to his knowledge Mr. Reyna was not a user of narcotics), or that Reyna's wife was a narcotic addict. The questions in no way tended to show a motive adverse to the appellant and were properly excluded. [6] There is no merit in appellant's contention that the trial court committed error in allowing witness Reyna to consult certain memoranda during the course of the trial. He refers to the provisions of the Code of Civil Procedure, section 2047, which provides that a witness may be allowed to refresh his memory by reference to notes or writings made by himself or under his direction at the time when the facts related occurred or when the facts were fresh in his memory. During the course of the trial in the present case, it appeared that Mr. Reyna while on the witness stand had with him certain notes which had been typed by his wife from the witness' original notes made at the time that the facts related therein occurred. The appellant assumes in his argument on appeal that after objection by counsel for the appellant the court permitted the witness to use the notes on the stand and that the witness did so. The appellant has pointed to no portion of the record on appeal which would support any such contention, and an examination of the record clearly indicates that the witness did not consult his notes on the stand after the appellant's objection to the use of the notes was sustained. [7] There is some indication from the record that this witness may have refreshed his memory during the recess or prior to coming to court. However, it is clearly established that there is no objection to a witness refreshing his recollection and memory prior to taking the witness stand, and there can be no objection to the use of notes for this purpose so long as the notes are not actually used on the witness stand. (People v. Gallardo, 41 Cal.2d 57 [257 P.2d 29].) [8a] Appellant contends further that the evidence in support of the charge of possession of narcotics is supported solely by incompetent evidence and is therefore insufficient. It is argued that there exists only hearsay evidence to show that *378 the appellant occupied room 12 of the Manx Hotel where the narcotics were found in the chair. The testimony in support of this count consists of the testimony of Officer Horan and Inspector McBee. After the arrest of the appellant, these officers went to the Manx Hotel where they examined the register and discovered that the appellant was registered in room 12; they further ascertained from the landlady that the defendant was the only one living in the room, and with the assistance of the landlady they entered the room and searched and discovered the marijuana cigarettes. The appellant was seen entering the Manx Hotel just before his arrest. However, the record shows that there was no objection by counsel for the appellant to the introduction of any of this evidence relating to Count IV charging possession of narcotics. In fact, counsel for the appellant not only failed to object, but much of the testimony on this point was brought out on cross-examination by appellant's counsel. [9] It is a general principle of law, well established in this state, that material and relevant evidence on an issue, even though hearsay and technically incompetent and inadmissible, which is offered and received without objection will be considered in support of the judgment. (People v. Stepp, 82 Cal.App.2d 49 [185 P.2d 417]; People v. Kelly, 77 Cal.App.2d 23 [174 P.2d 342].) [8b] In the absence of any objection by the appellant, the evidence consisting of the testimony of Inspector McBee and Officer Horan adequately established that the appellant resided in and was the sole occupant of room 12 of the Manx Hotel in which the narcotics were discovered hidden in a chair. The evidence is therefore sufficient to support the judgment on this count. (People v. Vice, 147 Cal.App.2d 269 [305 P.2d 270]; People v. Noland, 61 Cal.App.2d 364 [143 P.2d 86].) [10a] Appellant contends also that the evidence relating to the count of possession was obtained by illegal search and seizure. Appellant argues that even assuming that the room in which the marijuana cigarettes were found was shown to have been occupied by the defendant the evidence of the possession of the narcotics in the room was obtained by an illegal search and seizure. The record shows that the arresting officers after having arrested the appellant went to his room and there conducted the search in question. Even if it could be inferred that there was a possible illegal search and seizure in the present case, it is clearly established that this contention may not be raised for the first time on *379 appeal. The record in the present case shows that there was no objection to the introduction of marijuana cigarettes into evidence and there was no objection to the testimony of the officers who searched the room and found the narcotics. [11] It is now clearly established by numerous decisions that the exclusionary rule of People v. Cahan, 44 Cal.2d 434 [282 P.2d 905, 50 A.L.R.2d 513], is strictly a rule of evidence, and that objections to the introduction of illegally obtained evidence cannot be reviewed on appeal in the absence of a proper objection in the trial court. (See People v. Shannon, 147 Cal.App.2d 300 [305 P.2d 101]; People v. Mann, 148 Cal.App.2d 525 [307 P.2d 48]; People v. Brittain, 149 Cal.App.2d 201 [308 P.2d 38].) [10b] An exception to this rule has been made in cases where the trial occurred prior to the issuance of the Cahan decision. (See People v. Maddox, 46 Cal.2d 301 [294 P.2d 6].) However, the present case was tried long after the decision in the Cahan case, and at the time of trial the Cahan rule was well known throughout the legal profession. If there was any objection which could have been made to the introduction of this evidence on the grounds of illegal search and seizure, that objection should have been made in the trial court; and in the absence of such objection the point must be deemed to have been waived and cannot be raised for the first time on appeal. (People v. Howard, 150 Cal.App.2d 428 [310 P.2d 120]; People v. Davis, 157 Cal.App.2d 33 [320 P.2d 88].) [12a] Appellant's final contention is that the trial court erred in sustaining an objection to the introduction in evidence of a hotel register. The appellant sought to introduce in evidence at the trial a partial or mutilated register of the Hotel Manx. A Mrs. Bell was called as a witness and testified that she was the part-time manager of the hotel in the fall of 1957 and that she was familiar with the hotel register. She was shown a package containing pages which she identified as the hotel register for the periods of September, October, and November, 1957. The pages had been part of a book but had been cut out. The pages had been given to the witness by "her boss." The witness testified that there were two registers, one for "transients" and one for "regulars." These pages were taken from the book for "regulars." An objection was sustained to the introduction of the pages on the ground that the pages were only a partial record and no sufficient foundation had been laid. This witness then *380 returned to the hotel and picked up the rest of the register which she brought to court. The witness testified that these were all of the records that she knew of; that she had "access to these books" and "recognized" them. After further argument by counsel, the court denied the appellant's offer to introduce them in evidence. The appellant states in his opening brief, "It will be admitted that an imperfect foundation was laid for the admission of the records, but the witness testified that they were full and complete records." However, the record very clearly shows that the records were mutilated and that a number of the pages had been removed from the register. The witness when asked whether these were full and complete records replied, "All I know of, yes" and "For all I know about." The trial court refused to permit the introduction of these records upon the grounds that an insufficient foundation had been laid and they were not shown to be true and complete. The records were in fact mutilated, some of the pages having been removed. The Code of Civil Procedure, section 1953f, provides as follows: "A record of an act, condition or event, shall, insofar as relevant, be competent evidence if the custodian or other qualified witness testifies to its identity and the mode of its preparation, and if it was made in the regular course of business, at or near the time of the act, condition or event, and if, in the opinion of the court, the sources of information, method and time of preparation were such as to justify its admission." (Emphasis added.) [13] It has been held that this section gives to the trial court a wide discretion in determining whether or not the mode of preparation of business records, etc., justifies their admission. The section specifically provides that the records are admissible "if in the opinion of the court" the sources of information, methods of preparation, etc., justify their admission. This places a broad discretion in the trial court which will not be disturbed on appeal. (Richmond v. Frederick, 116 Cal.App.2d 541 [253 P.2d 977].) [12b] In the present case the foundation for the admission of these alleged business records was not established. The section above quoted clearly provides that the foundation must include evidence as to the mode of preparation and the fact that the entries were made in the regular course of business at or near the time of the act, condition or event. The only *381 fact established by the appellant in the present case was the identity of the hotel register. Having failed to show the mode of preparation, there was not sufficient foundation for the introduction of the records. (Luthringer v. Moore, 31 Cal.2d 489 [190 P.2d 1].) The records were also properly excluded on the grounds that they were not shown to have been made in the regular course of business. (Pruett v. Burr, 118 Cal.App.2d 188 [257 P.2d 690].) The judgment is affirmed. Van Dyke, P. J., concurred.

Background {#Sec1} ========== Rectal cancer (RC) is one of the most common malignancies in the USA, and the incidence of RC in Asian countries is increasing rapidly and has been considered to be similar to that of the Western countries \[[@CR1]\]. Preoperative radiotherapy (Pre-RT) has become part of standard practice offered to improve treatment outcomes in patients with RC because of the oncologic benefit of reduced local recurrence rate \[[@CR2]\]. But till now, there is still lack of effective means for accurate prognostic evaluation on the survival. It is widely thought that lymph node (LN) metastasis indicates worse tumor response grade and poorer survival. According to the guidelines for RC from the National Comprehensive Cancer Network, a minimum of twelve lymph nodes must be retrieved and examined for accurate staging and the number of metastatic LNs was validated as an independent prognostic factors \[[@CR3]\]. While the node-positive patients with RC are heterogeneous and the prognosis of these patients cannot be stratified by the node-stage only \[[@CR3], [@CR4]\]. Therefore, the concept of negative lymph node (NLN) counts has attracted attention recently as a prognostic indicator in various cancers, including breast \[[@CR5]\], cervical \[[@CR6]\], and esophagus \[[@CR7]\]. It has been reported that the number of NLNs was an independent prognostic factor for patients with colon cancer \[[@CR8]\]. However, Pre-RT can yield tumor downstaging, reduce the burden of residual microscopic disease at surgery and reduce the number of LNs retrieved in operation \[[@CR9]\]. With the decreased LNs retrieval, the prognostic value of the LN count might also diminish \[[@CR10]\]. It has been reported that increased number of NLNs is associated with improved survival in pathological IIIB and IIIC RC treated with Pre-RT \[[@CR7]\]. While it is still unclear whether NLN still has prognostic value count on survival of all patients with RC, including stage I and II, who received Pre-RT. The purpose of this study was to assess the association between NLN count and survival of patients with RC of all stages who received Pre-RT. In order to get convincing results in a larger series patients, we used the SEER (Surveillance, Epidemiology and End Results)-registered database to analyze this association, and determine the optimal cutoff value of NLN count. Methods {#Sec2} ======= Study population and data extracted {#Sec3} ----------------------------------- The SEER (Surveillance, Epidemiology, and End Results Program) database and SEER-stat software (SEER∗Stat 8.3.2) were used to identify patients whose pathological diagnosis as RC between 2004 and 2010. Only patients who underwent Pre-RT and surgical treatment with age of diagnosis more than 18 years were included. Histological type were limited to adenocarcinoma (8140/3), carcinoma (8010/3; 8020/3; 8021/3 and 8145/3) and signet ring cell carcinoma (8490/3). Patients were excluded if they had only local excision following Pre-RT, multiple primary malignant neoplasms, incomplete TNM staging, with distant metastasis (M1), no evaluation on LNs, died within 30 days after surgery or information on CSS and survival months unavailable. Year of diagnosis, age, sex, race, grade, histologic type, ypT stage, number of LNs examined, number of positive LNs and CSS were assessed. TNM classification was restaged according to the criteria described in the AJCC Cancer Staging Manual (7th edition, 2010). Statistical analysis {#Sec4} -------------------- The NLNs cutoff points were determined using the X-tile program, which identified the cutoff value with the minimum *P* values from log-rank χ2 statistics for the categorical NLNs in terms of CSS. Baseline characteristics were compared using the X2 test for nominal variables. Survival curves were generated using Kaplan-Meier analyses, and the differences between the curves were analyzed by log-rank test. Cox regression models were built for analysis of risk factors for survival outcomes. Statistical analyses were performed using the statistical software package SPSS for Windows, version 19.0 (SPSS Inc., Chicago, IL). All *P* values were two-sided. *P* \< 0.05 was considered statistically significant. Results {#Sec5} ======= Patient characteristics from SEER database {#Sec6} ------------------------------------------ In SEER database, we selected a total of 6068 patients with RC who received Pre-RT, including 3881 male and 2187 female from 2004 to 2010. The median age of patients was 59 years. There were 4042 patients with stage ypN0, 1352 with stage ypN1 and 674 with stage ypN2. The optimal cutoff value for NLN count calculated by X-tile {#Sec7} ----------------------------------------------------------- To assess the influence of different NLN count on CSS, we analyzed the individual result using different NLN count ranging from 0 to 23. The 5-year CSS was calculated for patients with N (NLNs number) or more nodes and less than N nodes. As shown in Table [1](#Tab1){ref-type="table"}, NLN count in patients with RC who received Pre-RT was a prognosis factor for number ranging from 0 to 23. With the NLN count increased from 0 to 23, the 5-year CSS rate increased from 51.8 to 88.8% (Table [1](#Tab1){ref-type="table"}). Next X-tile plots were constructed and the maximum χ2 log-rank value of 78.060 (the number as 9, Fig. [1](#Fig1){ref-type="fig"}, *P* \< 0.001) was produced, applying 9 as the optimal cutoff value to divide the cohort into high and low risk subsets in terms of CSS. There was a significant improvement in 5-year CSS between two subsets (74.3% v.s. 82.8%, Table [1](#Tab1){ref-type="table"}). As shown in Table [2](#Tab2){ref-type="table"}, the year of diagnosis, sex, age and the average number of LNs dissected were significantly different between patients with NLN ≤ 9 or \>9 (*P* \< 0.05).Table 1Univariate analysis of the influence of different NLN count on CSS in RC patients who received Pre-RTLNsNo.5-year CCSχ2*P* valueLNsNo.5-year CCSχ2*P* value≤07251.8%41.7450.000≤12368576.5%42.7630.000\>0599679.5%\>12238383.3%≤123063.5%50.1000.000≤13402276.9%38.7470.000\>1583879.7%\>13204683.6%≤244468.2%44.1320.000≤14432077.3%33.9390.000\>2562480.0%\>14174883.7%≤372069.0%54.4960.000≤15458577.3%36.4350.000\>3534880.5%\>15148384.8%≤4101570.0%67.3750.000≤16482277.6%33.0370.000\>4505381.0%\>16124685.3%≤5131471.8%68.4320.000≤17501372.8%27.8270.000\>5475481.2%\>17105585.4%≤6162572.5%74.9790.000≤18517778.0%23.5460.000\>6444381.6%\>1889185.5%≤7197473.5%74.3020.000≤19530278.0%25.4480.000\>7409481.9%\>1976686.8%≤8228574.2%70.4050.000≤20542278.2%25.2570.000\>8378382.1%\>2064687.2%≤9261374.3%78.0600.000≤21552877.9%21.1200.000\>9345582.8%\>2154087.5%≤10297375.0%67.2360.000≤22560678.4%21.7300.000\>10309583.1%\>2246288.0%≤11332075.6%57.6630.000≤23567178.5%18.8720.000\>11274883.4%\>2339788.8% Fig. 1X-tile analysis of survival data from the SEER registry. X-tile analysis was performed using patient data, equally divided into training and validation sets, from the SEER registry. In X-tile plots of the training sets (**a**), the plots of matched validation sets are shown in the smaller inset. The optimal cut-point highlighted by the *black circle* (**a**) is shown on a histogram of the entire cohort (**b**), and a Kaplan-Meier plot (**c**). *P* values were determined using the cutoff point defined in the training set and applying it to the validation set. (The optimal cutoff value for NLN count is 9, χ2 = 78.060, *P* \< 0.001) Table 2Comparison of clinical characteristics of patients with NLN ≤ 9 or NLN \> 9CharacteristicTotalNLN ≤ 9NLN \> 9*P* value606826133455Follow upMedian (IQU)58 (42-81) monthsYear of diagnosis0.0002004--20073122155315692008--2010294610601886Sex0.007Male388116252256Female21879881199Age0.000\<60336813652003≥60270012481452Race0.593White492721372790Black511214297Others630262368Grade0.222Grade I/ II509821842914Grade III/ IV970429541Histologic type0.430Adenocarcinoma551723673150Mucinous adenocarcinoma490215275Signet ring cell carcinoma613130ypT stage3861891970.0621957425532243061820248634191792404LNs dissected12.796.9217.230.000 Impact of the NLN count on CSS in RC patients who received Pre-RT {#Sec8} ----------------------------------------------------------------- According to univariate analysis, age (≥ 60), race (black persons), grade (III/IV), histologic type (signet ring cell carcinoma), ypT stage (ypT3 and ypT4) and NLNs (≤ 9) were associated with poor outcomes in patients with RC who received Pre-RT (*P* \< 0.001) (Table [3](#Tab3){ref-type="table"}). In multivariate Cox analysis, age, grade, histologic type, ypT stage and NLN counts were independently prognostic factors (*P* \< 0.001, Table [3](#Tab3){ref-type="table"}). NLN counts (\> 9) exhibited a favorable effect on survival (HR = 1.623, 95% CI 1.457 \~ 1.809, *P* \< 0.001, Table [3](#Tab3){ref-type="table"}).Table 3Univariate and multivariate survival analyses of RC patients who received Pre-RTCharacteristic5-year CCSUnivariate analysisMultivariate analysisχ2 test*P*HR(95%CI)*P*Year of diagnosis2.4120.120NI 2004--200778.4% 2008--201080.2%Sex1.6550.198NI Male29.5% Female78.4%Age21.8050.0000.000 \< 6081.3%Ref ≥ 6076.4%0.777 (0.697 \~ 0.866)0.000Race14.8730.0000.909 White79.5%Ref Black72.7%1.129 (0.937 \~ 1.364)0.202 Others81.8%1.585 (1.246 \~ 2.017)0.000Grade112.3630.0000.000 Grade I/ II81.5%Ref Grade III/ IV66.9%0.596 (0.523 \~ 0.680)0.000Histologic type81.1280.0000.000 Adenocarcinoma80.4%Ref Mucinous adenocarcinoma69.2%0.412 (0.308 \~ 0.635)0.000 Signet ring cell carcinoma32.5%0.601 (0.408 \~ 0.885)0.010ypT stage148.3230.0000.000 188.6%Ref 287.9%0.293 (0.212 \~ 0.405)0.000 377.9%0.303 (0.239 \~ 0.384)0.000 462.6%0.584 (0.494 \~ 0.692)0.000LNs2.2340.135NI ≤ 1278.5% \> 1279.8%NLN78.0600.0000.000 ≤ 974.3%Ref \> 982.8%1.623 (1.457 \~ 1.809)0.000 Impact of the NLN count on CSS in RC patients based on each pathological grade {#Sec9} ------------------------------------------------------------------------------ We then further analyzed of the effects of NLN on survival in each subgroup of stage yp I, yp II and yp III. As shown in Fig. [2](#Fig2){ref-type="fig"}, subgroup analysis showed that NLN was a prognosis factor for patients with RC who received Pre-RT in stage ypI (χ2 = 7.080; *P* = 0.008), ypII (χ2 = 20.806; *P* \< 0.001) and ypIII (χ2 = 33.138; *P* \< 0.001), respectively. Moreover, as shown in Tables [4](#Tab4){ref-type="table"}, [5](#Tab5){ref-type="table"} and [6](#Tab6){ref-type="table"}, the NLN count was also an independently prognostic factor in stage ypII (HR: 1.520, 95%CI: 1.170 \~ 1.975; *P* = 0.002) and ypIII (HR: 1.466, 95%CI: 1.264 \~ 1.700; *P* \< 0.001) after adjustment for potential confounders.Fig. 2Log-rank tests of CSS comparing patients with NLNs (\<9 VS ≥9) for (**a**) stage ypI: *P* = 0.008; (**b**) stage ypII: *P* \< 0.001; and (**c**) stage ypIII: *P* \<0.001 Table 4Univariate and multivariate survival analyses of stage ypI RC patients who received Pre-RTCharacteristic5-year CCSUnivariate analysisMultivariate analysisχ2 test*P*HR(95%CI)*P*Year of diagnosis6.3240.0120.035 2004--200787.9%Ref 2008--201092.2%1.609 (1.029 \~ 2.517)0.037Sex1.2380.266NI Male90.0% Female89.3%Age2.3590.125NI \< 6091.3% ≥ 6088.0%Race6.2220.0450.053 White88.9%Ref Black81.0%3.792 (1.201 \~ 11.968)0.023 Others98.9%4.392 (1.251 \~ 15.415)0.021Grade0.4830.487NI Grade I/ II90.0% Grade III/ IV85.1%Histologic type3.2180.200NI Adenocarcinoma89.8% Mucinous adenocarcinoma89.5% Signet ring cell carcinoma50.0%ypT stage0.0010.972NI 190.5% 289.4%LNs9.4010.0020.284 ≤ 1287.8%Ref \> 1293.4%1.702 (0.949 \~ 3.052)0.074NLN7.0800.0080.600 ≤ 987.6%Ref \> 991.6%1.128 (0.682 \~ 1.866)0.638 Table 5Univariate and multivariate survival analyses of stage ypII RC patients who received Pre-RTCharacteristic5-year CCSUnivariate analysisMultivariate analysisχ2 test*P*HR(95%CI)*P*Year of diagnosis0.2550.614NI 2004--200784.1% 2008--201084.7%Sex1.4140.234NI Male85.1% Female83.0%Age21.4350.0000.000 \< 6087.2%Ref ≥ 6081.1%0.677 (0.566 \~ 0.810)0.000Race1.8120.404NI White84.6% Black81.4% Others84.4%Grade24.5520.0000.000 Grade I/ II85.6%Ref Grade III/ IV76.2%0.599 (0.479 \~ 0.748)0.000Histologic type6.7050.0350.042 Adenocarcinoma85.0%Ref Mucinous adenocarcinoma75.9%0.786 (0.249 \~ 2.481)0.682 Signet ring cell carcinoma71.6%1.103 (0.339 \~ 3.590)0.871ypT stage21.3010.0000.000 385.4%Ref 473.2%0.591 (0.445 \~ 0.767)0.000LNs9.6480.0020.892 ≤ 1282.5%Ref \> 1286.7%0.983 (0.749 \~ 1.289)0.900NLN20.8060.0000.002 ≤ 980.9%Ref \> 986.5%1.520 (1.170 \~ 1.975)0.002 Table 6Univariate and multivariate survival analyses of stage ypIII RC patients who received Pre-RTCharacteristic5-year CCSUnivariate analysisMultivariate analysisχ2 test*P*HR(95%CI)*P*Year of diagnosis0.0380.846NI 2004--200765.6% 2008--201067.0%Sex0.0260.872NI Male65.9% Female66.2%Age17.2450.0000.000 \< 6069.3%Ref ≥ 6060.9%0.747 (0.654 \~ 0.866)0.000Race17.5350.0000.625 White66.8%Ref Black51.6%1.125 (0.880 \~ 1.436)0.347 Others71.3%1.767 (1.290 \~ 2.421)0.000Grade41.7220.0000.000 Grade I/ II69.5%Ref Grade III/ IV53.9%0.670 (0.566 \~ 0.794)0.000Histologic type24.6170.0000.037 Adenocarcinoma67.4%Ref Mucinous adenocarcinoma60.7%0.562 (0.378 \~ 0.836)0.004 Signet ring cell carcinoma41.8%0.588 (0.383 \~ 0.904)0.016ypT stage66.2410.0000.000 173.0%Ref 283.7%0.442 (0.242 \~ 0.810)0.008 365.1%0.276 (0.195 \~ 0.391)0.000 446.8%0.564 (0.451 \~ 0.704)0.000LNs1.9750.160NI ≤ 1264.9% \> 1267.0%NLN33.1380.0000.000 ≤ 960.5%Ref \> 971.4%1.466 (1.264 \~ 1.700)0.000 Discussion {#Sec10} ========== LN metastasis is considered as one of the most significant prognostic factors in RC \[[@CR11]\]. The total number of LNs retrieved is fundamental in most pathological staging systems for RC. Inadequate LN evaluation is associated with worse outcomes in terms of tumor recurrence and patient survival \[[@CR12]\]. Thus, looking for effective means of assessment of LNs on survival can provide more accurate prognostic information. According to the AJCC-7 RC staging system, a 12-node minimum is required for proper tumor stage and associated with a good survival outcome in patients treated with surgery \[[@CR3]\]. Yet, the number of positive LN is often affected by many facts such as neoadjuvant therapy, and the number of LN retrieved and inspected \[[@CR3]\]. Once the range of LN retrieved is not enough, the prediction of survival would be inaccurate. Therefore, the concept of NLN has been developed recently. NLN count has a unique advantage that it is little influenced by the number of LN retrieved \[[@CR13]\]. The more NLN count is, the better the survival would be. Li et al. \[[@CR12]\] reported that the optimal cutoff value of 10 was validated as an independent prognostic factor in stage ypIIIB and ypIIIC RC patients treated with Pre-RT. In this study, we found that the NLN count was an independent prognosis factor for all patients with RC who received Pre-RT. And we identified the optimal cutoff value for NLN count as 9. Obviously, NLN count is a good supplement for LN stage and TNM stage on evaluating the prognosis of patients with RC who received Pre-RT, respectively for patients with stage ypI, ypII and ypIII. Until now, there has been no report confirming the mechanism of NLNs influencing on the prognosis of RC. But it is suggested that lymphatic micrometastasis is a key etiology of recurrence and metastasis after resection of RC \[[@CR14]\]. LN micrometastasis, is common in nodes with the size ranging from 0.2 to 2.0 mm which determined to be negative by HE staining, but positive for cytokeratin (CK) by immunohistochemical staining \[[@CR15]\]. Because it is difficult to find lymphatic micrometastasis during operation, we can retrieve more NLNs to reduce the residual micrometastases, in order to improve the prognosis of RC. The intended purpose of Pre-RT is tumor down-staging by decreasing the primary tumor bulk and reducing the burden of residual associated LN metastases at surgery, thus increasing the potential of margin-negative resections \[[@CR9]\]. It has been reported that Pre-RT may cause radiation-induced lymphocyte destruction and stromal fibrosis resulting in alterations of the morphology of the LNs, making LN detection during operation more difficult \[[@CR9]\]. Some researchers found that a decreased LN count after Pre-RT was related to good survival \[[@CR16], [@CR17]\]. The NLN count is particularly useful in the prediction of survival because it is little influenced by the number of LN retrieved, and has potential to reflect the dissection of lymphatic micrometastasis. In this study, we revealed that NLN count was an independent prognostic factor for patients with RC who received Pre-RT. Subgroup analysis showed that NLN was a prognosis factor for patients with RC who received Pre-RT in stage ypI (χ2 = 7.080; *P* = 0.008), ypII (χ2 = 20.806; *P* \< 0.001) and ypIII (χ2 = 33.138; *P* \< 0.001), respectively. It might provide more accurate prognostic information than the N stage alone in patients with Pre-RT. This study has several limitations. First, the SEER database does not include information of therapeutic options such as detailed information of chemotherapy, targeted therapy, immunotherapy, recurrence and metastasis, which may also impact patients' prognosis. Second, this data lack detailed description of preoperative clinical grading and the information about tumor and LN recession response to treatment, and our analyses could not adjust for these potential confounding factor. Third, different operative approaches, doctors and even pathologist would affect the detective rate of total LN and metastatic LN, but the SEER do not include these information \[[@CR10]\]. Although future clinical research will be required to confirm the role of NLN, our study has its convincing power for it is one of the largest population based study until now. Conclusions {#Sec11} =========== Our results firmly demonstrated that NLN count was an independent prognostic factor for patients with RC who received Pre-RT. It could provide more accurate prognostic information for RC patients with Pre-RT (stage ypI, ypII and ypIII, respectively). LN : Lymph node NLN : Negative lymph node Pre-RT : Preoperative radiotherapy RC : Rectal cancer SEER : Surveillance, Epidemiology, and End Results Program The authors acknowledged the efforts of the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER database. The interpretation and reporting of these data were the sole responsibility of the authors. Funding {#FPar1} ======= The design of the study and collection, analysis, and interpretation of data were supported by National Natural Science Foundation of China to Xinxing Li (Grant No. 81402002). Availability of data and materials {#FPar2} ================================== The cohort data are available to researchers and should be requested under the approval of the SEER Program administration. The other datasets supporting the conclusions of this article are included within the article. Authors' contributions {#FPar3} ====================== ZQH conceived and designed the study, XXL, HLW and XWL performed the analyses, KX, HLW and XWL provided assistance in writing the manuscript and support in interpreting results. All authors discussed the results and implications of the analysis and commented on the manuscript at all stages. All authors read and approved the final manuscript. Competing interests {#FPar4} =================== The authors declare that they have no competing interests. Consent for publication {#FPar5} ======================= Not applicable. Ethics approval and consent to participate {#FPar6} ========================================== Because the patients in the SEER database could not be identified, the analysis and reporting of the data in our study were exempt from review by the Ethics Board of Changzheng Hospital, the Second Military Medical University. The requirement for written informed consent to participate was waived. We were permitted to have Internet access after our signed data-use agreement (<http://seer.cancer.gov/data/sample-dua.html>) was approved by the SEER administration. Publisher's Note {#FPar7} ================ Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Q: How to create HTML element in Qt? Qt has its own wrapper on WebKit (QWebNode, QWebElement, etc). How can I create HTML element using that Qt wrapper (obtain QWebElement of new HTML element)? If it can help, say we have QWebFrame frame. A: The only method I found is to call appendInside, appendOutside, etc methods of existing QWebElement elements with QString html markup as an argument. QWebElement existingElement; existingElement.appendInside( '<div/>' ); QWebElement newElement = existingElement.lastChild();

Q: how do I get the index from this function this is demo of iOS Charts library (LineChart) and I want to input my data instead of arc4random data. My data is in Array so I have to approach with index but I can't understand the (0..<count).map { (i) -> ChartDataEntry code. func setChartValues(_ count : Int = 24) { let values = (0..<count).map { (i) -> ChartDataEntry in let val = Double(arc4random_uniform(UInt32(count))+3) return ChartDataEntry(x: Double(i), y: val) } let set1 = LineChartDataSet(entries: values , label : "DataSet 1") let data = LineChartData(dataSet: set1) self.lineChartView.data = data } A: It seems you are new to iOS and swift. What you are looking for is an understanding of the functionning of closures in swift, plus the map function which is called an high order function from apple doc ( https://developer.apple.com/documentation/swift/array/3017522-map ) : Returns an array containing the results of mapping the given closure over the sequence’s elements. In other words it maps your array into another array, according to the trailing closure you passed as a parameter. In your specific case here his how to read it : (0..<count) : creates an array of count lengh example : if count = 4 then (0..<count) is [0, 1, 2, 3] As said previously the map function will transform each of your element into another ( therefore keeping the length of the array ). in your case val = Double(arc4random_uniform(UInt32(count))+3) will be equal to a random number calculated with count value, and create a new ChartDataEntry with this random value. to sum it up the whole code is just saying "I will create a count length array of random ChartDataEntry", I guess as a mockup I suggest you to read about closures here : https://medium.com/the-andela-way/closures-in-swift-8aef8abc9474 and high order functions ( such as map(_:) ) here : https://medium.com/@abhimuralidharan/higher-order-functions-in-swift-filter-map-reduce-flatmap-1837646a63e8

/** ****************************************************************************** * @file stm32f0xx_hal_spi_ex.c * @author MCD Application Team * @brief Extended SPI HAL module driver. * This file provides firmware functions to manage the following * SPI peripheral extended functionalities : * + IO operation functions * ****************************************************************************** * @attention * * <h2><center>&copy; COPYRIGHT(c) 2016 STMicroelectronics</center></h2> * * Redistribution and use in source and binary forms, with or without modification, * are permitted provided that the following conditions are met: * 1. Redistributions of source code must retain the above copyright notice, * this list of conditions and the following disclaimer. * 2. Redistributions in binary form must reproduce the above copyright notice, * this list of conditions and the following disclaimer in the documentation * and/or other materials provided with the distribution. * 3. Neither the name of STMicroelectronics nor the names of its contributors * may be used to endorse or promote products derived from this software * without specific prior written permission. * * THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS "AS IS" * AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE * IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE ARE * DISCLAIMED. IN NO EVENT SHALL THE COPYRIGHT HOLDER OR CONTRIBUTORS BE LIABLE * FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR CONSEQUENTIAL * DAMAGES (INCLUDING, BUT NOT LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR * SERVICES; LOSS OF USE, DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER * CAUSED AND ON ANY THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, * OR TORT (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE * OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE. * ****************************************************************************** */ /* Includes ------------------------------------------------------------------*/ #include "stm32f0xx_hal.h" /** @addtogroup STM32F0xx_HAL_Driver * @{ */ /** @defgroup SPIEx SPIEx * @brief SPI Extended HAL module driver * @{ */ #ifdef HAL_SPI_MODULE_ENABLED /* Private typedef -----------------------------------------------------------*/ /* Private defines -----------------------------------------------------------*/ /** @defgroup SPIEx_Private_Constants SPIEx Private Constants * @{ */ #define SPI_FIFO_SIZE 4 /** * @} */ /* Private macros ------------------------------------------------------------*/ /* Private variables ---------------------------------------------------------*/ /* Private function prototypes -----------------------------------------------*/ /* Exported functions ---------------------------------------------------------*/ /** @defgroup SPIEx_Exported_Functions SPIEx Exported Functions * @{ */ /** @defgroup SPIEx_Exported_Functions_Group1 IO operation functions * @brief Data transfers functions * @verbatim ============================================================================== ##### IO operation functions ##### =============================================================================== [..] This subsection provides a set of extended functions to manage the SPI data transfers. (#) Rx data flush function: (++) HAL_SPIEx_FlushRxFifo() @endverbatim * @{ */ /** * @brief Flush the RX fifo. * @param hspi pointer to a SPI_HandleTypeDef structure that contains * the configuration information for the specified SPI module. * @retval HAL status */ HAL_StatusTypeDef HAL_SPIEx_FlushRxFifo(SPI_HandleTypeDef *hspi) { __IO uint32_t tmpreg; uint8_t count = 0U; while ((hspi->Instance->SR & SPI_FLAG_FRLVL) != SPI_FRLVL_EMPTY) { count++; tmpreg = hspi->Instance->DR; UNUSED(tmpreg); /* To avoid GCC warning */ if (count == SPI_FIFO_SIZE) { return HAL_TIMEOUT; } } return HAL_OK; } /** * @} */ /** * @} */ #endif /* HAL_SPI_MODULE_ENABLED */ /** * @} */ /** * @} */ /************************ (C) COPYRIGHT STMicroelectronics *****END OF FILE****/

Introduction ============ IgG3 is the predominant IgG subclass in responses against T cell--independent type 2 antigens in mice whereas it constitutes a very low fraction of IgG responses to T cell--dependent protein Ags ([@bib1], [@bib2]). A similar situation is seen with human IgG2 which is considered to be the equivalent of murine IgG3 ([@bib3], [@bib4]). These isotypes have been postulated to play an important biological role in the defense against bacterial infections. In support of this, IgG3-deficient mice were shown to be more susceptible to pneumococcal sepsis than wild-type animals ([@bib5]). IgG3 Abs are efficient activators of C, and although they were first believed to act only via the alternative pathway, it was recently shown that monoclonal anti-erythrocyte IgG3 can activate the classical pathway ([@bib6]). Some biological functions of IgG3 are dependent on C activation, such as the protective effect against *Candida albicans* infections and the pathogenicity in hemolytic anemia ([@bib6], [@bib7]). Another possible effector pathway of IgG3 is via Fc-receptors (FcRs).[\*](#fn1){ref-type="fn"} Early studies demonstrated that macrophages could phagocytose IgG3-coated particles and suggested the existence of a specific FcR for IgG3 ([@bib8]). This receptor has been elusive, and for many years IgG3 was not believed to bind to any of the known murine Fc-receptors for IgG (FcγRI, FcγRIIB, or FcγRIII; reference [@bib9]). However, recent data suggest that FcγRI is the IgG3-binding receptor ([@bib10], [@bib11]). Apart from mediating various effector functions, Abs have the ability to feedback regulate the production of themselves (for a review, see reference [@bib12]). Passively administered, or actively produced, specific Ab can enhance or suppress Ab responses to the Ag they bind to. Regulation is potent, frequently resulting in 99% suppression or several 100-fold enhancement, and only responses to determinants within the immune complex are affected. When TNP-specific IgG1, IgG2a, IgG2b, or IgE are administered together with soluble hapten-carriers, e.g. OVA-TNP, BSA-TNP, or KLH-TNP, the anti-carrier responses are enhanced ([@bib13]--[@bib15]). Enhancement by IgG2a and IgG1 takes place in the absence of C activation ([@bib16]) and in Cr2^−/−^ mice lacking CR1 (CD35) and CR2 (CD21; reference [@bib17]), but is severely impaired in FcRγ^−/−^ mice ([@bib14]). These mice lack the common signaling γ-chain used by both FcγRI and FcγRIII and do not express FcγRIII ([@bib18]), although 1/5 of FcγRI was recently shown to remain ([@bib11]). The data therefore suggest an important role for FcγRs in IgG1- and IgG2a-mediated enhancement. IgE-mediated enhancement is exclusively dependent on the low affinity receptor for IgE, CD23 ([@bib15], [@bib19], [@bib20]). Also, IgM can enhance Ab responses and this effect is dependent on C activation. Mutant monoclonal IgM that has lost its ability to activate C cannot enhance, normal IgM cannot enhance in C-depleted mice or in Cr2^−/−^ mice lacking CD35 and CD35 ([@bib17], [@bib21]), and monomeric IgM, which cannot activate C, does not enhance ([@bib22]). Murine CD21 and CD35 are alternatively spliced from the same Cr2 gene and knockout mice therefore lack both receptors ([@bib23], [@bib24]). CD21 associates with the signaling molecule CD19 in the B cell membrane and cocrosslinking of the B cell receptor (BCR) and CD21/CD19 lowers the threshold for B cell activation ([@bib25]). Cr2^−/−^ mice have poor Ab responses to suboptimal doses of various antigens (for a review, see references [@bib23] and [@bib24]) and it was recently shown that IgG3 was the most severely affected isotype ([@bib26]). These mice were more susceptible to *Streptococcus pneumoniae* infection than wild-type controls ([@bib26]), a finding agreeing well with a role for IgG3 ([@bib5]) and C3 ([@bib27]) in defense against bacterial infections. Whether IgG3, in addition to the isotypes discussed above, can act to enhance humoral responses has not been examined. We here report that TNP-specific IgG3 mAbs, administered in complex with BSA-TNP or OVA-TNP, dramatically increase the carrier-specific responses, sometimes \>1,000-fold. IgG3 enhances Ab responses equally well in FcRγ^−/−^ and FcγRIIB^−/−^ as in wild-type control mice. In contrast, the capacity of IgG3 to enhance Ab production was markedly reduced in C3-depleted as well as in Cr2^−/−^ mice, suggesting that IgG3, in analogy with IgM, enhances the Ab response via the C system. Materials and Methods ===================== Antigens. --------- BSA (fraction V, A-3059), OVA (grade V, A-5553), and TNP (picrylsulfonic acid/hydrate) were from Sigma-Aldrich and KLH from Calbiochem. TNP was conjugated to BSA or OVA as described ([@bib28]). The number of TNP residues/Ag molecule was 12 for BSA and 3 for OVA determined according to ([@bib29]). SRBC from the National Veterinary Institute (Uppsala, Sweden), were conjugated to TNP (SRBC-TNP) as described ([@bib30]). Antibodies. ----------- 5-mo-old BALB/c mice (Bommice) were immunized in the tail vein with 4 × 10^8^ SRBC-TNP in 0.1 ml PBS. 3 d before the fusion, mice were boosted intravenously with 4 × 10^8^ SRBC-TNP and 10 μg LPS (Sigma-Aldrich) intraperitoneally. Splenocytes were mixed with the fusion partner Sp 2/0 in a ratio of 5:1 in PBS containing 50% polyethylene glycol 4000 (Merck), at 37°C for 1 min. The fusion mixture was slowly diluted with serum-free DMEM, spun down, and incubated for 15 min at 37°C. The cells were then washed and diluted in DMEM containing 10% heat-inactivated FCS, seeded out in 96-well microtiter plates (Nunc), and cultured overnight at 37°C together with 3 × 10^6^ rat thymocytes per ml. Next day, HAT (Hypoxanthine-Aminopterin-Thymidine) medium (Sigma-Aldrich) was added and the cells were cultured in HAT until growing clones were established. Hybridomas were screened for production of IgG3 anti-TNP by ELISA. Positive hybridomas were expanded and cloned by limiting dilution and clones IM-F10 and IM-H11 were selected for further studies. IgG3 anti-TNP (IM-F10 and IM-H11), IgG2a anti-TNP (C4007B4, 7B4; reference [@bib13]), and IgE anti-TNP (IgEL-A5, mouse IgE/κ; reference [@bib31]) were cultured in DMEM (4.5 g/liter glucose) supplemented with 50 IU/ml penicillin, 50 μg/ml streptomycin, 2 mM [l]{.smallcaps}-glutamin, 10 mM HEPES, 0.05 mM 2-mercaptoethanol, and 5% heat-inactivated FCS. IgG mAbs were purified on a protein A Sepharose column (Amersham Biosciences) and IgE on a Sepharose column coupled with monoclonal rat anti--mouse κ 187.1.10 as described ([@bib17]). Abs were concentrated by Microsep^®^ 10K concentrator (Pall Filtration Corp.) and the storage buffer was changed to PBS using a PD10 column (Amersham Biosciences). Protein concentrations were determined by absorbance at 280 nm, assuming that an absorbance of 1.5 equals 1 mg/ml of Ab. The subclasses of each IgG preparation were confirmed by subclass-specific ELISA. mAbs were sterile filtered and IgG2a and IgE stored at --20°C whereas IgG3 was used immediately or stored in liquid nitrogen. Mice. ----- BALB/c, CBA/J, and DBA/1 were from Bommice. H-2^b^ mice have an I-A^b^-linked low responsiveness to IgE/BSA-TNP and IgG/BSA-TNP complexes ([@bib28], [@bib32]) and the knockout mice used in the present study were backcrossed to responder strains. FcRγ^−/−^ mice ([@bib18]) were backcrossed/intercrossed to DBA/1 (H-2^q^) for five generations and offspring from homozygous mutant FcRγ^−/−^/ H-2^q^ and wild-type FcRγ^+/+^/H-2^q^ animals were used in experiments. FcγRIIB^−/−^ mice ([@bib33]) were backcrossed to CBA/J mice (H-2^k^). The fifth generation was intercrossed and offspring from homozygous mutant FcγRIIB^−/−^/H-2^k^ and wild-type FcγRIIB^+/+^/H-2^k^ mice were used in experiments. Cr2^−/−^ mice ([@bib34]), first backcrossed to H-2^k^ mice ([@bib17]), were further backcrossed to DBA/1. Mice from the second generation were intercrossed and offspring from homozygous mutant Cr2^−/−^/H-2^q^ and wild-type Cr2^+/+^/H-2^q^ animals, identified by PCR analysis (described below), were used in experiments. Mice were bred and maintained at the Department of Genetics and Pathology, the Department of Animal Development and Genetics or at the Biomedical Center, Uppsala University. PCR Reactions. -------------- The FcRγ genotype was analyzed according to ([@bib18]), FcγRIIB as described ([@bib35]), and H-2^k^, H-2^b^, and the Cr2 genotype according to ([@bib17]). H-2^q^ was analyzed in a PCR reaction using two primers: αK1:2 (5′ TAT CAG TCT CCT GGA GAC ATT G 3′) and q2 (5′ GTC AAA GCT TGT CAA TTG GC 3′) resulting in a 128 bp band. Gene amplification was done in 20 μl 10 mM Tris-HCl, pH 8.3, 50 mM KCl, 5 mM MgCl~2~, 0.2 mM dNTPs, 0.22 μM of primers, and 2.5 U AmpliTaq DNA polymerase (PerkinElmer) for 35 cycles (30 s, 94°C; 40 s, 54°C; 50 s, 72°C). Immunizations. -------------- Mice were immunized in the tail vein with Ag alone or Ab/Ag complexes in 0.2 ml PBS. Complexes were formed by incubating TNP-conjugated Ag with TNP-specific mAb for 1 h at 37°C, immediately before the immunization. Non-crossreacting Ag (unconjugated OVA, BSA, or KLH) was included in the Ag mixture as a specificity control. Cobra Venom Factor Treatment. ----------------------------- Mice were injected intraperitoneally with four doses of 0.1 ml of 100 U/ml cobra venom factor (CVF) from *Naja haje* (Cordis Laboratories Inc.) during 24 h. Control groups received PBS in the same regimen. All mice were bled individually from the tail 7 d before the first and 2 h after the last CVF injection. C3 levels in sera were assayed by radial immunodiffusion using a polyclonal goat anti-mouse C3 antiserum (Cooper Biomedical, Inc.). Titers are expressed as the reciprocal of the highest dilution giving a precipitation line (e. g. dilution 1:27 = 27). ELISA. ------ Blood was collected from tail veins and sera were tested using IgG anti-BSA-, IgG anti-KLH, or IgG anti-OVA- specific ELISAs ([@bib36]). Statistical differences were determined by Student\'s *t* test. P values are presented as: not significant, NS; P \< 0.05, \*; P \< 0.01, \*\*; P \< 0.001, \*\*\*. Stimulation indices (SI) were calculated as the geometrical mean of the experimental group divided by the geometrical mean of the control group. Hemolysis. ---------- Hemolytic titers are defined as the highest antibody dilution able to lyse a 0.25% suspension of SRBC-TNP~5~ (prepared as described \[[@bib30]\] but with a fivefold lower concentration of picryl sulfonic acid) in the presence of a 1:160 dilution of guinea pig serum in veronal-buffered saline (VBS). Alternative pathway activation was assayed in VBS with Mg-EGTA ([@bib37]). Results ======= Monoclonal TNP-specific IgG3 Enhances Ab Responses to BSA-TNP and OVA-TNP. -------------------------------------------------------------------------- To assess the ability of IgG3 to augment Ab production, mAbs IM-F10 and IM-H11 were administered to CBA/J mice together with BSA-TNP and OVA. Both mAbs were able to enhance the IgG anti-BSA responses (51- and 13-fold respectively) compared with control groups immunized with Ag alone ([Table I](#tbl1){ref-type="table"} , experiments 1 and 2). The response to OVA, included as a specificity control, was not affected by IgG3. Ab responses to BSA in two other strains of mice, BALB/c and DBA/1, were also efficiently enhanced by IgG3 (1344- and 316-fold, respectively; [Table I](#tbl1){ref-type="table"}, experiments 3 and 4). IM-F10 administered to BALB/c mice together with another Ag, OVA-TNP, induced an 81-fold enhancement of the OVA-specific response (unpublished data). Thus, two out of two TNP-specific IgG3 mAbs were able to specifically enhance Ab responses to BSA-TNP or OVA-TNP in three different mouse strains. ###### Enhancement of Ab Responses by Monoclonal IgG3 Ab ---------------------------------------------------------------------------------------------------- IgG anti-BSA IgG anti-OVA --- -------- --------------------- -------------- -------------- --------- -------------- ----- ---- 1 CBA/J BSA-TNP + OVA 2.25 ± 0.35\ 1 c 1.64 ± 0.08\ 1 c (178) (44) BSA-TNP + OVA +\ 3.96 ± 0.26\ 51 \<0.001 1.54 ± 0.11\ 0.8 NS 50 μg IgG3 (IM-F10) (9,076) (35) 2 CBA/J BSA-TNP + OVA 2.20 ± 0.15\ 1 c 2.92 ± 0.19\ 1 c (160) (830) BSA-TNP + OVA +\ 3.30 ± 0.52\ 13 \<0.005 2.81 ± 0.11\ 0.8 NS 50 μg IgG3 (IM-H11) (2,010) (650) 3 BALB/c BSA-TNP + OVA 2.46 ± 0.40\ 1 c 1.98 ± 0.14\ 1 c (290) (97) BSA-TNP + OVA +\ 5.59 ± 0.15\ 1,344 \<0.001 1.74 ± 0.21\ 0.6 NS 50 μg IgG3 (IM-F10) (389,814) (54) 4 DBA/1 BSA-TNP + OVA 2.41 ± 0.05\ 1 c 2.21 ± 0.12\ 1 c (259) (162) BSA-TNP + OVA +\ 4.91 ± 0.43\ 316 \<0.001 2.38 ± 0.07\ 1.5 NS 50 μg IgG3 (IM-F10) (81,835) (240) ---------------------------------------------------------------------------------------------------- Groups of five mice were immunized intravenously with 20 μg BSA-TNP + 20 μg OVA, alone or together with 50 μg TNP-specific mAb IgG3, IM-F10 or IM-H11. 14 d after immunization, mice were bled and sera tested in ELISA. Mean of log~10~ ng/ml for IgG anti-BSA or IgG anti-OVA. Figures within parentheses represent geometrical mean (anti-log). SI, stimulation index, geometrical mean of the experimental group divided by the geometrical mean of the control group. P value vs. control value (c) as determined by Student\'s *t* test; NS, not significant (P \> 0.05). Impaired Ab Responses to IgG3/Ag Complexes in C3-depleted and Cr2^−/−^ Mice. ---------------------------------------------------------------------------- The hemolytic titer of purified IgG3 (1.8 mg/ml) in the presence of Ca^2+^ and Mg^2+^ (both required for C activation via the classical pathway) was 1:256 whereas the titer in the absence of Ca^2+^ (allowing only alternative pathway activation) was reduced to \<1:4. This established that IM-F10 is an efficient activator of the classical pathway, confirming previous data ([@bib6]). We next examined whether IgG3-mediated enhancement was C dependent. Mice where the MHC-II I-A region is of the b haplotype are low-responders to IgE/Ag ([@bib28]), IgG2a/Ag ([@bib32]), and IgG3/Ag (unpublished data). Available C3 and C4-deficient mice are on C57BL/6 and/or 129/Sv (H-2^b^) backgrounds. Since the C4 locus is located within the MHC region, backcrossing to a responder MHC is impossible. The C3 locus is located outside, but close to, the MHC region, and backcrossing to a responder MHC is feasible, albeit complicated. An alternative approach is to deplete mice of C3 using CVF which acts by replacing C3b in the formation of alternative pathway C3 convertase resulting in CVFBb instead of C3bBb complexes. Whereas C3bBb is relatively labile, CVFBb has a half-life of several hours, resulting in transient C3-depletion (production is not affected; reference [@bib38]). Normal CBA/J mice were treated with CVF or sham-treated with PBS. C3 levels in CVF-treated animals were \<5% of the titers in sham-treated mice (C3 titers ± SEM: 2.3 ± 0.25 vs. 49 ± 9.5, respectively). Both groups were immunized with BSA-TNP alone or in complex with 50 μg IgG3 (IM-F10) and tested for BSA-specific IgG. C3-depletion resulted in a significant reduction of responses to IgG3/BSA-TNP complexes ([Fig. 1, A and B](#fig1){ref-type="fig"}) . In contrast, C3-depletion had no significant effect on responses to IgE/BSA-TNP, included as a control ([Fig. 1, C and D](#fig1){ref-type="fig"}). IgE-mediated enhancement is exclusively dependent on the low affinity receptor for IgE, CD23 ([@bib15], [@bib19], [@bib20]) and therefore operates independently of C. Although IgG3-mediated enhancement was significantly impaired in CVF-treated mice, it was not completely absent ([Fig. 1](#fig1){ref-type="fig"} B). One reason for this could be the residual levels of C3. {#fig1} Cr2^−/−^ mice respond normally to complexes consisting of IgE/Ag and IgG2a/Ag whereas responses to IgM/Ag are very low ([@bib17]). To further test the C dependence of IgG3-mediated enhancement, Cr2^−/−^ and wild-type mice were immunized with OVA-TNP alone or in complex with 50 μg IM-F10 ([Fig. 2](#fig2){ref-type="fig"}) . IgG3-mediated enhancement was severely impaired in Cr2^−/−^ animals at all times tested. To verify that the impaired responses to IgG3/OVA-TNP were not just an effect of a general low-responsiveness, Cr2^−/−^ mice were immunized also with IgG2a/Ag ([Fig. 3](#fig3){ref-type="fig"}) . Whereas IgG3-mediated enhancement decreased markedly (SI = 16 in wild-type mice and 5.6 in Cr2^−/−^ mice), IgG2a-mediated enhancement was stronger in Cr2^−/−^ mice (SI = 17 in wild-type mice and 32 in Cr2^−/−^), thus confirming earlier studies ([@bib17]). The results show that IgG3, but not IgG2a, loses most of its enhancing capacity in mice lacking CD21/CD35. Unlike another Cr2^−/−^ line, which expresses a hypomorphic variant of CD21/CD35 ([@bib39]), the Cr2^−/−^ line used here completely lacks expression of CD21/CD31 ([@bib40]). Therefore, the residual enhancement seen in Cr2^−/−^ mice ([Fig. 2](#fig2){ref-type="fig"} B) cannot result from enhancement via a hypomorphic receptor. {#fig2} {#fig3} Normal Ab Responses to IgG3/Ag Complexes in FcRγ^−/−^ Mice. ----------------------------------------------------------- Since a small enhancement by IgG3 could be detected both in C3-depleted and Cr2^−/−^ mice ([Figs. 1](#fig1){ref-type="fig"}--[3](#fig3){ref-type="fig"}), we wanted to test whether FcγRs may also be involved. FcRγ^+/+^ and FcRγ^−/−^ mice were immunized with OVA-TNP alone or in complex with IgG3 (IM-10). IgG3 enhanced the OVA-specific Ab response equally efficiently in both strains ([Fig. 4](#fig4){ref-type="fig"}) . These experiments were repeated using BSA-TNP as the Ag and yielded similar results (unpublished data). Thus, IgG3 enhances well in mice lacking expression of FcγRIII and with reduced expression of FcγRI. {#fig4} Normal Ab Responses to IgG3/Ag Complexes in FcγRIIB^−/−^ Mice. -------------------------------------------------------------- Enhancement by TNP-specific IgG1, IgG2a, and IgG2b mAbs administered with BSA-TNP increases dramatically in FcγRIIB^−/−^ mice compared with wild-type controls ([@bib14]). IgG3 is the only IgG subclass reported not to bind to FcγRIIB and it was of interest to test whether IgG3-mediated enhancement was indeed independent on this receptor. Wild-type and FcγRIIB^−/−^ mice were immunized with BSA-TNP alone or in complex with 50 μg IgG3 (IM-F10) and their sera tested for BSA-specific IgG. The Ab responses were enhanced both in FcγRII^+/+^ (11--16-fold of controls) and FcγRIIB^−/−^ mice (16--25-fold of controls; [Fig. 5](#fig5){ref-type="fig"}) . Although IgG3 induced a twofold higher Ab response in FcγRIIB^−/−^ compared with wild-type mice, this difference was not significant and was far less pronounced than the 20--100-fold increased enhancement previously reported with IgG1-, IgG2a-, and IgG2b-complexes ([@bib14]). The response to uncomplexed Ag is similar in FcγRIIB^−/−^ and wild-type mice ([Fig. 5](#fig5){ref-type="fig"}). In light of the fact that immunization with proteins without adjuvant induces very little production of IgG, which is a prerequisite for ligation of FcγRIIB and initiation of its negative regulation, this is not surprising. Thus, IgG3-mediated enhancement takes place in the absence of FcγRIIB and this receptor does not exert a significant inhibitory influence on responses to IgG3-complexed Ags. {#fig5} Discussion ========== Here we provide the first evidence that IgG3 can positively feedback-regulate Ab production. The augmentation is impressive, frequently yielding several-hundred-fold increases in Ab titers, and is severely impaired in mice lacking CD21/CD35 or in mice with reduced C3 levels. It is well known that C plays an important role for primary as well as secondary Ab responses, and animals lacking C1q, C2, C4, C3, as well as CD21/CD35 have severely impaired Ab responses (for reviews, see references [@bib23] and [@bib24]). In contrast, factor B--deficient mice have normal Ab responses ([@bib41]; unpublished data) suggesting that the alternative pathway is not required for up-regulation of Ab responses and that classical pathway activation (via immune complexes) plays a major role. One explanation for the role of C in Ab responses is that immune complexes, containing C factors, cocrosslink BCR and the CD21/CD19-receptor complex on the B cell surface and thereby lowers the threshold for B cell activation, as shown to take place in vitro ([@bib25]). A mutually not exclusive hypothesis is that Ab/Ag/C complexes are captured by follicular dendritic cells in the spleen and lymph nodes, increasing the effective concentration of Ag ([@bib22], [@bib42], [@bib43]). Our present data suggest that not only IgM ([@bib17], [@bib21], [@bib22]), but also IgG3, uses the C system to initiate feedback "help" for early Ab production. Since classical pathway C activation is important for normal primary Ab responses in animals immunized with Ag alone, an interesting question is how specific Abs, able to recognize Ag and form immune complexes, can be available in naive mice. Mice lacking secretory IgM have impaired primary Ab responses to noncomplexed Ags ([@bib44]--[@bib46]) and a normal response could be reconstituted by transfer of IgM from naive mice. These animals may have several abnormalities in their immune system, secondary to the lack of secretory IgM, and were also reported to have developmental defects in their B cell compartment ([@bib45], [@bib47]). The underlying reason for the impaired IgG responses observed ([@bib44]--[@bib46]) is not known. However, one intriguing explanation would be that "natural" IgM, present without prior (deliberate) immunizations, initiates positive feedback of early responses. Should the enhancing effect of natural IgM be caused by its ability to activate C, which has not been formally proven, it is possible that recognition of Ag by natural IgM is the first step in the C-dependent chain of events leading to efficient early Ab responses to suboptimal doses of Ag. This would explain how classical C activation can play a role already for primary Ab responses. Our present data raises the question whether "natural" IgG3 has a similar role as IgM in enhancing early Ab responses. IgM has only been reported to enhance responses to large Ags such as erythrocytes ([@bib21], [@bib48]), malaria parasites ([@bib49]), and KLH ([@bib22]), whereas responses to small Ags, e.g. BSA-TNP, have not been reported to be enhanced (unpublished data). An explanation for this would be that IgM must bind to an Ag large enough to permit binding of several of its arms in order to achieve the conformation change necessary to bind C1q. IgG3, bound to the surface of e g group A streptococci, is able to facilitate the binding of other IgG3 molecules to the same Ag ([@bib50], [@bib51]). This so called cooperative binding is probably mediated by Fc--Fc interactions and increases the functional affinity of IgG3. The interaction between IgG3 molecules is also evidenced by their tendency to self-aggregate ([@bib52]) and to act as cryoglobulins, i.e. to precipitate in the cold ([@bib53]). Cooperative binding of IgG3 would increase the chances that two or more IgG3 molecules end up close together (and thereby can bind C1q) also on Ags which are too small for IgM to bind with all five arms. This may explain why IgG3, but not IgM, can utilize C to enhance responses to Ags like BSA and OVA. The probability that two IgG2a or IgG2b molecules, subclasses which do not show cooperative binding, bind to the same Ag close enough to be able to fix C1q is smaller and could be the reason that these subclasses preferentially utilize FcγRs for feedback enhancement. Unlike enhancement mediated by IgG1 and IgG2a, IgG3-mediated enhancement was unperturbed in FcRγ^−/−^ mice. Although FcγRI in these animals has lost its signaling function, 20% of the receptor is still expressed ([@bib11]). As FcγRI was also reported to bind IgG3 ([@bib10], [@bib11]), we cannot at this point exclude that FcγRI, or another yet unidentified IgG3-binding receptor, acts redundantly to C in IgG3-mediated enhancement. This would explain the small residual enhancement seen in C-depleted and Cr2^−/−^ mice. Direct experiments to prove this point will have to await the availability of FcγRI^−/−^ mice on a responder background, as H-2^b^ mice, commonly used to produce knockout mice, are nonresponders to soluble IgE- and IgG-immune complexes ([@bib28], [@bib32]). Mice lacking FcγRIIB have augmented humoral, anaphylactic, and inflammatory immune responses (for a review, see reference [@bib54]). This receptor contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM), which upon cocrosslinking to receptors containing immunoreceptor tyrosine-based activation motifs (ITAMs), such as the BCR, FcγRI, FcγRIII, and FcɛRI, inhibits activation of the ITAM receptor. Ab production after immunization with IgG1/Ag, IgG2a/Ag, or IgG2b/Ag complexes is considerably higher in FcγRIIB^−/−^ mice than in wild-type controls, implying that FcγRIIB negatively regulates the response to Ag complexed to these isotypes ([@bib14]). IgG3 does not bind FcγRIIB and we here show that enhancement by IgG3 is similar in FcγRIIB^−/−^ and wild-type mice. Therefore, IgG3/Ag complexes have the for IgG isotypes unique possibility to enhance Ab responses without inducing simultaneous negative feedback via cocrosslinking of BCR and FcγRIIB. This feature may be useful to quickly generate a potent primary Ab response to e g bacterial Ags. IgG3 is an isotype frequently involved in autoimmunity ([@bib55]--[@bib58]). In addition to its ability to initiate inflammation via C-activation, the ability of IgG3 to enhance autoantibody production without negative feedback via FcγRIIB may play a role in its pathogenicity. We thank Ms. I. Brogren and Ms. T. Wahlström for skillful technical assistance, Dr. M. Wabl for IgE, and Dr. P. Coulie for IgG2a hybridomas, Dr. H. Molina for Cr2^−/−^, Dr. J.V. Ravetch for FcRγ^−/−^ and FcγRIIB^−/−^, and Dr. S. Kleinau for FcRγ^+/+^ and FcRγ^−/−^ (H2^q^) founder animals. This work was supported by Agnes and Mac Rudberg\'s Foundation; Ellen, Walter and Lennart Hesselman\'s Foundation; Hans von Kantzow\'s Foundation; King Gustaf V:s 80 Years Foundation; Lilly and Ragnar Åkerhams\'s Foundation; The Swedish Foundation for Health Care Science and Allergy Research; The Swedish Medical Research Council; The Swedish Association against Rheumatism; and Ollie and Elof Ericsson\'s Foundation. *Abbreviations used in this paper:* BCR, B cell receptor; CVF, cobra venom factor; FcR, Fc-receptor. [^1]: Address correspondence to Birgitta Heyman, Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden. Phone: 46-18-6113868; Fax: 46-18-55-89-31; E-mail: <Birgitta.Heyman@genpat.uu.se>

Kynan stop being an idiot. You're accusing random people of hacking just because they got a random good score, or their playcount is lower than yours. "Oh there isn't any proof that he is legit, so that's proof that he cheats!" and gayz' top ranks are STREAM MAPS over anything else, so makes sense My accusations or not random AT ALL, and dude, stream maps or not, the guy doesn't even have 30k PC, with that much playcount, you shouldn't even be able to FC 5 star maps, you should realize that before calling me an idiot.

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"I'M SO STUPID!" "HAVE YOU SEEN ANY SUSPICIOUS PEOPLE" "OR VEHICLES IN THE NEIGHBORHOOD RECENTLY?" "WELL, I SAW A STRANGE CAR YESTERDAY." "IT WAS PARKED OUT IN FRONT." "AND THEN I SAW THAT SAME CAR" "SPEEDING UP THE STREET JUST A FEW HOURS AGO." "COULD YOU DESCRIBE THE CAR OR THE DRIVER?" "NO, I DIDN'T SEE THE DRIVER," "AND I'M NOT REALLY GOOD WITH CARS." "BUT I DID WRITE DOWN THE LICENSE-PLATE NUMBER" "JUST IN CASE." "HANG ON." "THANK YOU." "PUT OUT AN AMBER ALERT." "RIGHT AWAY." "SO, HOW WELL DO YOU KNOW LUCY HALPERN?" "WELL, SHE'S KIND OF THE QUIET, SHY TYPE." "STAYS TO HERSELF MOSTLY." "DO YOU EVER SEE HER WITH THE BABY?" "OH, YEAH." "SHE'S ALWAYS STROLLING HIM UP AND DOWN THE STREET HERE," "BUT SHE ALWAYS LOOKS SO EXHAUSTED." "I HALF WORRY SHE'S GONNA WANDER INTO TRAFFIC." "BOY, I'LL TELL YOU," "MOTHERHOOD IS NO PICNIC FOR THAT ONE, THAT'S FOR SURE." "OWENISONLY EIGHTWEEKSOLD." "PLEASE, IFTHEREIS ANYONEOUT THERE" "WHOHASANYINFORMATION ABOUTHISDISAPPEARANCE," "PLEASE,PLEASE HELPTHEPOLICEFINDHIM." "HENEEDSHISMOTHER." "IF THE PERSON WHO TOOK HIM IS WATCHING," "IDON'TCAREWHO YOU ARE ORWHYYOUDID IT." "[ Voice breaking ] I-IJUSTWANTHIM BACK!" "[ SOBS ]" "[ TELEPHONE RINGS ]" "LEWICKI, GET THAT." "DR. PIERCE'S RESIDENCE." "YEAH, RIGHT HERE." "IT'S KATE." "HEY." "HEY." "TURN ON CHANNEL 9?" "YEAH, WE'RE WATCHING IT." "COULD YOU COME OVER, TALK TO HER?" "FOR EMOTIONAL SUPPORT OR 'CAUSE YOU THINK" "SHE DID SOMETHING TO HER BABY?" "I DON'T KNOW, BUT IT WOULD BE HELPFUL" "IF YOU COULD..." "EVALUATE HER MENTAL HEALTH, DISCREETLY." "Daniel:" "YOU'VE GOT NOBODY TO -- TO HELP YOU," "NO FAMILY OR FRIENDS?" "NO, THERE'S JUST ME." "I CAN'T IMAGINE HOW HARD THAT MUST BE" "WITH ALL THE DIAPER CHANGES AND THE FEEDINGS AND THE CRYING." "YEAH." "DO YOU HAVE KIDS?" "NO." "NO." "SO, WHEN'S THE LAST TIME YOU HAD A FULL NIGHT'S REST?" "I DON'T KNOW." "PROBABLY NOT SINCE I BECAME A MOM." "CHRONIC SLEEP DEPRIVATION CAN WREAK HAVOC ON YOUR MOOD." "HAVE YOU BEEN FEELING IRRITATED OR ANGRY LATELY?" "WELL, YEAH, I GUESS A LITTLE." "YEAH, BUT WHO WOULDN'T FEEL A LITTLE FRUSTRATED" "TAKING CARE OF A SICK BABY ALL ALONE?" "OF COURSE." "WHAT DO YOU DO WHEN YOU FEEL FRUSTRATED?" "DO YOU THINK THAT I HURT MY OWN BABY?" "IS THAT WHAT THIS IS ABOUT?" "I'M NOT MAKING ANY ALLEGATIONS." "I'M JUST HERE TO HELP." "I WOULD NEVER HURT OWEN." "NEVER." "I WANT EVERYONE TO LAY BACK WHEN WE GET THERE." "LET ME MAKE THE FIRST APPROACH." "WE DON'T WANT TO SPOOK THE PERP." "ANY QUESTIONS?" "LET'S MOVE." "HEY, WHAT'S -- WHAT'S GOING ON?" "THE CAR THE NEIGHBOR I.D.'d WAS SPOTTED AT HEISE PARK." "HOW'D IT GO WITH LUCY?" "NOT GOOD." "TALK TO YOU WHEN I GET BACK." "EXCUSE ME, MISS?" "FBI." "I NEED TO SEE SOME IDENTIFICATION FROM YOU." "Woman:" "WHAT'S THIS ABOUT?" "MA'AM?" "Kate:" "MISS?" "STOP!" "FBI!" "[ INDISTINCT SHOUTING ]" "[ TIRES SCREECH ]" "[ PEOPLE SCREAM ]" "Woman:" "IS THE BABY ALL RIGHT?" "!" "SOMEBODY CALL AN AMBULANCE!" "SIR, IT'S OKAY." "WE DON'T NEED THE PARAMEDICS." "IT'S JUST A DOLL." "IT'S AMAZING HOW REAL THIS THING LOOKS." "HERE." "YOU WANT TO PRACTICE?" "OKAY, I DON'T KNOW WHAT'S CREEPING ME OUT MORE " "YOU OR THE DOLL." "ARE WE EVEN SURE THAT THIS IS LUCY'S BABY?" "YEAH." "SAME FACE." "LUCY'S GOT SOME 'SPLAININ' TO DO." "I HAVE AN AGENT BRINGING HER IN." "WHAT ABOUT THE DOLLNAPPER?" "FIGURED I'D CALL C.P.D., HAND HER OVER FOR LARCENY." "WELL, HANG ON A SEC." "IF BETSY WAS FOOLED BY THE DOLL LIKE WE ALL WERE" "AND HER ORIGINAL INTENT WAS TO STEAL A CHILD," "I COULD STILL PROSECUTE HER FOR KIDNAPPING." "I KNEW IT WAS A DOLL ALL ALONG." "I KNOW HOW CRAZY I MUST SEEM, BUT I COULDN'T HELP IT." "I HAD TO TAKE HIM." "WHY?" "SIX MONTHS AGO..." "I HAD A BABY." "CODY." "[ SNIFFLES ]" "HE WAS A BORN WITH A CONGENITAL HEART DEFECT." "HE ONLY SURVIVED SEVEN WEEKS." "I'M SO SORRY FOR YOUR LOSS." "I'VE BEEN HAVING A REALLY HARD TIME" "FIGURING OUT WHAT TO DO WITH MYSELF." "ITOLDMY THERAPIST THAT I'M ALWAYS FEELING" "THIS OVERWHELMING NEED TO JUST HOLD HIM AGAIN." "SHE SUGGESTED I GET A REBORN." "THEY'RE CRAFTED TO LOOK AS LIFELIKE AS POSSIBLE." "SOME WOMEN GET REALLY INTO THEM." "IN WHAT WAY?" "BUY THEM CLOTHES AND TOYS" "AND [SNIFFLES] HAVE BABY SHOWERS." "THEY TREAT THE DOLLS LIKE THEY'RE REAL?" "BUT FOR ME, IT WAS " "IT WAS JUST SUPPOSED TO BE A GRIEVING TOOL." "MYTHERAPISTSAID THATIFIHELDONE" "FOR A FEW MINUTES EACH DAY, ITMIGHTHELP." "AND AS..." "BIZARRE AS THAT SOUNDS," "I WAS WILLING TO TRY ANYTHING." "SO THAT'S WHY YOU STOLE LUCY'S DOLL?" "WELL, IT'S -- IT'S NOT HERS." "IT'S MINE." "I'D HEARD ABOUT THIS DOLLMAKER." "ASGAR SVENSDEN." "HE'S THE BEST REBORN ARTIST IN THE STATE." "I ASKED HIM IF HE COULD MAKE ONE TO LOOK LIKE MY SON." "HE SAID IT WOULD COST $4,500." "I HAD TO PUT DOWN A NON-REFUNDABLE DEPOSIT." "BUT I HAD A HARD TIME COMING UP WITH THE REST." "AND BY THE TIME I DID," "ASGAR HAD ALREADY SOLD MY DOLL TO SOMEONE ELSE." "I COULDN'T BELIEVE IT." "I MEAN, HOW CAN HE GIVE MY BABY TO ANOTHER WOMAN?" "IT'S NOT YOUR BABY." "IT'S MY DOLL." "I MADE IT." "I OWN IT." "I CAN SELL IT." "I REALIZED THAT IT WAS POINTLESS TO ARGUE WITH HIM," "SO I JUST ASKED HIM FOR THE BUYER'S NAME AND ADDRESS." "AND HE GAVE IT TO YOU?" "IT TOOK SOME CONVINCING," "BUT, YEAH, I FINALLY GOT IT." "I JUST WANTED TO TALK TO HER, TRY TO EXPLAIN." "BUT I SAW CODY STRAPPED IN THE CAR." "ASGAR SAID YOU'RE NOT SUPPOSED" "TO LEAVE THE DOLLS IN HOT CARS" "BECAUSE THE PAINT CAN WARP AND THE VINYL CAN MELT." "AND AS CRAZY AS IT SOUNDS, I COULDN'T STAND IT." "I HAD TO RESCUE HIM." "[ CAR DOOR UNLOCKS ]" "[ SCOFFS ]" "NEVER OCCURRED TO ME THAT LUCY MIGHT CALL THE FBI." "HOW MUCH TROUBLE AM I IN?" "I'M NOT GOING TO PROSECUTE A GRIEVING MOTHER," "BUT THAT WOMAN'S THERAPIST IS A WACKO." "WHO TELLS SOMEONE TO USE A DOLL" "TO GET OVER THEIR DEAD BABY?" "WELL, SOMETIMES PEOPLE HAVE TO DO" "WHATEVER GETS THEM THROUGH THE NIGHT." "SURE, BUT IT SOUNDS LIKE SOME OF THESE WOMEN" "ARE TAKING THIS STUFF TOO FAR." "YEAH, LIKE SOMEONE WHO REPORTS A KIDNAPPING" "BECAUSE HER DOLL WAS STOLEN?" "NOW, LUCY OBVIOUSLY KNEW IT WASN'T REAL," "BUT SINCE THE FBI DOESN'T FIND TOYS," "SHE LIED AND SAID THAT HER BABY WAS MISSING." "I'M GONNA CHARGE HER FOR KNOWINGLY FILING A FALSE REPORT." "WAIT." "T-THERE MIGHT BE MORE TO IT THAN THAT." "LET ME -- LET ME TALK TO HER." "[ GASPS ] OH, MY GOD!" "[ LAUGHS ]" "OH, MOMMY'S SO SORRY!" "[ SNIFFLES ]" "I'LL NEVER LEAVE YOU ALONE AGAIN." "JUST GLAD THE FBI WAS ABLE TO HELP." "WOULD YOU LIKE TO SIT DOWN FORA MINUTE?" "GETYOURBEARINGS?" "YEAH." "SURE." "[ SIGHS ]" "HI, BABY." "YOU'RE GOOD WITH HIM." "OH." "I DO MY BEST." "LUCY, DO YOU KNOW SOMEONE NAMED ASGAR SVENSDEN?" "YEAH, HE'S SUCH A NICE MAN." "WHAT IS YOUR RELATIONSHIP WITH HIM?" "HE ARRANGED THE ADOPTION." "I DIDN'T REALIZE THAT OWEN WAS ADOPTED." "IT WAS THE ONLY WAY I COULD BE A MOTHER." "OH." "UH-OH." "[ CHUCKLES, SNIFFLES ] SOMEBODY MADE A POOPY." "DOYOUMINDIFI CHANGEHIM WHILEWETALK?" "NOTATALL." "LUCY IS SUFFERING FROM DELUSIONAL DISORDER." "IT'S A PSYCHIATRIC CONDITION" "IN WHICH A PATIENT HOLDS A FIXED DELUSION," "BUT HAS NO OTHER OBVIOUS PROBLEMS WITH THOUGHT OR MOOD." "I DECIDED TO DROP THE CASE DURING THE DIAPER CHANGE." "ARE YOU SURE WE'RE DOING THE RIGHT THING" "BY GIVING THE DOLL BACK TO HER?" "TAKING IT AWAY NOW WOULD ONLY WORSEN HER MENTAL STATE." "HOPEFULLY OVER TIME SHE'LL RESPOND" "TO A COMBINATION OF DRUGS AND PSYCHOTHERAPY." "SHOULD WE CALL THE HOSPITAL, TRY AND GET HER ADMITTED?" "NO, NO, NO." "LISTEN, SHE'S GOT A SINGLE FIXED DELUSION," "BUT IT'S NOT HAMPERING HER ABILITY TO FUNCTION." "SENDING HER TO A HOSPITAL WOULD ONLY MAKE THINGS WORSE." "AND, AS YOU KNOW, WE HAVE NO AUTHORITY TO COMMIT HER." "WE JUST SEND HER HOME?" "I'LL MAKE SURE SHE SEES A DOCTOR FIRST THING IN THE MORNING." "Natalie:" "I NEED A PICKLE." "WHAT THE HELL?" "I WAS THINKING HARPER IF IT'S A GIRL AND KEITH IF IT'S A BOY." "WHAT DO YOU THINK?" "I THINK THE SIGHT OF YOU EXPECTING IS..." "VERY UNEXPECTED." "WELL, YOU OBVIOUSLY HAVE BABIES ON THE MIND." "AFTER TODAY'S CASE, HOW COULD I NOT?" "DANIEL, WE BOTH KNOW THERE'S ANOTHER REASON" "WHY YOU'RE SEEING ME THIS WAY." "WHICH IS?" "YOU WANT A BABY." "WHAT?" "!" "ARE YOU OUT OF YOUR MIND?" "[ Laughing ] I DON'T WANT A BABY." "WELL, CONSIDERING MY CURRENT STATE," "I FIND IT HARD TO BELIEVE." "THE CRYING AND THE DIRTY DIAPERS" "AND " " AND " " AND THE COMPLETE HAVOC" "BABIES WREAK ON ANY SEMBLANCE OF A SCHEDULE?" "NO, THANK YOU." "WELL, WHAT ABOUT THE GOOD STUFF?" "THE FEELING OF A BABY SLEEPING IN YOUR ARMS," "THE WAY THEY LAUGH." "IT'S OUT OF THE QUESTION." "WHY?" "YOU KNOW WHY." "I WOULD NEVER RISK PASSING THIS ON TO A CHILD." "IT'S BETTER NOT TO BE BORN THAN TO BE BORN WITH SCHIZOPHRENIA?" "THERE IS NO WAY YOU ARE DRAGGING ME" "INTO THAT PHILOSOPHICAL QUAGMIRE." "OOH." "WHAT?" "THE BABY'S KICKING." "YOU WANT TO FEEL?" "THIS IS TOO CRAZY, EVEN FOR ME." "IT'S NOT CRAZY" "TO CONSIDER WHAT LIFE WOULD BE LIKE WITH A BABY." "IT'S PERFECTLY NORMAL." "SAID THE PREGNANT HALLUCINATION." "YOU'RE NO FUN." "GO EAT A PICKLE." "Donnie:" "BAKERS MARBLE COUNTERTOPS, ABUNDANT NATURAL LIGHT." "WHAT'S NOT TO LOVE?" "WHAT WOULD WE DO WITH FOUR BEDROOMS ANYWAY?" "WELL, THE MASTER IS FOR US, A NURSERY, A GUEST ROOM," "AND THE FOURTH GIVES US ROOM TO GROW." "HERE." "LOOK." "LOOK AT THAT YARD." "HOW PERFECT IS THAT FOR KIDS?" "PUT A BIG SWING SET IN," "BIRTHDAY PARTIES, EASTER-EGG HUNTS." "PLUS IT'S IN A GREAT SCHOOL DISTRICT," "SO I THINK IT'S GONNA GO REALLY FAST." "YOU DID RESEARCH ON THE SCHOOL DISTRICT?" "YEAH." "GUESS MY BIOLOGICAL CLOCK IS TICKING." "ISN'T YOURS?" "WELL, YEAH." "I MEAN, I GUESS WE ARE AT THAT AGE." "SLOW DOWN, SAILOR." "IT'S GONNA BE A LONG VOYAGE." "I MEAN, REALLY, WE ARE HAVING A TRADITIONAL CATHOLIC WEDDING." "I'M NOT WALKING DOWN THE AISLE WITH A BABY BUMP, OKAY?" "[ CELLPHONE RINGS ]" "HELLO?" "I'LL BE RIGHT THERE." "WHAT'S WRONG?" "I JUST WANTED TO SEE HOW SHE WAS DOING." "OH." "[ POLICE RADIO CHATTER ]" "WHERE IS SHE?" "[ CAMERA SHUTTER CLICKING ]" "WHAT DO YOU GOT?" "MURDER WEAPON." "WELL, THAT'S A NEW ONE." "WHAT THE HELL HAPPENED?" "WHO DID THIS?" "I DON'T KNOW, BUT THE DOLL IS MISSING." "[ SIGHS ]" "WELL, WHAT'S HER NAME, BETSY, SHE " " SHE STOLE IT ONCE." "MAYBE -- NO, IT WASN'T HER." "SHE LEFT TOWN FOR HER SISTER'S AS SOON AS WE CUT HER LOOSE." "ANY SIGNS OF FORCED ENTRY?" "NO, BUT I MIGHT HAVE ANOTHER LEAD." "WHAT'S THAT?" "LUCY'S BABY DADDY." "SHE SAID THAT HE WALKED OUT ON HER." "WE TRACKED HIM DOWN TO A MILITARY BASE" "ABOUT THREE HOURS AWAY." "HE JUST GOT BACK FROM AFGHANISTAN." "I MET LUCY ABOUT SIX MONTHS BEFORE I GOT DEPLOYED." "I WAS AT A GAS STATION IN MY DRESS BLUES." "SHE CAME OVER TO THANK ME FOR MY SERVICE." "[ CHUCKLES ]" "I TOLD HER I'D NEVER BEEN THANKED BY A WOMAN SO PRETTY BEFORE." "HER WHOLE FACE WENT RED." "I ASKED HER OUT RIGHT THEN." "AND HOW LONG WERE YOU TOGETHER?" "ABOUT A YEAR AND A HALF." "I WAS CRAZY ABOUT HER." "SHE'D BEEN WITH A LOT OF JERKS WHO TREATED HER LIKE DIRT." "BUT I TREATED HER THE WAY SHE DESERVED." "HOW SERIOUS DID THINGS GET?" "I POPPED THE QUESTION BEFORE I GOT DEPLOYED." "SHE SAID YES?" "SHE SAID SHE'D BE COUNTING THE DAYS" "UNTIL I CAME HOME." "I TOLD HER WE'D BUY A HOUSE," "MAKE BEAUTIFUL BABIES TOGETHER." "ONLY A MONTH INTO MY DEPLOYMENT," "SHE SKYPED ME AND TOLD ME SHE WAS ALREADY PREGNANT." "HOW'D YOU TAKE THE NEWS?" "GUYS!" "I'M GONNA BE A DAD!" "[ MEN CHEERING ]" "I SENT HER MONEY OUT OF MY PAY FOR DOCTOR BILLS," "NURSERY STUFF." "I WAS IN LOVE WITH THAT KID BEFORE I EVEN MET HIM." "I WAS BUMMED WHEN I MISSED HIS BIRTH." "SO MY FRIENDS, THEY THREW ME A PARTY." "AND THE BEST GIFT CAME FROM MY C.O." "TRANSFERRED ME BACK STATESIDE" "SO I COULD GO HOME AND SEE MY SON." "I DIDN'T TELL LUCY THAT I WAS COMING" "BECAUSE I WANTED TO SURPRISE HER." "HEY." "WHAT THE HELL?" "ANDREW." "WHERE'S OWEN?" "I CAN EXPLAIN." "EXPLAIN WHAT?" "THAT YOU LIED TO ME?" "LOOK, NO." "OH, MY GOD." "TELL ME THIS IS NOT HAPPENING!" "TELL ME THIS IS SOME SORT OF A JOKE!" "PLEASE." "DON'T TOUCH ME!" "I WAS SUCH AN IDIOT." "ALL THAT BULLSHIT" "ABOUT THE DOCTOR BILLS, THE NURSERY STUFF." "SHE WAS JUST SCAMMING ME FOR MONEY THE WHOLE TIME." "IT WASN'T ABOUT THE MONEY, SERGEANT." "LUCY WAS A PSYCHOLOGICALLY FRAGILE WOMAN." "SHE TOLD ME SHE COULDN'T HAVE CHILDREN." "MAYBE SHE LIED ABOUT THE PREGNANCY" "BECAUSE SHE WAS AFRAID OF LOSING YOU." "I JUST DON'T UNDERSTAND HOW SHE COULD TAKE IT SO FAR." "IT'S ONE THING TO LIE ABOUT BEING PREGNANT," "BUT TO TRY TO FAKE ME OUT WITH A DOLL?" "I THINK SHE USED THE DOLL TO PERPETUATE THE LIE," "BUT AT SOME POINT, IT BECAME REAL FOR HER." "BUT THAT DOESN'T EXPLAIN" "WHY SHE WOULD HAVE TOLD ANDREW THAT SHE WAS PREGNANT" "AND TELL US THAT OWEN WAS ADOPTED." "WAIT." "ADOPTED?" "WHEN YOU WALKED OUT, SHE WAS PROBABLY DEVASTATED" "AND " " AND TURNED TO THE ONLY SOURCE OF COMFORT" "THAT SHE HAD AVAILABLE TO HER." "THE DOLL." "YES." "THAT'S WHEN HER FANTASY OF BEING A MOTHER" "BECAME A FULL-BLOWN DELUSION." "SHE GRABBED ON TO THE IDEA OF ADOPTION BECAUSE IT WAS LESS PAINFUL" "THAN THINKING OF YOU AS THE BIOLOGICAL FATHER." "IT'S ALL MY FAULT." "IF I'D HAVE GOTTEN HER HELP, MAYBE SHE'D STILL BE ALIVE." "NO, SERGEANT." "LUCY'S MENTAL ILLNESS MOST LIKELY BEGAN" "LONG BEFORE SHE MET YOU." "WHAT DO YOU KNOW ABOUT HER CHILDHOOD?" "LUCY DIDN'T LIKE TO TALK ABOUT HER CHILDHOOD MUCH." "BUT I KNOW HER MOTHER BEAT THE HELL OUT OF HER GROWING UP." "WHEN WAS THE LAST TIME YOU SAW YOUR DAUGHTER?" "TWO MONTHS AGO." "IF I'D KNOWN I'D NEVER SEE HER AGAIN," "I WOULD HAVE TOLD HER I LOVED HER." "WHAT HAPPENED THE LAST TIME YOU SPOKE?" "[ SIGHS ]" "SHE WASN'T EXPECTING ME." "SHE CAME TO THE DOOR HOLDING A BABY." "I ASKED WAS SHE BABYSITTING OR SOMETHING." "AND SHE SAID, NO, THE KID WAS HERS." "I COULDN'T BELIEVE IT." "I DIDN'T EVEN KNOW SHE WAS PREGNANT." "SO THEN WHAT HAPPENED?" "WELL, SHE WAS LOOKING KIND OF RUN-DOWN." "I TOLD HER TO GO DO SOMETHING NICE FOR HERSELF, YOU KNOW?" "TAKE A BREAK." "I'D WATCH THE LITTLE STINKER." "SHE SAID SHE COULDN'T TRUST ME." "WITH A DOLL?" "WHAT DO YOU MEAN, A DOLL?" "WE'RE TALKING ABOUT MY GRANDBABY, OWEN." "WAIT A MINUTE." "ARE YOU SAYING YOUR DAUGHTER HAD A REAL BABY?" "OF COURSE SHE HAD A REAL BABY." "THE DAMN THING PUKED ALL OVER ME." "THANK YOU." "WELL, THE M.E. CONFIRMED" "LUCY RECENTLY GAVE BIRTH." "SO SHE AND SERGEANT WHAT'S-HIS-NAME" "REALLY DID HAVE A CHILD TOGETHER." "BUT AT SOME POINT," "SHE SWITCHED OUT THE REAL INFANT FOR A DOLL." "WHY?" "[ SIGHS ]" "[ BABY CRYING ]" "DID -- DID YOU HEAR THAT?" "HEAR WHAT?" "NEVER MIND." "I CAN'T WATCH THIS ANYMORE." "I'LL BE INSIDE." "[ BABY CRYING ]" "[ LID CLATTERS ]" "THEY SWEPT THE WHOLE HOUSE AND THE YARD." "BODY'S NOT HERE." "LOOK AT THIS." "IT'S A TREASURE BOX." "SOUVENIRS." "ALWAYS TURNS MY STOMACH" "WHEN KILLERS KEEP THOSE." "I DON'T KNOW." "[ STAMMERS ]" "LOOK AROUND." "L-LOOK AT THIS NURSERY." "LOOK HOW WELL IT'S KEPT." "I " "EVERYTHING I'M SEEING TELLS ME SHE LOVED HER BABY." "I'M SURE SHE DID." "NO, NO, WHAT I MEAN IS I DON'T THINK SHE KILLED HIM." "LOOK, WE -- WE KNOW HER MOM WAS ABUSIVE." "THAT DOESN'T MEAN SHE BECAME ABUSIVE." "YOU KNOW, MAYBE SHE " "MAYBE SHE WAS AFRAID OF BEING A MOTHER" "AND SH-- AND SHE GAVE THE BABY AWAY." "LOOK, I'M NOT CALLING THE DOGS OFF YET " " LITERALLY " "BUT YOU'RE RIGHT." "WE SHOULD CHECK IN WITH SOCIAL SERVICES," "SEE IF THEY KNOW ANYTHING." "Woman:" "MALE INFANT, NEWBORN CAUCASIAN," "WAS RELINQUISHED AT A LOCAL FIRE STATION ABOUT A MONTH AGO." "GREAT." "SO WHERE " " WHERE IS HE?" "IN FOSTER CARE?" "SAYS HERE A CASE WORKER RESPONDED" "BUT WAS TOLD IT WAS A FALSE ALARM." "WHAT DOES THAT MEAN?" "THAT'S ALL I HAVE." "SO NOBODY ASKED ANY QUESTIONS?" "THE WHOLE POINT TO THE SAFE HAVEN LAW" "IS SO THAT PARENTS CAN GIVE UP A NEWBORN" "WITHOUT ANY QUESTIONS ASKED." "IF THEY HAD TO GIVE UP THEIR NAME, RANK," "AND SERIAL NUMBER, NO ONE WOULD DO IT." "CAN YOU TELL US WHAT FIRE STATION?" "YEAH, THAT'S HER." "CAN YOU EXPLAIN EXACTLY WHAT HAPPENED WHEN SHE CAME IN?" "IT WAS LATE, MAYBE 2:00 A.M." "EVERYONE ELSE HAD GONE OUT ON CALL," "SO I WAS THE ONLY ONE HERE." "SHE WAS PRETTY SHAKEN UP WHEN SHE CAME IN." "LOOKED LIKE SHE'D BEEN CRYING AWHILE." "I MEAN, SHE JUST HANDED ME THE BABY AND LEFT." "SO YOU CALLED DCFS?" "YEAH." "BUT TOOK AWHILE FOR THE SOCIAL WORKER TO GET HERE." "SO I JUST HELD THE BABY, TRIED TO KEEP HIM CALM." "CUTEST LITTLE BUGGER I EVER SAW." "SO THEN WHAT HAPPENED?" "WELL, NEXT THING I KNOW," "HIS MOM COMES WALKING BACK THROUGH THE DOOR." "WHAT DID SHE SAY?" "THAT SHE MADE A MISTAKE," "THAT SHE'D GIVEN HIM TO ME" "BECAUSE SHE WAS FEELING OVERWHELMED." "SHE TALKED TO HER FAMILY, AND THEY WERE GONNA HELP HER OUT." "SO WHAT DID YOU DO?" "WHAT COULD I DO?" "I FELT SORRY FOR HER." "SHE WAS OBVIOUSLY GOING THROUGH A HARD TIME." "AND I KNEW THAT ONCE HER KID WAS IN THE SYSTEM," "SHE'S GONNA HAVE A HELL OF A TIME GETTING HIM BACK." "SO I GAVE HIM BACK." "BUT YOU HAD ALREADY CALLED DCFS." "I MEAN -- I KNOW." "I KNOW." "I SCREWED UP." "I SHOULD HAVE STALLED HER" "TILL THE SOCIAL WORKER GOT HERE." "I JUST DIDN'T WANT TO MAKE THINGS HARDER ON HER." "DID SOMETHING BAD HAPPEN TO THAT BABY?" "IF LUCY HAD SOME SORT OF A SCARE" "THAT PROMPTED HER TO GIVE UP HER BABY," "BUT THEN SHE CAME BACK" "SAYING THAT FAMILY PROMISED TO HELP, THEN MAYBE " "MAYBE SHE WAS TALKING ABOUT HER MOM." "MAYBE SHE DID AGREE TO LET HER BABYSIT." "I MEAN, IT'S NOT INCONCEIVABLE" "THAT SHE KILLED HER OWN GRANDCHILD." "WHICH WOULD HAVE TRIGGERED LUCY'S PSYCHOSIS." "BUT THEN WHAT?" "MOTHER KILLS DAUGHTER?" "WHY?" "WELL, EITHER SHE WAS NERVOUS THAT LUCY" "WOULD TELL THE COPS SHE KILLED OWEN" "OR IT WAS ABOUT THE DOLL." "OKAY, YOU LOST ME THERE." "WELL, DON'T FORGET, IT'S MISSING." "AND IT'S WORTH A LOT OF MONEY." "I'LL SCOUR THE INTERNET AND THE LOCAL PAWNSHOPS," "SEE IF MOMMY DEAREST MIGHT BE TRYING TO SELL IT." "[ DOORBELL RINGS ]" "LEWICKI!" "[ DOORBELL RINGS ]" "LEWICKI!" "[ BABY COOING ]" "LEWICKI!" "[ BABY CRYING ]" "LEWICKI!" "YOU " " YOU -- YOU CALLING FOR ME, DOC?" "YES, I'M CALLING YOU." "I NEED SOME HELP HERE WITH THIS BABY." "WHAT BABY, DOC?" "NOTHING." "GO " " GO BACK TO BED, LEWICKI." "YOU'RE HAVING A NIGHTMARE." "OR I AM." "[ SCOFFS ]" "[ SIGHS ]" "[ BABY COOING ]" "[ NATALIE HUMMING ]" "IT'S NOT GONNA BITE." "WHO KNOWS WHERE MY SCHIZOPHRENIC BRAIN" "IS GONNA TAKE THIS." "OH, PLEASE." "ON SOME LEVEL, YOU WANT TO BE A FATHER," "OR YOU WOULDN'T BE HALLUCINATING A BABY." "THE VERY FACT THAT I AM" "IS EXACTLY WHY IT'S NOT SAFE FOR ME TO BE A PARENT." "IS THAT WHY YOU DON'T WANT KIDS?" "BECAUSE YOU DON'T THINK IT'S SAFE?" "I COULD NEVER FORGIVE MYSELF IF " "IF WHAT?" "I HAVE TO SPELL IT OUT FOR YOU?" "M-M-ME AND JUNIOR ARE PLAYING CATCH IN THE YARD ONE DAY" "AND " " AND SUDDENLY I START TALKING" "TO A FIGMENT OF MY IMAGINATION" "WHILE MY CHILD CHASES A BALL INTO THE STREET." "OR " " OR I-I LEAVE MY KID WITH A BABYSITTER" "AND SOMETHING HORRIBLE HAPPENS" "BECAUSE THE SITTER I HIRED WAS ALL IN MY HEAD." "DANIEL, YOU'VE DONE A GREAT JOB" "AT DEVELOPING COPING STRATEGIES TO KEEP YOURSELF SAFE." "IF YOU REALLY WANT TO BE A DAD, MAYBE YOU CAN ADOPT." "YEAH. [ CHUCKLES ] THAT'S A GREAT IDEA." "PSYCHOTIC SINGLE PROFESSOR IN HIS LATE 40s LOOKING TO ADOPT." "I THINK YOU'RE BEING HARD ON YOURSELF." "AND YOU ARE BEING UNREALISTIC." "A BABY IS OUT OF THE QUESTION." "THEN WHY ARE YOU HALLUCINATING ONE?" "MAYBE MY BRAIN'S JUST TRYING TO TELL ME SOMETHING." "WHAT?" "WHAT ARE YOU TRYING TO TELL ME?" "YEAH, YEAH, YOU'RE VERY GOOD AT BEING CUTE," "BUT I'M GONNA NEED MORE HELP THAN THAT." "[ CHUCKLES ] I KNOW WHAT YOU'RE DOING." "I KNOW WHAT YOU'RE DOING." "YOU'RE A VERY CUTE BABY" "WITH A HEAD AND EYES TOO LARGE FOR YOUR BODY," "AND RIGHT NOW, I CAN'T HELP BUT FEEL ATTACHED" "BECAUSE YOU'RE CAUSING DOPAMINE TO FLOOD MY NUCLEUS ACCUMBENS." "I KNOW ALL ABOUT THE SCIENCE OF CUTENESS," "YOU MANIPULATIVE, LITTLE RUNT." "THE VERY ESSENCE OF YOUR SURVIVAL" "LIES IN YOUR ABILITY TO STIMULATE" "THE GENETICALLY PROGRAMMED PROTECTIVE MECHANISMS" "OF THOSE AROUND YOU." "WELL, IT'S NOT GONNA WORK." "[ BABY COOS ]" "[ POLICE RADIO CHATTER ]" "WHAT'S GOING ON?" "PLEASE STEP OUTSIDE." "NO." "NOT UNTIL YOU TELL ME " "DO NOT MAKE THIS ANY HARDER THAN IT NEEDS TO BE." "STEP OUTSIDE." "[ BABY COOING ]" "[ EMMA SOBS ]" "OH, MY GOD." "PLEASE STOP THEM." "PLEASE." "PLEASE DON'T TAKE OUR BABY." "IT'S NOT YOUR BABY." "[ SOBBING ]" "Scott:" "EMMA AND I TRIED FOR YEARS TO GET PREGNANT." "IVF, FERTILITY DRUGS." "WE EVEN CONSIDERED A SURROGATE AT ONE POINT." "THEN LUCY COMES WALKING UP TO THE STATION." "SHE TOLD ME THAT SHE NEVER THOUGHT" "SHE'D BE CAPABLE OF HARMING HER OWN BABY," "BUT AN HOUR EARLIER," "SHE FOUND HERSELF ON THE VERGE OF SHAKING HIM." "AND I TOLD HER SHE DIDN'T HAVE TO GIVE UP THE BABY," "THAT SHE COULD GET HELP," "THAT THE IMPORTANT PART HERE WAS THAT SHE DIDN'T HARM HER BABY." "SHE SAID THAT SHE -- SHE COULDN'T TAKE ANY CHANCES." "SHE JUST TOOK OFF." "I CALLED DCFS AS SOON AS SHE LEFT." "THEN YOU SAT THERE WAITING, STARING AT OWEN," "THINKING ABOUT THE LIFE THAT HE'D HAVE IN FOSTER CARE." "WHAT'D YOU SAY?" "THE CUTEST, LITTLE BUGGER YOU EVER SAW?" "I COULDN'T TAKE IT." "HE DESERVES STABILITY" "AND A MOTHER AND FATHER WHO LOVE HIM." "SO WHEN THE SOCIAL WORKER SHOWED UP," "YOU LIED AND SAID THAT THE MOTHER HAD COME BACK." "LOOK, I KNOW I DIDN'T HANDLE EVERYTHING PERFECTLY," "BUT I SAVED THAT BABY." "NO, LUCY SAVED HER BABY." "SHE WAS AFRAID SHE WAS GONNA BECOME LIKE HER MOTHER," "AND SOMEHOW SHE FOUND THE STRENGTH TO DO THE RIGHT THING." "YOU, ON THE OTHER HAND," "TOOK SOMETHING THAT DIDN'T BELONG TO YOU." "I BELIEVE IT'S CALLED KIDNAPPING." "BUT YOU DID A WHOLE LOT MORE THAN THAT, DIDN'T YOU?" "WHAT?" "WHAT " " WHAT ARE YOU -- WHAT ARE YOU TALKING ABOUT?" "OH, COME ON, SCOTT." "YOU STOLE HER BABY," "AND THEN YOU KILLED HER TO COVER IT UP." "WHAT?" "YOU SAW LUCY ON THE NEWS" "SAYING THAT HER BABY HAD BEEN ABDUCTED." "YOU WERE AFRAID THAT SHE WAS GONNA TELL THE COPS" "THAT OWEN WAS WITH YOU." "NO." "NO, I WILL ADMIT THAT ME AND EMMA GOT SCARED" "WHEN WE SAW HER ON THE NEWS." "THE NEXT THING WE KNOW, SHE'S DEAD." "AND WE JUST FIGURED THAT THE SECRET DIED WITH HER." "YOU BUYING IT?" "I DON'T KNOW." "ME NEITHER." "I MEAN, IF HE DID WANT TO KILL LUCY" "TO KEEP HER FROM TALKING, WHY USE A TOY TRUCK?" "IT'S AN ODD CHOICE FOR A MURDER WEAPON." "WELL, MAYBE HE DIDN'T GO OVER THERE TO KILL HER." "MAYBE HE WENT TO TALK TO HER, THINGS GOT HEATED," "HE GRABBED THE CLOSEST THING TO HIM," "AND HE HIT HER WITH IT." "[ BABY CRYING ]" "DANIEL?" "WHAT'S GOING ON?" "MAYBE THIS ISN'T ABOUT THE BABY." "MAYBE IT'S ABOUT THE DOLL." "WE'RE HERE TO MAKE A BABY." "YOU'VE COME TO THE RIGHT PLACE." "I SPEND HUNDREDS OF HOURS ON EACH OF MY CREATIONS." "IT SEPARATES ME FROM OTHER REBORN ARTISTS." "EVERY TINY VEIN AND BIRTHMARK AND MILK SPOT" "IS HAND-PAINTED WITH EXQUISITE ATTENTION TO DETAIL." ""CONGRATULATIONS ON BECOMING A PROUD PARENT" ""OF AN ADOPTED REBORN." ""YOUR CHILD IS NOT A TOY BUT A DELICATE HEIRLOOM" ""THAT WILL BRING DECADES OF JOY" "TO YOU AND YOUR FAMILY IF PROPERLY MAINTAINED."" "HON?" "HMM?" "GET A LOAD OF ALL THESE RULES." ""DON'T SMOKE AROUND THE BABY." SURE." ""DON'T BATHE IT, DON'T PULL TOO HARD ON ITS LIMBS," ""DON'T WEAR LOTION WHEN HANDLING IT," ""DON'T LEAVE DOGS ALONE WITH IT" "LEST THEY MISTAKE IT FOR A CHEW TOY."" "WOW." "THIS MIGHT BE HARDER THAN TAKING CARE OF AN ACTUAL BABY." "NO, NO, NO." "KEEP IN MIND THAT EACH OF MY CREATIONS" "IS A ONE-OF-A-KIND COLLECTORS ITEM" "THAT REQUIRES PROTECTIVE CARE." "SO, YES, THERE ARE SOME RESPONSIBILITIES INVOLVED." ""JUST LIKE A REAL NEWBORN," ""YOUR BABY SHOULD BE KEPT SAFE FROM EXTREME HEAT AND COLD." ""NEVER LEAVE YOUR BABY IN A HOT CAR." ""IF YOU EVER FIND YOURSELF IN NEED OF REPAIRS," ""PLEASE DO NOT HESITATE TO CONTACT ME." ""AS YOUR BABY'S MAKER," "I CONSIDER MYSELF A COMMITTED GODPARENT."" "CAREFUL." "[ CHUCKLES ]" "RIGHT." "I DON'T KNOW, HON." "THESE THINGS JUST KIND OF SEEM LIKE A PAIN IN THE ASS." "MAYBE WE SHOULD JUST GET A DOG." "AAH!" "NO, NO, NO!" "YOU MUSTN'T HANDLE THE DOLL SO ROUGHLY." "THEY'RE WEIGHTED LIKE REAL INFANTS." "YOU CAN BREAK THE NECK HOLDING IT SO THOUGHTLESSLY." "TAKE A PILL, MAN." "IT'S JUST A DOLL." "GET OUT." "YOU DON'T DESERVE ONE OF MY CREATIONS." "AND IS THAT HOW YOU FELT ABOUT LUCY HALPERN?" "THAT SHE DIDN'T DESERVE ONE OF YOUR CREATIONS?" "WHAT IS THIS?" "SPECIAL AGENT KATE MORETTI, FBI." "THIS IS A MURDER INVESTIGATION." "WE DUSTED THE CRIME SCENE FOR PRINTS." "WE GOT SOME PRETTY CLEAN REMNANTS ON THAT TOY TRUCK." "UNLESS YOU HAVE A WARRANT, I WOULD LIKE YOU TO LEAVE." "LUCY DIDN'T TAKE CARE OF THAT DOLL, DID SHE?" "HOW WOULD I KNOW?" "YOU PUT YOUR WHOLE BEING INTO THAT DOLL." "YOU BREATHED LIFE INTO IT." "YOU COULDN'T HAVE FELT MORE CONNECTED" "IF IT REALLY WAS YOUR OWN CHILD." "AND LUCY WAS AN UNFIT MOTHER, WASN'T SHE?" "WHEN I SAW HER ON THE NEWS, I REALIZED SHE'D LOST HER MIND." "AND IF SHE WAS STUPIDLY TREATING THE DOLL LIKE A REAL INFANT," "THEN SHE WAS SURELY RUINING IT!" "SO I DECIDED TO PAY HER A HOUSE CALL." "THE PAINT JOB WAS SUFFERING FROM TOO MUCH SUNLIGHT." "I ALSO NOTICED A CRACK AT THE BASE OF THE HEAD" "AND MILDEW ON THE TORSO." "SHE'D OBVIOUSLY BEEN BATHING THE DOLL." "GOD KNOWS WHAT ELSE WITH IT." "I WAS INCENSED TO FIND THE DOLL IN SUCH POOR CONDITION." "I TOLD HER I SHOULD NEVER HAVE SOLD IT TO HER" "IN THE FIRST PLACE." "I WAS GOING TO GIVE HER MONEY BACK." "PLEASE." "PLEASE DON'T TAKE MY BABY." "I WARNED HER THAT SHE WAS GOING TO DESTROY IT" "IF SHE KEPT PULLING, BUT SHE WOULDN'T STOP!" "I WAS UP ALL NIGHT TRYING TO REPAIR THE DAMAGE." "BUT NOW..." "OH." "IT'S PERFECT." "YOU KILLED A WOMAN..." "OVER A DOLL." "IT'S -- IT'S MORE THAN A DOLL." "IT'S A WORK OF ART." "Andrew:" "HI." "THERE YOU GO." "AM I DOING THIS RIGHT?" "YEP." "YOU'RE DOING GREAT." "JUST MAKE SURE YOU SUPPORT HIS HEAD." "OH, MY GOSH." "THIS IS AWESOME." "CAN YOU IMAGINE?" "THE " " THE DIAPER CHANGING, THE CRYING, THE LACK OF SLEEP." "I MEAN, THAT POOR GUY HAS NO IDEA WHAT HE'S IN FOR." "I DON'T KNOW." "IT WOULDN'T BE THAT BAD." "YOU TOO?" "HUH?" "[ SIGHS ]" "DONNIE WANTS TO HAVE A WHOLE LITTER OF KIDS." "HE'S ON A MISSION TO BUY A GIGANTIC HOUSE" "SO I CAN START POPPING THEM OUT NOW." "WOW." "I HAD NO IDEA YOU GUYS WERE..." "[ CHUCKLES ] CONGRATULATIONS." "WELL, IT'S JUST " "I'M NOT SURE I'M READY FOR KIDS JUST YET." "YOU'VE GOT TIME." "WHAT IF TIME WASN'T THE ISSUE?" "YOU AFRAID YOU WON'T BE ABLE TO..." "NO, IT ISN'T THAT." "IT'S..." "I THINK WHAT I'M GETTING AT IS..." "I DON'T THINK I WANT KIDS AT ALL." "DID YOU TELL DONNIE THIS?" "I'M JUST WORRIED ABOUT DISAPPOINTING HIM." "OR WORSE." "WELL, YOU'RE GONNA HAVE TO BE HONEST WITH HIM, KATE." "Kate:" "SO, UM, WE'RE GETTING MARRIED AGAIN." "AND YOU'RE SHOWING ME PHOTOS OF A BIG HOUSE IN THE 'BURBS," "AND YOU'RE TALKING ABOUT YARDS AND SCHOOL DISTRICTS." "I KNEW IT." "I KNEW IT." "I KNEW IT." "YOU DON'T WANT TO LIVE IN THE SUBURBS, DO YOU?" "YOU KNOW WHAT?" "FORGET THE HOUSE." "YOU'RE RIGHT." "IT'S WAY TOO BIG FOR US," "AND THE COMMUTE WOULD PROBABLY BE HELL ANYWAY." "WE'RE CITY PEOPLE." "I'LL START LOOKING FOR AN AWESOME THREE-BEDROOM HERE." "MAYBE SOMETHING NEAR THE PARK." "AND WE'LL TAKE OUR KIDS TO MUSEUMS" "AND DINNER AT FANCY RESTAURANTS." "I MEAN, CULTURE IS REALLY GOOD FOR KIDS, RIGHT?" "I LOVE YOU." "[ CHUCKLES ]" "[ SIGHS ]" "Daniel:" "HOW MANY OF YOU HAVE HEARD THE TERM "MOMMY BRAIN"?" "FOR GENERATIONS, WOMEN HAVE BEEN TOLD" "THAT HAVING CHILDREN WILL TURN THEIR BRAINS TO MUSH," "THAT THE DEMANDS OF MOTHERHOOD" "WILL CAUSE THEM TO SPIRAL INTO MINDLESS BEHAVIOR," "LIKE PUTTING THE KEYS IN THE REFRIGERATOR" "OR THE MILK IN THE CLOSET." "BUT IN FACT, RECENT STUDIES SHOW" "THAT NEW MOTHERS DEVELOP CERTAIN COGNITIVE ENHANCEMENTS." "THE HYPOTHALAMUS, THE AMYGDALA, AND THE PREFRONTAL CORTEX" "ACTUALLY GROW POSTPARTUM." "THESE AREAS MOTIVATE A MOM TO, UH " " TO CARE FOR HER INFANT," "TO ENJOY THE SIMPLE INTERACTIONS," "AND TO BE MORE EFFECTIVE" "AT SKILLS LIKE REASONING, PLANNING, AND JUDGMENT." "PUT ANOTHER WAY, LOVE GROWS A MOTHER'S BRAIN." "LITERALLY." "BUT WHAT ABOUT DADS?" "MEN'S TESTOSTERONE LEVELS DROP BY ABOUT A THIRD" "IN THE WEEKS FOLLOWING THEIR CHILD'S ARRIVAL," "MAKING THEM MORE NURTURING, LESS AGGRESSIVE." "BUT BEFORE YOU GUYS START PANICKING" "ABOUT THE OTHER SIDE EFFECT OF LOW "T,"" "JUST KEEP IN MIND THAT YOUR WIFE WILL PROBABLY" "BE MORE INTERESTED IN THE BABY THAN IN YOUR BABY MAKER." "[ LAUGHTER ]" "AS AMAZING AS THESE BRAIN MAKEOVERS ARE," "ALL THE NEUROBIOLOGY IN THE WORLD" "CAN'T EXPLAIN THE JOY THAT COMES FROM HOLDING A NEWBORN." "OR FROM WITNESSING THE MIRACLE OF NEW LIFE." "OR SO I'M TOLD."

Q: Typescript style guide for interfaces this is a question that may not have a single correct answer, as I do realise coding styles are quite varied, especially between different languages, eg camel case function names in javascript vs pascal casing methods in C#. I can quite accept that. Maybe I am over worrying about this, but I am just starting to look into typescript, really like the looks of it and plan to use it along with Angular2, and want to establish a good style guide. What I really don't get is point 2 here, not to use I prefix for interfaces. Until this, I thought that was almost universal. I have a class Car, so a natural name if the interface is just to add an I in front... ICar. As soon as you see the I prefix you know you have an interface. I want to follow any suggested practice, but this one I really do not know which why to go. Does none know why, what I thought was an almost universal convention, is being discouraged here? I know you can use whatever conventions you like, just wondering if there is some reason for this common convention not to be used in Typescript. Thanks in advance for any opinions/info! A: I as prefix was big at some time for Java and C# (probably also others) but I don't think this is still considered a good idea but how can one change something that is used by the majority of developers and existing code base. It's similar to hungarian notation which is universally considered bad practice. Just give it a meaningful name. If you have different kinds of Cars than make Car the universal interface and class FancyCar implements Car is much more natural. Things like prefixes just prevent people from thinking about what they really want to express. See also http://c2.com/cgi/wiki?IntentionRevealingNames There are also languages like Dart (probably many others I don't know) where there is not such a clear distinction between interface and class. In Dart you can implement any class. The class' interface just acts as an interface. update I don't say naming is easy. In fact I think it's the most or at least among the most difficult parts of software development. It's just that the general consesus of "the elite" is that prefixes for technical reasons are not the best approach. This doesn't mean there are alternative that have only advantages and no drawbacks. It seems in this case naming like UserService, UserServiceImpl, MockUserService is used instead. This way in most parts of your code the most natural way UserService is used and the derivates only in prividers. Otherwise, as mentioned above, consistency is way more important. If some style is more common in the language you use, I suggest to use this in your code as well. A: Similar question is asked here Confused about the Interface and Class coding guidelines for TypeScript My answer on it: https://stackoverflow.com/a/41967120/586609 Reasons: The times of the Hungarian notation have passed I-prefix violates encapsulation principle Protection from bad naming Properly chosen names vaccinate you against API Design Myth: Interface as Contract.

Common variants in RB1 gene and risk of invasive ovarian cancer. Somatic alteration of the RB1 gene is common in several types of cancer, and germ-line variants are implicated in others. We have used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between common variants (SNP) in RB1 and risks of invasive ovarian cancer. We genotyped 11 tagging SNPs in three ovarian case-control studies from the United Kingdom, United States, and Denmark, comprising >1500 cases and 4,800 controls. Two SNPs showed significant association with ovarian cancer risk: carriers of the minor allele of rs2854344 were at reduced risk compared with the common homozygotes [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.61-0.89; P = 0.0009 dominant model]. Similarly, the minor allele of rs4151620 was found to be associated with reduced risk (rare versus common homozygote; OR, 0.19; 95% CI, 0.07-0.53; P = 0.00005 recessive model). After adjusting for multiple testing, the most significant association (rs4151620) was P = 0.001. A global test comparing common haplotype frequencies in cases and controls was of borderline significance (P(8df) = 0.04). There are no common coding SNPs in the RB1 gene. However, intron 17 of RB1 contains the open reading frame for the P2RY5 gene, and rs4151620 is perfectly correlated with rs2227311, which is located in the 5'-untranslated region of P2RY5 and is predicted to affect P2RY5 transcription. rs2854344 has been reported previously to be associated with breast cancer risk. The possible associations of rs2854344 and rs4151620 with ovarian cancer risk warrant confirmation in independent case-control studies before studies on their biological mode of action.

The data underlying the results presented in the study are available from the John Hopkins Coronavirus resource center. URL: <https://coronavirus.jhu.edu/map.html>. Introduction {#sec001} ============ The first reported case of the novel coronavirus (SARS-CoV-2) in South Africa was announced on 5 March 2020, following the initial manifestation of the virus in Wuhan China in December 2019 \[[@pone.0237126.ref001]--[@pone.0237126.ref003]\]. Due to its further spread and the severity of its associated clinical outcomes, the disease was subsequently declared a pandemic by the World Health Organisation (WHO) on 11 March 2020 \[[@pone.0237126.ref001], [@pone.0237126.ref002]\]. In South Africa, by 26 April 2020, 4546 people had been confirmed to have been infected by the coronavirus with 87 fatalities \[[@pone.0237126.ref004]\]. Numerous states have attempted to minimise the growth in number of COVID-19 infections \[[@pone.0237126.ref001], [@pone.0237126.ref005], [@pone.0237126.ref006]\]. These attempts are largely based on non-pharmaceutical interventions (NPIs) aimed at separating the infectious population from the susceptible population \[[@pone.0237126.ref001]\]. These initiatives aim to strategically reduce the increase in infections to a level where their healthcare systems stand a chance of minimising the number of fatalities \[[@pone.0237126.ref001]\]. Some of the critical indicators for policymaker response planning include projections of the infected population, estimates of health care service demand and whether current containment measures are effective \[[@pone.0237126.ref001]\]. As the pandemic develops in a rapid and varied manner in most countries, calibration of epidemiological models based on available data can prove to be \[[@pone.0237126.ref007]\]. This difficulty is further escalated by the high number of asymptomatic cases and the limited testing capacity \[[@pone.0237126.ref001], [@pone.0237126.ref002]\]. A fundamental issue when calibrating localised models is inferring parameters of compartmental models such as susceptible-infectious-recovered (SIR) and the susceptible-exposed-infectious-recovered (SEIR) that are widely used in infectious disease projections. In the view of public health policymakers, a critical aspect of projecting infections is the inference of parameters that align with the underlying trajectories in their jurisdictions. The spreading rate is a parameter of particular interest which is subject to changes due to voluntary social distancing measures and government-imposed contact bans. The uncertainty in utilising these models is compounded by the limited data in the initial phases and the rapidly changing dynamics due to rapid public policy changes. To address these complexities, we utilise the Bayesian Framework for the inference of epidemiological model parameters in South Africa. The Bayesian framework allows for both incorporation of prior knowledge and principled embedding of uncertainty in parameter estimation. In this work we combine Bayesian inference with the compartmental SEIR and SIR models to infer time varying spreading rates that allow for quantification of the impact of government interventions in South Africa. Methods {#sec002} ======= Epidemiological modelling {#sec003} ------------------------- Compartmental models are a class of models that is widely used in epidemiology to model transitions between various stages of disease \[[@pone.0237126.ref001], [@pone.0237126.ref008], [@pone.0237126.ref009]\]. We now introduce the Susceptible-Exposed-Infectious-Recovered (SEIR) and the related Susceptible-Infectious-Recovered (SIR) compartmental models that have been dominant in COVID-19 modelling literature \[[@pone.0237126.ref001], [@pone.0237126.ref005], [@pone.0237126.ref006], [@pone.0237126.ref010]\]. ### The Susceptible-Exposed-Infectious-Recovered Model {#sec004} The SEIR is an established epidemiological model for the projection of infectious diseases. The SEIR models the transition of individuals between four stages of a condition, namely: - being susceptible to the condition, - being infected and in incubation - having the condition and being infectious to others and - having recovered and built immunity for the disease. The SEIR can be interpreted as a four-state Markov chain which is illustrated diagrammatically in [Fig 1](#pone.0237126.g001){ref-type="fig"}. The SEIR relies on solving the system of ordinary differential equations below representing the analytic trajectory of the infectious disease \[[@pone.0237126.ref001]\]. $$\begin{array}{rc} \frac{dS}{dt} & {= - \frac{\lambda SI}{N}} \\ \end{array}$$ $$\begin{array}{rc} \frac{dE}{dt} & {= \frac{\lambda SI}{N} - \sigma E} \\ \end{array}$$ $$\begin{array}{rc} \frac{dI}{dt} & {= \sigma E - \mu I} \\ \end{array}$$ $$\begin{array}{rc} \frac{dR}{dt} & {= \mu I} \\ \end{array}$$ Where S is the susceptible population, I is the infected population, R is the recovered population and N is the total population where *N* = *S* + *E* + *I* + *R*. λ is the transmission rate, *σ* is the rate at which individuals in incubation become infectious, and *μ* is the recovery rate. 1/*σ* and 1/*μ* therefore, become the incubation period and contagious period respectively. {#pone.0237126.g001} We also consider the Susceptible-Infectious-Recovered (SIR) model which is a subclass of the SEIR model that assumes direct transition from the susceptible compartment to the infected (and infectious) compartment. The SIR is represented by three coupled ordinary differential equations rather than the four in the SEIR. [Fig 2](#pone.0237126.g002){ref-type="fig"} depicts the three states of the SIR model. {#pone.0237126.g002} ### The basic reproductive number *R*~0~ {#sec005} The basic reproductive number (*R*~0~) represents the mean number of additional infections created by one infectious individual in a susceptible population. According to the latest available literature, without accounting for any social distancing policies the *R*~0~ for COVID-19 is between 2 and 3.5 \[[@pone.0237126.ref002], [@pone.0237126.ref006], [@pone.0237126.ref010], [@pone.0237126.ref011]\]. *R*~0~ can be expressed in terms of λ and *μ* as: $$\begin{array}{r} {R_{0} = \frac{\lambda}{\mu}} \\ \end{array}$$ ### Extensions to the SEIR and SIR models {#sec006} We use an extended version of the SEIR and SIR models of \[[@pone.0237126.ref006]\] that incorporates some of the observed phenomena relating to COVID-19. First we include a delay *D* in becoming infected (*I*^new^) and being reported in the confirmed case statistics, such that the confirmed reported cases CR~*t*~ at some time *t* are in the form \[[@pone.0237126.ref006]\]: $$\begin{array}{r} {\text{CR}_{t} = I_{t - D}^{\text{new}}} \\ \end{array}$$ We further assume that the spreading rate λ is time-varying rather than constant with change points that are affected by government interventions and voluntary social distancing measures. Bayesian parameter inference {#sec007} ---------------------------- We follow the framework of \[[@pone.0237126.ref006]\] to perform Bayesian inference for model parameters on the South African COVID-19 data. The Bayesian framework allows for the posterior inference of parameters which updates prior beliefs based on a data-driven likelihood. The posterior inference is governed by Bayes theorem as follows: $$\begin{array}{r} {P\left( W \middle| D,M \right) = \frac{P\left( D \middle| W,M \right)P\left( W \right)}{P\left( D \right)}} \\ \end{array}$$ Where *P*(*W*\|*D*, *M*) is the posterior distribution of a vector of model parameters (*W*) given the model(M) and observed data(D), *P*(*D*\|*W*, *M*) is the data likelihood and *P*(*D*) is the evidence. ### The likelihood {#sec008} The Likelihood indicates the probability of observing the reported case data given the assumed model. In our study, we adopt the Student-T distribution as the Likelihood as suggested by \[[@pone.0237126.ref006]\]. Similar to a Gaussian likelihood, the Student-T likelihood allows for parameter updates that minimise discrepancies between the predicted and observed reported cases. ### Priors {#sec009} Parameter prior distributions encode some prior subject matter knowledge into parameter estimation. In the case of epidemiological model parameters, priors incorporate literature based expected values of parameters such as recovery rate(*μ*), spreading rate(λ), change points based on policy interventions etc. The prior settings for the model parameters are listed in [Table 1](#pone.0237126.t001){ref-type="table"}. We follow \[[@pone.0237126.ref006]\] by selecting LogNormal distributions for λ and *σ* such that the initial mean basic reproductive number is 3.2 which is consistent with literature \[[@pone.0237126.ref002], [@pone.0237126.ref005], [@pone.0237126.ref006], [@pone.0237126.ref010], [@pone.0237126.ref012]\]. We set a LogNormal prior for the *σ* such that the mean incubation period is five days. We use the history of government interventions to set priors on change points in the spreading rate. The priors on change-points include 19/03/2020 when a travel ban and school closures were announced, and 28/03/2020 when a national lockdown was enforced. We keep the priors for the Lognormal distributions of the spreading rates after the change points weakly-informative by setting the same mean as λ~0~ and higher variances across all change points. This has the effect of placing greater weight on the data driven likelihood. Similar to \[[@pone.0237126.ref006]\] we adopt weakly-informative Half-Cauchy priors for the initial conditions for the infected and exposed populations. 10.1371/journal.pone.0237126.t001 ###### Prior distribution settings for SEIR and SIR model parameters. {#pone.0237126.t001g} Parameter Prior Distribution ----------------------------------- ------------------------- Spreading rate λ~0~ LogNormal(log(0.4),0.5) Spreading rate λ~1~ LogNormal(log(0.4),0.7) Spreading rate λ~2~ LogNormal(log(0.4),0.7) Incubation to infectious rate *σ* LogNormal(log(1/5),0.5) Recovery rate *μ* LogNormal(log(1/8),0.2) Reporting Delay *D* LogNormal(log(8),0.2) Initial Infectious *I*~0~ Half-Cauchy(20) Initial Exposed *E*~0~ Half-Cauchy(20) Change Point *t*~1~ Normal(2020/03/18,1) Change Point *t*~2~ Normal(2020/03/28,1) ### Markov Chain Monte Carlo (MCMC) {#sec010} Given that the closed-form inference of the posterior distributions on the parameters listed in [Table 1](#pone.0237126.t001){ref-type="table"} is infeasible, we make use of Markov Chain Monte Carlo to sample from the posterior. Monte Carlo methods approximate solutions to complex numerical problems by simulating a random process. MCMC uses a Markov Chain to sample from the posterior distribution, where a Markov Chain is a sequence of random variables *W*~*t*~ such that: $$P\left( W_{t + 1} \middle| W_{1},...,W_{t} \right) = P\left( W_{t + 1} \middle| W_{t} \right)$$ MCMC techniques have been widely used in COVID-19 parameter inference \[[@pone.0237126.ref006], [@pone.0237126.ref010]\]. In this work, we explore inference using Metropolis-Hastings (MH), Slice Sampling and No-U-Turn Sampler (NUTS). ### Metropolis Hastings (MH) {#sec011} MH is one of the simplest algorithms for generating a Markov Chain which converges to the correct stationary distribution. The MH generates proposed samples using a proposal distribution. A new parameter state *W*~*t*\*~ is accepted or rejected probabilistically based on the posterior likelihood ratio: $$\begin{array}{r} {P\left( accept\left( W_{t*} \right) \right) = min\left( 1,\frac{P\left( W_{t*} \middle| D,M \right)}{P\left( W^{t - 1} \middle| D,M \right)} \right)} \\ \end{array}$$ A common proposal distribution is a symmetric random walk obtained by adding Gaussian noise to a previously accepted parameter state. Random walk behaviour of such a proposal typically results in low sample acceptance rates. ### Slice sampling {#sec012} Slice sampling facilitates sampling from the posterior distribution *P*(*W*\|*D*, *M*) by adding an auxiliary variable *u* such that the joint posterior distribution becomes: $$\begin{array}{r} {P\left( W,u \middle| D,M \right) = \left\{ \begin{array}{ll} \frac{1}{Z} & {\mspace{720mu}{0 \leq U \leq P\left( W \middle| D,M \right)}} \\ 0 & \text{Otherwise} \\ \end{array}\operatorname{} \right.} \\ \end{array}$$ Where *Z* = ∫*P*(*W*\|*D*, *M*)*dW* which is a normalisation constant. Marginal samples for the parameters W can then be obtained by ignoring *u* samples from the joint samples. This process corresponds to sampling above the slice of the posterior density function around a predefined window. [Fig 3](#pone.0237126.g003){ref-type="fig"} shows an illustration of slice sampling. {#pone.0237126.g003} While sample acceptance is guaranteed with slice sampling, a large slice window can lead to computationally inefficient sampling while a small window can lead to poor mixing. ### Hybrid Monte Carlo (HMC) and the No-U-Turn Sampler (NUTS) {#sec013} Metropolis-Hastings (MH) and slice sampling tend to exhibit excessive random walk behaviour---where the next state of the Markov Chain is randomly proposed from a proposal distribution \[[@pone.0237126.ref013]--[@pone.0237126.ref015]\]. This results in low proposal acceptance rates and small effective sample sizes. HMC proposed by \[[@pone.0237126.ref016]\] reduces random walk behaviour by adding auxiliary momentum variables to the parameter space \[[@pone.0237126.ref015]\]. HMC creates a vector field around the current state using gradient information, which assigns the current state a trajectory towards a high probability next state \[[@pone.0237126.ref015]\]. The dynamical system formed by the model parameters *W* and the auxiliary momentum variables *p* is represented by the Hamiltonian *H*(*W*, *p*) written as follows \[[@pone.0237126.ref015], [@pone.0237126.ref016]\]: $$\begin{array}{r} {H\left( W,p \right) = M\left( W \right) + K\left( p \right)} \\ \end{array}$$ Where *M*(*W*) is the negative log-likelihood of the posterior distribution in [Eq 7](#pone.0237126.e007){ref-type="disp-formula"}, also referred to as the potential energy. *K*(*p*) is the kinetic energy defined by the kernel of a Gaussian with a covariance matrix *M* \[[@pone.0237126.ref017]\]: $$\begin{array}{r} {K\left( p \right) = \frac{p^{T}M^{- 1}p}{2}.} \\ \end{array}$$ The trajectory vector field is defined by considering the parameter space as a physical system that follows Hamiltonian Dynamics \[[@pone.0237126.ref015]\]. The dynamical equations governing the trajectory of the chain are then defined by Hamiltonian equations at a fictitious time *t* as follows \[[@pone.0237126.ref016]\]: $$\begin{array}{r} {\frac{\partial w_{i}}{\partial t} = \frac{\partial H}{\partial p_{i}}} \\ \end{array}$$ $$\begin{array}{r} {\frac{\partial p_{i}}{\partial t} = - \frac{\partial H}{\partial w_{i}}} \\ \end{array}$$ In practical terms, the dynamical trajectory is discretised using the leapfrog integrator. In the leapfrog integrator to reach the next point in the path, we take half a step in the momentum direction, followed by a full step in the direction of the model parameters---then ending with another half step in the momentum direction. Due to the discretising errors arising from leapfrog integration a Metropolis acceptance step is then performed in order to accept or reject the new sample proposed by the trajectory \[[@pone.0237126.ref015], [@pone.0237126.ref018]\]. In the Metropolis step the parameters proposed by the HMC trajectory *w*\* are accepted with the probability \[[@pone.0237126.ref016]\]: $$\begin{array}{r} {P\left( accept \right) = \min\left( 1,\frac{P\left( w^{*} \middle| D,\alpha,\beta,H \right)}{P\left( w \middle| D,\alpha,\beta,H \right)} \right)} \\ \end{array}$$ Algorithm 1 shows the pseudo-code for the HMC where *ϵ* is a discretisation stepsize. The leapfrog steps are repeated until the maximum trajectory length *L* is reached. **Algorithm 1**: Hybrid Monte Carlo Algorithm **Data**: Confirmed Cases dataset {**C**^(*t*)^} **Result**: *N* Samples of model parameters **W** **for** *n* ← 1 **to** *N* **do**  *w*~0~ ← *w*~init~  *sample the auxiliary momentum variables p*   $\text{p} \sim \mathcal{N}\left( 0,\mathbf{M} \right)$  Use leapfrog steps to generate proposals for *w*  **for** *t* ← 1 **to** *L* **do**    $$\left. p\left( t + \epsilon/2 \right)\leftarrow p\left( t \right) + \left( \epsilon/2 \right)\frac{\partial H}{\partial w}\left( w\left( t \right) \right) \right.$$    $$\left. w\left( t + \epsilon \right)\leftarrow w\left( t \right) + \epsilon\frac{p\left( t + \epsilon/2 \right)}{M} \right.$$    $$\left. p\left( t + \epsilon \right)\leftarrow p\left( t + \epsilon/2 \right) + \left( \epsilon/2 \right)\frac{\partial H}{\partial w}\left( w\left( t + \epsilon \right) \right) \right.$$  **end**  *Metropolis Update step*:  (*p*, *w*)~*n*~ ← (*p*(*L*), *w*(*L*)) with probability:   $$min\left( 1,\frac{P\left( w_{t*} \middle| D,M \right)}{P\left( w \middle| D,M \right)} \right)$$ **end** The HMC algorithm has multiple parameters that require tuning for efficient sampling, such as the step size and the trajectory length. In terms of trajectory length, a trajectory length that is too short leads to random walk behaviour similar to MH. While a trajectory length that is too long results in a trajectory that inefficiently traces back. The stepsize is also a critical parameter for sampling, small stepsizes are computationally inefficient leading to correlated samples and poor mixing while large stepsizes compound discretisation errors leading to low acceptance rates. Tuning these parameters requires multiple time consuming trial runs. NUTS automates the tuning of the leapfrog stepsize and trajectory length. In NUTS the stepsize is tuned during an initial burn-in phase by targeting particular levels of sample acceptance. The trajectory length is tuned by iteratively adding steps until either the chain starts to trace back (U-turn) or the Hamiltonian explodes (becomes infinite). We use the samplers described above to calibrate the SEIR and SIR models on daily new cases and cumulative cases data for South Africa up to and including 20 April 2020 provided by Johns Hopkins University's Center for Systems Science and Engineering(CSSE) \[[@pone.0237126.ref003]\]. Results {#sec014} ======= SIR and SEIR model parameter inference was performed using confirmed cases data up to and including 20 April 2020 and MCMC samplers described in the methodology section. Each of the samplers are run such that 5000 samples are drawn with 1000 burn-in and tuning steps. We use leave-one-out(LOO) cross-validation error of \[[@pone.0237126.ref019]\] to evaluate the goodness of fit of each model. [Table 2](#pone.0237126.t002){ref-type="table"} shows the LOO validation errors of the various models. It can be seen that the SIR model with two change points as the best model fit with the lowest mean LOO of 448.00. The SEIR model with two change points showed a mean LOO of 459.94. We note that \[[@pone.0237126.ref006]\] similarly finds that the SIR model displayed superior goodness of fit to the SEIR on German data. 10.1371/journal.pone.0237126.t002 ###### Leave-one out (LOO) statistics comparing SEIR and SIR models with different number of change points. {#pone.0237126.t002g} Model Change Points LOO Effective Parameters ------- --------------- -------- ---------------------- SIR 2 448.00 10.27 SEIR 1 457.77 11.60 SEIR 2 459.94 12.00 SIR 1 463.03 8.51 SEIR 0 464.69 16.14 SIR 0 517.72 4.72 We now further present detailed results of the SIR and SEIR models with inference using NUTS, the trace plots from these models indicating stationarity in the sampling chains are provided in [S2](#pone.0237126.s002){ref-type="supplementary-material"} and [S5](#pone.0237126.s005){ref-type="supplementary-material"} Figs. The trace plots for the SIR and SEIR models using MH are provided in [S3](#pone.0237126.s003){ref-type="supplementary-material"} and [S6](#pone.0237126.s006){ref-type="supplementary-material"} Figs, while similar trace plots for slice sampling are provided in [S4](#pone.0237126.s004){ref-type="supplementary-material"} and [S7](#pone.0237126.s007){ref-type="supplementary-material"} Figs. The trace plots largely indicate that the NUTS sampler displays greater agreement between parallel chains thus lower rhat values. Posterior parameter distributions {#sec015} --------------------------------- [Fig 4](#pone.0237126.g004){ref-type="fig"} shows the posterior distributions of the SIR model parameters. The parameter estimates are λ~0~ ≈ 0.495 (CI\[0.41, 0.564\]), λ~1~ ≈ 0.099 (CI\[0.065, 0.145\]), λ~2~ ≈ 0.197 (CI\[0.134, 0.264\]), *μ* ≈ 0.151 (CI\[0.09, 0.205\]) and reporting delay (*D*) ≈ 6.848 (CI\[5.178, 8.165\]). This corresponds to *R*~0~ values of 3.278 (CI\[2.715, 3.73\]), 0.655 (CI\[0.430, 0.960\]) and 1.304 (CI\[0.887, 1.7748\]) at the respective change points. [S1 Fig](#pone.0237126.s001){ref-type="supplementary-material"} further shows the joint posterior distributions of λ~*t*~ and *μ* at each of the change points. {#pone.0237126.g004} Time-varying spread rates allow for inference of the impact of various state and societal interventions on the spreading rate. [Fig 5](#pone.0237126.g005){ref-type="fig"} shows the fit and projections based on SIR models with zero, one and two change points. As can be seen from the plot the two change point model best captures the trajectory in the development of new cases relative to the zero and one change point models. The superior goodness of fit of the two change point model is also illustrated in [Table 2](#pone.0237126.t002){ref-type="table"}. The fit and projections showing similar behaviour on the SEIR model with various change points are shown in [Fig 6](#pone.0237126.g006){ref-type="fig"}. {#pone.0237126.g005} {#pone.0237126.g006} Reporting delays, incubation and infectious period {#sec016} -------------------------------------------------- The mean reporting delay time in days was found to be 6.848 (CI\[5.178, 8.165\]), literature suggests this delay includes both the incubation period and the test reporting lags. The posterior distribution incubation period from the SEIR model in [Fig 7](#pone.0237126.g007){ref-type="fig"} yields a median incubation period of 4.537 days (CI\[2.499, 6.787\]). Thus suggesting a mean laboratory reporting delay of approximately 2.311 days. A mean recovery rate *μ* ≈ 0.151 implies mean infectious period of 6.620 days which is in line with related literature \[[@pone.0237126.ref002], [@pone.0237126.ref006], [@pone.0237126.ref010]\]. {#pone.0237126.g007} Timing and impact of interventions {#sec017} ---------------------------------- [Fig 8](#pone.0237126.g008){ref-type="fig"} depicts the posterior distributions of the spreading rates and times corresponding to each change point. We observe that the first change point is on a mean date of 18 March 2020 (CI:\[16/03/2020, 20/03/2020\]). This date is consistent with the travel ban, school closures and social distancing recommendations. This change point resulted in a substantial decrease in the spreading rate (80%) primarily due to the reduction in imported infections. {#pone.0237126.g008} The second change point is observed on 28 March 2020 (CI:\[26/03/2020, 30/03/2020\]). This time point coincides with the announcement of mass screening and testing by the government on 30 March 2020. The resulting mean *R*~0~ of 1.304 implies a 60% decrease from the initial value. The inference of parameters is dependent on the underlying testing processes that generate the confirmed case data. The effect of the mass screening and testing campaign was to change the underlying confirmed case data generating process by widening the criteria of those eligible for testing. While initial testing focused on individuals that either had exposure to known cases or travelled to known COVID-19 affected countries, mass screening and testing further introduced detection of community level transmissions which may contain undocumented contact and exposure to COVID-19 positive individuals. Discussion {#sec018} ========== We have performed Bayesian parameter inference of the SIR and SEIR models using MCMC and publicly available data as at 20 April 2020. The resulting parameter estimates fall in-line with the existing literature in-terms of mean baseline *R*~0~ (before government action), mean incubation time and mean infectious period \[[@pone.0237126.ref002], [@pone.0237126.ref005], [@pone.0237126.ref006], [@pone.0237126.ref010]\]. We find that initial government action that mainly included a travel ban, school closures and stay-home orders resulted in a mean decline of 80% in the spreading rate. Further government action through mass screening and testing campaigns resulted in a second trajectory change point. This latter change point is mainly driven by the widening of the population eligible for testing, from travellers (and their known contacts) to include the generalised community who would have probably not afforded private lab testing which dominated the initial data. This resulted in an increase of *R*~0~ to 1.304. The effect of mass screening and testing can also be seen in [Fig 9](#pone.0237126.g009){ref-type="fig"} indicating a mean increase in daily tests preformed from 1639 to 4374. {#pone.0237126.g009} The second change point illustrates the possible existence of multiple pandemics, as suggested by \[[@pone.0237126.ref020]\]. Thus testing after 28 March is more indicative of community-level transmissions that were possibly not as well documented in-terms of contact tracing and isolation relative to the initial imported infection driven pandemic. This is also supported by the documented increase in public laboratory testing (relative to private) past this change point, suggesting health care access might also play a role in the detection of community-level infections \[[@pone.0237126.ref021]\]. Conclusion {#sec019} ========== We have utilised a Bayesian inference framework to infer time-varying spreading rates of COVID-19 in South Africa. The time-varying spreading rates allow us to estimate the effects of government actions on the dynamics of the pandemic. The results indicate a decrease in the mean spreading rate of 60%, which mainly coincides with the containment of imported infections, school closures and stay at home orders. The results also indicate the emergence of community-level infections which are increasingly being highlighted by the mass screening and testing campaign. The development of the community level transmissions (*R*~0~ ≈ 1.3041 (CI\[0.887, 1.7748\])) of the pandemic at the time of publication appears to be slower than that of the initial traveller based pandemic (*R*~0~ ≈ 3.278 (CI\[2.715, 3.73\])). A future improvement to this work could include extensions to regional and provincial studies as current data suggests varied spreading rates both regionally and provincially. As more government interventions come to play priors on more change points might also be necessary. Supporting information {#sec020} ====================== ###### Two dimensional heat maps of the joint posterior distributions of the spreading rate(λ) and the recovery rate(*μ*) at various change points of the SIR model. The high joint density areas (in yellow) indicate likely values of *R*~0~. The baseline mean *R*~0~ estimate in S1 Fig (a) is 3.278, the first change point estimate in Fig S1 Fig (b) is 0.655 while the second change point in S1 Fig (c) has resulted in a mean *R*~0~ estimate of 1.304. (TIFF) ###### Click here for additional data file. ###### Shows diagnostic trace plots for the SIR model inferred using NUTS. (TIFF) ###### Click here for additional data file. ###### Shows diagnostic trace plots for the SIR model inferred using MH. (TIFF) ###### Click here for additional data file. ###### Shows diagnostic trace plots for the SIR model inferred using slice sampling. (TIFF) ###### Click here for additional data file. ###### Shows diagnostic trace plots for the SEIR model inferred using NUTS. (TIFF) ###### Click here for additional data file. ###### Shows diagnostic trace plots for the SEIR model inferred using MH. (TIFF) ###### Click here for additional data file. ###### Shows diagnostic trace plots for the SEIR model inferred using slice sampling. (TIFF) ###### Click here for additional data file. 10.1371/journal.pone.0237126.r001 Decision Letter 0 Shaman Jeffrey Academic Editor © 2020 Jeffrey Shaman 2020 Jeffrey Shaman This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 11 Jun 2020 PONE-D-20-12397 Bayesian Inference of COVID-19 Spreading Rates in South Africa PLOS ONE Dear Dr. Mbuvha, Thank you for submitting your manuscript to PLOS ONE. 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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer \#1: Yes \*\*\*\*\*\*\*\*\*\* 5\. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer \#1: In their paper the authors analyse with Bayesian methods the increase of COVID-19 case numbers in South Africa. They find two change points in the propagation that they link to respectively to travel bans/containment of infections and onset of massive testing. They conclude that the governmental interventions linked to the first change point were effective. I recommend this paper for publication because of its timeliness and well described methods and would suggest a few minor revisions: \- In table 2 the authors list compare different sampling methods by their LOO statistic. As far as I understand it this is not useful and misleading. The LOO statistic was developed to compare different models (which are also correctly shown in this table). The lower LOO statistic of the MH sampling probably arises from a incomplete sampling of the posterior which could potentially be fixed letting the chains run longer and/or with a longer burn-in period. A useful statistic to check convergence is the Rhat statistic (<https://docs.pymc.io/api/stats.html#pymc3.stats.rhat>). \- The scale of the lambda_2 prior in the table 1 doesn\'t seem to match the prior distribution plotted in Fig. 4. The authors could also think about whether the lambda 1 and 2 priors are well motivated, and eventually make them wider/more uninformative. The posterior of the Lambda 1 prior is in the tail of the prior distribution (Fig. 4). \- In the algorithm of the HMC, in the third line of the leapfrog loop, the closing bracket after \"p(t\" should be removed. \*\*\*\*\*\*\*\*\*\* 6\. PLOS authors have the option to publish the peer review history of their article ([what does this mean?](https://journals.plos.org/plosone/s/editorial-and-peer-review-process#loc-peer-review-history)). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. **Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our [Privacy Policy](https://www.plos.org/privacy-policy). Reviewer \#1: Yes: Jonas Dehning \[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link \"View Attachments\". If this link does not appear, there are no attachment files.\] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, <https://pacev2.apexcovantage.com/>. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at <figures@plos.org>. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0237126.r002 Author response to Decision Letter 0 7 Jul 2020 Dear Editor Kindly find our responses to reviews below. Best, Rendani Mbuvha \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-- Responses to Academic Editor 1\. Please ensure that your manuscript meets PLOS ONE\'s style requirements, including those for file naming. The PLOS ONE style templates can be found at <https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf> and <https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf> Response We have made changes in line with the formatting guidelines, including: Changing the affiliation of one author from \'office of the vice-chancellor(his office)\' to the institute that he is affiliated to at the university Changing \'figure\' references to \'fig\' Moving supporting information to an appropriately named appendix Changing subsection headings accordingly 2.We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed: \- arXiv:1906.06382v1 \-<https://www.medrxiv.org/content/10.1101/2020.04.07.20057133v2> In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed. Response: We have made changes in terms of rewriting, rephrasing(with referencing) and inserting quotations in areas where there was previous overlapping text with our earlier preprints outside the methods section. Please see highlighted changes. Please also ensure you have described the source of your data in the methods section, including a link or citation which can be used to access the data. Response: We have added a description of our data source, including the necessary citation. 3\. Please ensure that you refer to Figures 10,11 & 12 in your text as, if accepted, production will need this reference to link the reader to the figure. Response: These figures have now been moved to the supporting information files with the relevant references included in the main text. 4\. Please upload a copy of Supporting Information Appendix S1 which you refer to in your text on page 11. Response: Now included as separate files - ( this mainly consists of the previous 'figures' 10-12 and other diagnostic plots) \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-- Responses to Reviewer 1 I recommend this paper for publication because of its timeliness and well described methods and would suggest a few minor revisions: \- In table 2 the authors list compare different sampling methods by their LOO statistic. As far as I understand it this is not useful and misleading. The LOO statistic was developed to compare different models (which are also correctly shown in this table). The lower LOO statistic of the MH sampling probably arises from a incomplete sampling of the posterior which could potentially be fixed letting the chains run longer and/or with a longer burn-in period. A useful statistic to check convergence is the Rhat statistic (<https://docs.pymc.io/api/stats.html#pymc3.stats.rhat>). Response: We agree with the reviewer. We have revised table 2 to only refer to the comparison between models rather than include samplers. We have also increased the number of chain runs to 5000 and increased burn-in to 1000 runs with ten concurrent chains rather than four to increase the likelihood of convergence. \- The scale of the lambda_2 prior in the table 1 doesn\'t seem to match the prior distribution plotted in Fig. 4. The authors could also think about whether the lambda 1 and 2 priors are well motivated, and eventually make them wider/more uninformative. The posterior of the Lambda 1 prior is in the tail of the prior distribution (Fig. 4). Response: We have now changed both priors for lambda 1 and lambda 2 to a wider and relatively less informative LogNormal(log(0.4),0.7). The change in priors and running the chains for longer marginally changes mean estimates of posterior parameters \-- this does not seem to change the overall findings in a material way. \- In the algorithm of the HMC, in the third line of the leapfrog loop, the closing bracket after \"p(t\" should be removed. Response: We have amended the formula typo accordingly. ###### Submitted filename: Response to Reviewers.pdf ###### Click here for additional data file. 10.1371/journal.pone.0237126.r003 Decision Letter 1 Shaman Jeffrey Academic Editor © 2020 Jeffrey Shaman 2020 Jeffrey Shaman This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 22 Jul 2020 Bayesian Inference of COVID-19 Spreading Rates in South Africa PONE-D-20-12397R1 Dear Dr. Mbuvha, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you'll receive an e-mail detailing the required amendments. 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latest news Meaning Of Iowa Straw Poll Is That There Isn't One August 13, 2011 8:00 PM ET Frank James What was the meaning of the Ames Straw Poll in Iowa Saturday? In terms of the big picture, essentially nothing. The presumptive frontrunner for the Republican presidential nomination and winner of the 2007 straw poll, Mitt Romney, didn't even compete. Meanwhile, Texas Gov. Rick Perry, who entered the race Saturday and had polling numbers near Romney's even before entering the race, also didn't compete in the straw poll. That doesn't mean that the win won't help to further energize Rep. Michele Bachmann who came in first. But her charisma, her fundamentalist Christianity, her Iowa connection (she spent part of her early life there) and being from neighboring Minnesota all conspired to give her certain advantages with the social conservatives who powered her to victory. So she was expected to do well and did. It's still difficult to see how she gets past Romney and Perry to the nomination. The Iowa caucuses in February will be a different matter since, presumably, Romney and Perry will make a full push to win that contest. Also, while the Ames Straw Poll has occasionally aligned with the eventual winner of the nomination, it hasn't always. George H.W. Bush won it in 1979 but Ronald Reagan won the nomination. Preacher Pat Robertson won it it 1987 and also didn't win the nomination. Same for Romney in 2007. So it's definitely not a reliable predictor. The Latest On Pawlenty's Campaign The straw poll results actually did likely have serious consequences for Tim Pawlenty. The former Minnesota governor reportedly spent big to make a statement in the straw poll, about $1 million according to some reports. Despite all that, he still came in behind Paul and not by a little. He's also been far back in national polls. With Perry now in the race with his strong appeal to fiscal and social conservatives as well as Tea Party voters, Pawlenty will likely find himself even further back in the pack. It leaves Pawlenty in a difficult spot, having to ask himself just how much further he can go. Money-raising is likely to be an even bigger problem now for him. Pawlenty's campaign issued a message congratulating Bachmann and saying his campaign was headed to the next phase, including visits to New Hampshire and South Carolina, early primary states: "I need your support to continue the journey," was his message to voters. It was a brave message. But presidential nominations aren't won on courage alone. It takes money and a credible path to victory and Saturday's Iowa results hurt him in reaching either of those two goals.

Det statliga forskningsbolaget VTT i Finland har börjat utveckla en liten kärnreaktor som ska ge fjärrvärme. Syftet är att skapa en ny inhemsk industri kring tekniken. Den finska fjärrvärmen produceras i dag från flera olika källor. Ungefär hälften kommer från koldioxidneutrala källor, det vill säga biomassa (42 procent) och värmeåtervinning (10 procent). Den andra halvan produceras av kol (18 procent), torv (14 procent), naturgas (11 procent) och en mindre del olja (2 procent). Enligt forskningsbolaget VTT gav den finska fjärrvärmen upphov till över fyra miljoner ton i koldioxidutsläpp förra året. I många städer blir värmeproduktionen en av de största klimatutmaningarna eftersom Finland har bestämt sig för att sluta använda kol 2029. – Tidplanen är utmanande och det finns få billiga alternativ. För att åstadkomma detta behövs nya innovationer och introduktion av ny teknik. Kärnkraft som ger fjärrvärme kan åstadkomma riktigt stora utsläppsminskningar, säger Ville Tulkki, forskningschef på VTT, i ett pressmeddelande. Värma vatten till 100 grader Celsius Men reaktorkonceptet behöver inte vara färdigt och förverkligat till kolförbudet 2029, anser han. Även efter det årtalet kommer fjärrvärmen att använda sig av många andra bränslen som kan ersättas av kärnkraft. – Vi försöker så klart se om vi kan hinna till 2029. Men om du frågar när vi kan ha en anläggning i drift så kan det bli när som helst mellan 2029 och 2035, säger Ville Tulkki till Ny Teknik. Koncept för små och modulära kärnreaktorer utvecklas världen över som ett svar på kostsamma förseningar i byggen av nya stora kärnkraftverk. Tanken är att små reaktorer ska kunna tillverkas snabbt och billigt i fabrik och transporteras i moduler till rätt plats, där de monteras. Enligt VTT avser de flesta av dessa koncept reaktorer som ska producera el eller värme med hög temperatur för olika industriprocesser. VTT:s plan är i stället att fokusera på en reaktor som kan värma vatten till ungefär 100 grader Celsius för fjärrvärme. Då blir det möjligt att nå ännu enklare och billigare lösningar, menar forskningsföretaget. "Trycksättning i nivå med däcken på en buss" Just nu tänker sig VTT att det blir en tryckvattenreaktor som antingen placeras i en 25 meter djup vattenbassäng eller i en reaktortank ovan eller under mark. Oavsett vilket spår som bolaget väljer är en reaktor för fjärrvärme betydligt enklare än en som ska ge el, enligt Ville Tulkki. – Vid elproduktion vill man ha högsta möjliga temperatur på ångan som driver turbinerna. Temperaturen är runt 350 grader Celsius och trycket blir runt 15 megapascal. För fjärrvärme behöver man en del trycksättning, men inte så mycket som 15 megapascals, mer i nivå med vad däcken på en buss har. Och väggarna i ett vanligt kärnkraftverk måste vara 20-25 centimeter tjocka men för fjärrvärme behöver de bara vara omkring en centimeter, säger Ville Tulkki. Genom att använda kärnkraft för att producera fjärrvärme behöver inte biomassa eldas upp för att ge värme. Det är en fördel, påtalar VTT, eftersom biomassa i framtiden kan bli en värdefull råvara som till exempel kan ersätta olja i industrin eller användas för att framställa transportbränslen. Kärnkraftverk i Schweiz värmer bostäder I dag är det relativt ovanligt att kärnkraftverk producerar fjärrvärme. Men Sveriges första kommersiella kärnkraftverk, som drevs på 1960- och 1970-talen i Ågesta söder om Stockholm, levererade faktiskt både fjärrvärme och el. Det var en liten reaktor som kunde ge som mest 68 MW fjärrvärme och 12 MW el. Ågesta kärnkraftverk drevs under 1960- och 1970-talen. Här syns kontrollrummet. Foto: Lennart Ström I Östeuropa är det dock betydligt vanligare att kärnkraftverk levererar både fjärrvärme och el. Ryssland har till exempel flera sådana kärnkraftverk. Även i Schweiz nyttjas kärnkraftverket Beznau för att värma omkring 2 400 bostäder. VTT:s reaktorkoncept ska tas fram genom avancerad modellering som blivit möjlig tack vare utvecklingen av processorkraft och parallellberäkningar. Målet med projektet är att skapa en ny industri runt tekniken där merparten av komponenterna kan tillverkas i Finland. Kärnenergilagen ses över Omkring 200 forskare på VTT ägnar sig åt kärnkraft. Under de senaste fem åren har företaget drivit flera projekt som rör små reaktorer. På Europanivå koordinerar VTT projektet Elsmor, som handlar om tillståndsprocesser för små modulära reaktorer. Dagens regelverk för kärnkraft är anpassat för stora anläggningar som ligger långt ifrån städerna. Men i Finland lanserades nyligen ett arbete för att göra om kärnenergilagen så att den bättre lämpar sig för prövning av små kärnkraftverk. Den finska strålskyddsmyndigheten, Stuk, förbereder också prövning av sådana reaktorer, rapporterar World Nuclear News.

Comparison of BTA stat and NMP22 tests in the detection of bladder cancer. This study aimed to compare the BTA (bladder tumour antigen) stat and urinary nuclear matrix protein (NMP22) tests in the detection of bladder cancer. The office-based qualitative BTA stat and the laboratory-based quantitative NMP22 tests were studied in the same urine samples obtained from 49 patients with a high suspicion of bladder cancer and 20 healthy subjects. A tumour was identified in 36 patients after the cystoscopy. BTA stat demonstrated a sensitivity of 89%, which was superior to the sensitivity of 66.6% with the NMP22 test in detecting the bladder cancer (p < 0.02). The sensitivities for grade I tumours with BTA stat and NMP22 were 55.5% and 33.3%, respectively. The sensitivity of BTA stat was 100% for tumour categories except for the pTa and grade I tumours. No positive result was observed with both tests among the healthy subjects. The specificities for BTA stat and NMP22 were 78.7% and 69.6%, respectively. The BTA stat test was significantly more sensitive than the NMP22 test in the detection of bladder cancer. Although the sensitivity of BTA stat was not sufficient to replace cystoscopy, its ease and low cost may play a role in reducing the number of control cystoscopies, especially in patients with low risk of progression.

Tissue fusion, a new opportunity for sutureless bypass surgery. Microsurgical suturing is the standard for cerebral bypass surgery, a technique where temporary occlusion is usually necessary. Non-occlusive techniques such as excimer laser-assisted non-occlusive anastomosis (ELANA) have certainly widened the spectrum of treatment of complex cerebrovascular situations, such as giant cerebral aneurysms, that were otherwise non-treatable. Nevertheless, the reduction of surgical risks while widening the spectrum of indications, such as a prophylactic cerebral bypass, is still a main aim, that we would like to pursue with our sutureless tissue fusion research. The primary concern in sutureless tissue fusion- and especially in tissue fusion of cerebral vessels- is the lack of reproducibility, often caused by variations in the thermal damage of the vessel. This has prevented this novel fusion technique from being applicable in daily surgical use. In this overview, we present three ways to further improve the laser tissue soldering technique.In the first section entitled "Laser Tissue Soldering Using a Biodegradable Polymer," a porous polymer scaffold doped with albumin (BSA) and indocyanine green (ICG) is presented, leading to strong and reproducible tensile strengths in tissue soldering. Histologies and future developments are discussed.In the section "Numerical Simulation for Improvement of Laser Tissue Soldering," a powerful theoretical simulation model is used to calculate temperature distribution during soldering. The goal of this research is to have a tool in hand that allows us to determine laser irradiation parameters that guarantee strong vessel fusion without thermally damaging the inner structures such as the intima and endothelium.In a third section, "Nanoparticles in Laser Tissue Soldering," we demonstrate that nanoparticles can be used to produce a stable and well-defined spatial absorption profile in the scaffold, which is an important step towards increasing the reproducibility. The risks of implanting nanoparticles into a biodegradable scaffold are discussed.Step by step, these developments in sutureless tissue fusion have improved the tensile strength and the reproducibility, and are constantly evolving towards a clinically applicable anastomosis technique.

Hydraulically actuated boat hoists are shown in U.S. Pat. No. 6,823,809 to Hey, U.S. Pat. No. 6,976,442 to Hey U.S. Pat. No. 7,246,970 to Hey, U.S. Pat. No. 7,413,378 to Way and U.S. Pat. No. 8,267,621 to Way, all of which are incorporated herein by reference in their entirety. Southern U.S. States and coastal regions commonly use one of these three methods to store/moor boats: (1) Moor the boat to a fixed or floating pier using ropes. In this case, the boat remains in the water, (2) lift the boat using a platform or sling type lift mounted to a set of pilings or roof structure mounted on pilings, or (3) lift the boat using a floating lift system. The most common method used depends on the region and regulations governing the body of water. Many reservoirs do not allow private ownership of waterfront property. In these lakes, there tends to be large marinas or “dockominum” structures. In these structures in-water mooring is the most common. A small percentage of the boats are lifted using a floating lift. Floating lifts are usually the only type allowed on a large dock structure. Marina managers discourage any structure being fixed to these floating systems. Many lakes and waterways allow private waterfront ownership. In these cases, a permanent, fixed pier can be installed. Often a permanent roof structure is built over the slip intended for the boat commonly called a “boat house”. When these structures are present, a large percentage will have a mounted lift system. Some permanent docks do not have a roof structure. A lift is usually mounted on the top of large pilings when no roof is present. Pile and roof mounted lift systems have been around for decades. The lift designs are basically the same. Galvanized poles are mounted in bearings hanging from a beam in the roof or a beam mounted along the pilings. A “plate-gear” motor is connected to the end of the pole that causes the entire pole to turn. Cables are attached to the pole and wind as the pole turns. In lower capacity, roof-mount applications, one pole can be used, but in pile mount applications and higher capacity roof-mounts, two poles and motors are used. Some differentiation exists in the pole winding products. Some have improved on the motor and controls to included wireless operation. Some have added machined cable grooves to improve cable winding. There is even one company that uses a “level cable” technique to make a single motor/pole piling application. They also have some variation on the platform, bunks, and load guide features. Low-cost kits use a sling instead of a platform. Pole-winders have many weaknesses that present opportunities. Cable fatigue, motor synchronization, slow speed, poor corrosion resistance, and power supply issues are a short list of issues with current products. Cable fatigue is in a guaranteed failure mode if cables are not replaced every 2-3 years, depending on frequency of use. All of the designs on the market use wire rope. The galvanized poles used in these designs cause rapid fatigue of the cables because of the small winding diameter. Compounding the issue is the large lift height requirement for most installations. It is common to lift the boat 6-10′ to accommodate the fluctuating water heights. This requires many winds on the pole and in most cases, the cable winds over itself. This not only fatigues the cable, but also damages the individual wires with the wire rope. Cable failure modes are severe and cause the boat to fall in one direction endangering people and equipment. The most common approach to avoiding this failure is to replace cables often. Motor synchronization is also an issue in multi-pole/motor setups. Piling mount systems have at least two motors because there is no overhead structure to route cables to a single pipe. The speed of the motors will vary causing one to lift faster or slower than the other. Most systems require the user to use a switch to momentarily shut off one of the motors to allow the slower motor(s) to catch up. This requires constant user attention when lifting or lowering the boat. Compounding this issue is the slow speed of the pole winding systems. Some lifts can take over 6 minutes to lift the boat to the needed elevation above the water. The galvanized construction of the pole winding systems is adequate for most environments, but they eventually rust as the wound areas of the poles lose their zinc coating. The bearing locations are generally welded components. Aluminum or other naturally corrosion resistant materials are avoided because of the high stresses in these areas. Cable materials are often galvanized also due to the high replacement rate. The cable will be replaced due to fatigue before corrosion becomes an issue. Pole-winding systems are predominately A/C power systems. Piling mount systems require a long supply from the dock to the opposite motor. This can often be a 40-50′ length of cord to run down from the dock, tinder the water, and back up to the opposite motor. This length is too long for a DC (12-24V) power supply to run without extremely heavy wire. The length of the circuit from the supplying A/C panel to the motors is also very long. This often creates a large voltage drop along the circuit. The voltage drop can cause the system to malfunction and reduce the life of the motor(s) in the system. Often new installations require new circuits to be installed with heavier cable. A/C power can be dangerous system in wet environments. GFCI (ground fault circuit interrupts) are and absolute requirement on docks. Many lives have been lost due to damaged A/C circuits causing stray A/C currents in lakes and waterfronts with inadequate circuit protection. Pole winding systems are commonly used primarily because they can be easily installed in most existing structures with little modification and they are inexpensive when compared to floating or free-standing lift designs. The vast majority of floating lift systems are called “Air Displacement” systems. Air displacement systems raise and lower a lift structure using floats. The floats are filled with air that is evacuated to allow the structure to sink. The floats are then filled using vacuum pumps to raise the structure with the boat on it. Floating systems such as U.S. Pat. No. 6,823,809 to Hey have a few advantages over free standing and mounted lift structures. They can be used in very deep water where pile mounted systems are not an option. They can also be used in dockominium structures where a very limited structural connection is available. U.S. Pat. No. 6,823,809 to Hey shows a boat lift that mechanically lifts the boat using a unique linkage to lift the boat without requiring air evacuation. This hydraulic system is innovative, but expensive. The system also places critical hydraulic components at the waterline. This jeopardizes the durability of the system. Those boat hoists do not require any structural connection to the pier and can be moored similarly to the boat. But air displacement lifts require a mounted structure on the dock. As air is evacuated from the floats gravity will cause the structured to sink to the lakebed unless a structure is in place to limit the travel. This lift style does not work well in shallow areas because of the size of the floating structure. Lift capacity of floating lift systems is determined by the amount of flotation. The float structure is also designed to allow the structure to lift the boat sufficiently above the water. As the lift capacity increases, the number of air chambers increases. Larger structures require the user to evacuate the chambers at different rates to ensure a balanced movement. Users often complain about this requirement and the difficulty controlling it. U.S. Pat. No. 6,976,442 to Hey and U.S. Pat. No. 7,246,970 to Hey show boat lifts that use a cantilever method to lift the platform. The lift will be in the elevated position most of the time, so that in these systems, the rod surface spends most of its life exposed to the harsh marine environment. This can cause corrosion and pitting of the rod surface which will cause leaking of the hydraulic seals. Accordingly, there is a need for a boat lift for pilings and boat houses that will overcome the aforementioned problems.

Q: Java day counter for discounts I am programming a card that allows you to pay bus tickets,it has a special discount for "Students"(80% off) in the first two tickets you pay in the day. I placed a variable that counts the amount of times you travel and then it discounts according if you haven't exceeded the 2 discounts that you are granted, but i cant find i way to make the variables value back to 0 when a day has passed. I must specify that the code i will pas you is an extension(inheritance) of the object TravelCard and there are several variables as priceXtravel, and balance that where inherited from it. public class StudentTravelCard { private double discount; private int discountCounter; public StudentTravelCard(int cardiD){ super(cardiD); discount = 0.8; } public void newTravel() { if(discountCounter < 2) { super.newTravel(); balance += (priceXtravel*discount); discountCounter ++; } else { super.newTravel; //discountCounter = 0;? what if they continue to travel on that day? } } } A: In your newTravel() you can just remove the commented line and add another method resetDay() to reset the back to 0 discounts in a new day. Of course resetDay() will have to be called by something that knows about the current time, etc. public class StudentTravelCard { private double discount; private int discountCounter; public StudentTravelCard(int cardiD){ super(cardiD); discount = 0.8; } public void newTravel() { if(discountCounter < 2) { super.newTravel(); balance += (priceXtravel*discount); discountCounter ++; } else { super.newTravel(); } } public void resetDay() { discountCounter = 0; } }

India is truly a land of events and festivals! Such is the charm and grandeur of theirs that people from all across the world visit India to witness these events and festivals. Be it a Hindu or a Muslim, a Sikh or a Christian, in India there is something for everyone. After all, it is not for nothing that the country is known as the melting pot of all the cultures. In India, over 100 festivals are celebrated but out of them all, a few are celebrated pan India with much zeal and great fervour. So, without any ado, we would discuss a few popular festivals in India that you ought to witness, at least once in your lifetime. Here we go! 1. Holi Known as a festival that is all about colours, Holi is a very popular festival wherein people forget all their grudges and cover each other in different vibrant colours, making way for love and strong bonds. Before the day of the festival, on Holi eve, Holika Dahan takes place which is a bonfire around which people dance and have a whale of a time. On the day of Holi, people play with dry colours, wet colours, pichkari (water guns), water/colour filled balloons and whatnot. They end their day with some lip-smacking food. 2. Diwali This is undeniably one of the best events and festivals in India which is celebrated by one and all, no matter what religion, community or caste they belong to. Diwali is observed with much pomp and show wherein earthen lamps and candles are lit, the houses are decorated with lights and Rangoli. Apart from that, friends and families also exchange sweets, dry fruits, and other expensive gifts. People get in the festive mood by getting all decked up in new ethnic outfits ahead of the evening puja of Goddess Lakshmi and Lord Ganesha. 3. Janmashtami Another important religious festival of India, Janmashtami is a beautiful festival to witness, especially when you are on a pilgrimage tour in India in Vrindavan or Mathura. This day marks the birthday of the eighth avatar of Vishnu, Krishna. People, on this day, observe fast and, in the evening, celebrate the birthday pf bal gopal with much pomp and show. While some do just the evening puja, others cut the cake, dress Krishna up in new clothes as well as seat him in a palanquin, decorate their homes and prepare scrumptious dishes to treat the family. 4. Eid-ul-Fitr This one is the biggest Muslim festival that is, again, celebrated pan India. Eid-ul-Fitr marks the end of the religious month of Ramzan. People don the best of their outfits on this day. While the morning is dedicated to special community prayer, in the evening people visit their friends and relatives to exchange sweets. Elders give children or those younger to them Eidi which can either be money or gifts. 5. Dussehra Also known as Vijayadashami, Dussehra is celebrated a day after Navratri, a religious festival of 9 days, concludes. On this day and a few days ahead of this festival, Ramlila takes place which is enacting the popular scenes and stories of Ramayana. This enactment concludes with Ravana Dahan, a ritual wherein the effigies of Ravana, Kumbhkaran, and Meghnath are put on fire. This festival celebrates the death of Ravana, who was killed by Rama. 6. Independence Day It is nothing but the celebration of freedom, as it is on this day, in 1947, that India got freedom from the shackles of the British rule. The highlights of this day are tableaus, parades, 21 gunshots, the speech of the Prime Minister from the Red Fort and Indian flag hoisting. 7. Republic Day Apart from Independence Day, Republic day, one of the noted holidays in India, also evokes the feeling of patriotism in people. For the unversed, 3 years post-independence, in 1950, on this day, the Constitution of India came into being and India became a republic, after being under the British Raj for ages. This annual event is observed with great pride and much excitement, annually. To celebrate this day, grand parades are held that start from Rashtrapati Bhavan and end at Red Fort, via India Gate. 8. Rath Yatra Millions of people gather from all over the world everyday, especially in the month of July to see Rath Yatra. 9. Christmas While this festival is celebrated across India, Christmas is celebrated the best in one of the most popular travel destinations in India, that is, Goa. This day is quite significant in Christianity as it marks the birthday of Jesus Christ. Christmas is so much fun that children and adults are equally excited about this festival. On this day, families get to do everything together – preparing food, decorating home, the Christmas tree, and whatnot! Now, that you have all the details about these festivals, experience the same as well as the culture and heritage of India in all its essence during your stay in the country. For all the information on these festivals, events, Indian destinations, and cities, visit Adotrip, a one-stop solution to all your travel queries. Author Bio: Stella Wilson is an avid travel blogger currently working with Adotrip. She loves to write first-hand accounts of her travels. Apart from writing, her hobbies include reading and travelling. She has travelled extensively in India and her favourite destinations are Jaipur, Goa and Manali.

From Rambles to Rants to Reviews Archive for September, 2008 The American Heritage Dictionary of the English Language defines a voyeur as 1. A person who derives sexual gratification from observing the naked bodies or sexual acts of others, especially from a secret vantage point. Voyeur is also a very hot and stylish story of romance and obsession by Jon Michaelsen, a wonderful new author. The story can be found in the MEN anthology on the Loveyoudivine His and His Kisses imprint from loveyoudivine Alterotica. The story follows Kevin, a gay accountant, who lives a rather mundane life before discovering a man in an adjacent high-rise that could well be his dream man. But what begins as an entertaining diversion, and a rather harmless fantasy soon spirals out of control to become a full-blown obsession. Along the way there is romance and steamy love to be found and enough Hitchcockian twists to make the master proud. (For fear of spoiling some of the suspense I am keeping the details rather vague). Voyeur is set in modern day Atlanta and Jon does a splendid job of evoking one of the most wonderful cities in America. Jon’s descriptive pictures make one feel as if they are truly there, cruising down Peachtree Street on a warm spring afternoon, the peach blossoms turning everything pink. (Having lived there for several years in the 1990s I was reminded of such diverse things as kudzu vines, the Allman Brothers Band at the Fox Theater, the Underground, MARTA, and going up to Seeger’s in Buckhead for one of the best meals ever!) Jon Michaelsen is one of the exciting new voices in the all male romance genre, and will next year have his first gay detective novel published by loveyoudivine. I am predicting that Jon is poised to break out as one of the premier romance writers in the field of gay fiction, as well as the author of suspense novels that will not only keep readers in suspense, but will keep them anxiously awaiting his next book. I can highly recommend Voyeur along with the rest of the MEN anthology that I have read (which is admitedly only two other stories). It is certainly hard for me to believe that The Angel Singers is the twelfth book in the Dick Hardesty mystery series. It doesn’t seem that long ago that The Butcher’s Son kicked off this wonderful series with a tale of arson and mayhem, and introduced us to one of the most endearing, not to mention enduring gay investigators, Dick Hardesty. The Angel Singers takes us into the world of a gay men’s chorus (and by the way gives quite good information and insight into that particularly fascinating world) and introduces us to a particulary nasty man named Grant Jefferson who happens to be sponsored by one of the choral group’s benefactors. It is not long however until Grant is scattered far and wide by a car bomb which lets the reader know there was some serious dislike for Mister Jefferson. Due to his nastiness there is no shortage of suspects for Dick to sift through on the way to revealing the somewhat surprising solution of this murder. However as entertaining as the solving of the crime is, it is in making the characters come to life that Grey really shines. Just like an elegant merlot chablais, this series has gotten better with time and age, each novel seeming to improve on the last to create a rich tapestry of not only Hardesty’s professional life, but also his home life. Dick, Jonathan and the adorable Joshua are characters we have come to love and to really care about, and I find the home and family life is every bit as entertaining as the mystery. Grey is a master at writing tongue-in-cheek wit, and there is plenty of that to be found in The Angel Singers. If you already love the Dick Hardesty series, as I do, you will love this one too, and if you have never read a Dick Hardesty book (and shame on you if you have not) this is as good as any of them as a place to start. As Robbie Burns wrote in his poem regarding the mouse turned up by the plough (To A Mouse, on Turning Her Up in Her Nest, With The Plough), “the best-laid schemes o’ mice an’ men aft gang agley”. Many years ago (i.e. the mid 1970s) as a very young writer, armed with a B.A. in Journalism, I began what I hoped would be a career in writing. And while there were early successes such as a volume of short stories published and two volumes of poetry published in addition to short-stories placed in various publications, the writing career was diverted by the intervention of life. The particular “plough” that disturbed my sod was a chance at careers in both music, and in the corporate business world, neither of which I can honestly say I regret. However a devastating and debilitating illness intervened to put an end to the music career as the hands upon the instrument would no longer cooperate with what the brain was coaxing them to do, and through a set of circumstances the Multiple Schlerosis also put an end to the business career. There followed many years of searching for direction, and the feeling that somehow my particular muse had taken permanent flight, before somehow arriving at the place where I made the decision that it is (past) time to jumpstart the writing career again. It came to me that after the ploughing comes the planting. So applying the seed of ideas to the fertile soil of the imagination, I found the ideas were indeed still there. To that end, I have at least three projects in various stages of completion which I will talk about soon, two being novels and one a short-story I am working on for an anthology. Now if the hands will only cooperate to tell the story my imagination is growing. At any rate this blog will be a place where I will not only discuss my own writing projects, but it will serve as a place to discuss the works of some of my writer friends and maybe do a fun interview or two of some of the writers I truly admire. (The B.A. in Journalism needs to be used occasionally afterall,) I also want to hear from you good folks that take time out of your busy day and kindly come by to peruse my words. If there is something you think should be here that is not please feel free to let me know, and if you like what you see here let me know that too.

Backblaze Builds a Data Center It Hopes to Fill with 500 Petabytes of Data Building a data center in the cloud Cloud backup company Backblaze has a secret and it's a big one. How big? Try an exabyte. That's how much data Backblaze hopes to be able to store at its relatively new data center in the Sacramento area. We didn't know about it because Backblaze never revealed any details about the facility until now. It's located just outside of Sacramento and away from any earthquake fault zones and flood plains. It's also considered to be an area that's "very low risk" for tornadoes, so that's one less thing to worry about. Furthermore, the data center has SAS 70 Type II and ISO 9001 certifications and is PCI-DSS compliant, in case you're interested in counting bullet points. Backblaze says it's been a year since the Sacramento data center first began accepting customer data, and by September 2013, all new customer accounts were being serviced there. At the time Backblaze started looking for a new data center (August 2012), it was hosting 40 petabytes of data. "We expect to be able to store about 1/2 an exabyte (500 petabytes) of customer data at our new data center," Backblaze said. "That should last us a little while but just in case the operations folks are already scouting locations in Lake Tahoe for the next data center."

package(default_visibility = ["//visibility:public"]) load( "@io_bazel_rules_go//go:def.bzl", "go_library", "go_test", ) go_test( name = "go_default_test", srcs = ["streaming_test.go"], embed = [":go_default_library"], deps = [ "//vendor/k8s.io/apimachinery/pkg/runtime:go_default_library", "//vendor/k8s.io/apimachinery/pkg/runtime/schema:go_default_library", "//vendor/k8s.io/apimachinery/pkg/util/framer:go_default_library", ], ) go_library( name = "go_default_library", srcs = ["streaming.go"], importpath = "k8s.io/apimachinery/pkg/runtime/serializer/streaming", deps = [ "//vendor/k8s.io/apimachinery/pkg/runtime:go_default_library", "//vendor/k8s.io/apimachinery/pkg/runtime/schema:go_default_library", ], ) filegroup( name = "package-srcs", srcs = glob(["**"]), tags = ["automanaged"], visibility = ["//visibility:private"], ) filegroup( name = "all-srcs", srcs = [":package-srcs"], tags = ["automanaged"], )

Monday, 20 August 2012 Featured Photo: Union Flags in Long Acre I’m a great fan of flags and I’ve just loved seeing all of the Union Flags around the United Kingdom in the past 18 months or so. It used to be that the British seemed embarrassed of their flag but the Royal Wedding, Diamond Jubilee and Olympics have seemed to change that. I hope the flags are here to stay because it is such a beautiful flag. Not as pretty as the South African flag, naturally, but still one of the best. Which is your favourite flag and which do you like that are not your national flag? I’m quite fond of the American flag too. This photo was taken in Long Acre near Covent Garden on Saturday. Always look up. i love your flag! when i see it being incorporated into clothing, it reminds me of the mod '60's, like a pair of white go-go boots! but anytime i see the american flag being worn, it looks cheesy to me. i'm not sure why. and even though it's just a state flag, i kind of like that of arizona's. It's great to flag. We do not have so much flagging here but some use a small pennant. The Norwegian is of beautiful with the cross and colors. The Israeli flag is my favorite and great for several reasons and in Israel they have flags everywhere:-)

1. Field of the Invention The field of invention relates to snow melting apparatus, and more particularly pertains to a new and improved snow melting heater mat apparatus wherein the same is arranged to be positioned adjacent a vehicle permitting ease of access to the vehicle. 2. Description of the Prior Art Snow melting apparatus in mat construction has been utilized in the prior art. The access to vehicles, particularly during snow storms, is awkward, difficult, and even dangerous due to melting and freezing of snow. The instant invention attempts to provide an organization to melt and direct snow through a cellular matrix of the mat structures to provide for a grid construction to permit a relatively non-slip surface, as well as directing melting snow therethrough. The prior art has addressed snow melting mats of various types and such mats are set forth in the U.S. Pat. Nos. 4,976,057; 3,976,855; 4,258,248; and 4,314,772. Accordingly, it may be appreciated that there continues to be a need for a new and improved snow melting heater mat apparatus as set forth by the instant invention which addresses both the problems of ease of use as well as effectiveness in construction and in this respect, the present invention substantially fulfills this need.

Show Sort By Now it's easy to take along a raincoat for your dog wherever you go! Our Casual Canine® Rainy Day Dog Jackets are great for rainy days. Each jacket zips into a compact pouch for easy transport and storage.

ZHYTOMYR, UKRAINE - Ukraine's Prosecutor General said on Friday that his office is reviewing all the cases that were closed by his predecessors, including several related to the owner of a gas company where former Vice President Joe Biden's son sat on the board. Ruslan Ryaboshapka's comments came amid an impeachment inquiry against U.S. President Donald Trump that relates to a call he made to the Ukrainian president asking him to investigate the Democratic presidential candidate and his son's work in Ukraine. Ryaboshapka told reporters in Kyiv that prosecutors are auditing all the cases that were closed or dismissed by former prosecutors, including several related to Mykola Zlochevsky, owner of the gas company Burisma that hired Hunter Biden in 2014, at the same time his father was leading the Obama administration's diplomatic dealings with Kyiv. Though the timing raised concerns among anti-corruption advocates, there has been no evidence of wrongdoing by either the former vice president or his son. “We are now reviewing all the cases that were closed or split into several parts or were investigated before, in order to be able to rule to reverse those cases where illegal procedural steps were taken," Ryaboshapka said. The Prosecutor General's Office later said that among the cases they are reviewing, there are 15 where Zlochevsky is mentioned. None of the Zlochevsky-related cases has been revived yet, they said. They did not specify how many, if any, were related to Hunter Biden's work at Burisma. Ryaboshapka was mentioned in the July 25 call between Trump and Ukrainian President Volodymyr Zelenskiy, who assured Trump that Ryaboshapka was “his man" and that he would resume investigations into Burisma. The prosecutor general insisted on Friday that he did not feel any pressure over the Burisma case. “Not a single foreign or Ukrainian official or politician has called me or tried to influence my decisions regarding specific criminal cases," he said. A whistleblower last month revealed that Trump in a phone call asked Zelenskiy to resume the probe into Joe Biden and his son. The July 25 call has since triggered an impeachment inquiry against Trump.

Pe 28 iunie, reprezentantii societatii civile au sugerat, in cadrul primei dezbaterii referitoare la redefinirea abuzului in servicu, eliminarea pragului prin transformarea infractiunii in una "de pericol", fie stabilirea unui prag minim.Codru Vrabie, reprezentant al Asociatiei Funky Citizens, a sugerat modificarea infractiunii de abuz in serviciu, astfel incat ea sa nu mai fie o infractiune de rezultat, ci sa fie o infractiune de pericol, in acest fel nemaifiind nevoie de prag."Nu credem ca este neaparat nevoie de prag. (...) Parlamentul si dumneavoastra, prin Ministerul Justitiei, aveti posibilitatea sa inaintati o astfel de propunere Parlamentului, pentru ca tine de politica penala a statului roman, de filozofia penala din Codul penal. Va sugeram sa modificati infractiunea de abuz in serviciu din articolul 297, in asa fel incat ea sa nu mai fie o infractiune de rezultat, ci sa fie o infractiune de pericol. In momentul in care face aceasta redefinire, nu mai incape niciun fel de discutie despre vreun prag, pentru ca pragul este indisolubil legat de existenta rezultatului", a propus Codru Vrabie in cadrul dezbaterii.El a explicat ca in istorie a existat o perioada in care abuzul in serviciu era reglementat ca o "infractiune de pericol"."Infractiunea de abuz in serviciu, inca de la Dongoroz (Vintila Dongoroz ￢ n.r.) incoace, pare sa fie o infractiune de rezultat, insa, in Codul lui Cuza din 1865, infractiunea era una de pericol. In filozofia capitolului de infractiuni de serviciu exista si infractiuni de pericol, si infractiuni de rezultat, dar, daca ne uitam la abuzul in serviciu, ne intrebam care este valoarea ocrotita. Noi credem ca valoarea ocrotita este exercitarea atributiilor de serviciu cu respectarea legii. Nu poate sa fie ocrotita valoarea rezultata din incalcarea legii si cauzarea unei vatamari sau unui prejudiciu", a motivat Vrabie.In schimb, Asociatia APADOR-CH a sustinut ca este pentru introducerea unui prag rezonabil.Curtea Constitutionala considera, in motivarea deciziei prin care a fost solutionata exceptia de neconstitutionalitate ridicata de Bombonica Prodana, fosta sotie a presedintelui PSD, Liviu Dragnea, ca dispozitiile penale in vigoare cu privire la infractiunea de abuz in serviciu "sunt formulate in sens larg si in termeni vagi".Conform sursei citate, o astfel de omisiune are relevanta constitutionala, deoarece afecteaza drepturi si libertati fundamentale ale persoanei impotriva careia se formuleaza o acuzatie penala. In aceasta situatie, CCR considera necesara instituirea unui prag al pagubei si circumstantierea vatamarii produse prin comiterea faptei, in functie de care sa se aprecieze daca este sau nu vorba de o infractiune.CCR preciza, totodata, ca nu are competenta de a remedia acest viciu normativ, intrucat ar intra in sfera exclusiva de competenta a legiuitorului primar sau delegat si, astfel, si-ar depasi atributiile legale.

Q: After Log.d(TAG, "downloadImgsUriArrayList:$downloadImagesUriList ") upload codes excute before for iterator's .addOnCompleteListener After Log.d(TAG, "downloadImgsUriArrayList:$downloadImagesUriList ") upload codes excute before for iterator's .addOnCompleteListener lead to var downloadImagesUriList: MutableList<String> = mutableListOf() is empty. How to solve this problem? var downloadImagesUriList: MutableList<String> = mutableListOf() //Upload images button upload_imgs_button.setOnClickListener { Log.d(TAG, "uploadImgsPath: $uploadImgsPath"); //Upload images to firebase storage if (uploadImgsPath != null) { for (uriForUpload in imagesList) { val imgNameUUID = UUID.randomUUID().toString() val withAppendedPath = Uri.withAppendedPath(uriForUpload, imgNameUUID).toString() var imgFileRef = uploadImgsPath!!.child(withAppendedPath) imgFileRef.putFile(uriForUpload) .continueWithTask { if (!it.isSuccessful) { it.exception?.let { throw it } } imgFileRef.downloadUrl }.addOnCompleteListener { if (it.isSuccessful) { var uriForDownload = it.result.toString() Log.d(TAG, "uriForDownload:$uriForDownload "); downloadImagesUriList.add(uriForDownload) } } } //The process will run here before downloadImagesUriList.add(uriForDownload) was excuted. //How to solve this problem? Log.d(TAG, "downloadImgsUriArrayList:$downloadImagesUriList "); var uploadedImages = UploadedImages( categoryDesignID, user!!.uid, downloadImagesUriList, Timestamp.now() ) //Save uploaded images path info to firestore firestore.collection("uploadedImages").add(uploadedImages) .addOnSuccessListener { Toast.makeText(context, "Upload successful", Toast.LENGTH_LONG) .show() } } else { Toast.makeText(context,"Please choose a category",Toast.LENGTH_LONG).show() } A: Firebase APIs, like most modern cloud APIs, are asynchronous, since they interact with a (potentially time-consuming) server. Instead of blocking your main thread while the cloud interaction happens, the clients allow your main code to continue, and then call back once the cloud API has completed its work. In your code that means that the Log.d(TAG, "downloadImgsUriArrayList:$downloadImagesUriList "); runs before the imgFileRef.downloadUrl. This explains why nothing is written to the database by add(uploadedImages): the download URLs haven't been determined yet, because the upload is still in progress. To solve this problem, all code that requires the download URL of an upload, must be inside the completion listener of that upload. The simplest way to do this, is to add a new URL each time the upload of that file completes: for (uriForUpload in imagesList) { val imgNameUUID = UUID.randomUUID().toString() val withAppendedPath = Uri.withAppendedPath(uriForUpload, imgNameUUID).toString() var imgFileRef = uploadImgsPath!!.child(withAppendedPath) imgFileRef.putFile(uriForUpload) .continueWithTask { if (!it.isSuccessful) { it.exception?.let { throw it } } imgFileRef.downloadUrl }.addOnCompleteListener { if (it.isSuccessful) { var uriForDownload = it.result.toString() Log.d(TAG, "uriForDownload:$uriForDownload "); downloadImagesUriList.add(uriForDownload) Log.d(TAG, "downloadImgsUriArrayList:$downloadImagesUriList "); var uploadedImages = UploadedImages( categoryDesignID, user!!.uid, downloadImagesUriList, Timestamp.now() ) //Save uploaded images path info to firestore firestore.collection("uploadedImages").add(uploadedImages) } } } The above will create a new document each time an upload completes. You'll either want to update the same document after each file completes or wait until the last file has uploaded before creating the document. There are many ways to do either, but a simple way is to simply keep a counter of how many files have completed uploading: var uploadedCount = 0 for (uriForUpload in imagesList) { ... }.addOnCompleteListener { if (it.isSuccessful) { var uriForDownload = it.result.toString() Log.d(TAG, "uriForDownload:$uriForDownload "); downloadImagesUriList.add(uriForDownload) if (uploadedCount++ >= imagesList.size) { Log.d(TAG, "downloadImgsUriArrayList:$downloadImagesUriList "); var uploadedImages = UploadedImages( categoryDesignID, user!!.uid, downloadImagesUriList, Timestamp.now() ) //Save uploaded images path info to firestore firestore.collection("uploadedImages").add(uploadedImages) } ... }

Glucocorticoid therapy-induced skin atrophy. Glucocorticoids (GCs) are highly effective for the topical treatment of inflammatory skin diseases. Their long-term use, however, is often accompanied by severe and partially irreversible adverse effects, with atrophy being the most prominent limitation. Progress in the understanding of GC-mediated molecular action as well as some advances in technologies to determine the atrophogenic potential of compounds has been made recently. It is likely that the detailed mechanisms of GC-induced skin atrophy will be discovered and in vitro models for the reliable prediction of atrophy will be established in the foreseeable future. This knowledge will not only facilitate safety profiling of established drugs but will also foster further drug discovery by improving compound characterization processes. New insights into GC modes of action will guide optimization strategies aiming at novel GC receptor ligands with improved effect/side effect profile.

Eiffel I'm in Love Eiffel I'm in Love is a 2003 Indonesian teen romantic comedy film directed by was Nasri Cheppy. The film stars Samuel Rizal and Shandy Aulia as the main characters, the film adaptation of the bestselling novel of the same name by Rachmania Arunita. Other people appearing in the film include Titi Kamal, Helmy Yahya, Didi Petet, and Hilda Arifin. The movie won an award for "Most Favorite Movie" and nomination for "Best Movie" at the 2004 MTV Indonesia Movie Awards. Cast Samuel Rizal as Adit Shandy Aulia as Tita Yogi Finanda as Ergi Titi Kamal as Intan Didi Petet Hilda Arifin Plot Based on the book with the same title, Eiffel I'm in Love tells the story about a teenage girl, Tita (Shandy Aulia), who led a perfect life. She had a lovely family, a patient boyfriend and 2 best friends who are always by her side. However, her mother was overly protective towards her and she is not allowed to go out. Her life completely changes when her parents good friend and his son, Adit (Samuel Rizal), came from France to stay with them. Tita was supposed to pick both of them from the airport. However, she waited at the wrong terminal and only realized that when Adit accidentally bumped into her and asked her whether she was the one who supposed to picked him and his father up. Adit was very cold to Tita from the start, however, her parents saw him as a reliable man and trust him to take care of their daughter. Things became worse when Adit told Tita that their parents were planning to forcibly match them as a couple. Extended version This film has an extended version, to review the story in this film in more depth. Awards and nominations External links Category:2003 films Category:Indonesian films Category:Indonesian-language films Category:2000s romantic comedy films Category:Teen comedy films Category:Films shot in Indonesia Category:Films shot in France

It often is desired to feed a load (such as material to be destroyed, food to be shredded, etc.) towards a processing mechanism (such as a shredding mechanism, cutting mechanism, etc.). Conventionally, feeding mechanisms have been established for continuously moving materials within a certain range of dimensions towards the processing mechanism. For example, a load within a first range of thickness could be handled continuously, but the feeding mechanism would need to be stopped and manually adjusted before trying to feed a load of a second range of thickness. It has long been commonly appreciated that care is usually required in feeding an input load into most machines as to proper orientation of pieces of the load, uniform quality of pieces of the load, etc. This has long been applicable for machines involving cutting and especially the specific case of paper shredders. It conventionally had been recognized that the operative cutting mechanisms in paper shredders were designed to accommodate a particular thickness of paper and that inputting too thick a stack of pages, for example, could damage or at least “stall” or jam the shredder. For accomplishing high-security destruction, in the past, each kind of material needing to be destroyed had a particular destruction mechanism designed to destroy the material based on its dimensions, kind of material, etc. Other than the present inventor's recent work being brought to the market, there has not yet been a destruction mechanism that would destroy paper to high-security small pieces as well as also destroy non-paper materials such as a polyester-type material (such as key tape), a thick material (such as a book), etc. Rather, conventionally no more was expected of a paper shredder than that it shred paper. Merely meeting the recent security requirements demanding yet smaller-sized residue has occupied the shredder industry, as most of the shredder industry seemingly has been unable to design products to satisfy the new high-security shredder requirements. Only a few companies have actually managed to do so with actual viable products in the marketplace. In the case of an expensive category of machine called a disintegrator, paper shredding and different types of to-be-destroyed material ultimately may be accommodated. However, within the disintegrator machine the different materials may travel non-identical feed paths. See US 2003/0201353 A1 by Lefrancois et al., titled “Dual-path office product disintegrator” published Oct. 30, 2003. Different input ports are provided for different types of input materials. Disintegrators are heavy, large-dimensioned (non-portable) machinery. Several commercially-available disintegrators actually are two machines combined, in order to perform the destruction function. Typically, a conventional shredder is typically atop a conventional disintegrator. It pre-shreds paper (and some other materials), and then feeds the-pre-shredded material to the disintegrator. This is usually necessary to obtain adequate throughput rates. In high-security destruction, before the present inventor's own work it had not been possible to destroy different to-be-destroyed materials in a single shredder or a single disintegrator. Thus, the question of feeding a significantly non-uniform load of to-be-destroyed material had not been encountered in the area of high-security destruction. Examples of conventional feeding mechanisms are mentioned. U.S. Pat. No. 3,958,737 issued May 25, 1976 to Scott (Precision Sales Corp.) for “Adjustable Feed Mechanism.” U.S. Pat. No. 5,622,330 issued Apr. 22, 1997 to Sharp et al. (ASC Machine Tools, Inc.) for “Self-adjusting Feed Stock Accumulator System.” U.S. Pat. No. 5,348,282 issued Sep. 20, 1994 to Choi et al. (Xerox Corp.) for “Self Adjusting Feed Roll.” U.S. Pat. No. 4,621,798 issued Nov. 11, 1986 to Akers (Bell & Howell Co.) for “Envelope Feeding Mechanism for Mail Sorting Machines.”

Q: Displaying weekday on Active Admin column How it's possible to display the weekday next to a date ? column :start_date #displaying for example 29 Jan. 2016 How to echo it as Friday, 29 Jan. 2016? A: You can use strftime method. column "Start Date:" do |post| post.start_date.strftime("%A, %d %b. %Y") end

Over the last six years, women's rugby has been growing in Nova Scotia and gaining recognition as a high-performance sport. "The big success right now for our Keltics program is now all the universities are offering scholarships because the level of play within Nova Scotia has improved so much," said Jack Hanratty, provincial coach for Nova Scotia Keltics. Hanratty said the growth can be shown by results, membership or through experience playing the sport. The Keltics program focuses on all three. Changing attitudes "The one thing we've noticed is that you used to play rugby because somebody you knew, or somebody in your family, had a history in rugby," said Hanratty. "And now people are seeing the game, because now it's an Olympic sport, as … a real option of being a student-athlete." This summer, the Keltics senior women's team won the silver medal at the Canadian championship tournament, finishing ahead of B.C. and Ontario. "We are continuing to improve and it's showing when we do go to compete," said Sarah Boudreau, captain of the Acadia Axewomen and a member of the Keltics program. Competing for national honours Boudreau and the Axewomen, the host team, will be competing for a medal at the national university championship event starting Thursday in Wolfville. Eight teams representing all of the U Sports conferences, including Atlantic University Sport champion St. Francis Xavier, will compete for the national banner. "This is the first year that Acadia is hosting and it's kind of cool to be able to compete for that on your own home turf," said Boudreau. "I'm feeling very confident." There will be approximately 200 athletes attending, with 25 of them having played with the Keltics. Calgary, Laval, Queen's, Guelph, Victoria and Ottawa are the other teams competing. There are four quarter-final matches on Thursday with the final on Sunday afternoon.

Musings, Inspirations & All Things Marang Tuesday, November 15, 2011 Ok, so by now I'm sure you've heard about all the changes Etsy has made on the whole changing your shop name. I had given an account on how I went about changing my shop name, here, before these newest updates were made. And since I see a lot of people still refering to that post, I thought I'd give a few links from Etsy's Storque on their updates. This should make the whole process SO much easier!! Monday, August 8, 2011 I know I've been absent and quiet for a while. I have a good excuse, I promise! I moved across the country from Santa Fe, NM to Columbus, OH. It took me longer to get everything situated in Santa Fe and then getting settled and looking for a job has been taken longer than I'd like also. But, I have been having way too much fun discovering this new city! New people, new experiences, new places to find and new things to do. I've even gotten to cross off a few things from my 100 List!! 9. Learn to water ski. I tried water skiing this past weekend and although I didn't quite get the hang of it yet, I'm very close and very sore! It even hurts to type! 78. Go to a drive-in theater. This past weekend (after the water skiing attempt!) I was treated to a relaxing evening at the drive-in movie theater. :) I've gotten a new-to-me car also. My uncle was kind enough to pass down my Grandmother's car after she passed away. The Silvery Minnow, as she is now named, is an '89 Mercury Grand Marquis. I drive a boat!! I am trying to get situated with a job and back on a 'normal' schedule of life, creating and blogging. Please stay in touch and come back to see what's new!! Tuesday, June 14, 2011 I may have skipped a few treasuries, so I apologize if your's doesn't get posted. But, here are some more treasuries that feature my items! Thank you to urbancreatures and RenewableCrafts for these great treasuries!! Wednesday, June 8, 2011 Well the promotional creations I ended up making for the Trashion Team swap are seed packets. I had small envelopes that I had already made or had ready to go in my stash (of way too many things!). From last years vegetable garden, I had a huge jar of marigold seeds waiting to be used. I added a note with a coupon code and my business cards and tied them up! A bunch of flowers just for you!!

forceinline overload Bool() : Bool = false; [I when Integer?(I)] forceinline overload I(a:Bool) : I = if (a) I(1) else I(0); [I when Integer?(I)] forceinline overload Bool(a:I) : Bool = (a != I(0)); forceinline overload equals?(a:Bool, b:Bool) : Bool = if (a) b else not b; forceinline overload lesser?(a:Bool, b:Bool) : Bool = ((not a) and b);

Q: R populate column based on several criteria I have a dataset in which I want to create a new column that takes existing values from another column when available, when no values are available, it should instead take values one year in the past. Example, I have the following data: Date Market Campaign Impressions 1/1/2017 SE Home 150 1/2/2017 SE Home 100 1/1/2017 GB Home 50 1/2/2017 GB Home 55 1/1/2018 SE Home NA 1/2/2018 SE Home NA I would like to write something that will provide me with: Date Market Campaign Impressions Future_impressions 1/1/2017 SE Home 150 150 1/2/2017 SE Home 100 100 1/1/2017 GB Home 50 50 1/2/2017 GB Home 55 55 1/1/2018 SE Home NA 150 1/2/2018 SE Home NA 100 I have managed to populate Future_impressions with the Impressions for historic months using: df$Future_impressions[is.na(df$Impressions)] <- NA But I have no idea how get the future months populated. I basically want to write something that says: - IF Impressions=NA - THEN MATCH (Date minus 12 months) AND MATCH Market and Campaign and retrieve Impressions I am a very new R user but I've searched around extensively, so I hope I haven't asked a redundant question! Thank you all so much in advance! A: Here is an option using apply df$Date <- as.Date(df$Date,'%m/%d/%Y') get.last.year <- function(dt, mk, cp){ ly <- as.POSIXlt(dt) ly$year <- ly$year - 1 ly <- as.Date(ly) x <- df[df$Date == ly & df$Market == mk & df$Campaign == cp, "Impressions"] return(x) } df$Future.impressions <- apply(df, 1, function(x) ifelse(!is.na(x[["Impressions"]]), x[["Impressions"]], get.last.year(x[["Date"]], x[["Market"]], x[["Campaign"]])))

Q: is there a significant speed difference between attributing a boolean to a variable and a string to variable in python? I am currently developing a python project where I am concerned with performance because my CPU is always using like 90-98% of its computing capacity. So I was thinking about what could I change in my code to make it faster, and noticed that I have a string variable which always receives one of two values: state = "ok" state = "notOk" Since it only has 2 values, I tought about changing it to a boolean like: isStateOk = True isStateOk = False Does it make any sense to do that? Is there a big difference, or any difference at all, in the speed of attributing a string to a variable and attributing a boolean to a variable? I should also mention that I am using this variable in like 30 if comparisons in my code, so maybe the speed of comparison would be a benefit? if (state == "ok) # Original comparison if (isStateOk) # New comparison A: That's not going to fix the program using 90-98% CPU, but technically yes, using a Boolean is better. You can also use is instead of ==: isStateOk = True if isStateOk is True: # Do stuff Edit: Nevermind, in https://hg.python.org/cpython/rev/01a7e66525c2/ they already made == True get converted by the Python interpreter to is True under the hood, so there is no performance difference to writing it either way. While it is all around a good idea to use Booleans here since the purpose of Booleans is to represent ok/not ok state, it's not going to give any type of noticeable performance improvement.

#!/usr/bin/env python3 ''' s3qlstat - this file is part of S3QL (http://s3ql.googlecode.com) Copyright © 2008 Nikolaus Rath <Nikolaus@rath.org> This program can be distributed under the terms of the GNU GPLv3. ''' import sys import os.path # We are running from the S3QL source directory, make sure # that we use modules from this directory basedir = os.path.abspath(os.path.join(os.path.dirname(sys.argv[0]), '..')) if (os.path.exists(os.path.join(basedir, 'setup.py')) and os.path.exists(os.path.join(basedir, 'src', 's3ql', '__init__.py'))): sys.path = [os.path.join(basedir, 'src')] + sys.path import s3ql.statfs s3ql.statfs.main(sys.argv[1:])

Tuesday, August 2, 2011 Took me about 4 evenings work to model and paint this guy, but here he is. I'm pretty pleased with how he came out. I got in a game with him the other day vs this a**hole. Merv brought a Zoraida/Collodi crew and I learned the meaning of frustration dealing with the latter. He is such a bloody pain to put down. Anyway, to cut a long story short, I lost, badly, but by no fault of the rider. He pretty much held up the entire enemy crew for 2 turns - on his own (while Seamus missed stuff with his flintlock, the gunslinger trudged through a forest and the Belles just flopped around the place being Obey-ed). On an unrelated note, some of you may recognise the fat and thin Daemon princes in the background in these pics. Saturday, July 23, 2011 Anyway, this line is tapped, so I'll be brief (stupidest line from the Matrix, if the line is bloody tapped it means someone is listening - don't arrange to meet under the bridge dumbass). I pre-ordered some shiny new Malifaux stuff last month, and it arrived bright and early (the girlfriend answered the door for it, my precious sleep was not disturbed) on Thursday. Here's what I got: I think I'll put this chap up as a prize in the Tournament I'm planning next month. Mr. Dead Rider is currently undercoated black and sitting on my painting station. Snow Storm is pretty. Very much living up to the hype, Storm's body is cast in resin with metal horns. I checked for air bubbles and only found a few superficial ones on the soles of his feet and the flat areas where his arms connect. Citadel Fineass could learn something from this. Snow is entirely metal, only her hands need to be attached, they'll need pinning and possibly a small drill bit to do the job. I reckon a paperclip is the right size. Dead Rider is entirely metal. There was very little flash, and besides the scythe arm being a bit tricky he was pretty easy to pin, about an hours work altogether (while watching an episode of Dexter). After pinning I used a tiny bit of green stuff to blend in the joins. The rocky part under the steeds right hoof is actually part of the model, so I built up a rocky outcrop out of thin cork tile. Monday, February 7, 2011 I have to do a post on this mini. I'm a fan of simple well executed colour schemes on models, but this one really takes the cake. And I thought I did well painting some Onryu with only 5 different colours... In other news GW is still promoting their flying toaster. One of the lads from out LGS has one painted up. It's actually very nice in the flesh. Tuesday, February 1, 2011 Ok Forgeworld, you did bad in the past but after this I'll forgive you. Now that's the quality we expect from the price tag. Wyrd posted some pics of their February releases today and once again they do not disappoint. Check out the paint job on the Lost Love! I want to do my spirits like that now. As regards sculpt so far Nix seems to be a crowd pleaser (and I must agree) though I think the rats and Stolen ooze character. Special mention on the release of the Malifaux rules manual. Now I can't comment on the content besides the fact that it claims to contain up to date errata'd rules for the game, so I guess that's what it'll contain, but I can say the cover looks nice. Which is the main thing. Tuesday, January 11, 2011 Seriously? What, you're serious Games Workshop? Tyberos The Red Wake is the best you lads can think up? Look at his bloody hands. Damn that's ugly. I can just imagine the board meeting; "Guys, guys!""What?""Y'know what'd be cooler than a power fist, lightning claws and chainswords...? All of them! At once! Combined!""... Incredible. We'll do it! It totally won't look stupid and our unwaveringly loyal customers will want to spend a mint on it for sure! This is totally the best idea we've had all week since the revival of the S-shaped monster's no-one liked. Quick - think up some bullshit reason for it.""Uh... 'ancient relic-gauntlets'...?""... Wow! Someone's getting a promotion!"

Introduction {#s1} ============ Dendritic cells (DCs) orchestrate immune responses, linking innate to adaptive immunity. DCs, which are important professional antigen-presenting cells (APCs) depending on their maturation state, take up a broad range of antigens and present them to T cells. Several endogenous and exogenous stimuli, such as Toll-like receptor (TLR) ligands and inflammatory cytokines, phenotypically and functionally activate DCs. Upon activation, DCs display phenotypic changes, including upregulation of the expression of MHC II and costimulatory molecules, and changes in expression patterns of chemotactic and homing receptors. Activated DCs also exhibit functional changes, including the downregulation of antigen uptake and secretion of chemokines and cytokines ([@B1]--[@B6]). DCs are classified as classical DCs (cDCs), which are further subdivided into classical type 1 DCs (cDC1s) and classical type 2 DCs (cDC2s), plasmacytoid DCs (pDCs), and monocyte-derived DCs (MoDCs) ([@B7], [@B8]). Inflammatory MoDCs are differentiated from murine bone marrow (BM) cells by treatment with granulocyte macrophage-colony stimulating factor (GM-CSF) *in vitro* ([@B9]). In contrast to the treatment with GM-CSF, BM cells treated with Flt3 ligand differentiate into cDC1s, cDC2s, and pDCs ([@B10]). GM-CSF-induced BM-derived DCs (BMDCs) are similar to *in vivo* inflammatory and TNF/iNOS-producing DCs rather than DCs in the steady state ([@B4], [@B11]). GM-CSF promotes the maturation and activation of monocytes, macrophages, DCs, and granulocytes during inflammation ([@B4], [@B12]--[@B14]). GM-CSF also acts on the myeloid cell-dependent Th17 inflammatory response, which is mediated by TNF, IL-6, IL-23, and IL1β that are produced by macrophages and MoDCs ([@B15]--[@B17]). Besides the important roles of GM-CSF *in vivo*, it was originally identified by its ability to induce inflammatory DCs from mouse BM precursor cells *in vitro* ([@B9], [@B16]). The binding of GM-CSF to its receptor initiates the activation of downstream pathways, such as MAPK, PI3K/Akt, NF-κB, and STAT5. The PI3K/Akt signaling pathway regulates the GM-CSF-induced proliferation, survival, and development of DCs ([@B17], [@B18]). Mst1, mammalian STE20-like kinase 1, is a multifunctional serine/threonine kinase highly expressed in immune organs, such as the thymus, spleen, and lymph nodes ([@B19], [@B20]). Mst1 plays important roles in cell proliferation, differentiation, apoptosis, and organ size regulation ([@B21]--[@B24]) as well as in the regulation of survival, proliferation, trafficking, and function of T cells, a type of lymphocytes in adaptive immunity ([@B19], [@B20], [@B25]--[@B30]). Furthermore, recent studies revealed that Mst1-deficient DCs promote the overproduction of IL-6, which induces Th17 differentiation in DC-specific (CD11c-Cre) conditional Mst1-knockout (KO) mice ([@B31]) and Mst1 signaling contributes to CD8^+^ DC function in mediating CD8^+^ T cell priming through the regulation of mitochondrial activity and IL-12 signaling ([@B32]). However, the roles of Mst1 in the activation and maturation of MoDCs are still poorly understood. In this study, we aimed to elucidate the role of Mst1 in GM-CSF-induced BMDCs, which mimic *in vivo* inflammatory MoDCs more closely. We found that *Mst1*^−/−^ BMDCs displayed higher expression levels of cell surface CD40, B7, and MHC II molecules as well as increased production of inflammatory cytokines than the *Mst1*^+/+^ BMDCs. Mst1 deficiency also increased the surface expression level of B7.2 in migratory monocyte-derived cells (MCs) *in vivo*. In addition, hyperactivated *Mst1*^−/−^ BMDCs stimulated *in vitro* T cell proliferation and activation to a greater extent than *Mst1*^+/+^ BMDCs. We also found that *Mst1*^−/−^ BMDCs enhanced GM-CSF-induced Akt/c-myc pathway. Inhibition of the Akt/c-myc pathway reversed the hyperactivation of BMDCs induced by the loss of Mst1. The findings of the present study establish that Mst1 is implicated in the regulation of GM-CSF-mediated Akt/c-myc pathway in DCs, suggesting that Mst1 is one of the endogenous factors that determine the activation status of GM-CSF-stimulated inflammatory DCs. To our knowledge, this is the first observation of Akt1/c-myc-mediated functions of Mst1 in the immune system. Materials and Methods {#s2} ===================== Mice ---- *Mst1*^−/−^ mice on the C57BL/6 background were kindly provided by Dr. Dae-Sik Lim (Korea Advanced Institute of Science and Technology, Daejeon, Korea) ([@B33]). Mice used in the experimental protocols were backcrossed more than twelve generations to C57BL/6 mice. *Mst1*^−/−^ and littermate control were maintained in a specific pathogen-free animal facility at Korea University, Seoul, Korea. These mice experiments were performed according to the guidelines of Korea University Institutional Animal Care and Use Committee (KUIACUC-2017-109 and 2019-0013). Chemicals and Reagents ---------------------- Murine recombinant GM-CSF was purchased from ProSpec. CpG DNA (ODN 1826) was purchased from Invivogen. The following chemicals were used: Akt1 inhibitor MK-2206 (AdooQ Bioscience), myc inhibitors 10074-G5 (Cayman) and (+)-JQ1 (Sigma-Aldrich). Antibodies against the following proteins were used in western blot analyses: Mst1 (Cell Signaling, no. 3682), Mst2 (Cell Signaling, no. 3952), phospho-Akt (Cell Signaling, no. 4060), phospho-YAP (Cell Signaling, no. 13008), YAP (Cell Signaling, no. 14074), c-myc (Cell Signaling, no. 13987), Akt (Santa Cruz, sc-1618), GAPDH (Santa Cruz, sc-32233), Lamin B (Santa Cruz, sc-6217), and β-actin (Santa Cruz, sc-47778). Cell Numbers and Phenotyping of Primary Cells in Mouse Lymphoid Organs ---------------------------------------------------------------------- Sex- and age-matched, 7- to 8-weeks old mice (female) were used in this study. Primary cells of BM, spleen, and mesenteric lymph nodes (MLN) in *Mst1*^+/+^ and *Mst1*^−/−^ littermates were used. BM cells were collected from femurs and tibias of mice. All organs were homogenized and cell suspensions were filtered through a 40-μm cell strainer for the removal of any cell clumps, and erythrocytes were removed via treatment with red blood cells lysis buffer (BioVision). For immuno-fluorescenct staining of cells, cells were resuspended in fluorescence-activated cell sorting (FACS) buffer, which consists of phosphate-buffered saline (PBS) containing 1% fetal bovine serum (FBS) and 0.05% sodium azide. We first gated on the myeloid cells based on their forward (FSC) vs. side (SSC) scatter properties, and then identify each cell type by at least two specific surface marker as follow: CD11b^+^Ly6C^+^ cells for monocytes, CD11c^+^ MHC II^+^ cells for splenic cDCs, and CD11c^+^CD103^−^CD11b^+^ cells for MCs. Generation of BMDCs ------------------- BMDCs were differentiated by culture of *Mst1*^+/+^ and *Mst1*^−/−^ mouse BM cells in the presence of 20 ng/ml GM-CSF for 8 days ([@B9]). Briefly, BM cells were isolated from the femur and tibia bones of *Mst1*^+/+^ and *Mst1*^−/−^ 8- to 10-weeks old mouse (female), followed by RBC lysis. The BM cells were then cultured at a concentration of 2 × 10^5^ cells per ml. The cells were cultured in RPMI containing 10% heat-inactivated FBS (Gibco), 2 mM glutamine, 1 mM sodium pyruvate, 10 mM HEPES, 100 U/ml penicillin, 100 μg/ml streptomycin (Corning), and 50 μM 2-mercaptoethanol (Sigma-Aldrich). The cells were supplemented with 20 ng/ml GM-CSF after 3, 5, and 7 days in the course of the 8-days culture or after 3, 5, 7, and 8 days in the course of the 10-days culture. Antibodies and Flow Cytometric Analysis --------------------------------------- The expression of cell surface molecules on CD11c^+^ BMDCs was investigated in *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs after 8 days in culture unless otherwise specified. One hundred microliters of cells were blocked with Fc blocker (anti-CD16/32 antibody, 2.4G2; BD Bioscience) for 10 min at 4°C, and then incubated with an antibody cocktail for 30 min at 4°C, and washed with FACS buffer. Fluorescent antibodies (eBioscience, BD Biosciences, and Biolegend) were used as follows: CD11c (HL3), CD11b (M1/70), B220 (RA3-6B2), Ly6c (HK1.4), MHC II (NIMR-4 and AF6-120.1), CD40 (3/23), CD80 (16-10A1), CD86 (GL1), and CD131 (JORO50) monoclonal antibodies for cell surface staining. For intracellular staining of TLR9 and CD206, *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs after 8 days of culture were stained for CD11c by incubation with anti-CD11c antibody; subsequently, the cells were fixed and permeabilized using a cytofix/cytoperm kit (BD Biosciences, San Jose, CA), according to the manufacturer\'s instructions, and then stained with anti-TLR9 (M9.D6) or -CD206 (C068C2) antibody. The stained cells were examined by FACS Calibur (BD Biosciences, San Diego, CA), and analyzed using Cell Quest Pro software (BD Biosciences). Mst1 siRNA-mediated knockdown BMDCs were used to analyze the expression of cell surface CD40 and MHC II molecules on CD11c^+^ BMDCs after 36 h culture in the presence of GM-CSF following microporation of Mst1 siRNA. Semi-quantitative RT-PCR ------------------------ *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs after 8 days in culture were used in analysis of cytokine mRNA expression. RNAs were isolated using Ribo-EX reagent (GeneAll), as described by the manufacturer. RNA samples (1 μg) were converted to cDNA by reverse transcription using oligo (dT)18 primer and moloney murine leukemia virus (M-MLV) reverse transcriptase (Enzynomics). The PCR was performed within a range of cycles (24--37 cycles). The sequences of PCR primers used in this study are described in [Table S1](#SM1){ref-type="supplementary-material"}. In Mst1 siRNA-mediated knockdown system, BMDCs were used after 36 h culture in the presence of GM-CSF following microporation of Mst1 siRNA and media change. Cytokine Assay -------------- The quantities of IL-12p40 and IL-23 in the culture supernatants were determined by a sandwich ELISA. To enhance cytokine production, BMDCs were stimulated with 0.1 μM CpG DNA. Production of the proinflammatory cytokines IL-23 and TNF-α secreted by Mst1-knockdown BMDCs was analyzed in the culture supernatants stimulated for 3 or 30 h, respectively, with 0.1 μM CpG DNA by a sandwich ELISA. Mouse IL-12p40 and TNF-α ELISA sets and anti-mouse IL-23p19 (5B2) and anti-mouse IL-12/23 p40 (C17.8) for IL-23 ELISA were purchased from eBioscience. The assays were performed according to the manufacturer\'s instructions. Quantitation of Antigen Uptake ------------------------------ To measure antigen uptake ability, *Mst1*^+/+^ and *Mst1*^−/−^ CD11c^+^ BMDCs after 8 days in culture were incubated with FITC-labeled dextran (Sigma-Aldrich). Briefly, 2 × 10^5^ cells were equilibrated at 4°C or 37°C for 30min and then incubated at 37°C (for a negative control, BMDCs were incubated at 4°C) in medium containing 1 mg/ml FITC-dextran for 1 h. After incubation, the cells were washed twice in PBS to remove excess dextran. The quantitative uptake of FITC-dextran by BMDCs was determined by flow cytometric analysis. We measured percentage of FITC-dextran^+^ *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs following incubation after FITC-dextran treatment. Mixed Leukocyte Reaction (MLR) ------------------------------ *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs (I-A^b^) after 8 days in culture were replated and cultured for 24 h in the presence of GM-CSF and used as stimulators. Allogeneic CD4^+^ T cells from spleen and lymph node of BALB/c mice (I-A^d^) were isolated by positive immunomagnetic selection using MACS with CD4 MicroBeads (Miltenyi Biotec). CD4^+^ T cells were labeled for 10 min at 37°C with 1 μM CFSE. After CFSE staining of CD4^+^ T cells, 1 × 10^5^ CD4^+^ T cells were cultured with *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs at a ratio of 1:10, 20, 40, and 80 (BMDCs:CD4^+^ T cells) for 4 days in order to perform proliferation assay. The proliferation activity of CD4^+^ T cell was measured as dilution of CFSE. For detection of IL-2 production, CD4^+^ T cells were cultured with *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs at a ratio of 1:10 for 3 days, and then supernatants were collected to analyze through ELISA. IL-2--expressing CD4^+^ T cells were analyzed by BD Accuri C6 Plus (BD Biosciences) at a ratio of 1:20 for 3 days after cocultured with *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs. Small Interfering RNA (siRNA) Transfection ------------------------------------------ The siRNA-mediated interference technique was used to silence mouse Mst1 expression. The Mst1-specific sense siRNA sequence (5′-CCG UCU UUC CUU GAA UAC UUU-3′) ([@B34]) was synthesized by ST Pharm (Seoul, Korea), and a scrambled control siRNA was synthesized by Bioneer (Daejon, Korea). siRNAs were transfected into BMDCs after 8 days in culture by Neon Transfection System (Invitrogen), according to the manufacturer\'s instructions. Western Blot Analysis --------------------- *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs were harvested for cell lysis after 7 days in culture. The cells were harvested and then were lysed in lysis buffer (50 mM Tris-Cl pH 8.0, 150 mM NaCl, 1% Triton X-100, 0.1% SDS, 10 mM NaF, 1 mM Na~3~VO~4~, 0.3 mM PMSF, and protease inhibitor cocktail which was from Sigma-Aldrich). Protein concentration was measured using Pierce BCA protein assay kit (Thermo Fisher Scientific), as described by the manufacturer. Equal amounts of protein from whole-cell extracts were separated on 8--10% SDS-PAGE (Bio-Rad) and transferred onto polyvinylidene difluoride (PVDF) membranes (Merck Millipore). The PVDF membrane was then incubated in blocking buffer (Tris-buffered saline containing 0.1% Tween 20 and 5% BSA) for 1 h at room temperature. Then the membranes were incubated with appropriate primary antibody overnight at 4°C with gentle shaking, followed by 1 h of incubation at room temperature with the appropriate horseradish peroxidase-conjugated secondary antibody. The blots were visualized using Amersham ECL Prime Western Blotting Detection Reagent (GE Healthcare and Life Sciences) according to the manufacturer\'s instructions. Western blot digital images were obtained using the Fujifilm LAS-3000 imager. Treatment of DCs With Inhibitors -------------------------------- In case of the experiments using inhibitors, the *Mst1*^−/−^ and Mst1-knockdown BMDCs were treated with each specific inhibitor. *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs after 7 days of differentiation in culture were replated in the presence of GM-CSF for additional 6 h in culture. Vehicle control and MK-2206 (2 μM) were added in culture medium of *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs for western blotting. For flow cytometric analysis, *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs after 8 days of differentiation in culture were replated in the presence of GM-CSF and the following inhibitors: MK-2206 (2 μM), 10074-G5 (25 μM), and (+)JQ-1 (250 nM), and then annexin V^−^CD11c^+^ BMDCs were examined by BD Accuri C6 Plus after 20 h of culture. In Mst1 siRNA-mediated knockdown system, BMDCs were used after 36 h culture in the presence of GM-CSF following microporation of Mst1 siRNA and media change. Vehicle control and the indicated inhibitors were added in culture medium of scrambled control-transfected and Mst1-knockdown BMDCs during the last 6 h. Statistical Analyses -------------------- Statistically significant differences of all data expressed as mean ± SD were assessed by the unpaired Student *t*-test using SigmaPlot 10 software. The statistical differences in cell numbers of *Mst1*^+/+^ and *Mst1*^−/−^ mouse lymphoid organs were analyzed by Mann-Whitney U test using IBM SPSS Statistics 25 software. A *p*-value \< 0.05 was considered statistically significant. Results {#s3} ======= Mst1-Deficiency Triggers a Hyperactivated Phenotype in BMDCs ------------------------------------------------------------ A previous report showed that Mst1 is expressed abundantly in GM-CSF-induced BMDCs compared to their precursor BM cells ([@B20]). In agreement with this report, we also observed that protein levels of Mst1 in BM cells were gradually increased in a time-dependent manner when cultured with GM-CSF, which suggests that Mst1 is involved in GM-CSFR signaling ([Figure S1A](#SM1){ref-type="supplementary-material"}). Previous reports showed that Hippo pathway phosphorylates and suppresses transcriptional coactivator YAP, the component of Hippo pathway ([@B24]). We further investigated whether the protein level of YAP was altered in the BM cell differentiation into BMDCs. The protein level of YAP was inversely correlated with Mst1 expression ([Figure S1A](#SM1){ref-type="supplementary-material"}). Furthermore, the nuclear level of YAP increased in *Mst1*^−/−^ BMDCs ([Figure S1B](#SM1){ref-type="supplementary-material"}). Thus, these results suggest that Hippo pathway is activated in GM-CSF-induced BMDCs and has indispensable roles in GM-CSF-induced activation and maturation of DCs. To clarify the involvement of Mst1 in the activation and maturation of DCs, we compared cell surface expression levels of costimulatory and MHC II molecules, activation/maturation-related cell surface markers, between *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs. There was a greater proportion of *Mst1*^−/−^ BMDCs with high expression of the costimulatory molecules CD40, B7.1, and B7.2 ([Figure 1A](#F1){ref-type="fig"}). Similarly, the percentage of MHC II^hi^ *Mst1*^−/−^ BMDCs was significantly higher than that of MHC II^hi^ *Mst1*^+/+^ BMDCs ([Figure 1A](#F1){ref-type="fig"}). To further investigate the role of Mst1 in the regulation of cell surface expression of costimulatory and MHC II molecules, we compared expression levels of these cell surface molecules in *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs at 4, 6, 8, and 10 days after initiation of culture. *Mst1*^−/−^ BMDCs showed an increase in the expression of the costimulatory molecules, CD40, B7.1, and B7.2, and MHC II in a time-dependent manner compared with that of *Mst1*^+/+^ BMDCs ([Figure 1B](#F1){ref-type="fig"}). To investigate whether *Mst1*^−/−^ MoDCs display phenotypic differences *in vivo*, we compared expression levels of cell surface costimulatory molecules on MCs in the MLN of *Mst1*^+/+^ and *Mst1*^−/−^ mice. The number of migratory MCs was higher in the MLN of *Mst1*^−/−^ mice ([Figure S2A](#SM1){ref-type="supplementary-material"}). Moreover, *Mst1*^−/−^ MCs showed higher expression level of B7.2 than *Mst1*^+/+^ MCs ([Figure S2B](#SM1){ref-type="supplementary-material"}). {#F1} Decreased Ag-uptake activity and the level of mannose receptor (MR) are the hallmarks of mature DCs. Dextran is captured by pinocytosis and MR-mediated endocytosis ([@B5], [@B35], [@B36]). To compare the endocytic activity between *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs, we measured the activity of MR-mediated FITC-dextran uptake. *Mst1*^−/−^ BMDCs showed decreased MFI and percentage of FITC-dextran^+^ cells in a flow cytometry analysis, suggesting a reduced antigen uptake activity of *Mst1*^−/−^ BMDCs ([Figures 2A,B](#F2){ref-type="fig"}). In agreement with this data, the expression level of MR (CD206) was lower on *Mst1*^−/−^ BMDCs than on *Mst1*^+/+^ BMDCs ([Figures 2C,D](#F2){ref-type="fig"}), indicating that Mst1-deficiency induced maturation of GM-CSF-derived BMDCs with the reduced endocytic activity. {#F2} DC maturation and activation are known to affect the expression of a series of inflammatory genes; as a result, they modulate subsequent immune responses ([@B6]). Therefore, we hypothesized that Mst1-deficiency leads to an overproduction of inflammatory cytokines. To explore this hypothesis, we compared mRNA expression and secretion levels of inflammatory cytokines between *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs. The mRNA expression levels of IL-6, IL-12p40, IL-23p19, and TNF-α levels were higher in *Mst1*^−/−^ BMDCs than in *Mst1*^+/+^ BMDCs ([Figure 3A](#F3){ref-type="fig"}). To confirm these increased mRNA expression levels at the protein level, we compared the production of these inflammatory cytokines by *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs stimulated by CpG DNA to amplify activation. Consistent with mRNA expression levels, IL-12p40 and IL-23 production levels were notably higher in CpG-stimulated *Mst1*^−/−^ BMDCs than in *Mst1*^+/+^ BMDCs ([Figures 3B,C](#F3){ref-type="fig"}). We excluded the possibility that the increased production of inflammatory cytokines of *Mst1*^−/−^ BMDCs stimulated through TLR may be due to an increase in TLR expression of *Mst1*^−/−^ BMDCs by determining the intracellular TLR9 expression levels of *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs ([Figure S3](#SM1){ref-type="supplementary-material"}). {#F3} Taken together, Mst1-deficiency in BMDCs induced higher expression levels of cell surface molecules and proinflammatory cytokines, suggesting that Mst1 negatively regulates the activation and maturation of BMDCs. *Mst1*^−/−^ BMDCs Have a Greater Allostimulatory Capacity Than *Mst1*^+/+^ BMDCs -------------------------------------------------------------------------------- To investigate whether hyperactivated *Mst1*^−/−^ BMDCs induce a stronger activation of T cells, we compared the capacity of *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs to stimulate T cells in an *in vitro* allogeneic coculture. As the activation of *Mst1*^−/−^ BMDCs was enhanced in a time-dependent manner ([Figure 1B](#F1){ref-type="fig"}), we replated *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs, generated after 8 days of culture, for a further 24 h in the presence of GM-CSF ([Figure 4A](#F4){ref-type="fig"}) to enhance the allogeneic activity of BMDCs. As expected, *Mst1*^−/−^ BMDCs enhanced allogeneic T cell proliferation ([Figure 4B](#F4){ref-type="fig"}). Moreover, CD4 T cells cocultured with *Mst1*^−/−^ BMDCs comprised a greater proportion of the activated CD44^hi^ T cell subset ([Figure 4C](#F4){ref-type="fig"}). As CD4 T cells strongly produce IL-2 upon activation ([@B37]), we measured IL-2 production levels of CD4 T cells stimulated by *Mst1*^+/+^ or *Mst1*^−/−^ BMDCs. The percentage of IL-2-producing T cells and secretion level of IL-2 were higher in CD4 T cells cocultured with *Mst1*^−/−^ BMDCs than with *Mst1*^+/+^ BMDCs ([Figures 4D,E](#F4){ref-type="fig"}). Accordingly, Mst1-deficiency in BMDCs induced the activation of allogeneic T cells to a greater extent than *Mst1*^+/+^ BMDCs *in vitro*. Collectively, these results show that Mst1 plays an important role in determining the phenotypic and functional activation degree of BMDCs. {#F4} Mst1 Silencing in BMDCs Exhibits the Hyperactivated Phenotype Similar to That Observed in *Mst1*^−/−^ BMDCs ----------------------------------------------------------------------------------------------------------- Next, we confirmed phenotype of the hyperactivated *Mst1*^−/−^ BMDCs in an Mst1-specific siRNA-mediated knockdown system. The efficiency of Mst1 silencing was validated by semi-quantitative RT-PCR ([Figure 5A](#F5){ref-type="fig"}, top) and western blot analysis ([Figure 5A](#F5){ref-type="fig"}, bottom). Silencing of the Mst1 gene in BMDCs increased the surface expression levels of CD40 and MHC II molecules ([Figure 5B](#F5){ref-type="fig"}). The mRNA expression levels of IL-1β, IL-6, IL-23p19, and TNF-α were increased in Mst1-knockdown BMDCs ([Figure 5C](#F5){ref-type="fig"}). In agreement with these data, secretion of these proinflammatory cytokines was enhanced in Mst1-knockdown BMDCs, with IL-23 and TNF-α levels significantly elevated ([Figures 5D,E](#F5){ref-type="fig"}). Accordingly, silencing of Mst1 promoted BMDC hyperactivation, similar to the hyperactivation observed in *Mst1*^−/−^ BMDCs. To perform these Mst1-knockdown experiments, we transfected siRNA targeting Mst1 into BMDCs differentiated after 8 days of culture, which are different from *Mst1*^−/−^ BMDCs in which Mst1 is absent in cells before the differentiation of BM cells into BMDCs. Differentiation rates and cell numbers of BM cells into BMDCs between *Mst1*^+/+^ and *Mst1*^−/−^ cells were similarly obtained ([Figures S4A,B](#SM1){ref-type="supplementary-material"}), which means that *Mst1*^−/−^ BMDCs normally differentiate from BM cells. Furthermore, both *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs induced by GM-CSF had no difference in the percentages of CD11c^+^B220^+^ pDC population ([Figure S4C](#SM1){ref-type="supplementary-material"}). It convinced us to exclude the possibility that BMDC hyperactivation is due to an effect of Mst1-deficiency on cell development *in vitro*. These results are consistent with the idea that Mst1-deficiency in differentiated BMDCs, and not in precursors, gives rise to their hyperactivation. Taken together, these data suggest that endogenous Mst1 in differentiated BMDCs suppresses their hyperactivation. {#F5} Hyperactivated Phenotype Induced by Loss of Mst1 in BMDCs Is Not Due to a Change in GM-CSFR Expression ------------------------------------------------------------------------------------------------------ GM-CSF is involved in the inflammatory phenotype of DCs ([@B4], [@B12], [@B13]). The α subunit of GM-CSF receptor (GM-CSFRα) recruits GM-CSFRβc ([@B38]), which results in the initiation of GM-CSF signal transduction and activation of downstream pathways followed by regulation of the development, survival, and activation of GM-CSF-induced DCs ([@B18]). We first compared the absolute cell numbers of monocytes, the main precursor of BMDCs, in BM of *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs. Cell numbers of monocytes were comparable in BM from *Mst1*^−/−^ and *Mst1*^+/+^ mice ([Figure 6A](#F6){ref-type="fig"}). Next, we checked the expression level of cell surface GM-CSFRβc, which transmit GM-CSF signaling, to check whether the hyperactivation of *Mst1*^−/−^ BMDCs was due to hyperresponsiveness of monocytes to GM-CSF. The expression of cell surface GM-CSFRβc was slightly increased in *Mst1*^−/−^ monocytes but not significantly ([Figure 6B](#F6){ref-type="fig"}). Mst1-knockdown BMDCs showed comparable mRNA expression level of GM-CSFRα ([Figure 6C](#F6){ref-type="fig"}) and the cell surface expression level of GM-CSFRβc [(Figure 6D)](#F6){ref-type="fig"}. As expected, the mRNA expression level of IL-23p19 increased in Mst1-knockdown BMDCs, regardless of the presence of GM-CSF ([Figure 6E](#F6){ref-type="fig"}). These data suggest that responsiveness to GM-CSF does not play a role in the hyperactivation of BMDCs induced by the loss of Mst1. {#F6} Mst1-Deficiency Causes Hyperactivation of BMDCs Through Enhanced Akt1/c-myc Signaling ------------------------------------------------------------------------------------- Previous reports showed that Mst1 antagonizes Akt1 activation in various cell types ([@B39]--[@B41]), including regulatory T cells in which FoxO1/3 proteins, directly and indirectly regulated by Mst1, are involved in their development ([@B29]). We hypothesized that Mst1-deficiency triggers the hyperactivation of GM-CSF-induced BMDCs by regulating Akt1 activity. To test this hypothesis, we investigated Akt1 activity in Mst1-deficient BMDCs after 7 days in culture. Consistent with our hypothesis, the phosphorylation of Akt1 increased in *Mst1*^−/−^ BMDCs compared to that in *Mst1*^+/+^ BMDCs ([Figure 7A](#F7){ref-type="fig"}). Akt1-mediated regulation of c-myc expression plays a crucial role in the determination of an inflammatory phenotype of GM-CSF-induced macrophages ([@B42]), and contributes DC development, regulating survival and maturation ([@B43]). Therefore, we compared the protein level of c-myc in *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs. After 7 days in culture, the protein level of c-myc increased in *Mst1*^−/−^ BMDCs ([Figure 7A](#F7){ref-type="fig"}). We confirmed the gene induction of c-myc in Mst1-knockdown BMDCs. The mRNA expression level of c-myc also increased in Mst1-knockdown BMDCs compared to that in cells transfected with a scrambled control ([Figure 7B](#F7){ref-type="fig"}). To investigate whether Akt1 is a potent inducer of c-myc, *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs after 7 days in culture were further cultured in the presence of GM-CSF and MK-2206. The treatment of BMDCs with MK-2206 decreased the phosphorylation of Akt1, and partially reversed the protein level of c-myc in *Mst1*^−/−^ BMDCs ([Figure 7C](#F7){ref-type="fig"}). Together, these results indicate that Akt1 is involved in the de novo synthesis of c-myc in Mst1-deficient DCs. {#F7} Next, to determine whether the Akt1/c-myc axis is responsible for the hyperactivation of *Mst1*^−/−^ BMDCs, we compared expression levels of the costimulatory molecules, B7.1 and B7.2, on the cell surface of *Mst1*^−/−^ BMDCs treated with a vehicle control or the indicated inhibitors. As Akt1 and c-myc are involved in the survival of DCs, we excluded the dead cells in this comparison. *Mst1*^−/−^ BMDCs treated with inhibitors of c-myc reversed the increase in expression levels of the costimulatory molecules in *Mst1*^−/−^ BMDCs although MK-2206 failed to decrease expression levels of the costimulatory molecules in *Mst1*^−/−^ BMDCs ([Figure 7D](#F7){ref-type="fig"}). To further investigate whether the Akt1/c-myc axis mediates the hyperactivation of BMDCs induced by the loss of Mst1, the mRNA expression level of IL-23p19 was compared in Mst1-knockdown BMDCs treated with the vehicle control or the indicated inhibitors. The mRNA expression level of IL-23p19 in Mst1-knockdown BMDCs treated with inhibitors of Akt1 and c-myc was downregulated compared to that in Mst1-knockdown BMDCs treated with the vehicle control ([Figure 7E](#F7){ref-type="fig"}). Therefore, these data suggest that the enhanced Akt1/c-myc signaling is responsible for the hyperactivation of *Mst1*^−/−^ BMDCs. Thus, Mst1 negatively regulates the Akt1/c-myc axis, which determines the inflammatory phenotype of GM-CSF-induced DCs. Discussion {#s4} ========== Given that DCs are used in vaccination, connecting innate and antigen-specific responses, understanding how the maturation and activation of DCs are regulated is important ([@B14], [@B44], [@B45]). Mst1 is a multifunctional serine/threonine kinase involved in cell proliferation, differentiation, apoptosis, and organ size regulation ([@B21]--[@B24]). Several recent studies have revealed crucial roles for Mst1 in the immune system; specifically, it regulates the survival, proliferation, trafficking, and function of T cells ([@B19], [@B20], [@B25]--[@B30]). Although previous studies have revealed that Mst1 is involved in the induction of reactive oxygen species to clear bacterial infection in macrophages ([@B46]) and in the production of IL-6 ([@B31]) and IL-12 ([@B32]) from DCs, the roles of Mst1 in the activation and maturation of MoDCs are still largely unknown. In the present study, we aimed to clarify the intrinsic role of Mst1 in the determination of the activation status of GM-CSF-induced inflammatory DCs. We found that *Mst1*^−/−^ BMDCs exhibited an increased expression of costimulatory and MHC II molecules and production of several inflammatory cytokines *in vitro*; moreover, the results of Mst1 knockdown in BMDCs are consistent with the idea that Mst1 suppresses the overexpression of several inflammatory cytokines and cell surface molecules in fully differentiated BMDCs. In conclusion, our results suggest that Mst1 negatively regulates the phenotypical and functional activation of GM-CSF-induced DCs. DCs have functional properties depending on their maturation status. Their distinctive intrinsic properties lead to maturation of different subsets ([@B2], [@B11], [@B47], [@B48]). Furthermore, the previous study showed that Mst1 is the negative regulator of proliferation in naïve T cells ([@B19]) and regulates development and function of regulatory T cells ([@B29]). To investigate whether the hyperactivation of *Mst1*^−/−^ GM-CSF-derived DCs is due to a differential development, we compared cell numbers and percentages of the CD11c^+^CD11b^+^ population in *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs. Comparable percentages and cell numbers of the CD11c^+^CD11b^+^ population at an earlier culture time were observed ([Figures S4A,B](#SM1){ref-type="supplementary-material"}). The previous study showed that GM-CSF suppresses the differentiation of pDCs ([@B49]). Consistent with the previous study, we observed that both *Mst1*^+/+^ and *Mst1*^−/−^ BMDCs induced by GM-CSF had no apparent percentage of CD11c^+^B220^+^ pDC population ([Figure S4C](#SM1){ref-type="supplementary-material"}). Thus, these data show that *Mst1*^−/−^ BMDCs from mouse BM cells normally differentiate into CD11c^+^CD11b^+^ inflammatory DCs, which suggests that Mst1 has a redundant role in the *in vitro* differentiation of BMDCs by GM-CSF. Taken together, these data demonstrate that BMDC hyperactivation is not due to an effect of Mst1-deficiency on cell development *in vitro*. In the present study, we did not observe any abnormal death of Mst1-KO mice as a result of a spontaneous autoimmune response *in vivo*, which seems inconsistent with the *in vitro* hyperactivation of *Mst1*^−/−^ GM-CSF-induced DCs. Previous reports have reported a systemic T cell lymphopenia due to defects in homing and survival in Mst1-KO mice ([@B20], [@B25], [@B50]), and Mst1-mutated patients with impaired T cell survival that resulted in primary T cell immunodeficiency ([@B26]). However, a recent study has revealed that DC-specific (CD11c-Cre) conditional Mst1-KO mice exhibit overproduction of IL-6 by DCs, inducing Th17 differentiation and autoimmune response *in vivo* ([@B31]). We speculate that the inconsistency between the normal phenotype of Mst1-KO mice and the hyperactivation of *Mst1*^−/−^ BMDCs *in vitro* may have several explanations. First, Mst1-KO mice have severe T cell lymphopenia in peripheral lymphoid organs (data not shown), which is consistent with the previous reports ([@B19], [@B20]). Second, consistent with a previous report ([@B32]), we did not observe any critical differences in numbers and phenotypic changes of DCs in the spleen of Mst1-KO mice ([Figure S5](#SM1){ref-type="supplementary-material"}). Finally, the critical roles of GM-CSF in inflammation rather than steady state *in vivo* might explain the absence of spontaneous autoimmune responses in Mst1-KO mice. These findings shed light on our understanding of the physiological role of Mst1 in the regulation of activation status of GM-CSF-induced DCs. Mst1 dampens the hyperactivation of BMDCs by regulating the Akt1/c-myc axis rather than GM-CSFR expression. A previous report showed that Mst1 antagonizes Akt1 activation in regulatory T cells in which FoxO1/3 proteins that are directly and indirectly regulated by Mst1 act on their development ([@B29]). Thus, we hypothesized that Mst1-deficiency triggers an enhanced activity of Akt1, which results in the hyperactivation of BMDCs. As expected, phosphorylation of Akt1 was increased in *Mst1*^−/−^ BMDCs ([Figure 7A](#F7){ref-type="fig"}), and the blockade of Akt1 activity reversed the hyperactivation of Mst1-knockdown BMDCs ([Figure 7E](#F7){ref-type="fig"}). Akt1 is also known for controlling the cellular metabolism. Activation-induced T cell metabolic reprogramming ([@B51]) and glycolytic metabolism in TLR-activated DCs ([@B52]) have been suggested, with clear evidence of the involvement of cellular metabolism in immune cell function. The PI3K/Akt1-induced transcription factor, c-myc, is a regulator of cellular metabolism, especially glycolysis, and thereby of the activation of macrophages ([@B42]). Moreover, c-myc, the downstream effector of mTORC1, is involved in the development of DCs ([@B43]). Thus, we tested whether c-myc is involved in the hyperactivation of *Mst1*^−/−^ BMDCs. Consistent with our hypothesis, we demonstrated elevated protein ([Figure 7A](#F7){ref-type="fig"}) and mRNA ([Figure 7B](#F7){ref-type="fig"}) levels of c-myc in Mst1-deficient BMDCs. Inhibitors of c-myc reversed the hyperactivation of Mst1-KO ([Figure 7D](#F7){ref-type="fig"}) and knockdown ([Figure 7E](#F7){ref-type="fig"}) in BMDCs. Although previous studies showed that PI3K/Akt signaling regulates GM-CSF-induced proliferation, survival, and development of DCs ([@B18]), we observed a normal development and yield of CD11b^+^CD11c^+^ *Mst1*^−/−^ BMDCs in an *in vitro* culture ([Figure S4](#SM1){ref-type="supplementary-material"}), which means that the Mst1/Akt1/c-myc pathway has a redundant role in the proliferation and differentiation of BM precursor cells into BMDCs, whereas it is required to maintain a moderate maturation phenotype of GM-CSF-induced DCs. Collectively, Mst1-deficiency triggers the hyperactivation of BMDCs through the overactivation of GM-CSF-induced Akt1/c-myc signaling pathway. We observed that the treatment of Mst1-deficient BMDCs with Akt1 inhibitor partially decreased the protein level of c-myc ([Figure 7C](#F7){ref-type="fig"}) and also failed to reverse expression levels of the costimulatory molecules ([Figure 7D](#F7){ref-type="fig"}), which means that the blockade of Akt1 activity was not sufficient to suppress c-myc-mediated hyperactivation in GM-CSF-stimulated DCs. The recovery of increased costimulatory B7 expression levels in *Mst1*^−/−^ BMDCs might be required for complete inhibition of c-myc expression, even though the modest reduction of c-myc level was sufficient to reverse the mRNA expression level of IL-23p19, a proinflammatory cytokine. Thus, although we have elucidated one crucial mechanism underlying inhibition of hyperactivation of GM-CSF-stimulated DCs, we expect that unknown other mediators might also exist. In summary, we have demonstrated that Mst1 dampens the hyperactivation of DCs via downregulation of the Akt1/c-myc axis in response to GM-CSF, suggesting that Mst1 in mouse inflammatory DCs correlates with GM-CSF-driven disease state. The Mst1/Akt1/c-myc pathway in the regulation of DC activation will give a new insight into understanding of the way how Mst1 regulates appropriate immune responses. These findings shed light on how the maturation and activation of DCs are regulated by a novel endogenous serine/threonine kinase factor. Furthermore, since GM-CSF-induced DCs are a key player in inflammation and autoimmunity ([@B17]), Mst1 can be a new and considerable therapeutic target in the treatment of GM-CSF-derived inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease ([@B17], [@B53]). Data Availability {#s5} ================= The datasets generated for this study are available on request to the corresponding author. Ethics Statement {#s6} ================ The experimental protocols adopted in this study were approved by the Institutional Animal Care and Use Committee of Korea University. Author Contributions {#s7} ==================== K-MC designed and performed all the experiments. K-MC, MK, and TK analyzed and interpreted the experimental results. H-JJ maintained the mice used in this study. E-JC played a role in discussing the results and provided crucial Mst1-related reagents. K-MC and TK collaborated on the manuscript writing. TK supervised the study and corrected the manuscript. Conflict of Interest Statement ------------------------------ The 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. We thank Dr. Dae-Sik Lim (Korea Advanced Institute of Science and Technology, Korea), M.Sc. Jae Hwan Kim and Dr. Ji-Yun Lee (Korea University, Korea) for providing valuable reagents and technical assistance. **Funding.** This work was supported by the National Research Foundation of Korea (NRF) grant (NRF-2017R1A2B2009442). Supplementary Material {#s8} ====================== The Supplementary Material for this article can be found online at: <https://www.frontiersin.org/articles/10.3389/fimmu.2019.02142/full#supplementary-material> ###### Click here for additional data file. [^1]: Edited by: Elodie Segura, Institut Curie, France [^2]: Reviewed by: Loredana Saveanu, Institut National de la Santé et de la Recherche Médicale (INSERM), France; Chaohong Liu, Huazhong University of Science and Technology, China [^3]: This article was submitted to Antigen Presenting Cell Biology, a section of the journal Frontiers in Immunology

Realistically recreate the set of your children&65533;s favourite animated series, UNDERWATER! Nickelodeon brings you Dora the Explorer aquarium ornaments and accessories. Complete your collection with Dora&65533;s house, and make this detailed and colourful decoration part of your very own underwater creation. A hiding place for tiny fish or simply a decorative artifact, this piece is sure to put a big smile on your youngster&65533;s face. COLLECT THE ENTIRE SET!!!, while supplies last. (Approximately 4&65533;L x 4&65533;W x 3&65533;H).

Categories The Brain Boosting Power of Walking “All truly great thoughts are conceived by walking” Friedrich Nietzche There’s a harmonious effect that happens when we walk and think at the same time. Walking in a natural environment can improve our attention. Our working memory is also better when we walk at a pace of our own choosing. A brisk walk will produce more brain cells. What’s even more amazing is that stimulation from an enriching environment will increase the connectivity between those brain cells. Those connections will also be more stable. Our consciousness can be shaped more subtly outside in nature. It’s a much more proactive process when we are not distracted by the intrusions of an urban environment. “It is you who decides to examine a plant more closely or to focus on a far flung horizon one moment, then perhaps to lean up against a tree the next. This internally driven sequence of events will then have the additional benefit of restoring control, of giving you a longer time frame in which to develop and deepen your thoughts” Walking Therapy takes advantage of all these brain benefits and adds in even more. There’s an opportunity to think (and feel) more deeply and powerfully as we walk together side by side.

Q: Box: How to download a file to a specific folder? I'm using java sdk provided by box and I saw in the documentation, how to download a file: String fileID = "11111"; BoxFile file = new BoxFile(api, fileID); BoxFile.Info info = file.getInfo(); FileOutputStream stream = new FileOutputStream(info.getName()); file.download(stream); stream.close(); I'm able to download it, but it's putting everything inside my project structure and I want to give a specific path so I can get all my outputs there. A: the BoxFile documentation does not provide an attribute for the file path, where to store the downloaded file. But the API for the FileOutPutStream is providing a solution for this: new FileOutputStream("this/path/to/my/file.txt"); You can find all possible values for the constructor of this class under https://docs.oracle.com/javase/8/docs/api/?java/io/FileOutputStream.html

Agora que as taxas de juro dos novos créditos à habitação estão nos mínimos mais baixos de que há registo — 1,41% em maio passado, em média, segundo o Banco de Portugal —, quem compra casa procura outras vantagens além dos custos reduzidos. Maximizar o montante financiado pode ser uma delas. A maioria dos 29 grupos bancários que preveem conceder financiamento para a compra de casa não empresta mais de 80% do valor do imóvel. Todavia, nos últimos meses, algumas entidades começaram a subir o montante máximo financiado. Agora, alguns consumidores podem conseguir que um banco lhe financie a totalidade do valor de compra. O EuroBic empresta até “100% do valor do investimento”, desde que esse montante não ultrapasse “90% do valor da avaliação” do imóvel, de acordo com o preçário da instituição, atualizado a 3 de julho de 2018. Assim, o EuroBic pode emprestar 100 mil euros a um cliente que queira comprar uma habitação própria por 100 mil euros, se a avaliação bancária apontar para um valor superior a 111.111,11 euros, por exemplo. No início deste mês de julho, entrou em vigor uma recomendação do Banco de Portugal que impõe um empréstimo máximo de 90% do menor entre a avaliação e preço de compra nos financiamentos para aquisição de habitação própria. O EuroBic não está sozinho nos empréstimo superiores a 80% do valor da casa. O Crédito Agrícola e a sucursal portuguesa da Unión de Créditos Inmobiliarios (UCI) fornecem crédito até 90% do preço de aquisição, desde que o valor de avaliação bancária seja igual ou superior a esse montante. O Santander Totta também pode emprestar até 90% do preço de compra, mas atribui um teto máximo de 85% do valor de avaliação. Quem dá crédito à habitação superior a 80% do preço de compra? Foram considerados os empréstimos a taxa variável com garantia hipotecária para compra de habitação própria no regime geral. Há pouco mais de dois anos, nenhum emprestava mais de 85% do valor do imóvel. Instituição Taxa de juro Montante máximo financiado EuroBic Euribor 6 ou 12 meses + 1,49% a 3,10% 90% do valor de avaliação, até 100% do valor de compra Crédito Agrícola Euribor 12 meses + 1,20% a 2,65% 90% do valor do imóvel (o menor entre avaliação e compra) UCI Euribor 6 meses + 1,75% a 2,75% 90% do valor do imóvel (o menor entre avaliação e compra) Santander Totta Euribor 12 meses + 1,15% a 2,50% 85% do valor de avaliação, até 90% do valor de compra Banco BPI Euribor 12 meses + 1,50% a 4,10% 85% do valor do imóvel (o menor entre avaliação e compra) Banco CTT Euribor 12 meses + 1,20% a 2,10% 85% do valor do imóvel (o menor entre avaliação e compra) Caixa Geral de Depósitos Euribor a 12 meses + 1,30% a 5,35% 80% do valor de avaliação, até 90% do valor de compra Millennium bcp Euribor 12 meses + 1,25% a 3,00% 80% do valor de avaliação, até 90% do valor de compra Novo Banco Euribor 12 meses + 1,25% a 5,00% 80% do valor de avaliação, até 90% do valor de compra Fonte: bancos a 13 de julho de 2018. É possível que, em situações específicas, outros bancos além dos que estão na lista anterior emprestem mais de 80% do valor da habitação. É o caso, por exemplo, dos empréstimos dos clientes que adquirem imóveis nas carteiras dos bancos financiadores. A lista anterior inclui algumas das instituições financeiras que propõem os spreads — a margem de lucro na operação — mais baixos da banca, como o Santander Totta (desde 1,15%), o Crédito Agrícola (1,20%) e o Banco CTT (1,20%), mas exclui outras, como o Bankinter, que tem um spread mínimo de 1,15%, mas financia até 80% do valor do imóvel.

Explanation: What makes comet tails so colorful? This photograph of Comet Hyakutake was taken the night of April 18th and highlights different components of the tail. The gold and red tail features are dust, made predominately of little bits of rock and carbon. The dust tail shines by reflecting sunlight. Extending past the dust tail is the comet's ion tail, shown here glowing in blue. The ion tail is composed mostly of ions of water, carbon monoxide, and cyanogen. The ion tail glows by emitting light when elections re-combine with electrically charged ions to make uncharged molecules. The photograph was taken just north of Kansas City, Missouri, USA.

208 Okla. 192 (1953) 255 P.2d 277 BOETTCHER OIL & GAS CO. et al. v. LAMB et al. No. 35567. Supreme Court of Oklahoma. March 17, 1953. Mont R. Powell, Sam Hill, and William R. Saied, Oklahoma City, for petitioners. Kerr, Lambert, Conn & Roberts, Ada, and Mac Q. Williamson, Atty. Gen., for respondents. *193 WELCH, J. In this case it appears that on the 20th day of September, 1951, John David Lamb, deceased, was employed by the Boettcher Oil & Gas Company as a welder and mechanic; that on said day he suffered a heart injury from which he died. On November 9, 1951, Lois L. Lamb, wife of deceased, filed a claim for compensation before the State Industrial Commission on her behalf, and on behalf of two minor dependent children of deceased against Boettcher Oil & Gas Company, employer of deceased, and the State Insurance Fund. Compensation is claimed under the provisions of Title 85, chap. 2, S.L. 1951, pp. 267 to 270, inclusive, commonly called the Death Benefit Act. The trial commissioner, in substance, found: That on the 20th day of September, 1951, John David Lamb, deceased, while in the employ of Boettcher Oil & Gas Company sustained an accidental personal injury consisting of an injury to his heart; that decedent left surviving him Lois L. Lamb, his widow, David Harold Lamb, a son age 16 years, and Linda Kay Lamb, a daughter age 8 years, all of whom were dependent upon deceased for their support, and that said persons are entitled to receive compensation in the sum of $13,500 to be divided proportionately between them, each to receive $4,500. An award was entered accordingly which was sustained on appeal to the commission en banc. Boettcher Oil & Gas Company and State Insurance Fund, hereinafter referred to as petitioners, bring the case here to review this award and rely solely to vacate the award on the ground that deceased sustained no accidental injury while in the employ of Boettcher Oil & Gas Company; that his death was not caused by an accidental injury, but was due to other causes. This assignment requires a review of the evidence. The evidence shows that deceased, on the 20th day of September, 1951, while in the employ as above stated, sustained an injury to his heart caused while cranking a motor. A fellow employee testified in behalf of respondent, in substance, as follows: On the morning of the day Mr. Lamb sustained his injury he and Mr. Lamb were engaged in overhauling a motor; that they completed that task about noon of that day; that at about 1:30 p.m., Mr. Lamb attempted to start the motor for the purpose of placing it on a pump. It was necessary to crank the motor by the use of a hand crank. The motor was hard to crank, it required very heavy lifting to turn the motor over. After he had succeeded in turning the motor over about five times he stepped back and shrugged and twisted his shoulders and stated that he was suffering severe pain in his chest. The witness then started to crank the motor, but was unable to get it started, and he and Mr. Lamb eventually succeeded in starting the motor. About 20 minutes after the motor was started Mr. Lamb, this witness, and two other employees started over to another lease owned by the Boettcher Oil & Gas Company. The lease was about three quarters of a mile from the place where the motor was cranked. In arriving at that lease Mr. Lamb cranked another and smaller motor. This task he completed about 3:30 p.m. Mr. Lamb, the witness, and two other employees then started to play dominoes. Just as the game started Mr. Lamb arose, walked to the door and stated that he could not get his breath, and that he was still suffering great pain in his chest. He was then taken to a hospital at Ada, Oklahoma, for treatment *194 and examination. An intern met him at the hospital and obtained a history of the case from him, reduced it to writing and delivered it to the doctor. The intern testified at the hearing as to the history obtained which is substantially the same as above detailed. The doctor testified that he first saw John David Lamb at the Valley View Hospital at Ada, Oklahoma, at about 4 o'clock in the afternoon of September 20, 1951. He was then in a dying condition. He was pulseless, but had a slight heartbeat. He was given oxygen and other stimulants in an effort to revive him, but without success and that Mr. Lamb died; that he was furnished a history of the case by the intern, and from such history, his examination and experience as a physician, expressed the opinion that Mr. Lamb's death was caused by overexertion, that it produced a coronary occlusion which means that one or more of the arteries was blocked by an embolus. The doctor further testified: "Q. What, in your opinion, Doctor, was the thing that produced his death? A. Well, the coronary occlusion produced the death, but when you go to classifying them, you have a little bit of difficulty, because everything depends on what a person means by accident or injury. If you mean by a blow or something like that, then it — he didn't receive a blow or anything of that nature. The overexertion produced a marked increase in the heart beat, an exertion of the heart, which tore an embolus loose. If it lodges in the coronary arteries, then you may have sudden death. If it lodges away in the stomach or in the chest muscles or in the legs, then you may have a little pain for a day or two, and you are over it. But your heart, you have a different matter. "Q. Then, Doctor, if I understand your explanation, it was the strain and stress under which he was working that produced the injury to that artery? A. That's right." No other physician testified in the case. Other employees of petitioner Boettcher Oil & Gas Company, however, testified that they did not hear respondent complain of any pain in his chest until they started playing dominoes. The evidence further shows that deceased had worked for petitioner Boettcher Oil & Gas Company doing the same kind of work for about three years prior to September 20, 1951, and that he had never complained of any pain in his chest or any kind of heart trouble. We think the evidence above detailed is sufficient to sustain the finding of the commission that the injury sustained by deceased constituted an accidental injury within the meaning of the Workmen's Compensation Act. We have heretofore held that an injury sustained by a workman to his heart caused by overexertion and strain constitutes an accidental injury within the meaning of the Workmen's Compensation Act. Carden Mining & Milling Co. v. Yost, 193 Okla. 423, 144 P.2d 969; Clarksburg Paper Co. v. Roper, 196 Okla. 504, 166 P.2d 425; Gulf Oil Corporation v. Rouse, 202 Okla. 395, 214 P.2d 251. In Producers Drilling Co. v. Percival, 207 Okla. 17, 246 P.2d 374, we held: "An injury sustained by an employee consisting of a strain to his back while engaged in cranking a motor constitutes an accidental injury within the meaning of the Workmen's Compensation Act, 85 O.S. 1951, § 3, subd. 7." We think the evidence also sufficient to sustain the finding of the commission that Mr. Lamb's death occurred from a heart injury sustained by him on the 20th day of September, 1951, while in the employ of petitioner Boettcher Oil & Gas Company. Award sustained. HALLEY, C.J., JOHNSON. V.C.J., and CORN, DAVISON, O'NEAL, WILLIAMS, and BLACKBIRD, JJ., concur.

ALBANY — Some uptown residents want to halt dense development in their neighborhoods that they say isn’t following proper regulations, will drastically change the character of the area, and put stress on the city’s infrastructure. Others are pushing back, saying those in opposition simply don’t want development in their backyards, or things to change in Albany. They argue that denser development will make Albany more walkable and increase the tax base. Eagle Hill resident Vincent Riguso has launched a ‘Stop the Stories’ campaign calling for a moratorium on development in Albany. It is supported by other residents opposed to recent developments and named to reflect their concerns over building heights. He questioned why the new Unified Sustainable Development Ordinance, or USDO, isn’t keeping development consistent with existing neighborhood characteristics and isn’t considering impacts from the development on traffic, infrastructure and environmental concerns. “It feels as if the goal, in actuality, is to bring in loads of renters at the expense of those of us who have been here for decades, if not generations, and who have been contributing to the community in all kinds of ways,” Riguso wrote in a letter to city officials recently. The growing vocal opposition has prompted Walkable Albany founder Andrew Neidhardt to organize a counter rally to provide a different perspective. “We have seen recently in the city that folks are opposing developments that are creating walkable communities in our city. They’re opposing it simply because it’s a change to the way things were,” he said. “We just want to be a voice in favor of development where it’s appropriate and it’s improving walkability for people.” Both groups are expected to converge around 6 p.m. Monday at City Hall prior to the regular Common Council meeting. Many of the proposed projects in Albany have brought up similar concerns among residents – increased traffic, possible exacerbation of stormwater issues, and destruction of the character of their neighborhoods. Key among those concerns is the height of the buildings. The proposed six-story building at 1211 Western Ave. is one of several projects that has drawn the ire of the Stop the Stories group. “We don’t want to stop development. That’s the last thing we want to do,” Riguso said. He said a building of that size doesn’t belong in his neighborhood. The Western Avenue project would demolish an existing three-story office building to make way for a six-story, 137-unit apartment complex. It would be located next to the University at Albany’s administration building, which is four-stories, and is next to a gas station and strip mall along Western. Opponents also suggest that the building material creates a fire hazard because it’s a wood structure. However, Albany Fire Chief Joseph Gregory said the projects are up to federal, state and local code and he’s approved the plans for the Western Avenue project. The site is zoned for up to five stories and the developer plans to install a blue or green roof as part of an incentive that will allow another story. Albany Planning Commissioner Chris Spencer said previous zoning would have allowed for a building up to 85 feet, which is roughly eight stories. The additional story incentive offered through installing green or blue roofs – those with either vegetation on top to absorb rainfall or retention tanks to collect water until it can be released during dry weather – has become popular among developers looking to make a proposal financially viable. Each new development’s stormwater runoff can be no more than what would come from the site undeveloped during a 10-year storm, Albany Water Department Commissioner Joseph Coffey said. That means each project is doing “significant” stormwater detention, meanwhile the city continues to invest millions in stormwater management efforts from diversion and detention to new technology for monitoring and management, he said. “We have requirements that we have to meet with best management projects as part of our Combined Sewer Overflow permit, and we’re meeting those,” Coffey said. “They are factored into our reviews of every one of those projects, and if they can’t be done, we can’t approve the project.” Common Councilperson Judy Doesschate has proposed postponing the blue/green roof incentive until at least the end of June 2020 to determine whether it's benefiting the city. The planning department is proposing something similar, but the moratorium isn’t as long. “If we’re getting no additional benefit from this blue roof or green roof technology, why are we upsetting the general scheme of the USDO with regard to what we already determined were appropriate height requirements for each individual zone?” Doesschate said. She said the multi-building, mixed-use project proposed for 563 New Scotland Ave. will rise as high as five stories, with one of its buildings contrasting with the majority of the one and two-story buildings in the neighborhood. It is across from St. Peter’s Hospital. The area is zoned for buildings to be as high as 3 ½ stories, but the developer is installing a green roof and has received a variance to allow for five stories. Spencer said the planning and the water departments are assessing the benefits of the mechanisms but noted the water department does see value in them. Development overall can benefit the city, he said. “Adding development and growing the tax base has benefits for people’s property taxes, for the services we can provide and the quality we can have throughout the city,” Spencer said. “You can’t tax your way out of things, you have to grow your way out.” Doesschate cautioned that with developers receiving tax breaks, the city gets a fraction of the tax money due for several years before the payment-in-lieu-of-taxes, or PILOT, expires. The city receives at least the taxes due based on the undeveloped property’s value, but taxes on the improvements are phased in depending on the agreement.

El acuerdo es por 9 millones de dólares (1,2 millones son para Cerro Porteño y a Racing le quedarán 7,8 millones) y restan definirse detalles del contrato y ver la documentación necesaria por parte del jugador. Atlanta United, dirigido por Gerardo Martino, jugará su primera temporada en la Major League Soccer y ya contrató a otro paraguayo, Miguel Almirón, de Lanús, como una de sus principales figuras. Según Martino, los dos futbolistas paraguayos son los mejores extranjeros en el torneo argentino en la temporada 2016 y cuenta con ambos para formar una delantera demoledora en su sueño de triunfar en la millonaria liga estadounidense.

Tag Archives: IKEA What a cool idea! IKEA wanted customers to be able to view their digital catalog on-the-go, so they introduced a new sewing kit that includes conductive thread to customize your gloves or mittens to be touchscreen-compatible. That way, you can … Continue reading →

Role of glia in K+ and pH homeostasis in the neonatal rat spinal cord. Stimulation-evoked transient changes in extracellular potassium ([K+]e) and pH (pHe) were studied in the neonatal rat spinal cords isolated from 3-13-day-old pups. In unstimulated pups the [K+]e baseline was elevated and pHe was more acid than that in Ringer's solution (3.5 mM K+, pH 7.3-7.35). The [K+]e and pHe in 3-6-day-old pups was 3.91 +/- 0.12 mM and pHe 7.19 +/- 0.01, respectively, while in 10-13-day-old pups it was 4.35 +/- 0.15 mM and 7.11 +/- 0.01, respectively. The [K+]e changes evoked in the dorsal horn by a single electrical stimulus were as large as 1.5-2.5 mM. Such changes in [K+]e are evoked in the adult rat spinal cord with stimulation at a frequency of 10-30 Hz. The maximal changes of 2.1-6.5 mM were found at a stimulation frequency of 10 Hz in 3-6-day-old animals. In older animals the [K+]e changes progressively decreased. The poststimulation K(+)-undershoot was found after a single stimulus as well as after repetitive stimulation. In 3-8-day-old pups, the stimulation evoked an alkaline shift, which was followed by a smaller poststimulation acid shift when the stimulation was discontinued. In pups 3-4-days-old the stimulation evoked the greatest alkaline shifts, i.e., by as much as 0.05 pH units after a single pulse and by about 0.1 pH units during stimulation at a frequency of 10 Hz. In 5-8-day-old pups, the alkaline shift became smaller and the poststimulation acid shift increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Q: Meaning of かまって in the following title At the end of each tankōbon, the manga DEAD Tube has always an extra page with a funny drawing/short story. Every time it has a different title. In the volume in question the title of the extra page is: かまって！？水野さん！ In the page, the character called Mizuno is just bored while their friends are away. What is the meaning of かまって in the title? I guess it comes from 構う, but I don't know how to interpret in this context. Is it related to this question? How would you translate the title? You can see the original page here. Thank you for your help! A: Basically, 「かまって！」 only has one usage at least in Standard Japanese. It is the "casual request" form of 「構{かま}う」, meaning: "Please pay (more) attention to me!" "Talk to me!" or "Look at me!" "Don't ignore me!" "Take (better) care of me!" It is most often uttered by children, followed by women. In your manga, a question mark is used, so I would interprete it as: "Mizuno looks as if she wanted to say 「かまって！」 to someone/people". I know that sounds wordy, but that would be the "feel" of the title to me. Thus. this is directly related to the other question that you linked to. 「かまってちゃん」 means an "attention-seeker" in colloquial Japanese.

Hurrah for Ants! Many of us are familiar with the children’s counting song, “The ants go marching one by one…” Scientists have now discovered that at least some species of ants do appear to be counting their steps when they go marching out in search of food. After training some desert ants to look for food in a specific location, scientists investigated how the ants could consistently locate the same source of food with seeming ease. It is known that ants will leave scent markers to guide their nest mates back to a food source. This is a rather laborious process, however, and slows the ants down. The scientists glued extensions on the legs of some ants, lengthening their strides. When these stilt-walking ants were released to search for food, they started out in the right direction, but overshot the food source every time. Scientists then cut the legs off other ants at the first joint, shortening their stride. Again the ants were released to search for food. This time they stopped short of the food source. The scientists concluded the scout probably lays a scent trail initially, but then the workers memorize the number of steps needed to arrive at the food. This is surprising evidence of relatively complicated communication from such a tiny creature. Ants have a variety of ways to tell each other not only of food, but also warn the colony of danger. As mentioned above, scents, or pheromones, are an integral part of ant communication. Weaver ants have two scent glands in their abdomens and four more in their heads. They can release one or more of these chemicals at a time to convey a variety of messages. Entomologists estimate they can employ between 10 and 20 chemical “phrases” or “words” to communicate with their nest mates. These pheromone messages may be left on a hard surface or released into the air. Weaver ants also appear to use their feces to mark their territory. It is suspected there are scent components at work here, too. A majority of species also communicate with sound. They can produce a high pitched squeak by rubbing a thin scraper located on their waist against a series of tiny parallel ridges on the adjacent abdomen. The signal is barely audible to humans. The squeaking is used for a variety of messages. Ironically, the ants are not influenced by the audible sound of the signal, but rather by the portion of the vibrations that come to them through the soil. Ants have amazingly complicated communication systems. Are these the product of random chance, or complex by design? We don’t have to guess; God has already told us “look to the ant” (Prov. 6) for instruction. We can only add, “Hurrah! Hurrah!”

Q: XNA Collision Detection - Vector2.Reflect - Help Calculating the Normal of a Circle Sprite - C# I'm having trouble wrapping my mind around how to calculate the normal for a moving circle in a 2d space. I've gotten as far as that I'm suppose to calculate the Normal of the Velocity(Directional Speed) of the object, but that's where my college algebra mind over-heats, any I'm working with to 2d Circles that I have the centerpoint, radius, velocity, and position. Ultimately I'm wanting to use the Vector2.Reflect Method to get a bit more realistic physics out of this exercise. thanks ahead of time. EDIT: Added some code trying out suggestion(with no avail), probably misunderstanding the suggestion. Here I'm using a basketball and a baseball, hence base and basket. I also have Position, and Velocity which is being added to position to create the movement. if ((Vector2.Distance(baseMid, basketMid)) < baseRadius + basketRadius) { Vector2 baseNorm = basketMid - baseMid; baseNorm.Normalize(); Vector2 basketNorm = baseMid - basketMid; basketNorm.Normalize(); baseVelocity = Vector2.Reflect(baseVelocity, baseNorm); basketVelocity = Vector2.Reflect(basketVelocity, basketNorm); } basePos.Y += baseVelocity.Y; basePos.X += baseVelocity.X; basketPos.Y += basketVelocity.Y; basketPos.X += basketVelocity.X; basketMid = new Vector2((basketballTex.Width / 2 + basketPos.X), (basketballTex.Height / 2 + basketPos.Y)); baseMid = new Vector2((baseballTex.Width / 2 + basePos.X), (baseballTex.Height / 2 + basePos.Y)); A: First the reflection. If I'm reading your code right, the second argument to Vector2.Reflect is a normal to a surface. A level floor has a normal of (0,1), and a ball with velocity (4,-3) hits it and flies away with velocity (4,3). Is that right? If that's not right then we'll have to change the body of the if statement. (Note that you can save some cycles by setting basketNorm = -baseNorm.) Now the physics. As written, when the two balls collide, each bounces off as if it had hit a glass wall tangent to both spheres, and that's not realistic. Imagine playing pool: a fast red ball hits a stationary blue ball dead center. Does the red ball rebound and leave the blue ball where it was? No, the blue ball gets knocked away and the red ball loses most of its speed (all, in the perfect case). How about a cannonball and a golf ball, both moving at the same speed but in opposite directions, colliding head-on. Will they both bounce equally? No, the cannonball will continue, barely noticing the impact, but the golf ball will reverse direction and fly away faster than it came. To understand these collisions you have to understand momentum (and if you want collisions that aren't perfectly elastic, like when beanbags collide, you also have to understand energy). A basic physics textbook will cover this in an early chapter. If you just want to be able to simulate these things, use the center-of-mass frame: Vector2 CMVelocity = (basket.Mass*basket.Velocity + base.Mass*base.Velocity)/(basket.Mass + base.Mass); baseVelocity -= CMVelocity; baseVelocity = Vector2.Reflect(baseVelocity, baseNorm); baseVelocity += CMVelocity; basketVelocity -= CMVelocity; basketVelocity = Vector2.Reflect(basketVelocity, basketNorm); basketVelocity += CMVelocity;

A new approach for extracellular spin trapping of nitroglycerin-induced superoxide radicals both in vitro and in vivo. Anti-ischemic therapy with nitrates is complicated by the induction of tolerance that potentially results from an unwanted coproduction of superoxide radicals. Therefore, we analyzed the localization of in vitro and in vivo, glyceryl trinitrate (GTN)-induced formation of superoxide radicals and the effect of the antioxidant vitamin C and of superoxide dismutase (SOD). Sterically hindered hydroxylamines 1-hydroxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine (CP-H) and 1-hydroxy-4-phosphonooxy-2,2,6,6-tetramethylpiperidin (PP-H) can be used for in vitro and in vivo quantification of superoxide radical formation. The penetration/incorporation of CP-H or PP-H and of their corresponding nitroxyl radicals was examined by fractionation of the blood and blood cells during a 1-h incubation. For monitoring in vivo, GTN-induced (130 microg/kg) O2*- formation CP-H or PP-H were continuously infused (actual concentration, 800 microM) for 90 to 120 min into rabbits. Formation of superoxide was determined by SOD- or vitamin C-inhibited contents of nitroxide radicals in the blood from A. carotis. The incubation of whole blood with CP-H, PP-H, or corresponding nitroxyl radicals clearly shows that during a 1-h incubation, as much as 8.3% of CP-H but only 0.9% of PP-H is incorporated in cytoplasm. Acute GTN treatment of whole blood and in vivo bolus infusion significantly increased superoxide radical formation as much as 4-fold. Pretreatment with 20 mg/kg vitamin C or 15,000 U/kg superoxide dismutase prevented GTN-induced nitroxide formation. The decrease of trapped radicals after treatment with extracellularly added superoxide dismutase or vitamin C leads to the conclusion that GTN increases the amount of extracellular superoxide radicals both in vitro and in vivo.

The world of esports has lately been gaining the attention of the world. The number of multiplayer games and players increase day by day. But that is not all as the prize pools for these competitive multiplayer gaming tournaments skyrocket as well. Derived from the words “electronic sports,” esports are multiplayer video games played by professional gamers competing with each other or one another. These tournaments are usually shown live for real-time viewing, and sometimes for real-money betting. The popularity of esports even got players into making it as a legitimate career path since the prize pools of each tournament can actually match, or even surpass, the earnings of professional athletes. But how are these massive prize pools accumulated? And how do each team earn from this growing industry? Massive Prize Pools Explained The reward given to players during tournaments is called a prize pool. It is collected money given to all the competing teams at the end of the tournament, with the winner getting the biggest share. Normally, the prize pool comes from the buy-ins of players’ entry fees. But that is not the case with esports. Companies get the prize pool from crowdfunding. They raise small amounts of money, usually via internet marketing, from a huge number of people or supporters of the game. For instance, this year, Dota 2 The International 2018’s prize pool was worth $25,532,177. But how did Valve, the developer of the game, come up with this massive prize pool? A blog post from The Esports Observer said that the prize pool was accumulated from Valve’s US$1.6 million contribution plus the sales of its in-game digital compendium called Battle Pass. The post said: “Valve takes 25% of Battle Pass sales and dumps them directly into the annual International prize pool, generating millions of dollars of additional reward for pro teams while amplifying the stakes for both players and viewers alike.” The Battle Pass can give players exclusive deals such as in-game treasure, cursor packs, new music, digital packs, and bonus game modes for US$9.99. Having a Battle Pass also gives players points that will help them level up. Players can buy a Battle Pass worth US$2.49 to increase five levels. To increase 11 levels, players need to buy a pass for US$4.99, and those planning to go up 24 levels should buy a pass for US$9.99. According to Statistica, there were over 739,000 players online at the same time on Steam on October 13, 2018. There was even a time in March 2016 that the number of players reached 1.29 million. With that huge number, it came as no surprise when Valve was able to accumulate a prize pool worth more than US$20 million, mostly out of the Battle Pass purchases. The more players and supporters an esport has, the higher the in-game purchases it can earn, and the bigger its prize pool can get. Biggest Prize Pools in Esports History As of this writing, the biggest esport in terms of prize pool is Fortnite. On May 21, 2018, The Fortnite Team released a statement through its Twitter account that its game developer, Epic Games, will provide US$100,000,000 for the 2018 to 2019 season tournament. The tweet read: “Grab your gear, drop in and start training. Epic Games will provide $100,000,000 to fund prize pools for Fortnite competitions.” Grab your gear, drop in and start training. Epic Games will provide $100,000,000 to fund prize pools for Fortnite competitions.https://t.co/ZcBe9fZD0S — Fortnite (@FortniteGame) May 21, 2018 After the announcement, esports analysts shared their thoughts on this massive prize pool. Bethany Lyons, SuperData esports analyst, said: “By dedicating $100MM to fund prize pools competitions, Epic has made Fortnite the biggest esports in the world in terms of prize money.” Before this announcement, the biggest prize pool in the history of esports was from Dota 2 The International 2018. The prize pool of that event was worth US$25,532,177. But that enormous prize was given not only to the winner. The money was divided among all the teams in the said tournament. When The International 2018 ended, the prize money was shared among 18 teams. According to Dota 2 Prize Pool Tracker, the following was the prize pool distribution: 18 th and 17 th place – US$63,830 and 17 place – US$63,830 16 th to 13 th place – US$127,661 to 13 place – US$127,661 9 TH to 12 th place – US$382,983 to 12 place – US$382,983 7 th to 8 th place – US$638,304 to 8 place – US$638,304 5 th to 6 th place – 1,148,948 to 6 place – 1,148,948 4 th place – US$1,787,252 place – US$1,787,252 3 rd place – US$2,680,879 place – US$2,680,879 2 nd place – US$4,085,148 place – US$4,085,148 1st place –US$11,234,158 In related manner, The International 2017 is the third in rank with its more than US$24 million prize pool. The fourth top esport tournament based on prize pool is The International 2016 with its prize money worth more than US$20 million. Confederations Cup, Other Sporting Events Outprized The increasing prize pools of esports tournaments are so massive that some even outprized the wins a player or a team could get from traditional sporting events. For one, last year’s Confederations Cup had only US$20 million prize pool. Indy 500 2018’s US$13 million also lost to The International 2018’s over US$25 million prize money. Other sports outprized were US Open 2018, The Masters 2017, Stanley Cup 2018, and ICC Championship Trophy. Even US Open 2017 Tennis’ US$50 million prize pool lost to Fortnite’s announced US$100 million. The International 2018 has a bigger prize pool than the US Open 2018. A report by ESPN said: “The 2018 U.S. Open announced a record $53 million prize pool for the tennis tournament later this month. When broken down by event, both the Men’s and Women’s singles tournaments have a total prize pool of approximately $20 million. The singles champion and runner up will receive $3.8 million and $1.85 million respectively.” Apparently, the Singles champion prize of US$1.85 million is still too far from The International 2018’s first-place prize of more than US$11 million. Esports in Online Betting Industry Esports have already reached too wide an audience that popular sportsbooks now add these gaming tournaments to the betting markets on offer. Not surprisingly, there are now online bookies that offer betting options for the biggest esports tournaments including CS:GO, Dota 2, StarCraft 2, Overwatch, and League of Legends, among others. Before, only basketball, baseball, football, soccer, and other popular physical sports were included in the list of betting options for online sportsbook punters. But today, esports now secured their own betting category in online betting portals. Among the popular sites that have esports betting are bet365, OneHash, Pinnacle, and Unibet. Who knows how much bigger the future esports prize pools can get? But given the immense support the industry has been getting, some people predict that there will come a time when the prize money offered by these gaming tournaments will reach $100,000,000.

Q: how to remap I want to use the following code to quickly go from insert mode -> command mode. The problem is it just doesnt seem to be registering my keys. I've tried with control (nothing happens) and i've also tried with command (D) and it just says spellcheck not activated. " Quick command mode from insert imap <C-;> <esc>: How do i go about doing this? is there an easier vim way that I'm not aware of? A: Certain Ctrl chords can't be mapped, including Ctrl-;. This is mentioned in this FAQ, see also the Vim FAQ: 20.4. I am not able to create a mapping for the <xxx> key. What is wrong? First make sure that the key is passed to Vim. In insert mode, press Ctrl-V followed by the desired key. You should see the keycode corresponding to the key. If you do see the keycode, then you can create a mapping for the key using the following command: :map <C-V><xxx> <your_command_to_be_mapped> For more information, read :help map-keys-fails :help :map-special-keys :help key-codes The tip about trying to print the character using Ctrl-V is good to remember if you run into this problem with another key combo.

Filed 8/12/14 P. v. Nava CA5 NOT TO BE PUBLISHED IN THE OFFICIAL REPORTS California Rules of Court, rule 8.1115(a), prohibits courts and parties from citing or relying on opinions not certified for publication or ordered published, except as specified by rule 8.1115(b). This opinion has not been certified for publication or ordered published for purposes of rule 8.1115. IN THE COURT OF APPEAL OF THE STATE OF CALIFORNIA FIFTH APPELLATE DISTRICT THE PEOPLE, F065082 Plaintiff and Respondent, (Super. Ct. No. 11CM2478) v. JOSE AMEZCUA NAVA, OPINION Defendant and Appellant. F068148 In re JOSE AMEZCUA NAVA, On Habeas Corpus. APPEAL from a judgment of the Superior Court of Kings County. Donna Tarter, Judge. ORIGINAL PROCEEDINGS; petition for writ of habeas corpus. Robert J. Beles and Manisha Daryani for Defendant and Appellant and for Petitioner.  Kamala D. Harris, Attorney General, Dane R. Gillette, Chief Assistant Attorney General, Michael P. Farrell, Assistant Attorney General, Catherine Chatman and Daniel B. Bernstein, Deputy Attorneys General, for Plaintiff and Respondent and for Respondent. -ooOoo- A jury convicted appellant Jose Amezcua Nava of one count of committing a lewd and lascivious act on a child under the age of 14 years, his 10-year-old niece. Nava contends reversal is required because of several evidentiary errors, prosecutorial misconduct, and ineffective assistance of counsel. We reject Nava’s contentions and affirm the judgment. FACTUAL AND PROCEDURAL SUMMARY Prosecution Evidence In July 2011, Nava was 59 years old. The victim would often come over to Nava’s house to play, swim in the pool, and get help with her homework from her 28- year-old cousin, Jesse. The charged offense occurred when the victim was staying at Nava’s house for a three-day visit from Friday, July 22, 2011, to Sunday, July 24. The victim testified that on Saturday morning Jesse, Nava’s 28-year-old daughter, asked her to get milk from a refrigerator located in a detached garage at the residence. The milk was for a baby that was staying at the house. The victim went alone to the garage. When she went inside, Nava was already there fixing something. The victim asked him if he could help her get milk from the refrigerator. Nava opened the refrigerator door and the victim started looking for the milk. While the victim was looking for the milk, Nava came up behind her, put his hand under her shirt, and started squeezing her breasts. Leaving one hand on her breasts, Nava put his other hand inside the victim’s shorts and underwear and started squeezing her vagina. It hurt and the victim told Nava to leave her alone. Nava stopped and warned the 2. victim that if she told her mom or dad, they would hit her, and if she told her aunt, her aunt would kick him out of the house. On Sunday the victim walked back to her own nearby house and told her mother, A.B., what had happened. The victim testified that after what happened in the garage, she was scared of Nava and did not walk past his house anymore. The victim acknowledged she sometimes laughed and smiled when she was nervous or scared. The victim consistently described the incident in the garage during interviews with Sheriff’s Deputy Rod Schulman and social service practitioner Delia Acosta-Perez. A.B. is Nava’s sister. She testified she went to Nava’s house after the victim told her about the incident in the garage. At Nava’s house, Jesse threatened that if A.B. called the police, the victim would be taken from her and A.B. would be deported to Mexico. A.B. had planned to call the police after she had had a chance to speak with her daughter thoroughly about what happened, but the police came to her house before she had a chance to call them. A.B. also testified she had always had a good relationship with Nava before he touched her daughter. Sheriff’s Deputy Lionel Alvarez assisted Schulman in interviewing the victim on July 27, 2011. Schulman testified that at one point during the interview, he asked Alvarez to go get a diagram. When Alvarez stepped out of the room, the victim became very upset and started to cry. The victim told Schulman she was crying because “she was afraid to be in the room with [him], as an older male, because of what her uncle had done to her.” Uncharged Sexual Offenses At trial, the parties and the court focused on one uncharged sexual offense involving allegations by another of Nava’s sisters, M.N., which allegedly occurred in 1969. The record, however, reflects considerable testimony by the victim, both live and via video recording, of three and possibly more uncharged sexual offenses committed by 3. Nava on the victim during the summer of 2011 where Nava touched her in a similar manner. M.N., who was 52 years old at the time of trial, testified that when she was around nine or 10 years old and living with Nava in Mexico, Nava had put his finger inside her vagina, causing it to hurt. She told their mother what happened and it never happened again. Since then, her relationship with Nava had been fine and she never spoke to him about what happened. She could not remember a lot about the incident but recalled it occurred in a bathroom. She previously had told Schulman, however, that the incident occurred in a bedroom. Acosta-Perez interviewed the victim on August 24, 2011. The video recording of the interview was played for the jury. There, the victim, verbally and with hand motions, described how Nava had touched her in the same manner as the charged offense on each of the three days she stayed with him over the weekend of July 22. Those occurred when Jesse would ask that she retrieve things from the garage refrigerator.1 She also testified that one night during the same weekend, Nava touched her in a similar manner while she was sitting on a couch in Nava’s house, after he locked the door to the room.2 Defense Evidence Nava testified and denied the victim’s accusation that he molested her on Saturday morning when she was getting milk from the refrigerator in the garage. According to Nava’s testimony, the only time he and the victim were in the garage together during her 1Thevictim also stated in the interview that “he touched me more, but like I don’t know to count .…” 2Nava did not object to the introduction of the video interview containing the evidence of the other instances of sexual touching in the garage or the testimony regarding the incident on the couch. 4. stay was on the night of Friday, July 22, 2011, when Nava went to get a cake out of the refrigerator. Nava explained that on Friday night he had more than 15 guests at his house for a church celebration. At some point Jesse asked him to bring the cake to her. Nava headed to the garage, followed by his wife. The victim ran up behind them and Nava handed her the cake when he took it out of the refrigerator. He did not touch the victim in any way at this time. Also, they never kept milk in the refrigerator in the garage but kept it in the refrigerator in the kitchen. Around 4:00 a.m. on Saturday morning, when it was still dark, Nava and his wife left the house to drive to Tehachapi to visit their son, who was in prison. Nava did not talk to the victim or say goodbye to anybody before they left. The drive to Tehachapi took approximately one hour 45 minutes. Nava did not see the victim until later that day when he met Jesse in front of a store to help her repair a flat tire. Nava saw the victim briefly on Sunday morning when they were getting ready for church, but they were never alone together that day. The next time he saw the victim was Monday, when he first found out about her accusation, which surprised him. Jesse called Nava while he was working and he came back to the house. When Nava arrived at the house, the victim’s mother was there and he asked her to bring the victim over to the house so the victim’s mother could see what the victim was saying was not true. Nava denied his sister’s allegations that he molested her approximately 43 years earlier. He testified the house in Mexico, where she alleged the molestation occurred, did not have a bathroom. Nava claimed he and his sister had had disagreements over the years. He explained that when his sister came to Los Angeles, she sold drugs and legal documents and they would argue about that. She would get mad and tell him to “butt [out of] her life.” Jesse also testified and described the Friday night church celebration at Nava’s house. During the celebration, Jesse sent Nava to get the cake from the refrigerator in the 5. garage. Jesse saw the victim run after Nava and his wife. The victim then returned carrying the cake, which Jesse took from the victim because it looked like she was going to drop it. The victim slept with Jesse in Jesse’s room on Friday night. On Saturday morning, Nava and his wife went to visit Jesse’s brother in prison, leaving the house around 4:00 a.m. Jesse did not see Nava again that Saturday until around 1:00 p.m. The victim was never alone with Nava on Saturday morning. Jesse was with the victim the whole time, except once when the victim went to change, but that was after Nava and Jesse’s mother had left the house. Jesse did not send the victim to get milk either for her or for a baby on Saturday morning. The only time the victim asked Jesse for milk was while Nava and his wife were away visiting Jesse’s brother in prison. Jesse and the victim were in the living room when the victim asked if she could get milk so she could eat cornflakes. Jesse said yes and the victim went into the kitchen to get it. Jesse learned about the victim’s accusations against Nava on Monday, when the victim’s mother called her. Jesse met the victim and the victim’s mother at Nava’s house. Jesse called Nava to come home. Jesse’s mother also was present. Jesse then asked the victim to show them what had happened to her. The victim brushed her hand down the middle of her chest and below her waist. While she did this, the victim was laughing and continued to laugh until her mother told her it was not a game. Jesse denied threatening to turn the victim’s mother in to immigration. After Nava was arrested, Jesse saw the victim walk past Nava’s house with other people on three separate occasions. As they passed by the house, the victim would turn and laugh. Stephanie Estrada testified she had known Nava for 24 to 25 years. She used to work at a school where she would see him two to three times a month and had had sufficient contacts with him to form an opinion as to his reputation for honesty. 6. According to Estrada, Nava was a very honest individual. He was a God-fearing and loving individual who cared about his community and the people with whom he was acquainted. He had a very excellent reputation for the way he treated women and children. Charges, Trial and Sentence On August 23, 2011, Nava was charged with one count of committing a lewd and lascivious act on a child under the age of 14 on or about July 23, 2011, in violation of Penal Code section 288, subdivision (a). Nava’s jury trial commenced on March 26, 2012, and concluded on March 29. After deliberating for just over an hour, the jury found Nava guilty as charged. On April 27, 2012, Nava was sentenced to six years in prison. DISCUSSION I. Admission of 1969 Uncharged Sexual Offense Nava contends the trial court abused its discretion in admitting the evidence of the 1969 uncharged sexual offense under Evidence Code section 1108. He also claims admission of the evidence violated his constitutional due process rights. Prior to the commencement of trial, the prosecution filed a motion seeking to admit evidence of Nava’s uncharged sexual offense against his sister pursuant to section 1108.3 In anticipation of the prosecution’s motion, the defense filed a separate motion asking the trial court to exclude the evidence under section 352. The trial court conducted a hearing pursuant to section 402, heard argument, and concluded the evidence was admissible. The trial court explained: “In this case, the amount of time between the incident with [Nava’s sister] and the new victim is 43 years. That is very remote in time. However, the victims were the same age, or approximately the same age when the alleged assault took place. They were family members; Mr. Nava had a position of 3All further statutory references are to the Evidence Code. 7.  either trust or authority over the two victims; the acts are substantially similar; the evidence that [Nava’s sister] … testified to is not particularly inflammatory; and there is very little possibility of confusion of the issues. The … testimony that was elicited from [Nava’s sister] took a very short period of time and, therefore, the amount of time involved in introducing and refuting the evidence is not lengthy. So the court—based on viewing the [section] 352 analysis, there is propensity evidence that is highly probative to show intent and far outweighs the prejudicial effect. Court is going to allow the [section] 1108 evidence.” Section 1108 was intended to sweep away the narrow categories of admissibility of other crimes evidence that had existed under section 1101. (People v. Britt (2002) 104 Cal.App.4th 500, 505.) Instead, such evidence is admissible whenever it may be helpful to the trier of fact, on a commonsense basis, for resolution of any issue in the case, including the probability or improbability that the defendant has been falsely accused. (See Britt, at p. 506.) A trial court, however, retains the discretion to admit or exclude evidence of another sexual offense under section 352. (People v. Rodriguez (1999) 20 Cal.4th 1, 9; People v. Callahan (1999) 74 Cal.App.4th 356, 367-368.) A trial court’s exercise of its discretion under section 352 is reviewed for abuse of discretion and will not be disturbed on appeal absent a showing the trial court exercised its discretion in an arbitrary, capricious or patently absurd manner. (Rodriguez, at pp. 9-10.) In People v. Harris (1998) 60 Cal.App.4th 727, the court set out five factors for evaluating the admissibility of prior offense evidence: (1) the inflammatory nature of the evidence; (2) the probability of confusion; (3) the remoteness in time of the prior incidents; (4) the consumption of time involved; and (5) the probative value of the prior offense evidence. (Id. at pp. 737-741.) Here, the trial court found these factors weighed in favor of admission of the evidence. Nava argues the evidence should have been excluded because it was too remote in time, particularly since he had led an unblemished life since the uncharged incident with his sister. But similarities between the charged and uncharged acts can balance out remoteness. (People v. Waples (2000) 79 Cal.App.4th 1389, 1395.) Here, the uncharged 8. and charged offenses were substantially similar. Both victims were young girls, were family members, and were staying in the same house as Nava at the time of the offenses. Both offenses included touching of the victims’ vaginas. The uncharged offense against Nava’s sister, which involved digital penetration of the vagina, was more inflammatory than the charged offense against the victim, but not greatly so. The sister’s testimony did not consume an undue amount of time. And the jury was instructed properly with CALCRIM No. 1191 that they could, but were not required to, consider this evidence for propensity purposes.4 No specific time limit is set forth in the statute and appellate courts have upheld admission of evidence of uncharged offenses that occurred 30 years before. (People v. Branch (2001) 91 Cal.App.4th 274, 285.) Remoteness is but one factor to be considered by the trial court. But 43 years is a long time, and if the sexual misconduct evidence was not similar, we likely would reach a different result. Because it is solely within the trial court’s discretion to determine whether sexual misconduct evidence is too remote, and where the record demonstrates the court wrestled with the issue and exercised its discretion, we will not disturb the court’s ruling. But, even assuming the trial court erred in allowing the introduction of the 43- year-old uncharged and unadjudicated sexual act, based on the evidence of the other three or more recent uncharged acts involving the victim, we conclude any such error not prejudicial, under either the Watson or Chapman standards. (People v. Watson (1956) 46 Cal.2d 818,836; Chapman v. California (1967) 386 U.S. 19, 24.) We can infer from the jury’s guilty verdict that they found the victim credible and not Nava. 4This instruction was not modified to identify the 1969 prior uncharged incident specifically, so the jury also could have considered the evidence of the recent uncharged sexual misconduct involving the victim for propensity purposes. 9.  Nava also claims the probative value of the uncharged sexual offense was “substantially diminished” because his sister’s testimony indicated he was between the ages of 16 and 18 and was, therefore, likely a juvenile at the time of the offense. He argues this is significant because of the language in recent United States Supreme Court cases recognizing that juvenile offenders have lessened culpability for crimes they commit and are less deserving of severe punishment than their adult counterparts. (See Graham v. Florida (2010) 560 U.S. 48; Roper v. Simmons (2005) 543 U.S. 551, 570.) These authorities do not help Nava, however, because they address the issue of culpability, not propensity. It is not unreasonable to conclude that a defendant with a juvenile history of committing sexual abuse would be more likely to commit sexual abuse as an adult than a defendant without such history. Evidence that Nava as a teenager sexually abused his young sister was highly probative on the issue of the likelihood he would as an adult sexually abuse his young niece. In short, there is no indication here that the trial court exercised its discretion in an arbitrary, capricious, or patently absurd manner. We thus conclude the trial court did not abuse its discretion in admitting evidence of Nava’s prior sexual offense under section 1108. Nava also has forfeited his challenge to admissibility of the evidence on constitutional due process grounds. “An appellate contention that the erroneous admission or exclusion of evidence violated a constitutional right is not preserved in the absence of an objection on that ground below. [Citations.]” (People v. Daniels (2009) 176 Cal.App.4th 304, 320, fn. 10.) No objection on the basis of a violation of constitutional rights was made by Nava. II. Exclusion of Proffered Testimony Nava contends the trial court erred in excluding as cumulative the proffered testimony of Luis Hernandez that he saw Nava and the victim getting a cake out of the refrigerator in the garage and nothing happened. 10.  The issue of Hernandez’s proposed testimony came up during a discussion of additional witnesses the defense planned to call: “THE COURT: [Hernandez is] going to testify about the cake, refrigerator incident? “[DEFENSE COUNSEL]: Yeah, about being in that area and seeing … him and [the victim], and that nothing happened. “THE COURT: I’m going to preclude you from calling Luis Hernandez as cumulative, undue consumption of time. I think it’s pretty— it’s been pretty well settled that both [the victim] and Mr. Nava got cake from the refrigerator and nothing happened. I’ll bet [the prosecutor] would even stipulate to that. “[THE PROSECUTOR]: I don’t know if I’d go quite that far, but— “[DEFENSE COUNSEL]: Well, your Honor, I think it’s the Government’s theory that that’s when the touching happened. “THE COURT: That is not. “[DEFENSE COUNSEL]: They’re going to stipulate to that? “THE COURT: It’s clear that the Government’s theory is when she went to get the milk is when the touching happened, not the cake. So it’s different. “[DEFENSE COUNSEL]: Well, can we have that stipulation on the record? “THE COURT: No, I’m just telling you that from the testimony, it is clear. You’ve had two witnesses now testify that [the victim] and the defendant went to the refrigerator to get the cake and there were people around and nothing happened. And actually, there’s three people that testified. Well, [the victim] testified that it was during the milk incident. “[THE PROSECUTOR]: And just for the record, Luis Hernandez’s testimony is going to be that he wasn’t—he was standing in the yard. He couldn’t even see the garage. So for the record, again, for appeal purposes, that’s what his testimony would be. That’s not relevant. 11.  “THE COURT: My ruling is that it would be cumulative, assuming that he would testify that he witnessed [the] getting of the cake from the refrigerator.” Section 352 gives “the court discretion to ‘exclude evidence if its probative value is substantially outweighed by the probability that its admission will (a) necessitate undue consumption of time or (b) create substantial danger of undue prejudice, of confusing the issues, or of misleading the jury.’ [Citation.]” (People v. Brown (2000) 77 Cal.App.4th 1324, 1337.) Here, the trial court excluded Hernandez’s proffered testimony as an undue consumption of time and cumulative of other evidence. This was a proper exercise of its discretion. The testimony had limited probative value. As the trial court observed in making its ruling, based on the evidence presented, the prosecution’s theory was that Nava molested the victim when she went into the garage in the morning to get milk, not when she followed Nava into the garage in the evening to get the cake. Hernandez’s proffered testimony tended to show Nava was telling the truth in testifying he did not molest the victim in the garage during the Friday evening church celebration when others were present at his house. It did not, however, tend to prove this was the only time Nava had gone into the garage with the victim or that the separate incident she described did not occur. We therefore disagree with Nava’s assertion that in excluding Hernandez’s testimony, the trial court prevented Nava from presenting “strong evidence” he was “innocent of the charged crime.” Contrary to Nava’s assertions, the prosecution did not suggest to the jury that it could find the charged offense occurred during the Friday evening celebration when Nava and the victim took the cake out of the refrigerator in the garage. Despite the prosecutor’s expressed reluctance to stipulate that nothing happened, she presented no evidence or argument suggesting Nava molested the victim during the cake incident or even disputing the incident occurred. Although, as Nava points out, the prosecutor did state in her opening argument that the charged offense occurred at night, she corrected 12. herself at the beginning of closing argument and explained to the jury she misspoke in opening argument. Nava also claims the prosecutor argued the alleged touching could have happened at any time over the weekend. Not so. On the pages of the reporter’s transcript Nava cites to support his assertion, the prosecutor argued that the alleged molestation could have “happened Friday morning, Saturday morning, or Sunday morning. You don’t have to agree on which day it happened, you just have to agree it happened on or about Saturday morning.” The trial court’s conclusion the proffered evidence was cumulative of other evidence also was reasonable. Both Nava and Jesse presented undisputed testimony that a number of guests attended the Friday evening church celebration at Nava’s house when he went to get the cake from the refrigerator in the garage. Jesse also testified she saw Nava’s wife go with him into the garage, followed by the victim, who reappeared shortly carrying the cake. Although Jesse did not testify she could see what was happening inside the garage after the victim followed Nava and his wife inside, Jesse’s testimony corroborated Nava’s testimony that his wife was present in the garage when he took the cake out of the refrigerator and gave it to the victim and was circumstantial evidence Nava did not molest the victim at that time. On the record before us, we cannot agree with Nava’s argument that Hernandez’s proffered testimony added significant details to the testimony already presented or was crucial to his defense. III. Exclusion of Evidence Relevant to the Victim’s Credibility Nava contends the trial court abused its discretion in excluding evidence he claims was relevant to the issue of the victim’s credibility. He also claims the exclusion of the evidence violated his constitutional rights to present evidence in his own defense and to confront and cross-examine witnesses. 13.  Specifically, Nava argues the trial court erred in excluding evidence of (1) four accusations of molestation “against other people by other family members” of the victim’s family; (2) Nava’s statement to Schulman that he maintained a certain distance from the victim because she gets angry and makes accusations, like accusing her neighbor, a young man, of “touch[ing] her butt,” and that Nava told the victim’s mother to watch over the victim closely; (3) “bad blood” between Nava and the victim’s mother; and (4) molestation of the victim’s older sister by Nava’s “brother, Silvano B.”5 We agree with the People that Nava forfeited most of his claims by failing to seek appropriate evidentiary rulings, and, to the extent his claims have been preserved for appellate review, he has failed to demonstrate an abuse of discretion by the trial court. Standard of Review A trial court’s rulings on the admissibility of evidence, including under section 352, are reviewed for abuse of discretion. (People v. Scott (2011) 52 Cal.4th 452, 490- 491 (Scott).) We will not set aside a judgment by reason of the erroneous exclusion of evidence unless the error resulted in a miscarriage of justice. (§ 354.) An error has resulted in a miscarriage of justice and warrants reversal “if in the absence of the error, the appealing party would have probably obtained a more favorable result. (See Cal. Const., art. VI, § 13; Code Civ. Proc., § 475; Evid. Code, § 354; [citations].)” (Greenspan v. LADT LLC (2010) 191 Cal.App.4th 486, 526-527.) “‘As a general matter, the “[a]pplication of the ordinary rules of evidence … does not impermissibly infringe on a defendant’s right to present a defense.” [Citations.]’ [Citation.]” (People v. McNeal (2009) 46 Cal.4th 1183, 1203.) Where the trial court 5Nava’s fourth claim of evidentiary error refers to evidence that Nava’s brother-in- law (not his brother) Silvano B. was charged in 1999 with molesting the victim’s older sister and the charges later were dropped. This is discussed in Nava’s petition for writ of habeas corpus filed approximately nine months after the appeal. (See part VII. of the DISCUSSION, post.) 14. does not preclude the defendant from presenting a defense but rejects some evidence concerning that defense, the error is reversible only if it has resulted in a miscarriage of justice. (Ibid.) With certain statutory exceptions, all relevant evidence is admissible. (§ 351.) “‘Relevant evidence’ means evidence, including evidence relevant to the credibility of a witness …, having any tendency in reason to prove or disprove any disputed fact that is of consequence to the determination of the action.” (§ 210.) The test is whether the evidence tends “‘“‘“‘“logically, naturally, and by reasonable inference” to establish material facts .… [Citations.]’ [Citation.]”’”’” (People v. Fields (2009) 175 Cal.App.4th 1001, 1016.) Circumstantial evidence is evidence from which a fact may be inferred. (People v. Nealy (1991) 228 Cal.App.3d 447, 451.) “An inference is a deduction of fact that may logically and reasonably be drawn from another fact or group of facts found or otherwise established in the action.” (§ 600, subd. (b).) The trial court has broad discretion to determine whether evidence, including circumstantial evidence, is relevant. (Scott, supra, 52 Cal.4th at p. 490; People v. Harris (2005) 37 Cal.4th 310, 337-338.) However, even relevant evidence may be excluded if its probative value is substantially outweighed by concerns of undue prejudice. (§ 352.) “Generally, in order to preserve any evidentiary point for appellate review, the proponent of the evidence must make an offer of proof regarding the anticipated testimony or ask questions which presage the expected response. [Citations.] Failure to make an adequate offer of proof precludes consideration of the alleged error on appeal. [Citation.]” (People v. Eid (1994) 31 Cal.App.4th 114, 126.) “An offer of proof should give the trial court an opportunity to change or clarify its ruling and in the event of appeal would provide the reviewing court with the means of determining error and assessing prejudice. [Citation.] To accomplish these purposes an offer of proof must be specific. It must set forth the actual evidence to be produced and not merely the facts or issues to be addressed and argued. [Citations.]” (People v. Schmies (1996) 44 Cal.App.4th 38, 53 15. (Schmies).) “An offer of proof must consist of material that is admissible, it must be specific in indicating the purpose of the testimony, the name of the witness and the content of the answer to be elicited.” (Semsch v. Henry Mayo Newhall Memorial Hospital (1985) 171 Cal.App.3d 162, 167.) Four Accusations of Molestation by Members of the Victim’s Family Nava’s failure to make a specific offer of proof forfeited his claim that the trial court erred in excluding evidence of four accusations of molestation by members of the victim’s family against other people. To counter the forfeiture argument, Nava correctly points out the prosecution preemptively sought to exclude such evidence in one of its in limine motions. When the prosecution asked the court to rule on the motion, however, defense counsel stated, “I think I can probably shortcut that because I recognize that I don’t have—although I’ve shared with the prosecutor the names of people and some other incidents, I don’t have any [of] these people available to testify.” When the issue arose during trial, defense counsel again indicated he was not planning to go into the area of the four prior accusations of molestation. Thereafter, the trial court indicated it agreed with the prosecutor’s argument that such evidence was irrelevant and unduly prejudicial as its only apparent purpose was to show that “this victim’s family is out to just accuse people.” Defense counsel did not object to this characterization of the evidence or attempt to make a showing that the evidence was relevant to any of the issues at trial. In the absence of a specific offer of proof, the trial court acted well within its discretion in excluding the evidence as irrelevant. Nava’s Statement to Schulman Nava has similarly forfeited his claim concerning the exclusion of his statement he made during his interview with Schulman regarding the victim’s claim that a young man in the neighborhood “touch[ed] her butt.” 16.  Nava argues the evidence was relevant because “it shows that [the victim] was familiar with sexual touching and had a basis and experience upon which to fabricate testimony.” (See People v. Daggett (1990) 225 Cal.App.3d 751, 757.) Nava, however, did not offer the evidence on this ground in the trial court. Rather, it was the prosecutor who brought the evidence of Nava’s statement to the court’s attention and pointed out she did not see how it was relevant.6 In response, defense counsel stated he thought the evidence had “some probative value” because Nava’s statement was given in response to the deputy’s question asking Nava why a 10-year-old girl would lie, which “tends to be a major question in a case like this.” The trial court deferred a ruling on the admissibility of the statement but indicated it disagreed with counsel’s relevancy argument, pointing out that for Nava to say “she’s accused other people, she may have been molested before” did not really answer the deputy’s question of why the victim would lie in this instance. It does not appear the court thereafter made a specific evidentiary ruling regarding Nava’s statement to Schulman. On the merits, assuming the trial court’s statements can be interpreted as a ruling to exclude Nava’s statement to Schulman, Nava has not demonstrated the trial court abused its discretion in excluding this evidence as irrelevant. Nava exaggerates his proffered statement by suggesting it established the victim had been sexually molested in 6The prosecutor read the relevant portion of the interview transcript as follows: “[Schulman:] ‘Why would a ten-year-old girl make an accusation against you? Who’s the family member if you did not do it?’ [¶] The defendant: ‘I’m going to tell you. When that little girl gets angry she says a lot of things from her house. She has said a lot of things and she has talked to—talked to about another young man who lives next to the house, that the young man would touch her—her butt area. And I told my sister, take care of that little girl because they want to touch her, and she did not listen. But for me to touch someone, no one.’” 17. the past. Nava merely reported that the victim claimed a young man touched her “butt area.” His statement disclosed nothing about the circumstances or the extent of the alleged touching. The minimal information presented by Nava’s statement, which may very well have been the extent of any possible testimony on the subject, was very different than the allegations the victim made against Nava of squeezing her breasts and vagina underneath her clothes. Because the jury would have to speculate to reach the conclusions asserted by Nava, the evidence was properly excluded. Bad Blood between Nava and the Victim’s Mother During Nava’s direct examination defense counsel asked, “[W]as one of your sisters angry at you before this accusation came out?” The prosecutor objected on relevancy grounds, and the trial court called for the jurors to take a break. Outside the presence of the jury, the trial court noted that it looked like defense counsel was “going to go into an area where—to establish some sort of bad blood between the victim’s mother and the defendant; is that correct?” Defense counsel responded, “I understood there was some bad blood between him and his sister … and she’d come in and said there was none.” The court asked what the relevance was and defense counsel stated: “Well, what if the mother has—is encouraging the daughter to lie about this? That’s the relevance.” The trial court replied: “There’s no evidence that if there was—assuming for the purpose of this discussion that there was bad blood between … the victim’s mother and the defendant, unless the victim knew about these problems, this conflict, then it’s not relevant. And there’s no evidence of any coaching or anything like that. So this area is not relevant. It’s—it is prejudicial and it’s undue consumption of time.” In response, defense counsel stated: “Well, to save time, I’m not going to disagree with you. I mean I disagree with you, but I’m not going to try to go into that area any further because what I’m really fishing for is why would [the victim] say this if it wasn’t true.” 18.  Nava argues that because the victim was only 10 years old at the time of the alleged molestation, we should infer that the victim’s mother likely was the person who instigated the criminal investigation. Therefore, evidence of the mother’s bias against Nava was relevant and should have been admitted. (See People v. Haxby (1962) 204 Cal.App.2d 791, 792, 795-796 [trial court erred in refusing to allow defense counsel to show hostile relationship existed between defendant and his next-door neighbors, who instigated investigation of defendant’s conduct that led to his conviction of committing lewd acts on his daughter and a neighbor girl].) But there was no evidence here the victim’s mother instigated the investigation into Nava’s conduct. Rather, there was evidence to the contrary in that the victim’s mother testified she was planning to call the police, but they came to her house before she had a chance to call them. We do not think the trial court abused its discretion in excluding the evidence. The evidence had minimal probative value. As the court noted, even assuming there was some kind of bad blood or hostility between Nava and the victim’s mother, it did not tend to prove the victim lied about Nava molesting her, absent evidence the victim was aware of the hostility or that her mother influenced her somehow in making her allegation against Nava. Victim’s Older Sister Was Molested Nava contends the trial court erred in excluding as irrelevant evidence that the victim’s older sister was molested by Nava’s brother because this was “direct evidence of a potential bias between not only the families, but also [the victim], if she had been informed of the conduct.” We disagree. Like the alleged bad blood between Nava and the victim’s mother, evidence the victim’s family was biased against Nava, based on his brother’s alleged molestation of the victim’s older sister, was irrelevant. There was no evidence the victim was aware of the molestation or that the victim’s family somehow influenced the victim in bringing her 19. accusation against Nava. Nor was there any evidence the victim’s family instigated the criminal investigation against Nava. The trial court did not err. Constitutional Challenge Nava forfeited his constitutional challenge by failing to raise in the trial court his claim that the exclusion of the evidence violated his constitutional rights to present a defense and confront witnesses. IV. Admission of Victim’s Hearsay Statement Nava claims the trial court erred when it admitted, over his hearsay objection, Schulman’s testimony that the victim said she was crying because “she was afraid to be in the room with [him], as an older male, because of what her uncle had done to her.” After holding a sidebar conference, the trial court allowed the evidence to be admitted under the exception to the hearsay rule contained in section 1360. Nava now contends section 1360 was inapplicable because the victim’s statement to Schulman was not “describing any act of child abuse … or describing any attempted act of child abuse .…” (§ 1360, subd. (a).) The rationale used by the trial court for admitting the evidence, however, is not a matter for this court’s review. (Davey v. Southern Pacific Co. (1897) 116 Cal. 325, 329.) It is judicial action and not judicial reasoning that is the proper subject of appellate review. (El Centro Grain Co. v. Bank of Italy, etc. (1932) 123 Cal.App. 564, 567.) As the victim’s statement was admissible under at least one exception to the hearsay rule, the trial court’s admission of the evidence must be upheld. (People v. Brown (2004) 33 Cal.4th 892, 901 [“If a judgment rests on admissible evidence it will not be reversed because the trial court admitted that evidence upon a different theory, a mistaken theory, or one not raised below”].) Section 1250 permits admission of “evidence of a statement of the declarant’s then existing state of mind, emotion, or physical sensation (including a statement of intent, plan, motive, design, mental feeling, pain, or bodily health) … when: [¶] (1) The 20. evidence is offered to prove the declarant’s state of mind, emotion, or physical sensation at that time or at any other time when it is itself an issue in the action; or [¶] (2) The evidence is offered to prove or explain acts or conduct of the declarant.” (Id., subd. (a).) “‘“[A] victim’s out-of-court statements of fear of an accused are admissible under section 1250 only when the victim’s conduct in conformity with that fear is in dispute. Absent such dispute, the statements are irrelevant. [Citations.]”’ [Citation.]” (People v. Jablonski (2006) 37 Cal.4th 774, 819 (Jablonski).) Nava placed the victim’s state of mind at issue. He asserted the victim fabricated her claims of molestation against him as a means of gaining attention. He also maintained her conduct in laughing and smiling when describing the molestation was inconsistent with the behavior one would expect to see in a sexual abuse victim who feared her abuser or was traumatized as a result of the abuse. (Jablonski, supra, 37 Cal.4th at p. 820 [victim’s fear of accused may be relevant where, according to defendant, victim behaved in manner inconsistent with that fear].)7 Evidence that the victim cried and said she feared being in the room with Schulman, as an older man, after what her uncle did to her, implicitly expressed the victim’s fear of Nava. It was relevant to dispute the defense theory that her behavior was 7For example, defense counsel argued: “Did you notice that [the victim] was depressed or quiet? Common sense tells us that’s what would happen if somebody’s traumatized or victimized like she said. But instead, you see the exact opposite. You see the laughing and smiling and in an effort to short that up, they try to bring up, well, she cried once during the interview and said she was afraid. I think the candid capture of this young girl on the video [of her interview with social services practitioner Acosta-Perez] is more revealing of what’s going on with her. She likes this moment. She’s finally getting what she wants. She’s getting more attention from her mom who has left her with this family. She’s getting the attention she finally wants. She’s getting attention from the lady on the video. She loves it. She basks in it.” A little later defense counsel argued: “So does it matter that her story’s consistent or does it matter that her behavior is inconsistent with the story? There are things that don’t fit.” 21. inconsistent with someone who had been sexually abused and indicated she fabricated her accusations because she wanted (and enjoyed) the resulting attention. As Schulman’s testimony was admissible under section 1250, the trial court did not err in allowing it. V. Prosecutorial Misconduct Nava argues the prosecutor committed misconduct by using, in cross-examination and closing argument, “reprehensible and deceptive means” to portray Nava “as an extraordinarily arrogant man with a family of criminals.” We disagree. During cross-examination, the prosecutor questioned Nava about his interview with Schulman, in relevant part, as follows: “Q. Okay. And then when you told the officer that your son, who you went to go visit in prison, was being falsely imprisoned, you told the officer that people lied there and that’s why he was being falsely imprisoned? “[DEFENSE COUNSEL]: Objection, irrelevant. “THE COURT: Sustained. “[DEFENSE COUNSEL]: Move to strike. “THE COURT: Stricken. “[DEFENSE COUNSEL]: The question and the answer. “[THE PROSECTUOR]: “Q. Is your son in prison? [¶] … [¶] “[DEFENDANT]: Yes. “[THE PROSECUTOR]: Is he being illegally incarcerated, in your opinion? “[DEFENSE COUNSEL]: Objection irrelevant. “THE COURT: Sustained. Sustained. You don’t answer that, sir. Don’t answer that. [¶] Go ahead. “[THE PROSECUTOR]: 22.  “Q. Is it always somebody else’s fault, Mr. Nava? “[DEFENSE COUNSEL]: Objection, argumentative. “THE COURT: Sustained.” In closing argument, the prosecutor stated: “Another one of his responses was asked about making mistakes. This is an arrogant man, that’s what the defendant is. And when asked if you ever have made a mistake, his response is, no, he’s never made a mistake. And talking the deputy, what about a traffic accident? [Sic.] Well, yeah, but it wasn’t my fault. It’s all somebody else’s fault with this defendant. It’s never his fault.” No objection was made to these statements. “‘“The applicable federal and state standards regarding prosecutorial misconduct are well established. ‘“A prosecutor’s … intemperate behavior violates the federal Constitution when it comprises a pattern of conduct ‘so egregious that it infects the trial with such unfairness as to make the conviction a denial of due process.’”’ [Citations.] Conduct by a prosecutor that does not render a criminal trial fundamentally unfair is prosecutorial misconduct under state law only if it involves ‘“‘the use of deceptive or reprehensible methods to attempt to persuade either the court or the jury.’”’ [Citation.]” [Citation.]’ [Citation.] [¶] Regarding the scope of permissible prosecutorial argument, ‘“‘a prosecutor is given wide latitude during argument. The argument may be vigorous as long as it amounts to fair comment on the evidence, which can include reasonable inferences, or deductions to be drawn therefrom. [Citations.] It is also clear that counsel during summation may state matters not in evidence, but which are common knowledge or are illustrations drawn from common experience, history or literature.’ [Citation.] ‘A prosecutor may “vigorously argue his case and is not limited to ‘Chesterfieldian politeness’” [citation], and he may “use appropriate epithets .…”’” [Citation.]’ [Citation.] [¶] Finally, ‘a defendant may not complain on appeal of prosecutorial misconduct unless in a timely fashion—and on the same ground—the defendant made an 23. assignment of misconduct and requested that the jury be admonished to disregard the impropriety. [Citation.]’ [Citation.]” (People v. Stanley (2006) 39 Cal.4th 913, 951- 952.) Any claim of prosecutorial misconduct has been forfeited because Nava did not object on that basis and did not request the jury be admonished to disregard any impropriety. Nava concedes no objection on the ground of prosecutorial misconduct or request for admonishment was made in the trial court but contends the issue is reviewable on appeal because an admonishment would not have cured the harm. He fails, however, to provide a meaningful explanation to support this contention. He simply asserts the challenged cross-examination questions were “so argumentative in nature and so aimed at developing an irrelevant character attack of [him] and his family that an admonition would not have cured the harm.” Merely asserting that the misconduct is “incurable” is insufficient. (People v. Foster (2010) 50 Cal.4th 1301, 1354 [California Supreme Court rejected defendant’s assertion he did not forfeit claim of prosecutorial misconduct by his failure to object and seek curative admonition where defendant did not explain why a curative admonition would not have cured any harm].) The circumstance of Nava’s son being in prison was already before the jury through defense evidence that Nava was visiting him there at the time the victim claimed she was molested. Therefore, the prosecutor’s referring to Nava’s son being in prison did not render the questions incurably inflammatory. We see no support in the record for Nava’s suggestion that the questions were aimed at showing he had “a family of criminals” or a son who was “a serious criminal.” Regardless, even assuming Nava preserved his claim of prosecutorial misconduct for appellate review, it fails on the merits for two reasons. First, there is no indication the jury construed or applied the prosecutor’s cross-examination questions in a manner contrary to the trial court’s instructions. The court sustained defense counsel’s objections to the complained-of questions on the grounds they were irrelevant and argumentative. 24. The court also granted defense counsel’s motion to strike the prosecutor’s question asking Nava whether he told Schulman his son was falsely imprisoned and that his son was in prison because people had lied. A jury is presumed to follow a court’s instruction in the absence of any indication that it was unwilling or unable to do so. (People v. Letner and Tobin (2010) 50 Cal.4th 99, 196.) The jurors were instructed: “During the trial, the attorneys may have objected to questions or moved to strike answers given by the witnesses. I ruled on the objections according to the law. If I sustained an objection, you must ignore the question. If the witness was not permitted to answer, do not guess what the answer might have been or why I ruled as I did. If I ordered testimony stricken from the record you must disregard it and must not consider that testimony for any purpose.” Here, there is no evidence in the record, and Nava has cited none, indicating the jury was unwilling or unable to follow these instructions. Second, it is clear the challenged remarks in closing argument were not objectionable. The prosecutor’s argument did not, as Nava suggests, refer back to the prosecutor’s objectionable questions during cross-examination. Rather, the prosecutor’s argument refers to questions preceding those. In cross-examination, Nava acknowledged he told Schulman he never made any mistakes, testifying, “No, I have never made mistakes.” Nava also acknowledged denying he was at fault when Schulman challenged his assertion about never making mistakes by observing Nava had hit someone in a car accident. Thus, Nava testified, “Yes, but it’s never been my fault. Never.” In light of Nava’s testimony professing never to make any mistakes, the prosecutor’s remark that Nava was an arrogant man constituted fair comment on the evidence and did not amount to misconduct. Even if we were to view the prosecutor’s remarks as improper, the jurors were instructed that comments from counsel were not evidence and they were to decide the case based upon the evidence, not bias, sympathy, 25. prejudice, or public opinion. Again, we see no evidence in the record that the jurors were unable or unwilling to follow these instructions. VI. Exclusion of Character Evidence Nava contends the trial court erred in excluding evidence of “specific instances of good conduct around young girls” to rebut the prosecution’s section 1108 evidence. We agree with the People that Nava’s failure to make a specific offer of proof regarding such evidence forfeited his claim on appeal. To avoid forfeiture Nava argues it would have been futile for him to make a specific offer of proof because the trial court made a “blanket ruling” excluding evidence of specific instances of good conduct. (§ 354, subd. (b); see Schmies, supra, 44 Cal.App.4th at p. 54, fn. 9.) Nava is correct that “[w]here an entire class of evidence has been declared inadmissible or the trial court has clearly intimated it will receive no evidence of a particular class or upon a particular issue, an offer of proof is not a prerequisite to raising the question on appeal, and an offer, if made, may be broad and general. [Citations.]” (Beneficial etc. Ins. Co. v. Kurt Hitke & Co. (1956) 46 Cal.2d 517, 522.) “An offer [or a more specific offer] under those circumstances would be an idle gesture.” (Caminetti v. Pacific Mut. Life Ins. Co. (1943) 23 Cal.2d 94, 100.) Such circumstances did not exist here. Nava failed to make an offer of proof before there was any indication by the trial court that a specific offer of proof would be futile. Instead, defense counsel expressly indicated he was not planning to introduce evidence of specific instances of good conduct and thus made no offer of proof before the trial court made its so-called blanket ruling to exclude such evidence. Moreover, throughout the trial, the trial court showed itself to be willing to revisit evidentiary issues addressed during the pretrial hearing based on evidence that had been presented. There is no indication the trial court would not have given meaningful 26. consideration to a specific offer of proof if counsel had come to view evidence of specific instances of good conduct as relevant to refute the prosecution’s section 1108 evidence. VII. Ineffective Assistance of Counsel Nava has filed a separate petition for writ of habeas corpus claiming his defense counsel rendered ineffective assistance at trial by (1) failing to obtain prison records corroborating his alibi defense; (2) neglecting to present good character evidence to rebut the prosecution’s section 1108 evidence; and (3) not making a specific relevance proffer about a prior accusation of molestation by the victim’s sister against his brother-in-law.8 Standard of Review The defendant has the burden of proving ineffective assistance of trial counsel. To prevail on a claim of ineffective assistance of trial counsel, the defendant must establish not only deficient performance, which is performance below an objective standard of reasonableness, but also prejudice. A court must indulge a strong presumption that counsel’s conduct falls within the wide range of reasonable professional assistance. Tactical errors generally are not deemed reversible. (People v. Maury (2003) 30 Cal.4th 342, 389 (Maury).) Counsel’s decisionmaking is evaluated in the context of the available facts. To the extent the record fails to disclose why counsel acted or failed to act in the manner challenged, appellate courts will affirm the judgment unless counsel was asked for an explanation and failed to provide one, or, unless there simply could be no satisfactory explanation. (Maury, supra, 30 Cal.4th at p. 389.) Prejudice must be affirmatively proved. The record must affirmatively demonstrate a reasonable probability that, but for counsel’s unprofessional errors, the result of the proceeding would have been different. (Maury, supra, 30 Cal.4th at p. 389.) 8By order filed June 5, 2014, we consolidated the appeal with the writ petition. 27. Attorneys are not expected to engage in tactics or to file motions that are futile. (Id. at p. 390; see also People v. Mendoza (2000) 24 Cal.4th 130, 166.) Analysis Nava’s contention fails for three reasons. First, he contends defense counsel rendered ineffective assistance by failing to obtain “easily obtainable” prison visitation records reflecting Nava and his wife visited their son at the prison in Tehachapi at 7:35 a.m. on Saturday, July 23, 2011, thereby corroborating Nava’s alibi defense. The record, however, discloses a reasonable explanation for counsel’s alleged omission. In a letter responding to questions posed by Nava’s retained appellate counsel, defense counsel explained he verified the prison visit with Nava, Nava’s wife, and Jesse. “The victim however testified that this happened early before he departed to visit the son.” Defense counsel further noted Nava’s wife “could have been a good witness but had an emotional meltdown suddenly just before I wanted to call her to the stand and had to be taken to the hospital. Later at sentencing she was back to normal.” On cross-examination, defense counsel elicited testimony from the victim that, to the best of her recollection, the molestation occurred early in the morning on Saturday, July 23, 2011, after Jesse woke her up to get milk from the refrigerator in the garage. Defense counsel’s clarification of the timing of the alleged incident demonstrates why presenting further corroborating evidence of Nava’s alibi would not have been particularly helpful to the defense and therefore counsel was not deficient for failing to develop it. The prosecution did not dispute that Nava and his wife visited their son in prison but posited the theory that if the molestation occurred Saturday morning as the victim recalled, then it must have occurred before Nava and his wife left to visit their son.9 9Forexample, the prosecutor argued: “We heard that the defendant left at 4:00 a.m. If Jesse’s got a baby in that house that early in the morning, doesn’t it make sense that she asked for milk? Doesn’t it make sense [the victim] was already up?... So if the 28.  These circumstances also demonstrate the absence of prejudice. As the prosecution did not dispute the prison trip occurred, Nava’s theory that the jury in this case would have expected him to present prison records to prove the trip and likely rejected his alibi defense based on his failure to do so fails. Second, Nava complains defense counsel was ineffective because “[d]espite being provided over 35 character letters, trial counsel did not request testimony from any number of young girls that were ready and willing to testify that either on family vacations, overnights, or dance rehearsals, despite being alone with [Nava], they were always treated with respect.” Again, the record reveals a satisfactory explanation for counsel’s alleged omission. In his letter to Nava’s appellate counsel, defense counsel explained that “[f]rom a tactical standpoint given the nature of the charges, where it happened, and his active involvement in cultural dancing with young girls I did not feel that would help.” In a case alleging the molestation of a young girl, it was not unreasonable for counsel to decide not to seek the admission of evidence calling the jury’s attention to Nava’s taking an interest in and participating in numerous activities bringing him in close proximity to young girls. Nava also claims defense counsel failed to call Arcelia Valdez as a character witness. She provided a declaration in which she described her long acquaintance and frequent contact with Nava. The record, however, does not disclose whether defense counsel even was aware of this witness. Finally, Nava contends defense counsel was ineffective for failing to investigate charges that were brought, and then later dropped, against Nava’s brother-in-law, Silvano B., for committing lewd acts on the victim’s sister in 1999. defendant’s up at 4:00 a.m. getting ready [to] go to Tehachapi to see his son in prison, then [the victim] was awake. So you can believe it happened Saturday morning because they were both there. There’s an opportunity there. Both there, they’re both awake, they’re moving around the house .…” 29.  Nava asserts that “evidence that there was a prior fabricated charge, or that there was an actual molestation, would both have been highly relevant” to his defense. This is so, he argues, because if the victim’s mother “encouraged her older daughter to lie, this would have significantly called into question her credibility.” On the other hand, if his brother-in-law molested the victim’s sister, this evidence would be relevant to show that the victim “was familiar with certain forms of sexual assault, since her older sister had experienced what, judging by the complaint, appears to be a similar type of sexual assault at a similar age.” This last claim of ineffective assistance of counsel fails because Nava cannot establish prejudice. His relevancy arguments are based entirely on speculation. They assume the victim’s mother either encouraged the victim to lie or the victim was familiar with the acts of sexual abuse allegedly inflicted on her sister over a decade before the alleged conduct in this case. Nava presents no evidence in his writ petition, and no evidence was presented at trial, suggesting the victim’s mother encouraged or coached the victim to fabricate her allegations against Nava, or that the victim was familiar with any prior allegations of sexual abuse against the victim’s sister. Thus, Nava has failed to establish that investigation into charges of sexual abuse by his brother-in-law against the victim’s sister would have yielded relevant evidence affecting the outcome of the proceedings. 30.  DISPOSITION The judgment is affirmed. The petition for a writ of habeas corpus is denied. _____________________ CORNELL, Acting P.J. WE CONCUR: _____________________ DETJEN, J. _____________________ FRANSON, J. 31. 

As one of the nation's leading academic research centers, the University of Pittsburgh has both an[unreadable] opportunity and an obligation to take the inherent risks associated with reengineering a successful research[unreadable] enterprise to undertake a transformative initiative that will result in the development and advancement of[unreadable] clinical and translational science as a distinct discipline in western Pennsylvania. The University is committed[unreadable] to transforming its culture, environment, and structure to achieve this goal by forming the Clinical and[unreadable] Translational Science Institute (CTSI). The CTSI will serve as the integrative academic home for clinical and[unreadable] translational scientists across the University's six health sciences schools; Carnegie Mellon University; the[unreadable] University of Pittsburgh Medical Center (UPMC), one of the nation's largest and most financially successful[unreadable] academic health care systems; and the region. The CTSI's primary focus is to develop, nurture, and support[unreadable] a cadre of clinical and translational scientists by building on the University's existing clinical research training[unreadable] programs (Roadmap K12, K30) to establish a comprehensive program with activities ranging from early[unreadable] research exposure for high school students to advanced doctoral programs. Through "integration and[unreadable] innovation," the CTSI will excel in the development of new biomedical knowledge and the translation of that[unreadable] knowledge from the basic and preclinical research settings to individuals, communities, and health practice.[unreadable] The Children's Hospital of Pittsburgh's General Clinical Research Center (GCRC) and the four sites of the[unreadable] University of Pittsburgh GCRC will be reengineered, integrated, and augmented by new CTSI communitybased[unreadable] and minority health focused centers to develop efficient, accessible, and widely used participant and[unreadable] clinical interaction resources. The CTSI Center for Clinical and Translational Informatics, which is developing[unreadable] translational research informatics tools for the NCI Cancer Biomedical Informatics Grid Initiative, will infuse[unreadable] informatics tools into the entire lifecycle of clinical research studies and develop an online collaborative[unreadable] research community. Innovative interdisciplinary research initiatives will be developed through the ten CTSI[unreadable] resource cores and translated to health practice via a novel CTSI community partnership program and[unreadable] through centralization of UPMC's extensive clinical networks. The resulting transformations in the institution,[unreadable] scientist, research, and health practice will improve health locally, regionally, and nationally.

Cytochrome P450 (CYP) enzymes are involved in numerous detoxification and synthetic processes in addition to generating potent lipid mediators from endogenous substrates. Even though many CYP isozymes can oxidize a spectrum of ω-6 and ω-3 polyunsaturated fatty acids such as retinoic acid, linoleic acid, eicosapentaenoic acid (EPA), and docosahexenoic acid (DHA), they are often referred to as the third pathway of arachidonic acid metabolism, mainly because the most is known about the biological actions of these products ([@bib28]). Angiogenesis is a tightly regulated and organized process, and although numerous studies have addressed the role of specific proteins at the different stages of vascular development ([@bib44]), the role of lipids is less clear. Although cyclooxygenases and prostaglandins have been the focus of some studies ([@bib48]), little is known about the role of CYP-derived lipid mediators. The first link between CYP enzymes and angiogenesis was obtained in co-cultures of astrocytes and endothelial cells in which arachidonic acid epoxides (epoxyeicosatrienoic acids \[EETs\]) released from astrocytes increased endothelial cell proliferation and elicited the formation of capillary-like structures ([@bib35]; [@bib65]). Also, the overexpression of the CYP2C9 epoxygenase in, and/or the application of 11,12- or 14,15-EET to monocultures of endothelial cells was associated with angiogenesis ([@bib32]; [@bib33]). In vivo data rapidly followed to support these in vitro findings, with EETs reported to induce angiogenesis in the chick chorioallantoic membrane ([@bib33]) and the vascularization of Matrigel plugs implanted into wild-type mice ([@bib32]; [@bib60]). Moreover, the overexpression of the human CYP2C11 and 2J2 enzymes in the ischemic rat hindlimb model was found to increase muscle capillary density ([@bib57]). However, such studies could not address the importance of endogenously generated CYP metabolites and were difficult to back up in knockout models, as there are major differences in CYP epoxygenase isoform expression between species. This is particularly true for the CYP2C family of proteins, which have been most frequently linked to angiogenesis ([@bib12]). The majority of studies have also concentrated on the signaling initiated by the EETs, despite the fact that CYP isozymes can oxidize other ω-6 and ω-3 polyunsaturated fatty acids. Intracellular levels of the lipid epoxides are carefully controlled and are determined by their rate of generation by the CYP enzymes, as well as by their metabolism to the corresponding diols by the soluble epoxide hydrolase (sEH; gene = Ephx2; [@bib28]; [@bib22]). The latter enzyme is highly conserved between species, and targeting its expression or activity in mice is an effective way of manipulating fatty acid epoxide and diol levels in vivo ([@bib49]). The aim of this study was to determine the consequences of sEH deletion/inhibition on retinal angiogenesis in mice and to use LC-MS/MS based lipid profiling to identify the lipid underlying the phenotype observed. Here, we report that an sEH-derived metabolite of the ω-3 fatty acid DHA, rather than arachidonic acid, regulates murine retinal angiogenesis, and that a DHA diol generated by Müller glia cells is a major determinant of postnatal retinal angiogenesis via its ability to inhibit the γ-secretase. RESULTS ======= Delayed angiogenesis in sEH^−/−^ retina --------------------------------------- sEH protein and activity were detected in retinas from adult and postnatal wild-type mice ([Fig. 1 A](#fig1){ref-type="fig"}), and although the highest sEH activity was detected in the liver, activity in the retina was greater than that detected in either the spleen or lung ([Fig. 1 B](#fig1){ref-type="fig"}). To study the importance of the sEH in sprouting angiogenesis in vivo, we focused on retinal angiogenesis during the first postnatal week. sEH^−/−^ mice displayed a significant delay in the radial extension of the vascular plexus from the optic nerve to the periphery at postnatal days 2 (P2) and 5, as well as fewer branch points ([Fig. 1 C](#fig1){ref-type="fig"}). The delay in retinal angiogenesis in sEH^−/−^ retinas at P5 was associated with a significant reduction in endothelial cell proliferation (BrdU incorporation) at the angiogenic front ([Fig. 1 D](#fig1){ref-type="fig"}) as well as with fewer tip cells and filopodia ([Fig. 1 E](#fig1){ref-type="fig"}). {#fig1} Because all of these processes are highly dependent on the Notch pathway ([@bib18]; [@bib53]), our findings suggested that Notch signaling may be activated in the sEH^−/−^ animals. We therefore studied the expression of the Notch receptor and ligands as well as the Notch downstream targets Hes1 and Hey1. Retinal Hey1 increased from P2 to P7 in sEH^−/−^ retina, whereas Hes1 levels were elevated in sEH^−/−^ retina on P2 and P5 but decreased by P7 ([Fig. 1 F](#fig1){ref-type="fig"}). Notch1 was up-regulated in sEH^−/−^ mice immediately after birth (P0) but RNA levels then decreased (after P2). A transient increase in retinal delta-like ligand (Dll) 1 was detected on P5 but there were no significant changes in Dll4, which is also a target of activated Notch receptors ([@bib42]). A more detailed analysis of purified (CD31 beads) sEH^−/−^ retinal endothelial cells confirmed the significant up-regulation of Dll4, Hes1, and Hey1 in 5-d-old sEH^−/−^ mice ([Fig. 1 G](#fig1){ref-type="fig"}). Although coverage of the retina by the primary vascular layer was almost complete at day 7 in both genotypes, delayed angiogenesis persisted so that the formation of the secondary capillary plexus was also attenuated at P9 in sEH^−/−^ mice ([Fig. 1 H](#fig1){ref-type="fig"}). Different approaches were taken to ensure that the phenotype observed was related to the lack of sEH activity during retinal development. First, floxed sEH mice (sEH^fl/fl^) mice were bred with CreERT2 mice to generate an inducible sEH knockout strain (sEH^iKO^). Then sEH^iKO^ pups were treated (on P1) with tamoxifen for 4 d, a procedure which decreased sEH expression by ∼80% from day 3 onwards ([Fig. 2 A](#fig2){ref-type="fig"}). The acute postnatal down-regulation of the sEH also attenuated retinal angiogenesis and increased retinal expression of Dll4, Hes1, and Hey1 ([Fig. 2, B--D](#fig2){ref-type="fig"}). The apparent difference in the sEH^−/−^ and sEH^iKO^ retinas can be most likely attributed to the fact that the sEH was still expressed at day 2 in the latter group of animals. The mammalian sEH protein is a homodimer, and each monomer consists of an N-terminal domain which displays lipid phosphatase activity and a larger C terminal which possesses classical α/β-hydrolase activity ([@bib9]; [@bib38]). Therefore, in a second approach to ensure that the defects observed in the sEH^−/−^ mice were due to the loss of epoxide hydrolase activity, newborn wild-type mice were treated with *trans*-4-\[4-(3-adamantan-1-ylureido)cyclohexyloxy\]-benzoic acid (*t*-AUCB), a specific sEH inhibitor which does not affect the activity of the lipid phosphatase domain ([@bib21]). Daily inhibitor treatment from P1 onwards significantly decreased retinal vascularization (assessed at P5) compared with vehicle-treated littermates, and this delay was accompanied by a significant increase in the expression of Dll4, Hes1, and Hey1 ([Fig. 2, E--G](#fig2){ref-type="fig"}). {#fig2} Expression of the sEH in Müller glia cells and astrocytes --------------------------------------------------------- In retinal cross sections, the sEH was detected in the ganglion cell, inner plexiform, and outer plexiform layers but did not colocalize with the Isolectin B4 staining of the vasculature. Rather, the sEH colocalized with glutamine synthase (GS; [Fig. 3 A](#fig3){ref-type="fig"}), as well as vimentin ([Fig. 3 B](#fig3){ref-type="fig"}), aquaporin 4 (AQP-4), and, to a certain extent, glial fibrillary acidic protein (GFAP; [Fig. 3 C](#fig3){ref-type="fig"}). In whole mount preparations, the sEH was detected in short AQP-4--positive processes surrounding the vasculature but not in the vessels themselves---i.e., consistent with expression in Müller cell processes ([Fig. 3 D](#fig3){ref-type="fig"}). Indeed, Müller cells freshly isolated from adult retinas displayed the typical morphology with multiple end-feet and expressed the sEH protein ([Fig. 3 E](#fig3){ref-type="fig"}). Although the morphology of the Müller cells in culture was markedly different from that of freshly isolated cells, they continued to express the sEH, as well as AQP-4 and the Müller cell marker cellular retinaldehyde binding-protein (CRALBP; [@bib6]; [Fig. 3 F](#fig3){ref-type="fig"}). {#fig3} To target sEH expression in Müller cells, sEH^fl/fl^ mice were crossed with platelet-derived growth factor receptor α polypeptide (Pdgfra)--cre deleter mice ([@bib47]). The resulting Müller cell--specific sEH knockout mice (sEH^ΔMC^) showed a greatly reduced expression of the sEH in the inner and outer plexiform layers of the retina ([Fig. 4 A](#fig4){ref-type="fig"}), decreased retinal epoxide hydrolase activity ([Fig. 4 B](#fig4){ref-type="fig"}), and reproduced the delay in angiogenesis ([Fig. 4, C--E](#fig4){ref-type="fig"}) as well as the altered tip cell morphology ([Fig. 4, F--H](#fig4){ref-type="fig"}) of the sEH^−/−^ mice. These phenomena were also linked to altered Notch signaling, as Hes1 and Hey1 expression were also increased in retinas from 5-d-old sEH^ΔMC^ mice ([Fig. 4 I](#fig4){ref-type="fig"}). {#fig4} Several studies have highlighted the role of the astrocyte framework as a template for the primary plexus outgrowth as well as a source of angiogenic growth factors ([@bib51]; [@bib15]). Given that the sEH is expressed in astrocytes ([@bib45]) and that the sEH was partially colocalized with GFAP, we generated mice with astrocyte-specific deletion of the sEH (sEH^fl/fl^ mice crossed with GFAP-cre deleter mice). Astrocyte-specific deletion of the sEH ([Fig. 5 A](#fig5){ref-type="fig"}) resulted in the development of a less dense upper capillary layer characterized by fewer branching points in central areas and at the leading edge ([Fig. 5 B](#fig5){ref-type="fig"}). The marked delay in radial extension observed in global sEH^−/−^ mice was, however, not observed. In addition, tip cell numbers and filopodia length were comparable in sEH^fl/fl^ and GFAP-sEH mice ([Fig. 5 C](#fig5){ref-type="fig"}), as were the expression of Hes1 and Hey1 ([Fig. 5 D](#fig5){ref-type="fig"}). These data indicated that the sEH expressed in Müller cells played a more prominent role in regulating angiogenesis than the sEH in astrocytes. {#fig5} Müller cell lipid profile ------------------------- Müller cells are a rich source of angiogenesis-promoting growth factors, in particular vascular endothelial cell growth factor (VEGF) A ([@bib43]; [@bib52]). Therefore, we compared the effects of conditioned medium (CM) from wild-type and sEH^−/−^ Müller cells on endothelial cell proliferation. CM from sEH-expressing Müller cells potentiated endothelial cell proliferation, whereas the CM from sEH^−/−^ Müller cells exhibited a weaker effect ([Fig. 6 A](#fig6){ref-type="fig"}). There were no differences in VEGFR1, VEGFR2, or VEGFR3 expression in retinas from wild-type and sEH^−/−^ mice over the first postnatal week (unpublished data). VEGF levels were also similar in whole retinas from wild-type and sEH^−/−^ mice up to day 9 ([Fig. 6 B](#fig6){ref-type="fig"}), but the generation of VEGF was reduced in Müller cells and in CM from sEH^−/−^ mice ([Fig. 6, C and D](#fig6){ref-type="fig"}). The expression of the anti-angiogenic pigment epithelium-derived factor ([@bib10]) was not different in CM from wild-type and sEH^−/−^ Müller cells. Despite the apparent difference in VEGF secretion, VEGF neutralizing antibodies elicited similar effects on endothelial cells treated with wild-type-CM or sEH^−/−^-CM ([Fig. 6 E](#fig6){ref-type="fig"}). {#fig6} However, a soluble factor was responsible for the observed phenotype, as when sEH^−/−^ Müller cells were co-cultured with, but kept physically separated from, endothelial cells (Transwell chambers), endothelial cell proliferation (assessed by BrdU incorporation) was attenuated. Moreover, the reexpression (adenoviral transduction) of the sEH in Müller cells normalized endothelial cell proliferation ([Fig. 6 F](#fig6){ref-type="fig"}). Similarly, the expression of Hes1 and Hey1 increased in endothelial cells cultured with sEH^−/−^ versus wild-type Müller cells ([Fig. 6 G](#fig6){ref-type="fig"}), and a rescue experiment, in which the sEH was reintroduced into sEH^−/−^ Müller cells, reversed these effects. To determine which of the sEH substrates or products could account for the delay in retinal angiogenesis, lipid profiles (LC-MS/MS) were generated from the retinas of 5-d-old wild-type and sEH^−/−^ mice. As expected, levels of 11,12- and 14,15-EET were increased in samples from sEH^−/−^ mice, whereas the levels of the corresponding diols were slightly decreased ([Fig. 7 A](#fig7){ref-type="fig"}). However, the most pronounced changes were in the levels of the DHA derivative 19,20-dihydroxydocosapentaenoic acid (DHDP). In CM from sEH^−/−^ Müller cells, 11,12-EET, 14,15-EET, and 19,20-epoxydocosapentaenoic acid (EDP) levels were significantly increased in CM and were restored to control by adenoviral transduction of the sEH ([Fig. 7 B](#fig7){ref-type="fig"}). The opposite was true for 19,20-DHDP, which was attenuated in CM from sEH^−/−^ Müller cells and restored by sEH overexpression. There was no significant change in 11,12-dihydroxyeicosatrienoic acid (DHET) levels, 14,15-DHET levels were below the limit of detection, and there were no apparent changes in the levels of the linoleic acid--derived fatty acids, 12,13-epoxyoctadecenoic acid (EpOME), or 12,13-dihydroxyoctadecenoic acid (DiHOME). {#fig7} 19,20-DHDP and Notch signaling ------------------------------ 19,20-DHDP is of particular interest, given that it was the most abundant lipid detected in the retinal lipid profile and that its precursor DPA has previously been reported to modulate the activity of the γ-secretase ([@bib11]; [@bib16]). When activated, the γ-secretase cleaves the Notch intracellular domain (NICD), which then either undergoes rapid proteasome degradation or translocates to the nucleus and binds to transcription factors ([@bib5]). We therefore compared the ability of 19,20-DHDP and the corresponding epoxide and sEH substrate 19,20-EDP to influence Dll4-stimulated Notch activity in murine endothelial cells. Although 19,20-EDP had no effect on the Dll4-induced increase in NICD cleavage, 19,20-DHDP decreased NICD levels by 54 ± 12% versus 89 ± 7% inhibition in the presence of the γ-secretase inhibitor *N*-\[*N*-(3,5-Difluorophenacetyl)-[l]{.smallcaps}-alanyl\]-S-phenylglycine t-butyl ester (DAPT; [Fig. 7 C](#fig7){ref-type="fig"}). Neither 19,20-EDP nor 19,20-DHDP affected VEFGR phosphorylation or downstream signaling in vascular endothelial cells (unpublished data). Treatment of cells with other sEH substrates, e.g., 11,12-EET, 14,15-EET, or 12,13-EpOME, or products, e.g., 11,12-DHET, 14,15-DHET, or 12,13-DiHOME, that were altered in the sEH^−/−^ retinas had no effect on the Dll4-induced cleavage of NICD ([Fig. 7, D--F](#fig7){ref-type="fig"}). When the nuclear translocation of the NICD was assessed by immunofluorescence ([Fig. 8 A](#fig8){ref-type="fig"}), 19,20-DHDP, but not 19,20-EDP, attenuated the Dll4-stimulated translocation. The fact that 19,20-DHDP also attenuated NICD levels in the presence of the proteasome inhibitor MG 132 ([Fig. 8 B](#fig8){ref-type="fig"}) suggested that the generation of the NICD, rather than its degradation, was targeted by the lipid. {#fig8} The binding of a Notch ligand to a Notch receptor initiates two steps of cleavage to generate the NICD, the first by ADAM (a disintegrin and metalloprotease) proteases and the second by the γ-secretase ([@bib29]). The effect of 19,20-DHDP on the γ-secretase was evaluated using cells expressing a Notch 1 mutant (NotchΔE) that lacks the extracellular domain of the protein and possesses only the γ-secretase cleavage site ([@bib17]). We found that 19,20-DHDP, but not 19,20-EDP, reduced the γ-secretase--dependent generation of NICD from NotchΔE ([Fig. 8 C](#fig8){ref-type="fig"}). The small effect observed at higher concentrations of 19,20-EDP can most likely be attributed to the endogenous expression of the sEH in the cells used ([@bib3]) and its conversion to 19,20-DHDP. The γ-secretase complex is made up of several proteins, including presenilin 1, nicastrin, anterior pharynx defective 1, and presenilin enhancer 2, and the active complex is localized to lipid rafts ([@bib56]; [@bib20]; [@bib55]). We therefore determined whether 19,20-DHDP could inhibit the γ-secretase by altering the localization of constituent proteins and concentrated on presenilin 1. After sucrose density gradient fractionation, presenilin 1 and the raft-associated protein flotillin-1/reggie-2 were detected in detergent-insoluble lipid raft fractions (fractions 5 and 6) isolated from solvent--treated cells. 19,20-DHDP caused the displacement of presenilin 1 from lipid rafts to non-raft fractions (fractions 10 to 12) without affecting the distribution of flotillin-1 ([Fig. 8 D](#fig8){ref-type="fig"}). The latter effect that was accompanied by a decrease in cholesterol levels in the raft fractions (fractions 5 and 6) and an increase in the non-raft fractions ([Fig. 8 E](#fig8){ref-type="fig"}). Neither 19,20-EDP (in the presence of the sEH inhibitor *t*-AUCB) nor DAPT affected the colocalization of presenilin 1 with flotillin-1 or the distribution of cholesterol between the different fractions. Finally, we determined whether or not 19,20-DHDP could rescue the retinal phenotype in sEH^−/−^ mice. Intravitreal injection of 19,20-DHDP was performed in 5-d-old wild-type and sEH^−/−^ pups and its effects compared with that of DAPT-treated mice. As before, the sEH^−/−^ retinas demonstrated a less dense vessel network as well as fewer tip cells and filopodia than their wild-type littermates, but this phenotype was largely reversed after the administration of 19,20-DHDP ([Fig. 9](#fig9){ref-type="fig"}). Similar effects were observed in retinas from animals receiving DAPT, whereas 19,20-EDP was without effect. In retinas from wild-type mice, 19,20-DHDP (but not 19,20-EDP) also induced a more complex vessel network, and increased tip cell and filopodia numbers ([Fig. 9](#fig9){ref-type="fig"}). {#fig9} The E3 ubiquitin ligase Fbxw7 is involved in the ubiquitination and degradation of the NICD ([@bib54]; [@bib61]), and endothelial cell-specific and inducible Fbxw7 mutant (Fbxw7^iECKO^) mice demonstrate retinal blood vessel growth impairment that is attributable to Notch activation ([@bib25]). To confirm the in vitro data suggesting that 19,20-DHDP inhibits γ-secretase activity, the lipid was given intravitrealy to Fbxw7^iECKO^ mice. Also in these animals, 19,20-DHDP increased sprouting and filopodia numbers ([Fig. 10](#fig10){ref-type="fig"}), confirming the inhibition of NICD generation by the lipid. Similar effects were observed in animals that received DAPT, whereas 19,20-EDP was without effect. {#fig10} DISCUSSION ========== The results of the present study show that the genetic deletion and inhibition of the sEH activates Notch signaling and attenuates physiological sprouting angiogenesis in the murine retina. Mechanistically, these effects could be attributed to the lack of the sEH product 19,20-DHDP, a fatty acid diol derived from DHA which inhibits the γ-secretase by inducing the redistribution of presenilin 1 from lipid rafts. Moreover, 19,20-DHDP, but not the parent epoxide, was able to rescue the defective angiogenesis in sEH^−/−^ mice as well as in animals lacking the Fbxw7 ubiquitin ligase which demonstrate strong basal activity of the Notch signaling cascade. Müller glia cells were identified as the major source of the sEH in the murine retina. These cells develop and maintain a close contact with both superficial vessels and deeper capillaries via their multiple end-feet ([@bib37]) and have been implicated in angiogenesis by virtue of their ability to produce angiogenic substances in response to hypoxia ([@bib43]; [@bib52]; [@bib46]). However, as the Müller cell--specific deletion of VEGF-A inhibited neovascularization in a mouse model of oxygen-induced retinopathy without affecting physiological vascularization or retinal morphology ([@bib2]), it was assumed that Müller cells play a greater role in proliferative retinopathy than physiological angiogenesis. In our study, the deletion of the sEH in Müller cells clearly affected endothelial cell proliferation as well as Notch signaling and tip cell filopodia formation in mice, indicating that Müller cells make a more important contribution to retinal angiogenesis than generally appreciated. Interestingly, several recent studies also support a role for VEGF-independent signaling by Müller cells in developmental angiogenesis. For example, Müller cells secrete Norrin, a retinal signaling molecule which binds to Frizzled-4 to activate canonical Wnt/β-catenin signaling, in the absence of which the development of the superficial vessels was attenuated and deeper intraretinal capillaries were not formed ([@bib63]; [@bib64]; [@bib39]). Also, the deletion of hypoxia inducible factor-1α in neuroretinal cells (includes Müller cells) results in impaired vascular development characterized by decreased tip cell filopodia and reduced vessel branching ([@bib36]), a phenotype very similar to that of sEH^−/−^ mice. The Müller cell--specific sEH knockout (sEH^ΔMC^) mice were generated using Pdgfra-cre mice ([@bib47]), which may also target astrocytes. Also, because astrocytes express the sEH ([@bib45]) and retinal angiogenesis is generally thought to be largely determined by astrocyte-derived VEGF ([@bib52]), we also focused on this interaction. However, although vessel branching was impaired in retinas from astrocyte-specific sEH knockout (GFAP-sEH) mice, the tip cell phenotype and Notch signaling (Hes1 and Hey1 expression) were unaltered, suggesting that another sEH-expressing cell type underlies the effects observed. Our findings do not completely rule out a role for astrocyte sEH in retinal angiogenesis but rather indicate that another source of the sEH plays a more dominant role. To date, the CYP--sEH axis has been linked with the promotion of angiogenesis, as the epoxides of arachidonic acid (particularly 11,12- and 14,15-EET) promote tube formation in vitro ([@bib35]; [@bib33]) and can promote the vascularization of matrix material and tumors in vivo ([@bib26]). For a while, sEH inhibitors looked like highly interesting compounds for the treatment of cardiovascular disorders ([@bib23]), but interest was dampened by speculation that the associated increase in EET levels could induce or promote cancer progression. Certainly, tumor growth and metastasis can be increased by sEH inhibition in transgenic mice with high vascular EET levels, i.e., animals that overexpressed either the human CYP2C8 or human CYP2J2 specifically in Tie-2--expressing cells or that were treated with high concentrations of 14,15-EET ([@bib40]). The latter models were somewhat artificial and focused on the products of arachidonic acid metabolism, largely ignoring the biological actions of other lipids that feed into the same CYP--sEH axis. It was partly to assess the role of the sEH in angiogenesis under more physiological conditions that we determined the effects of the global and induced deletion of the sEH, as well as its pharmacological inhibition in the postnatal murine retina. We found that sEH deletion and inhibition resulted in markedly decreased capillary branching and endothelial cell proliferation as well as reduced tip cell numbers and filopodia. If the epoxides of arachidonic acid possess angiogenic properties, why was angiogenesis attenuated in retinas from sEH^−/−^ mice which demonstrate higher than normal circulating and tissue levels of EETs? One logical explanation is that other lipids generated by the sequential activity of CYP epoxygenases and the sEH exert effects that dominate over, or antagonize those of, the EETs. The retinal phenotype observed could have been due to the accumulation of an anti-angiogenic epoxide or the loss of a pro-angiogenic diol, even though lipid diols are generally assumed to be either inactive or markedly less active than the parent epoxides ([@bib23]). To identify such lipids, we used an LC-MS/MS--based lipid profiling approach to screen for the lipid epoxide or diol most affected by the deletion of the sEH in the retina and found that 11,12-EET, 14,15-EET, and 12,13-EpOME were elevated, whereas 19,20-DHDP was attenuated in retinas from sEH^−/−^ mice. These findings could be confirmed in isolated Müller cells. Interestingly, DHA levels are known to be higher than those of arachidonic acid in the retina ([@bib1]), and we detected higher levels of the DHA-derived lipids 19,20-EDP and 19,20--DHDP than the epoxides and diols of arachidonic acid in retinas from 5-d-old mice. Which of the lipids affected by the deletion of the sEH could contribute to the development of the retinal phenotype in sEH^−/−^ mice? A significant delay in the radial extension of the vascular plexus, coupled with reduced endothelial cell proliferation as well as with fewer tip cells and filopodia, are indicative of Notch signaling activation ([@bib18]; [@bib53]). Therefore, we assessed the ability of all four candidate lipids to influence Dll4-stimulated Notch activity and the generation of the NICD. However, the sEH product 19,20,-DHDP and not the sEH substrates 19,20-EDP, 11,12-EET, 14,15-EET, or 12,13-EpOME attenuated NICD levels. Two distinct cleavage steps are required to generate the NICD; the first is dependent on ADAM proteases and the second on the activity of the γ-secretase ([@bib29]). To determine which of these proteases could be targeted by 19,20-DHDP, we assessed its ability to influence the Dll4-induced generation of the NICD from a so-called NotchΔE that possesses only the γ-secretase cleavage site ([@bib17]). The finding that 19,20-DHDP also affected NICD generation in this model indicated that its molecular target was the γ-secretase. To confirm this in vivo, we assessed the consequences of the intravitreal application of 19,20-EPD or 19,20-DHDP to 5-d-old mice with hyper-activated endothelial cell Notch signaling, i.e., animals lacking the E3 ubiquitin ligase involved in the ubiquitination and degradation of the NICD ([@bib25]). In the latter Fbxw7^iECKO^ animals, which demonstrate markedly impaired retinal blood vessel growth impairment that is attributable to Notch activation ([@bib25]), 19,20-DHDP increased vessel branching as well as tip cell and filopodia numbers. The γ-secretase inhibitor DAPT elicited similar effects, whereas 19,20-EDP was ineffective. Fatty acid epoxides such as the EETs are thought to act via a specific membrane receptor or the activation of peroxisome proliferator-activated receptors ([@bib50]; [@bib41]). How can fatty acid diols exert biological effects that could lead to the inhibition of the γ-secretase? A cell surface receptor may not be essential, as polyunsaturated fatty acids can incorporate into membrane phospholipids and potentially influence cell signaling and biological responses by modulating the lipid microenvironment therein ([@bib27]). Certainly, the fish oils EPA and DHA are readily incorporated into phospholipids and the resulting polyunsaturated phospholipids are able to infiltrate lipid rafts as well as form non-raft domains ([@bib62]). DHA, from which 19,20-DHDP is derived, is particularly interesting in this respect as it tends to incorporate more readily into lipid rafts than EPA ([@bib62]). Changes in the lipid composition of the plasma membrane can have marked consequences of the formation and stability of the γ-secretase complex ([@bib56]; [@bib55]). We found that 19,20-DHDP, but not the corresponding epoxide, altered cholesterol distribution in cellular membranes and displaced presenilin 1 from lipid rafts, where the processing of substrate proteins preferentially occurs, to non-raft fractions, thus disrupting the γ-secretase complex. Little is known about the incorporation of DHA-derived epoxides or diols into phospholipids, but this is highly likely given that the epoxides of arachidonic acid (the EETs) can be esterified to phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositols ([@bib7]). This is not the first time a link between DHA and the γ-secretase has been reported, and although DHA increased γ-secretase activity in vascular smooth muscle cells ([@bib11]), it was found to redistribute cholesterol out of lipid rafts ([@bib58], [@bib59]), thereby decreasing γ-secretase activity in a neuroblastoma cell line ([@bib16]). Our results agree with the latter study. Moreover, given that fatty acids such as DHA are rapidly metabolized by CYP and sEH enzymes and that the DHA epoxide 19,20-EDP had no effect on the γ-secretase, it is possible that the DHA diol 19,20-DHDP and the activity of the sEH may underlie the previously reported changes in lipid raft composition and biological responses rather than DHA on its own. These studies highlight the fact that consequences of sEH inhibition in vivo cannot be solely attributed to the accumulation of the epoxides or arachidonic acid. In fact, more and more evidence is being accumulated to demonstrate that other lipid products (epoxides and diols) of the CYP--sEH axis can affect different steps in vessel development and maturation. For example, the sEH products 12,13-DiHOME (generated from the linoleic acid epoxide 12,13-EpOME), and to a lesser extent 11,12-DHET (generated from 11,12-EET), attenuate angiogenesis and vascular repair via the activation of the canonical Wnt pathway ([@bib14]). Moreover, the combination of 19,20-EDP with an sEH inhibitor was reported to inhibit primary tumor growth and metastasis by preventing the VEGF-induced phosphorylation of VEGFR2 ([@bib66]). However, why the latter lipid failed to affect retinal angiogenesis is unclear at the moment but fits with our finding that the phenotype observed in the sEH^−/−^ mice was independent of VEGF signaling. Our study also highlights the role of the neuroretina and particularly the sEH in Müller cells in the regulation of retinal angiogenesis. It will be interesting to determine whether or not this mechanism can be exploited and whether the pathological retinal angiogenesis associated with Müller cell activation ([@bib8]), such as that observed in oxygen-induced retinopathy in preterm infants, can be linked to altered lipid signaling and modulated by sEH inhibition. MATERIALS AND METHODS ===================== ### Materials. The sEH inhibitor *t*-AUCB was provided by B. Hammock (University of California, Davis, Davis, CA). The proteasomal inhibitor MG-132 was obtained from EMD Millipore. Mouse and human Dll4 protein were obtained from R&D Systems. DAPT, tamoxifen, and all other chemicals were purchased from either Sigma-Aldrich or Merck and Roth. ### Animals. C57BL/6 mice (6--8 wk old) were purchased from Charles River. sEH^−/−^ mice ([@bib49]) were provided by F. Gonzalez (National Institutes of Health, Bethesda, MD) and cross-bred for ∼20 generations onto the C57BL/6 background in the animal house facility at Frankfurt University. Inducible and endothelial cell--specific Fbxw7^iECKO^ mutant mice, generated as described previously ([@bib25]), were treated with tamoxifen (1 mg/ml i.p., 2% ethanol in sunflower oil, 50 µl) once a day from days 1--4. Floxed sEH (sEH^fl/fl^) mice (Taconic) were generated using C57BL/6 embryonic stem cells for gene targeting. Positive selection cassettes flanked by FRT/F3 sites were deleted by crossing with a ubiquitously expressing FLP1 recombinase strain (Taconic). These animals were cross-bred with animals expressing Cre under the control of the GFAP promoter (FVB-TgGFAP-cre25Mes \[[@bib67]\] backcrossed in the C57BL/6 background) to generate mice lacking sEH in astrocytes. Inducible sEH knockout mice (iCreER-sEH) were generated by breeding sEH^fl/fl^ mice with the RosaCre-ER-T2 strain ([@bib24]; cross-bred to C57BL/6) and Müller cell--specific sEH-deficient mice (sEH^ΔMC^) were generated by crossing the sEH^fl/fl^ mice with C57BL/6-TgPdgfra-cre1Clc/J mice ([@bib47]; The Jackson Laboratory). Mice were housed in conditions that conform to the *Guide for the Care and Use of Laboratory Animals* published by the U.S. National Institutes of Health (publication no. 85--23). All experiments were approved by the governmental authorities (Regierungspräsidium Darmstadt: F28/06, F28/23, and F28/38; Münster: 84-02.04.2011.A257). Age-, gender-, and strain-matched animals (usually littermates) were used throughout. ### sEH inhibition and postnatal deletion studies. To inhibit epoxide hydrolase activity, C57BL/6 pups received *t*-AUCB (2 mg/kg i.p., twice per day) from days 1--4. To postnatally delete the sEH, iCreER-sEH transgenic mice were treated with tamoxifen (1 mg/ml i.p., 2% ethanol in sunflower oil, 50 µl) once a day from days 1--4 as previously described ([@bib4]). On day 5, retinas were isolated for Western blotting and immunohistochemistry. ### Intravitreal injection. Mice were anesthetized with 2% isoflurane. A drop of 0.5% proparacaine was administered as a topical local anesthesia. A fine glass micropipette connected to a 10 µl Hamilton glass syringe was inserted through the incision in the cornea and slid between the iris and the lens into the posterior chamber of the eye. Each eye received 0.5 µl 19,20-EDP, 100 µmol/liter 19,20-DHDP, or 200 µmol/liter DAPT or 0.5 µl of solvent (1% DMSO in PBS) as control. Injections were administered slowly over approximately one minute and monitored with a stereo microscope. ### Endothelial cell proliferation in vivo. Proliferating endothelial cells in P5 retinas were labeled by administering BrdU (50 mg/kg i.p.; BD) 4 h before sacrifice. After Isolectin B4 staining, retinas were post-fixed for 30 min in 4% paraformaldehyde (PFA), washed three times with PBS, incubated for 1 h in 1 M HCl, washed five times in PBS, blocked, and incubated overnight with anti-BrdU antibody (1:50; BD). Secondary detection was performed with Alexa Fluor--coupled secondary antibodies. ### Retina preparation and analysis. Retinas for whole-mount immunohistochemistry were fixed in 4% PFA for 2 h at room temperature, or overnight at 4°C. After fixation, retinas were blocked and permeabilized in 1% BSA and 0.5% Triton X-100 overnight at 4°C. Then retinas were washed three times in Pblec buffer (0.5% Triton X-100, 1 mM CaCl~2~, 1 mM MgCl~2~, and 1 mM MnCl~2~ in PBS, pH 6.8) and incubated overnight in Pblec containing Fitc-labeled Isolectin B4 (1:100; Sigma-Aldrich). The following primary antibodies were diluted in 1% BSA and 0.5% Triton X-100 and incubated overnight: sEH (1:250; provided by M. Arand, Institute of Pharmacology and Toxicology, Uinversity of Zurich, Zurich, Switzerland), GFAP (1:500; DAKO; or 1:1,000; EMD Millipore), NG-2 (1:1,000; EMD Millipore), AQP-4 (1:500; Santa Cruz Biotechnology, Inc.), GS (1:1,000; EMD Millipore), and vimentin (1:500; Nococastra). For secondary detection, Alexa Fluor--coupled secondary antibodies (1:200) were used. Cell nuclei were visualized with DAPI (1:200; Molecular Probes). After antibody staining, retinas were post-fixed in 4% PFA for 15 min before flat-mounting in mounting medium (Dako). 10-µm cryosections were cut after retinas were embedded within Tissue-Tek OCT Compound (Sakura). All quantification was done with high-resolution images taken using a meta laser scanning confocal microscope (LSM-510; Carl Zeiss) as previously described ([@bib30]). ### LC-MS/MS lipid profiles. Samples were extracted twice into ethyl acetate, evaporated under nitrogen, and resuspended in methanol/water (vol. 1:2). The eicosanoid profiles generated were determined with a mass spectrometer (API4000; AB Sciex) operating in multiple reaction monitoring (MRM) mode as previously described ([@bib34]; [@bib14]). Chromatography was performed on a Gemini C18 column (150 mm length, 2 mm inner diameter; particle size, 5 µm; Phenomenex). All fatty acid epoxides, diols, and deuterated analogues were obtained from Cayman Europe. ### Müller cell culture. Müller cells were isolated from 8--12-d-old mice, as previously described ([@bib19]), and cultured in DMEM/F12 containing 10% FCS (Biochrom), 100 U/ml penicillin, and 100 µg/ml streptomycin. After 6 d, the cultures were rinsed free of nonadherent tissue, and culture medium was replenished every 3--4 d. The purity of the Müller cell cultures was characterized after each passage by testing for the expression of vimentin, AQP-4, GS, and CRALBP ([@bib6]). Müller cell CM was generated by culturing confluent wild-type or sEH^−/−^ Müller cells for 48 h. ### Adenovirus generation and Müller cell transduction. The human sEH (Ephx2) cDNA sequence, with a C-terminal Myc/His tag, was excised via NotI--PmeI from *pcDNA3*.1myc/His as previously described ([@bib3]) and cloned into the NotI--EoRV site of the cloning plasmid pAdTrackCMV. The recombination into the adenoviral transfer plasmid and the generation of the viruses was performed as previously described ([@bib31]). For the sEH rescue experiments, sEH^−/−^ Müller cells were infected with sEH adenovirus for 6 h and then washed four times with Hank's solution. Experiments were performed after an additional 48 h and sEH expression was confirmed by immunoblotting. ### Müller cell and endothelial cell co-culture. 1 × 10^6^ endothelial cells isolated as previously described ([@bib13]) were seeded on 6-well plates coated with fibronectin. After 4 h, the nonadherent cells were removed and the medium was replaced with 1.1 ml DMEM/F12 containing 10% FCS. Then Transwell inserts (Millipore) were added to the wells and seeded with 6 × 10^5^ Müller cells. After 8 h, the insert was removed and RNA was extracted from the endothelial cells. ### Müller cell CM on endothelial cell proliferation. 5 × 10^4^ endothelial cells were seeded in 24-well plates and stimulated with M-CM from wild-type or sEH^−/−^ Müller cells (mixed with endothelial cell growth medium at 1:1 ratio), or solvent (DMEM/F12). Mouse VEGF at a final concentration of 50 ng/ml was used as a positive control. Viable cells were counted (CASY; Roche) after 24, 48, and 72 h of stimulation. For the BrdU incorporation, endothelial cells were seeded in 96-well plates (1 × 10^4^ cells/well) and stimulated with the same condition as described above for 48 h. BrdU was added to cells 4 h before the end of stimulation and then BrdU incorporation was assessed using BrdU ELISA kit (Roche) according to the manufacturer's instructions. ### Retinal endothelial cell isolation. Retinas were isolated from P5 mice. After digestion with 0.1% trypsin (Worthington Biochemical Corporation) and 70 U/ml collagenase type I (Biochrom) in DMEM/F12 medium at 37°C for 30 min, retinal endothelial cells were isolated with anti--mouse CD 31 antibody based on magnetic bead separation similar to that described above. CD-31--positive cells were used for gene expression analysis. ### RT-qPCR. Total RNA from retinas or cultured primary cells was extracted using an RNeasy kit (QIAGEN), and equal amounts (1 µg) of total RNA was reverse transcribed (Superscript III; Invitrogen). Gene expression levels were detected using SYBR Green (Absolute QPCR SYBR Green Mix; Thermo Fisher Scientific). The TaqMan probe used for the detection of the Dll4 RNA was from Applied Biosystems. The relative expression levels of the different genes studied was calculated using the 2^−ΔΔCt^ method with the 18S RNA as a reference. The primer sequences used were as follows: 18S forward, 5′-CTTTGGTCGCTCGCTCCTC-3′, reverse, 5′-CTGACCGGGTTGGTTTTGAT-3′; Dll1 forward, 5′-CATCCGATACCCAGGTTGTC-3′, reverse, 5′-ACGGCTTATGGTGAGTACAG-3′; Jagged1 forward, 5′-TCTCTGACCCCTGCCATAAC-3′, reverse, 5′-TTGAATCCATTCACCAGATCC-3′; Notch1 forward, 5′-CCTCAGATGGTGCTCTGATG-3′, reverse, 5′-CTCAGGTCAGGGAGAACTAC-3′, Hes1, forward, 5′-GAGGCGAAGGGCAAGAATAAA-3′, reverse, 5′-GTGGACAGGAAGCGGGTCA-3′; Hey1 forward, 5′-TGAGCTGAGAAGGCTGGTAC-3′, reverse, 5′-ACCCCAAACTCCGATAGTC-3′; and VEGF forward, 5′-GCACTGGACCCTGGCTTTACTGCTGTA-3′, and reverse, 5′-GAACTTGATCACTTCATGGGACTTCTGCTC-3′. ### Dll4-induced NICD production. Endothelial cells were seeded onto 6-well plates coated with or without 500 ng/ml recombinant mouse Dll4 protein (R&D Systems) in 0.1% BSA/PBS for 1 h at room temperature. Experiments were performed in the presence of solvent, 10 µmol/liter 19,20-EDP/DHDP, 10 µmol/liter 11,12-EET/DHET, 10 µmol/liter 14,15-EET/DHET, 3 µmol/liter 12,13-EpOME/DiHOME, 20 µmol/liter DAPT, or 10 µmol/liter MG 132. After an additional 4 h, cells were washed three times with PBS and lysed in a Triton X-100--containing buffer. Intracellular domain of Notch (NICD) levels were assessed by Western blotting with an S3 (γ-secretase) cleavage-specific antibody Val1744 (Cell Signaling Technology). For the nuclear translocation of NICD, cells were fixed with 4% PFA for 15 min at room temperature, followed by NICD and DAPI immunostaining. Co-localization of NICD with DAPI was quantified with ImageJ software (National Institutes of Health). ### γ-Secretase assay. HEK 293 cells were seeded in 10 cm culture dishes and transfected with 6 µg NotchΔE construct (provided by P. Greengard, Rockefeller University, New York, NY). Cells were then incubated with solvent, 19,20-EDP, 19,20-DHDP (0.1--10 µmol/liter), or DAPT (20 µmol/liter) for 24 h. The γ-secretase--dependent generation of NICD was detected as described above. ### Lipid rafts. HEK293 cells were incubated with solvent (0.1% DMSO), 10 µmol/liter 19,20-EDP, 10 µmol/liter 19,20-DHDP, or 20 µmol/liter DAPT in serum-free medium containing 10 µmol/liter of the sEH inhibitor *t*-AUCB for 2 h at 37°C. Cells were then washed twice with ice-cold PBS, harvested by scraping, recovered by centrifugation (300 g for 4 min), and resuspended in 2 ml MBS buffer (containing 1% CHAPSO in 25 mM MES, pH 6.5, 150 µmol/liter NaCl supplemented with a protease inhibitor mix, and 1 µmol/liter phenylmethylsulfonyl fluoride), and homogenized by using a glass homogenizer. Lipid rafts were isolated as previously described ([@bib56]). In brief, after 30 min at 4°C, equal amounts of protein were adjusted to a final sucrose concentration of 45% (final volume, 4 ml) and transferred to 12 ml ultracentrifuge tubes. A discontinuous sucrose gradient was then formed by sequentially overlaying 4 ml of 35% and 4 ml of 5% sucrose. Samples were subjected to ultracentrifugation (35,000 rpm, 4°C for 20 h) using a rotor (SW 41; Beckman). After centrifugation, twelve 1 ml fractions were collected using a capillary tube connected to a peristaltic pump, and equal volumes of each faction were analyzed by SDS-PAGE using antibodies against flotillin 1 (BD) and presenilin 1 (Santa Cruz Biotechnology, Inc.). Cholesterol levels in the different fractions were determined using the Amplex Red cholesterol assay (Invitrogen) according to the manufacturer's instructions. ### Statistical analysis. Data are expressed as mean ± SEM, and statistical evaluation was performed using Student's *t* test for unpaired data or one-way ANOVA, followed by a Bonferroni's *t* test where appropriate. Values of P \< 0.05 were considered statistically significant. The authors are indebted to Isabel Winter and Katharina Engel-Herbig for expert technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (SFB-TR 23/A6, GRK 880 and Exzellenzcluster 147 "Cardio-Pulmonary Systems"). J. Hu was supported by a research scholarship from China Scholarship Council (CSC). The authors declare no competing financial interests. Abbreviations used:AQP-4aquaporin 4CMconditioned mediumCRALBPcellular retinaldehyde binding-proteinCYPcytochrome P450DAPT*N*-\[*N*-(3,5-Difluorophenacetyl)-[l]{.smallcaps}-alanyl\]-S-phenylglycine t-butyl esterDHAdocosahexenoic acidDHDPdihydroxydocosapentaenoic acidDHETdihydroxyeicosatrienoic acidDiHOMEdihydroxyoctadecenoic acidDlldelta-like ligandEDPepoxydocosapentaenoic acidEETepoxyeicosatrienoic acidEPAeicosapentaenoic acidEpOMEepoxyoctadecenoic acidGFAPglial fibrillary acidic proteinGSglutamine synthaseNICDNotch intracellular domainPdgfraplatelet-derived growth factor receptor α polypeptidesEHsoluble epoxide hydrolase*t*-AUCB*trans*-4-\[4-(3-adamantan-1-ylureido)cyclohexyloxy\]-benzoic acidVEGFvascular endothelial cell growth factor

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Click here for the online Merit Badge ApplicationPrint on both sides of regular or blue paper or card stock and trim off the edges. This will print three blank forms per page. The back should line up with the front side. Ask your council what merit badge applications they will accept. Boy Scouts may work on merit badges from the time they join a Scout troop until they turn 18 years old. See Merit Badge for more details. The Merit Badge Application #34124 is known as a "blue card" due to its distinctive color. Though it has not been clearly stated in the past, units, districts, and local councils do not have the authority to implement a different system for merit badge approval and documentation. In any case, through the years, many councils have created new forms and approaches to the process, some including IT components. In an effort to gather and consider these potential best practices, councils are now asked to submit descriptions and copies of their blue card alternatives to the national Advancement Team. For very large events—such as the national Scout jamboree—the National Council may approve an alternative format and sizing for the blue card. This is done through the national Advancement Team.

Image copyright Getty Images Some 400 climate-change protesters have been arrested after several days of demonstrations in central London. Despite the arrests, the Extinction Rebellion activists say they will continue with their protests, which have caused traffic gridlock in places and disruption to parts of London's public transport network. Policing of the protests has been criticised by some, but what powers do officers have? And how have their tactics changed from previous protests? What powers are the police using? The majority of the arrests by the Metropolitan Police Service, have been for suspected breaches of a Section 14 Notice of the Public Order Act 1986. A "Section 14" is a "direction" that allows the police to impose conditions on a static protest - in other words, one where a group of people gather in one place and stay put - rather than marching somewhere. Media playback is unsupported on your device Media caption Who are Extinction Rebellion? In relation to the Extinction Rebellion protests, the Met has stipulated that activists should move to nearby Marble Arch if they wish to continue protesting. If individuals fail to follow the police instructions, they can be arrested and face the risk of criminal prosecution. The most likely sentence for breaching a Section 14 notice, especially if the convicted person was peaceful and has no recent convictions for similar offences, is a conditional discharge - where a court convicts but does not impose a sentence on the condition a further offence isn't committed. When are the police allowed to issue a Section 14 notice? Section 14 notices are quite rarely used, but they can be when police have advance notice of a big protest. Police officers can issue them if they "reasonably believe" that the protest "may result in serious public disorder, serious damage to property or serious disruption to the life of the community". They can also be be used if the police believe the purpose of the protest is to intimidate others. Image copyright Getty Images Image caption Met Commissioner Cressida Dick briefed the home secretary about the protests But protesters need to be aware that police have issued a Section 14 direction in respect of the protest before they can be arrested for a suspected breach. Police will often try to communicate that a Section 14 notice is in force through various means - for example, handing out leaflets, using social media or using a megaphone to address a crowd. But why isn't everyone being arrested? Officers have discretion over whether to make arrests. The Met said in a statement: "These are peaceful protesters; while disruptive their actions are not violent towards police, themselves or other members of the public. We are looking at other tactics such as tighter police cordons." In any protest, the police might take the view that attempting to carry out mass arrests could cause trouble - so by "waiting it out" they hope that the demonstrations might gradually wind down of their own accord. There is also a question of resources. Image copyright Getty Images Image caption One activist, Farhana Yamin, glued her own hands to the pavement outside Shell's headquarters One police officer at one of the protest spots told the BBC their tactic was to move people one-by-one. The officer added that while everyone was "technically arrestable", there were not enough officers to carry out mass arrests. Furthermore, there have been reports of some of those arrested being sent as far as Bromley, south London, due to a lack of police cells in central London. According to a 2017 Freedom of Information request, the Met has 683 cells across 27 custody suites. In response to concerns over capacity, the Met said it had "contingency plans" should cells become too crowded but refused to discuss its plans further for "operational reasons". How do the police tactics compare with previous protests? On May Day in 2000, the Metropolitan Police Service was accused of losing control of Westminster and the West End during a major anti-capitalism protest. There were running battles between officers and anarchist groups which led to significant damage. The following year, when some of the same groups returned, the Met responded in force. Thousands of officers used a tactic known as "kettling" to corral crowds until they were trapped in what amounted to a human pen at the very same Oxford Circus location now occupied by Extinction Rebellion. Some of the protesters turned violent - but many others were entirely peaceful and angry at being "kettled" and unable to leave. Police identified the "trouble-makers" and sent in snatch squads to arrest them. It took seven hours for the city to return to normal and the crowds to be dispersed. Kettling became the subject of an 11-year legal battle, which resulted in the European Court of Human Rights declaring that it was lawful. That landmark judgement meant the police could use this exceptional containment power if there was a genuine risk of violence. In 2005, more than 350 people were arrested at the Gleneagles G8 leaders' summit in Scotland following violent clashes between protesters and police. Extinction Rebellion is different because there is no threat of violence - just occupation and disruption, aided by DJs, mobile curry stalls and the occasional juggler. Image copyright Getty Images Image caption The 2019 Extinction Rebellion protest has focused on occupation and disruption So do the police have other tactics? In 2009, demonstrations against the UK meeting of G20 world leaders saw both peaceful and sporadically violent protests in London. Climate Camp, one of the peaceful demos, was similar to Extinction Rebellion. It was a sudden, no-notice occupation of a part of the City of London - home of the Bank of England and other financial institutions - which police couldn't stop. By early evening, the Met's commander on the ground was concerned there was going to be trouble - not from the Climate Campers, but from the dispersal of another nearby group which he feared could infiltrate the peaceful street occupation. His officers issued Section 14 orders telling the Climate Campers to depart by 19:00. When they failed to leave, he contained them while his officers dealt with the other group. What happened next deepened the controversy. Lines of police with riot shields and batons raised pushed through the Climate Camp to break up the occupation. Image copyright Getty Images Image caption The police "kettling" tactic was used during the 2009 G20 protests Eventually, after another mammoth legal battle, the courts backed the Met's decision-making that night, saying the commander was entitled to judge that violence would have been imminent had he not used the containment and dispersal strategy. It's worth pointing out that while the Met has won these two key legal cases over kettling and dispersal, a far more serious incident happened during the G20 protests. Ian Tomlinson, an entirely innocent newspaper vendor died after he was pushed over by a police officer as he tried to head home. An inquest jury found he had been unlawfully killed and the officer was later tried - but acquitted of manslaughter. No commander in charge of policing protests wants to go through that experience again. And that's why the right approach to containing and potentially dispersing a disruptive street demonstration on the scale of Extinction Rebellion comes down not only to the law and police resources, but the mood on the ground and some intelligence about the intentions of the demonstrators. Read more from Reality Check Send us your questions Follow us on Twitter

Experiences and problems in the disinfection of fibre endoscopes. The problem of the disinfection of fibre endoscopes is to achieve a good efficiency together with easy handling. There is not yet a disinfectant which shows a sufficient germicidal effect after a short time of contact with the fibre endoscope and which is harmless to the patient and medical staff. This paper deals with a two-stage disinfecting procedure in which the instrument undergoes a short intermediate disinfection using polyvidoneiodine (Betaisodona) between two investigations and a main disinfection at the end of a series of investigations using glutardialdehyde (Cidex). The measures lead to a sufficient reduction of the number of germs. The importance of the disinfection of all parts of the endoscopes, especially the channels and the accessories (water bottles etc.) is pointed out.

122 B.R. 527 (1990) In re GRAHAM SQUARE, INC. Bankruptcy No. 690-01182. United States Bankruptcy Court, N.D. Ohio. July 11, 1990. *528 John P. Van Abel, Amerman, Burt & Jones, Canton, Ohio, for debtor. Stephen D. Thompson, Black, McCuskey, Souers & Arbaugh, Canton, Ohio, for Union Nat. Bank of Pittsburgh. Russ Kendig, Krugliak, Wilkins, Griffiths & Dougherty, Canton, Ohio, for Central Trust Co. of Northeastern Ohio. MEMORANDUM OF DECISION JAMES H. WILLIAMS, Chief Judge. The court is presented with a motion for use of cash collateral filed by the debtor and debtor in possession, Graham Square, Inc. The debtor seeks to use the rental income secured to The Union National Bank of Pittsburgh (UNB) and The Central Trust Company of Northeastern Ohio (Central Trust) to operate its business as it attempts to reorganize. Both UNB and Central Trust strenuously contest the use of the rental income. A hearing was held pursuant to Bankruptcy Rule 4001(b), upon the conclusion of which the court took the matter under advisement. The court has jurisdiction in this matter by virtue of 28 U.S.C. § 1334(b) and General Order No. 84 entered in this district on July 16, 1984. This is a core proceeding under 28 U.S.C. § 157(b)(2)(M). This Memorandum of Decision constitutes the court's findings of fact and conclusions of law pursuant to Bankruptcy Rule 7052. FACTS The debtor obtained a construction loan from UNB in May, 1988, to build and operate a strip style shopping center located on Graham Road in the city of Stow, Ohio. The original amount of the loan was $8,550,000. At present, approximately $8,056,000 plus interest is due and owing UNB. As security for the loan, UNB possesses, among other things, a mortgage on the premises and an assignment of the rental income. In September, 1989, the debtor obtained an additional construction loan in the amount of $1,000,000 from Central Trust to construct several out-parcel buildings in front of the shopping center. Currently there is due Central Trust approximately $925,632 plus interest. Central Trust also possesses a mortgage on the real estate and an assignment of the rental income to secure the indebtedness. The debtor filed for relief under Chapter 11 of the Title 11 of the United States Code on June 6, 1990. It was stipulated at the hearing on the motion for the use of cash collateral that the debtor was in default of its loan obligations to UNB and Central Trust prior to its filing bankruptcy. At the hearing, the debtor presented income projections from rental income and common area maintenance fees for each of the months of July and August, 1990, of $68,826. This figure is based upon 89.8% occupancy of the shopping center. For these same months, the debtor estimates operating expenses of $11,649.72, leaving a balance of available cash each month of $57,176.28. The debtor has offered to pay this sum to UNB and Central Trust as adequate protection for the use of rent proceeds. The debt service to UNB and Central Trust at 11% interest, the original contract rate on each of the mortgages, is $82,332 per month. However, both loans provide that upon default the interest rate would increase to the prime rate plus 3%, or 14% interest.[1] At this level, the debt service is $99,587 per month. The debtor in its projections estimates that by December, 1990, it will be receiving $98,059.85 in monthly rental income and common area maintenance fees. Deducting projected monthly operating expenses of $14,709.14, there will remain a balance of $83,350.71. This increase in rental income from July to December reflects an expected increased occupancy rate of from 89.9% to 100%. However, to obtain the 100% occupancy status, an additional $404,000 *529 is needed to complete various portions of the project. The debtor anticipates obtaining an additional loan at 11.5% interest. Such an additional loan and the present obligations to UNB and Central Trust will create a monthly debt service load of approximately $86,202, assuming only an 11% interest rate. Both UNB and Central Trust argue that the debtor's offer of adequate protection, the payment of the debt service, is inadequate as the monthly payment falls short of the amount due per month, even at the 11% rate. Further, even if the debtor can achieve 100% occupancy, there remains a negative net cash flow when interest is paid on the three (3) loans that will, in the debtor's view, be necessary to accomplish its goals. DISCUSSION 11 U.S.C. § 363(c)(2) provides: (2) The trustee may not use, sell, or lease cash collateral under paragraph (1) of this subsection unless — (A) each entity that has an interest in such cash collateral consents; or (B) the court, after notice and a hearing, authorizes such use, sale, or lease in accordance with the provisions of this section. Section 363(e) further provides: Notwithstanding any other provision of this section, at any time, on request of an entity that has an interest in property used, sold, or leased, or proposed to be used, sold, or leased, by the trustee, the court, with or without a hearing, shall prohibit or condition such use, sale, or lease as is necessary to provide adequate protection of such interest. The threshold issue for the court to determine is whether the rental income that the debtor seeks to use is cash collateral within the meaning of Section 363(a).[2] Whether or not a mortgagee is entitled to rents and profits derived from the mortgaged property must be determined with reference to applicable state law. Butner v. United States, 440 U.S. 48, 99 S.Ct. 914, 59 L.Ed.2d 136 (1979); Saline State Bank v. Mahloch, 834 F.2d 690 (8th Cir.1987); In re Pfleiderer, Memorandum of Decision, Case No. 686-00198 (Bankr.N. D.Ohio, October 16, 1987). Ohio law has been summarized in 69 O.Jur.3d Mortgages, § 151 (1986): A mortgage of real property does not per se operate as a specific pledge of the rents and profits therefrom. To have that effect the mortgage must expressly include them. But even though a mortgage contains a pledge of rents and profits, and even though the condition is broken, the mortgagor is entitled to them so long as he retains possession. To be entitled to the rents and profits specifically pledged, the mortgagee must have taken possession of the premises, or must have taken some action, such as the appointment of a receiver, to reduce the rents and profits to possession. (footnotes omitted) (emphasis added). It appears to the court, from its review of the entire file, the papers relating to the motion for use of cash collateral and the statements made at the hearing, that neither UNB nor Central Trust took any affirmative steps prior to the debtor's bankruptcy filing to secure the rents in any fashion such as described above. Additionally, neither bank has filed any type of motion in this court to sequester the rents or a notice pursuant to Sections 546 or 552 of the Bankruptcy Code to exercise their rights to obtain possession of the rental income. Accordingly, the court must find that the rents and common area maintenance fees do not presently qualify as "cash collateral." As a result, the requirement of Section *530 363(e) that adequate protection be given by the debtor for the use of this rental income is not applicable. See, In the Matter of Hamlin's Landing Joint Venture, 77 B.R. 916 (Bkrtcy.M.D.Fla.1988); Saline State Bank v. Mahloch, supra. Graham Square, Inc., is entitled, therefore, for the present time, to use the rents and common area maintenance fees in the ordinary course of its business, subject of course, to the rules of this court and the provisions of the Bankruptcy Code. An order in accordance herewith shall issue. NOTES [1] The court assumes, from the testimony and statements made at the hearing that the default provisions in Central Trust's loan documents are the same as those of the UNB loan. The court, however, was never presented with any loan documents regarding Central Trust's loan to Graham Square. [2] 11 U.S.C. § 363(a) provides: In this section, "cash collateral" means cash, negotiable instruments, documents of title, securities, deposit accounts, or other cash equivalents whenever acquired in which the estate and an entity other than the estate have an interest and includes the proceeds, products, offspring, rents, or profits of property subject to a security interest as provided in section 552(b) of this title, whether existing before or after the commencement of a case under this title.

DoD News News Article Cohen Says U.S. Troops Are America's Ambassadors TOKYO, April 9, 1997 – One misdeed can destroy countless good works, U.S. Defense Secretary William S. Cohen told American troops stationed here. "Wherever you are stationed, you are carrying the honor of the United States," Cohen said. "Be always aware you are an ambassador as well as a soldier, sailor, airman or Marine." Cohen talked with airmen at Yokota Air Base and sailors at Naval Fleet Activities Yokosuka April 8 and with Marines at Marine Corps Air Station Iwakuni April 9. The defense secretary said the nation is indebted to its men and women in uniform for their service to the nation. "Many times you tend to forget how important the role is that each of you plays in our foreign and defense policies," he said. "You are a part of our strategy of engagement. By virtue of your presence, you are helping the United States carry out its role in stabilizing the entire region." The United States is a global superpower, Cohen said, but even the United States can't go it alone. "We have to have great allies like Japan," he said. Some in Japan, however, oppose continuing U.S. presence on their land, he said. Japanese support for U.S. forces in Japan took a severe blow last fall after two U.S. servicemen raped an Okinawan schoolgirl. The incident fueled the flames of other complaints against U.S. presence in Japan. "Any time you have an incident involving a member of the military in a country in which we are guests, it does create domestic concern," he said. "That's understandable. The difficulty is, there's so much good being done by our military day in and day out. Overwhelming effort is being devoted to community affairs, helping the local community with public works projects -- but it can all be overshadowed and undercut by one bad incident." The public tends to focus upon that one negative aspect, as opposed to all the good being done on day to day, he said. U.S. relations with Japan, however, have been and continue to be so strong they will not be unraveled by any one incident, Cohen said. While some object to the U.S. presence, Japanese Prime Minister Ryutaro Hashimoto has repeatedly assured U.S. officials he is committed to providing a stable, legal framework for continuing American forward-basing in Japan. The Okinawa case sparked U.S. efforts to reduce the intrusive footprint of U.S. military forces and activities on local communities. U.S. officials took steps to reduce noise and traffic, returned about 20 percent of the land formerly used for training and are working to relocate helicopter activities to an offshore base. Cohen asked U.S. troops to do their part in maintaining good relations by always being on their best behavior and acting responsibly. "Everything you do reflects upon our country wherever you're deployed," he said. "... On duty or off duty, you are having an impact and reflecting an image of who or what the United States is."

import React from 'react'; import { Link } from 'react-router-dom'; import theme from './Avatar.css'; import AvatarImage from '../image/avatar.gif'; function Avatar() { return ( <div className={theme.container}> <div className={theme['account-navs']}> <h2 className={theme['flex-1']}>头像</h2> <h2 className={theme['flex-1']}> <Link to="/account/information">信息</Link> </h2> </div> <img src={AvatarImage} alt="" width="100%" /> <div> <a href="/">首页</a> </div> </div> ); } export default Avatar;

History Killavullen GAA club is one of the oldest official clubs in North Cork, with the club being founded on the 15th of February 1888 in the parish under the auspices of the Gaelic Athletic Association, and with the exception of a North Cork Junior hurling championship that they came close to annexing in 1929; being narrowly defeated by Churchtown, in the final, the club toiled away without much initial success. However they had a proud tradition of promoting our Gaelic games, and the club is grateful to neighbouring parishes, particularly Shanballymore for inviting them to participate in hurling tournaments which sometimes brought success, but more importantly provided competitive games in preparation of championship fixtures. The prize for winning such tournaments was often the "Cut" of a suit, or gold watches, which in poorer times, were great incentives to do well. Persistence paid off and in 1962, the club contested the final of the Avondhu Novice hurling Championship, and won out this competition in 1968. In between, with the immense help of Johnny Beechinor, a native of Newmarket, who had come to settle in the parish Killavullen made a break through in Football in 1963, which was the clubs first football title, and went out to further glory in 1979, when they were crowned North Cork Junior (B) Hurling League Champions. Since the revival of the juvenile club in 1978, more success has been recorded in football rather than hurling, and with the growth in population of the parish, and trojan work been done within the juvenile structure of the club, the basis for the modern day success of the club has been laid. The club won North Cork Under-12 championships in 1980 and 1981 and won Avondhu championships at all age levels, including minor titles in 1986 and 1992. Indeed in 1992, we won North Cork Championships in Under 14 B hurling; minor football and we were league champions in minor hurling and junior football, which really was a historic year. In 1993 Killavullen won the North Cork Junior (B) Football Championship, won the divisional league title and contested, albeit unsuccessfully, the county Junior (B) Football Championship, which reflects the work done at the Juvenile level since 1978 by Johnny Beechinor, Owen O Neill, George Lane, Mattie Dorgan, Joe Taylor, Tim Nagle and other club members. The underage success of the club in the middle years on the 1980's came to fruition when the club contested the Junior Football ranks in North Cork, and won the league championship in 1997, before annexing their first North Cork Junior football championship in 1998. That same year, Killavullen were defeated in the county final by Newmarket. The team again won the North Cork junior Football Championship in 1999, before winning that same title again in the year 2000, and landing the County title, defeating Kiskeam in the final. This gained the club promotion to the intermediate grade. The Tadgh Crowley Cup was won in the year 2002, in our second year at the intermediate ranks, before the Tom Creedon cup was won in 2003, and again claimed in 2005. In the intervening year, Killavullen won the Munster Intermediate Football League in 2004. The club came within the width of a post of winning the Premier Intermediate Football title in 2007, being defeated by Mallow in a very closely fought final. Off the playing pitch, the club, to commemorate the centenary of the founding of the GAA, in 1984 the club were very grateful to the Browne Family from Killavullen from whom they purchased land near the village and since then have developed then into a magnificent playing field. Dressing Rooms were added in time, and recently, a second playing pitch and gym facilities have been added to the clubs portfolio. The playing pitch must surely be one of the most picturesque in all of Cork with it being on the banks of the Blackwater River, though it is subject to the vagaries of flooding. However careful sitting of the dressing rooms means that these do not flood. The club members are very grateful to the farmers who gave their fields down through the years, particularly the Lucey family, Ballymacmoy who provided the club with a playing pitch for over 30 years. Prior to that venue, games were played in the Inch Field of the property that is now part of the Nano Nagle Centre in Ballygriffin. Aside from these activities, Killavullen has been competing with success in Scor na n'Og and in Scor na bPaisti, and praise must be heaped upon the respective principals, both present and former, in the two schools in the parish, Killavullen National School, and Ballygown National School for all their help down through the years in this regard. Killavullen GAA Roll of Honour Year Titles Won 1963 North Cork Novice Football Championship 1968 North Cork Novice Hurling Championship 1974 North Cork Junior (B) Hurling Championship 1979 North Cork Junior (B) Hurling League Champions 1981 North Cork Junior (B) Hurling Championship 1986 North Cork Junior (B) Football Championship 1987 North Cork Under -21 (B) Hurling Championship 1992 North Cork Junior (B) Football League Champions 1993 North Cork Junior (B) Football Championship North Cork Junior (B) Football League Champions 1994 North Cork Under -21 (B) Football Championship 1995 North Cork Under -21 (B) Hurling Championship 1997 Winners of the North Cork Junior A Football "Avondhu" Cup1 North Cork Junior (A) Football League Champions - Fitzgerald Cup Winners of the North Cork Junior A Hurling "O'Leary" Cup2 1998 North Cork Junior (A) Football League Champions - Fitzgerald Cup North Cork Junior (A) Football Championship 1999 North Cork Junior (A) Football League Champions - Fitzgerald Cup North Cork Junior (A) Football Championship 2000 North Cork Junior (A) Football League Champions - Fitzgerald Cup North Cork Junior (A) Football Championship Cork County Junior (A) Football Championship 2001 Winners of the North Cork Junior A Hurling "O'Leary" Cup2 North Cork Under -21 (C) Football Championship

Battle of Cumberland Church The Battle of Cumberland Church was fought on April 7, 1865, between the Union Army's II Corps of the Army of the Potomac and the Confederate Army of Northern Virginia during the Appomattox Campaign of the American Civil War. After the Battle of Sailor's Creek on April 6, 1865, surviving Confederate troops of Lieutenant General Richard H. Anderson and Major General John B. Gordon headed for the High Bridge, a double-deck structure with a railroad bridge on top and a lower wagon road bridge over the Appomattox River to cross to the north side of the river and continue their retreat to the west. The Confederates intended to destroy the bridge, which they had fought to save the day before in the Battle of High Bridge, but through mistakes and delays did not start to do so until Union troops of Major General Andrew A. Humpreys's II Corps began to arrive at the bridges. After a second smaller Battle of High Bridge, the Union soldiers at the scene kept the railroad bridge from total destruction and saved the wagon bridge in shape for use. Humphreys's troops pursued the last division in the line of march, the division of Major General William Mahone to Cumberland Church about to the west and north of Farmville, Virginia where the Confederates began to fortify the high ground around the church. Soon, Lieutenant General James Longstreet with the entire remaining Confederate infantry moved up from Farmville, Virginia to join Mahone, burning the railroad and wagon bridges at Farmville after them. The Confederate cavalry and one infantry brigade that were left behind had to ford the river nearby. After some fighting in transit to Cumberland Church in which Brigadier General Thomas A. Smyth was mortally wounded, Humphreys ordered his two divisions, which reached the church soon after Mahone, to attack the Confederate line. Finding the Confederate position too strong to take, Humphreys recalled Brigadier General Francis Barlow's division, which had been heading directly to Farmville in pursuit of Gordon's corps, and sent a message to Army of the Potomac commander Major General George Meade that Lee's whole army was north of the river. Humphreys suggested that reinforcements be sent in order to engage the full Confederate Army. Neither Humphreys nor Meade knew until later that the Confederates had destroyed the bridges at Farmville and no reinforcements could reach Humphreys that afternoon. Mistaking a separate nearby cavalry engagement as the arrival of reinforcements engaging with Lee's infantry, Humphreys ordered another futile attack, which was repulsed by the Confederates. Colonel (Brevet Brigadier General) John Irvin Gregg was taken prisoner by the Confederates in the cavalry engagement. Since no reinforcements could quickly reach Humphreys and night was approaching, Humphreys ordered no further attacks. The II Corps had at least 571 casualties in the Battle at Cumberland Church and the cavalry had 74 in what is sometimes called the Battle of Farmville. Confederate casualties are unknown but have been estimated to be about half the number of the Union casualties. The National Park Service gives the number of Confederate casualties as 255. Realizing that the Union forces could close in on his men at Cumberland Church, General Robert E. Lee withdrew his army in another night march to the west at about 11:00 p.m. Although the Confederates held back the Union Army at Cumberland Church and had fewer casualties, they were delayed in their march, which helped other Union forces south of the Appomattox River to get past them to cut them off at the Battle of Appomattox Court House. Background Retreat from Sailor's Creek Because of the need to reduce steep grades in the vicinity of Farmville, the South Side Railroad crossed from the south side of the [Appomattox River to the north side over the High Bridge east of Farmville, about from Rice's Station. From High Bridge, the railroad ran parallel to the north bank of the river until it reached Farmville, Virginia, to the southwest. At Farmville, the railroad crossed back to the south side of the river and proceeded to the west. The railroad bridge at Farmville also had an adjacent wagon bridge. After the Battle of Sailor's Creek, Confederate Lieutenant General Richard H. Anderson and Major General John B. Gordon and the defeated survivors of their corps headed for the South Side Railroad's High Bridge and the wagon bridge below it to cross to the presumed relative safety of the north side of the Appomattox River. After fighting unsuccessfully to destroy the bridges after themselves, Gordon and his men followed the route of the railroad over the High Bridge, along the north bank of the river, and back to the south side of the river over the bridges at Farmville to obtain rations and then immediately return to the north side of the river from Farmville. Longstreet moves to, evacuates Farmville Lieutenant General James Longstreet's corps, which had reached Rice's Station on the morning of April 6, had moved past Sailor's Creek because they were at the head of the march and missed the battle there. After the minor Battle of Rice's Station on April 6, in a night march, Longstreet's corps slipped away from Major General John Gibbon's XXIV Corps of Major General Edward Ord's Army of the James, which had approached the Confederate lines at Rice's Station during afternoon. Longstreet's corps stayed south of the river and headed west for Farmville during the night. Confederate cavalry had been covering Longstreet's march but after crossing Bush River, Longstreet placed Alfred M. Scales's brigade (under the command of Colonel Joseph H. Hyman) of Major General Cadmus Wilcox's division as the rear guard. Longstreet's troops began to arrive at Farmville, under close pursuit by Union Major General George Crook's cavalry division, at about 9:00 a.m.on April 7. Gibbon's XXIV Corps of Ord's Army of the James, reinforced by Brigadier General William Birney's second division of the XXV Corps, followed closely behind Crook's cavalry. Rations were promptly issued to Longstreet's men at Farmville but the soldiers were told to march to the north side of the river to begin their meal preparations. When Confederate Commissary General Isaac M. St. John heard gunfire just outside town, he sent the ration trains west on the South Side Railroad to Pamplin's Depot or Pamplin's Station in an effort to prevent their capture. Sheridan's cavalry got to Pamplin's Station first and captured 3 engines and the rolling stock with the supplies. The Confederate provost guard and their prisoners were sent down the road without rations. Some rations were passed out to troops on the march out of Farmville and the empty wagons from which they were distributed were burned. Longstreet had to move his forces quickly from Farmville to the Cumberland Church vicinity to avoid Union forces closing in the town. Second Battle of High Bridge Major General Andrew A. Humphreys began to march the II Corps west from the Sailor's Creek Battlefield at 5:30 a.m. on April 7. When the leading unit of the Second Division of the II Corps under the command of Brigadier General Francis C. Barlow reached High Bridge at about 7:00 a.m., they found that the Confederates had blown up the redoubt at the bridgehead on the northern (and western) side of the bridge and were just starting to burn the railroad bridge and lower wagon and foot bridge. A mistaken or misunderstood order to Lieutenant General Anderson's guards not to allow anyone to pass kept Major General William Mahone's division from crossing until the order were clarified. Then more time was spent getting the required order to destroy the bridges to the Confederate engineers commanded by Colonel Thomas M. R. Talcott. This permitted the lead units of the II Corps to reach the bridge just as the Confederates were attempting to destroy it. The ensuing fight to save or destroy the bridges was the second Battle of High Bridge, following the battle the previous day when a Union raiding force tried to destroy the bridge to keep the Confederates on the south side of the Appomattox River and the Confederates successfully fought to save it, killing or capturing the Union force. On the morning of April 7, the Union troops led by the 19th Maine Volunteer Infantry Regiment under Colonel Isaac R. Starbird were able to prevent the total destruction of the railroad bridge, though it had been made unusable. They were able to preserve the wagon bridge for passage of the II Corps in their pursuit of Gordon, Anderson and Mahone. Colonel William A. Olmsted's First Brigade of Barlow's division and Brigadier General Thomas Alfred Smyth's Third Brigade, joined by Brigadier General Nelson Miles's division drove off a counterattack by Mahone's troops who were trying to complete the bridges' destruction. Mahone's division was in a defensive line with two redoubts on high ground on the north bank of the river when the II Corps began to arrive at the bridges but they moved to northwest when they could not destroy the bridges and prevent Humphreys's corps from crossing the river. Gordon's corps moved up river along the railroad bed toward Farmville. Humphreys, with Miles's and Brigadier General Regis de Trobriand's divisions, followed Mahone while Barlow's division followed Gordon. Pursuit; Smyth mortally wounded Gordon's corps and Barlow's division skirmished from High Bridge to the northern outskirts of Farmville. An advance Union party of 103 men from the 7th Michigan Infantry Regiment and the 59th New York Infantry Regiment were taken prisoner by the 9th (1st) North Carolina Battalion of Sharp Shooters of Brigadier General John A. Walker's division. Barlow's division caught up with part of Gordon's division and cut off and burned 135 wagons along the road. During this attack, Brigadier General Smyth was mortally wounded by a sniper shot as he rode with his skirmish line within of Gordon's rear guard near Farmville. Colonel Daniel Woodall of the 1st Delaware Infantry Regiment assumed command of the Third Brigade. Smyth's men were stunned by his fall and refused to move for several minutes as Gordon's men began to withdraw. Colonel William A. Olmsted's brigade moved to support Smyth's brigade but about 100 of his men were captured as Confederate rear guards rushed Smyth's hesitating troops. Barlow's men ceased the pursuit altogether as they reached the vicinity of the edge of Farmville north of the river. Union troops take Farmville; Confederates withdraw north While the VI Corps pursued Mahone's division and Gordon's corps north of the Appomattox River, Ord and Gibbons with the XXIV Corps and a brigade of cavalry from Crook's division engaged with Longstreet's rear guard, Scales's brigade and the cavalry, at Briery Creek, just short of Bush River. During this encounter, the other men of Cadmus Wilcox's division received rations at Farmville and moved to the north side of the river. The 1st Maine Cavalry Regiment, armed with 16-shot Henry repeating rifles, led the attack on the Confederate rear guard and the Union forces drove them toward Farmville. Wilcox led his division back across the river to protect the rear guard and the trains with rations just before they moved out toward Pamplin Station. Wilcox then took his men back to the north side of the river cross and Alexander's men started to burn the bridge. Since the Confederates burned the bridge before all their troops were across, Major General Thomas L. Rosser's and Colonel Thomas T. Munford's cavalry divisions and Brigadier General John Bratton's infantry brigade had to cross the river further upstream under fire from Crook's lead units. Crook's cavalry came into town and captured stragglers while the XXIV Corps was only away when the bridge was burned. By the time the main body of Crook's cavalry reached Farmville, most of the Confederates had crossed to the north side of the Appomattox River and burned the bridges leading from the main part of town to the north side of the river. The cavalry ford that Crook's men soon discovered was too deep for the infantry to cross. By 1:30 p.m., Union troops of the Army of the James and Major General Horatio Wright's VI Corps of the Army of the Potomac occupied Farmville while Crook's cavalry found a spot just northwest of town to ford the Appomattox River. Soon thereafter, Union Army General-in-Chief Lieutenant General Ulysses S. Grant and his staff arrived in Farmville, making the Randolph House (Prince Edward Hotel) his headquarters. When all of the Confederates crossed the river from Farmville, they formed a line of battle on Cumberland Heights overlooking the town. Artillery was set up to fire on the Union troops as they moved into Farmville. After a short period of time, the Confederates withdrew to the north to join Mahone's division around Cumberland Church. At this location, First Corps (Longstreet's) artillery chief Edward Porter Alexander told General Lee that the route of march to Appomattox Station was shorter on the south side of the river and they should have stayed there. About this time, Lee also learned that Union troops had followed the Confederates across High Bridge and he could not break away from them on the north side. Having burned the bridges at Farmville, Lee's troops could not cross back to the south side of the river there. Battle at Cumberland Church At Cumberland Church, about northwest of High Bridge and north of Farmville, Mahone's Confederates arrived first and controlled the high ground around the church. They entrenched on top of a long slope of open ground, covering the stage and plank roads to Lynchburg. Lieutenant General Anderson with little more than a few stragglers and a battalion of artillery headed west when Mahone told him that Humphreys was approaching on the same side of the river with them. Union II Corps commander Major General Humphreys, with Brigadier Generals Miles's and de Trobriand's divisions, arrived near the Lynchburg stage road at Cumberland Church about 1:00 p.m. and became engaged not just with Mahone's division, but with the entire remaining Confederate Army of Northern Virginia. As the Union force approached, Lieutenant Colonel William T. Poague's 16-gun artillery battalion opened fire on them. Soldiers from Miles's division temporarily captured the guns of Captain Arthur B. Williams's North Carolina Battery but troops of Major General Bryan Grimes's division recaptured them. Despite evident confusion and disorganization, especially among the survivors of commands hard hit at Sailor's Creek and Gordon's men who had not arrived at Farmville to get rations from the trains that had been there, the Confederates began to prepare defenses at Cumberland Church. As Humphreys's men approached, Gordon's men caught up with Mahone's and the entire effective Army of Northern Virginia was near Cumberland Church. Historian William Marvel stated that with artillery, about 12,000 effective Confederate men held the position at Cumberland Church. They immediately began to prepare a line of thin breastworks in a fish hook formation when they reached the hill. Mahone's division held the right of the line with Poague's battery on its right. Gordon's corps got in line to the right of Poague and Longstreet's corps moved into position next to Gordon. Some of Major General Fitzhugh Lee's cavalry moved to protect Mahone's left flank. Other Confederate cavalrymen were in the rear supported by Major General Henry Heth's division. Humphreys had about the same number of men, 12,000, but did not have the high ground, fortifications or interior lines of communication that the Confederate defenders had. A heavy Union skirmish line moved forward but Miles and de Trobriand found they were unable to make a successful flank attack against Mahone along the Jamestown Road. When Humphreys realized that the Confederates held a strong position in force, he recalled Barlow's division, which had been marching along the South Side Railroad following Gordon's corps toward Farmville and to guard against a Confederate move toward Danville, to rejoin the other II Corps divisions. At the same time, Humphreys sent a message to Army of the Potomac commander Major General George Meade telling him that Lee's entire army was at Cumberland Church and suggesting that a corps should come up from Farmville and attack the Confederates from the other side. Neither Humphreys nor Meade yet knew that the Confederates had destroyed the bridges at Farmville and infantry could not ford the swollen river there. After the initial Union foray was repulsed, Miles moved to his right and tried again to get his men around Mahone's left flank. Humphreys heard gunfire from the direction of Farmville and saw the Confederates shorten their right flank, so he thought the VI Corps had crossed the river and were starting their attack. He had Miles send Colonel George W. Scott's brigade to turn the Confederate left flank. Scott's men had to move uphill through some rolling hills, valleys and ravines to reach the Confederate fortifications. Despite heavy fire, including canister, and the movement of Brigadier General William Forney's Alabama brigade to the left to protect the flank, some of the Union force made it to the Confederate line. The 5th New Hampshire Infantry Regiment and their flag were captured when they got there. Reinforcements from Brigadier General George T. "Tige" Anderson's brigade of Georgians threw back other Union troops of Scott's brigade who were starting to have some success turning the Confederate flank. The counterattack forced Scott's men to withdraw since they were unsupported by the expected attack on the other side of the Confederate line. Mahone sent some of the men on his right to attack the Union skirmish line, but they were driven back twice. As night approached and no Union reinforcements had arrived to join the II Corps, Humphreys made no further attacks on the Confederate line. Barlow's division returned to the II Corps at Cumberland Church only in the evening. Barlow took Miles's place on the right flank of the Union line; Miles moved his division to the center of the line; de Trobriand held the left flank. Cavalry Battle of Farmville The gunfire heard by Humphreys was from Crook's cavalry, which had crossed the river and attacked a wagon train about up the Buckingham Plank Road from Farmville. Colonel (Brevet Brigadier General) J. Irvin Gregg's division led the attack, supported by Brigadier General Henry E. Davies's and Colonel (Brevet Brigadier General) Charles H. Smith's brigades and Lieutenant James H. Lord's Battery A of the 2nd United States Artillery Regiment. The wagon train was accompanied by the survivors of Anderson's (Johnson's) and Pickett's command, hundreds of stragglers, and several artillery batteries. As Gregg's brigade attacked the wagon train, Confederate Major General Thomas L. Rosser and Colonel Thomas T. Munford arrived and sent units of their cavalry divisions against Gregg's dispersed troopers, broke their attack and captured Gregg and some of his men as the others fell back. They were supported by Gordon's infantry having moved down from Cumberland Church. Colonel Samuel B.M. Young reformed the remainder of Gregg's brigade and with Davies's men and Lord's battery attacked the wagons again. By this time, the wagon train also had infantry and artillery support. Another Union attack was repulsed but Confederate Brigadier General William Gaston Lewis was severely wounded and captured. After Confederate troops prevented General Robert E. Lee from personally leading a counterattack by pledging to repulse the Union cavalrymen, they forced Crook's troopers to retreat across the Appomattox River to Farmville. At about this time, Sheridan had recalled Crook to Farmville and directed him to move his division to Prospect Station, or west of Farmville, where his division arrived about midnight. Casualties In the battle up to and at Cumberland Church, the II Corps sustained casualties of 40 killed, 210 wounded, 321 missing, total 571. Confederate casualties are unknown. In the cavalry fight, Crook's cavalry sustained casualties of 11 killed, 33 wounded and 30 missing (including General Gregg, taken prisoner), total 74. Confederate casualties, in what is sometimes separately called the Battle of Farmville, again are unknown. Confederate casualties have been estimated at about half the Union casualties. Aftermath Grant asks for surrender; Lee non-committal Grant wrote to Lee from Farmville at 5:00 p.m. on April 7: Grant's Adjutant-General, Brigadier General (Brevet Major General) Seth Williams, brought Grant's first message to Lee for delivery through the lines by General Humphreys's staff at about 8:30 p.m. Lee showed the message to Longstreet who said: "Not yet." Lee's reply to Grant stated that he disagreed with Grant about the hopelessness of his situation but he also was hoping to avoid "the useless effusion of blood" and asked Grant for the terms he would offer on condition of his army's surrender. Lee's answer came through the lines about one hour after it had been delivered and Williams returned with it to Farmville by a circuitous route over High Bridge. VI Corps cheers Grant, crosses river The VI Corps marched through Farmville on the night of April 7, lit bonfires and cheered General Grant as they passed his headquarters hotel. The corps then crossed the Appomattox River on a newly built footbridge, but waited for a pontoon bridge borrowed from the XXIV Corps for their artillery and wagons to cross after which they camped on the north bank. The XXIV Corps stayed south of the river and camped just to the west of Farmville. The second and third brigades of the XXV Corps were added to Gibbon's XXIV Corps as General Birney had been reassigned to the Petersburg area to command of the newly formed Division of Fort Powhatan, City Point and Wilson's Wharf. The first brigade from Birney's division did not catch up to the rest of the Army of the James until April 10. Cavalry, V Corps move west Brigadier General Ranald Mackenzie's small cavalry division rode from Burkeville (or Burke's Junction) to Prince Edward Court House (now Worsham, Virginia) to cut off the road to Farmville and the Richmond and Danville Railroad at Keysville, Virginia. They skirmished with some outpost troops and took 38 prisoners. By 3:00 p.m., units of Brigadier General (Brevet Major General) George Armstrong Custer's and Brigadier General Thomas Devins's divisions began to arrive at Prince Edward Court House from the Sailor's Creek Battlefield. After dinner, Union Cavalry commander Major General Philip Sheridan ordered them to move west and they eventually camped from Farmville and from Prospect Station. Brigadier General (Brevet Major General) Charles Griffin's V Corps arrived at Prince Edward Court House at about 7:30 p.m. and went into camp on the grounds of Hampden-Sydney College. Lee's night march west While Lee dealt with Grant's message, wagons continued west through roads that had become a quagmire from rain during the day and continued use, causing the death of some teams of mules and the burning of wagons that could not be moved. As the train moved on to the Richmond-Lynchburg Stage Road, conditions improved. Brigadier General Reuben Lindsay Walker had been moving the reserve artillery column independently of the main body of the Confederate army. He had moved through Cumberland Court House the previous afternoon. Having heard about the defeat at Sailor's Creek and the movement out of Farmville, Walker moved to the north, came to the Buckingham Plank Road and moved through Curdsville, Virginia about midday. There, the column moved toward New Store to the southwest and halted for the night, as did the wagon train and hospital train that had been moving from Farmville. Lee knew that his army again had to make a night march from Cumberland Church to get ahead of the Union forces, obtain rations at Appomattox Station and possibly still escape to Danville via Campbell Court House (now Rustburg, Virginia) and through Pittsylvania County, Virginia. Longstreet's corps, with General Lee, moved via the Piedmont Coal Mine Road, also known as the Buckingham Plank Road through Curdsville toward a back road to New Store, Virginia. They covered the retreat of the last wagon train before withdrawing from the Cumberland Church area. Gordon's corps, followed by Fitzhugh Lee's cavalry, moved via the Richmond-Lynchburg Stage Road, a shorter route, toward New Store. Humphreys sent intelligence to Meade at about 3:00 p.m. that Confederate prisoners had said that the Army of Northern Virginia was headed for Lynchburg so Meade and Sheridan had good intelligence about Lee's plan. That night at Cumberland Church, Humphreys's men slept while Lee's force withdrew. On the evening of April 7, Confederate Secretary of War John C. Breckinridge and the Confederacy's quartermaster general, commissary general, chief engineer and various War Department officials rode through Pamplin Station and saw the remainder of the supply trains from Farmville. The commissary general suggested the cars be moved because Union cavalry were not far from Pamplin but Breckinridge refused to do so without being able to notify Lee. On the next day, Crook's cavalry passed through Pamplin on their way to Appomattox Station and destroyed these cars. General Humphreys stated in his book that the delay forced upon the Confederate Army by the engagement at Cumberland Church lost Lee valuable time. It led to the loss of Confederate supplies on April 8 when Custer's division of Sheridan's cavalry arrived at Appomattox Station first and captured the supply trains there. Custer's cavalry captured Confederate supplies and about 25 cannons and took about 1,000 prisoners at the Battle of Appomattox Station. The delay also allowed the Union cavalry and the V Corps and XXIV Corp to reach Appomattox Court House on the morning of April 9 in order to prevent a Confederate breakthrough toward Lynchburg. Footnotes Notes References Calkins, Chris. The Appomattox Campaign, March 29 – April 9, 1865. Conshohocken, PA: Combined Books, 1997. . Humphreys, Andrew A., The Virginia Campaign of 1864 and 1865: The Army of the Potomac and the Army of the James. New York: Charles Scribners' Sons, 1883. . Retrieved March 5, 2015. Longacre, Edward G. The Cavalry at Appomattox: A Tactical Study of Mounted Operations During the Civil War's Climactic Campaign, March 27 – April 9, 1865. Mechanicsburg, PA: Stackpole Books, 2003. . Marvel, William. Lee's Last Retreat: The Flight to Appomattox. Chapel Hill: University of North Carolina Press, 2002. . Salmon, John S., The Official Virginia Civil War Battlefield Guide, Stackpole Books, 2001, . Starr, Steven. The Union Cavalry in the Civil War: The War in the East from Gettysburg to Appomattox, 1863–1865. Volume 2. Baton Rouge: Louisiana State University Press, 2007. Originally published 1981. . Trudeau, Noah Andre. Out of the Storm: The End of the Civil War, April–June 1865. Boston, New York: Little, Brown and Company, 1994. . Warner, Ezra J., Generals in Blue: Lives of the Union Commanders, Louisiana State University Press, 1964, . "CWSAC Battle Summary", National Park Service, Retrieved April 19, 2015. Further reading Calkins, Chris M. Thirty-Six Hours Before Appomattox: April 6 and 7, 1865: The Battles of Sayler's Creek, High Bridge, Farmville and Cumberland Church. Farmville, VA: Farmville Herald, 1980. . Category:Appomattox Campaign Category:Battles of the Eastern Theater of the American Civil War Category:Confederate victories of the American Civil War Category:Battles of the American Civil War in Virginia Category:Cumberland County, Virginia Category:1865 in the American Civil War Category:1865 in Virginia Category:April 1865 events

Q: SpecRun- Tests are not showing in Test Explorer I have a problem where my tests are not being shown in the Test Explorer, I have created a feature file and generated step definitions, I have the following packages installed - SpecFlow-3.1.97 - SpecFlow.Tools.MsBuild.Generation- 3.1.97 - SpecRun.SpecFlow.3-1-0 I have also tried to delete any related to specflow from the %TEMP% folder, It didn't help, also I have different project where I have set up specflow and everything is working fine. Note: without - SpecRun.SpecFlow.3-1-0 package, The test does get discorvered but i get the following error OneTimeSetUp: BoDi.ObjectContainerException : Interface cannot be resolved: TechTalk.SpecFlow.UnitTestProvider.IUnitTestRuntimeProvider('nunit') A: You get this error, because after you removed the SpecRun.SpecFlow.3-1-0 package, you don't have any package more, that configures the used unit test runner. One of the following packages has to be added to your specifications project (the one containing your tests) to select your unit test provider: SpecRun.Runner => for SpecFlow+ Runner SpecFlow.xUnit => for xUnit SpecFlow.MsTest => for MSTest SpecFlow.NUnit => for NUnit From https://specflow.org/2019/updating-to-specflow-3/ You get something discovered in Visual Studio because it has its own test discovery. But this has nothing to do when you execute them. We need stuff from the NuGet packages to execute the scenarios.

--- author: - Elena Kuchina title: | SOME ASPECTS OF\ DEEPLY VIRTUAL COMPTON SCATTERING --- =10000 I am grateful to many people for their help and support during all the years I have been a graduate student. I would particularly like to thank my thesis advisor Ian Balitsky for assigning me such a challenging and rewarding thesis project. I express my deep gratitude to Professor Anatoly Radyushkin for his continuing support during my graduate student career and for giving me many opportunities to learn good physics. It has been my privilege to collaborate with an amazing group of people, the Theory group at Jefferson Lab, who are equal parts teachers, scientists, and tireless workers. Igor Musatov, my colleague and friend, provided invaluable help in nearly every project I worked on. I would like to thank my family and friends for supporting me through what has been a difficult road. I thank my husband Sergey for his willingness to help and my mom for keeping my children safe and sound for me, for their patience, permanent spiritual support and encouragement. I would also like to extend my gratitude to the members of my committee, for taking time to read this manuscript and for their helpful comments and suggestions. Introduction ============ DVCS at small-$x$ ================= Generalized parton distributions ================================ Conclusion\[Summary\] ===================== [99]{}

Q: How to track multiple BackgroundworkerX.Runworkercompleted operations I am trying to use a single handler to cover the end of multiple backgroundworker activities and cannot find a way to get the information about the specific backgroundworker using the backgroundworkercompleted event. My code to catch the event is as below: Private Sub BGx_RunWorkerCompleted(ByVal sender As Object, ByVal e As System.ComponentModel.RunWorkerCompletedEventArgs) Handles BackgroundWorker1.RunWorkerCompleted, BackgroundWorker2.RunWorkerCompleted, BackgroundWorker3.RunWorkerCompleted, BackgroundWorker4.RunWorkerCompleted, BackgroundWorker5.RunWorkerCompleted, BackgroundWorker6.RunWorkerCompleted, BackgroundWorker7.RunWorkerCompleted, BackgroundWorker8.RunWorkerCompleted 'Do work here based on completed Backgroundworker For BG = 1 To 8 If Not DSWorkers(BG).IsBusy Then If DStatus(BG) = -2 Then : DStatus(BG) = -1 : End If End If Next Complete() End Sub There is nothing on the "Do Work Here" section because I do not know how to capture and have been unable to find details of the backgroundworkercompleted event id. Please - any pointers as to how I can identify the specific completed BackgroundWorker A: As with all event handlers, the sender parameter is a reference to the object that raised the event, so you can access the actual BackgroundWorker that has completed its work via that. If you need some data other than that, you assign it to the e.Result property in the DoWork event handler and get it back from the e.Result property in the RunWorkerCompleted event handler. e.Result works for getting data out of the DoWork event handler much as e.Argument works for getting data in. Check this out for some examples of using BackgroundWorker objects, including passing data out using e.Result. You might also like to checkout my own BackgroundMultiWorker class, which basically combines the functionality of multiple BackgroundWorker objects into a single BackgroundMultiWorker object. It identifies each task using a token. EDIT: Here's an example that may help with this issue and your task in general: Imports System.ComponentModel Imports System.Threading Public Class Form1 Private ReadOnly resultsByWorker As New Dictionary(Of BackgroundWorker, BackgroundWorkerResult) Private ReadOnly rng As New Random Private Sub Form1_Load(sender As Object, e As EventArgs) Handles MyBase.Load 'The NumericUpDown is used to select the index of a BackgroundWorker to cancel. With NumericUpDown1 .DecimalPlaces = 0 .Minimum = 0 .Maximum = 9 End With End Sub Private Sub Button1_Click(sender As Object, e As EventArgs) Handles Button1.Click 'Create 10 BackgroundWorkers and run them. For i = 1 To 10 Dim worker As New BackgroundWorker resultsByWorker.Add(worker, New BackgroundWorkerResult) AddHandler worker.DoWork, AddressOf workers_DoWork AddHandler worker.RunWorkerCompleted, AddressOf workers_RunWorkerCompleted worker.WorkerSupportsCancellation = True worker.RunWorkerAsync() Next End Sub Private Sub Button2_Click(sender As Object, e As EventArgs) Handles Button2.Click Dim index = Convert.ToInt32(NumericUpDown1.Value) Dim worker = resultsByWorker.Keys.ToArray()(index) If worker.IsBusy Then 'Cancel the BackgroundWorker at the specified index. worker.CancelAsync() End If End Sub Private Sub workers_DoWork(sender As Object, e As DoWorkEventArgs) Dim worker = DirectCast(sender, BackgroundWorker) 'Do work for a random number of seconds between 10 and 20. Dim period = rng.Next(10, 20 + 1) For i = 0 To period If worker.CancellationPending Then e.Cancel = True Return End If 'Simulate work. Thread.Sleep(1000) Next 'The work was completed without being cancelled. e.Result = period End Sub Private Sub workers_RunWorkerCompleted(sender As Object, e As RunWorkerCompletedEventArgs) Dim worker = DirectCast(sender, BackgroundWorker) Dim result = resultsByWorker(worker) If e.Cancelled Then result.WasCancelled = True Else result.Result = CInt(e.Result) End If Dim workers = resultsByWorker.Keys.ToArray() If Not workers.Any(Function(bgw) bgw.IsBusy) Then 'All work has completed so display the results. Dim results As New List(Of String) For i = 0 To workers.GetUpperBound(0) worker = workers(i) result = resultsByWorker(worker) results.Add($"Worker {i} {If(result.WasCancelled, "was cancelled", $"completed {result.Result} iterations")}.") Next MessageBox.Show(String.Join(Environment.NewLine, results)) End If End Sub End Class Public Class BackgroundWorkerResult Public Property WasCancelled As Boolean Public Property Result As Integer End Class Here is that example reworked to use a single instance of the BackgroundMultiWorker is linked to instead of multiple instances of the BackgroundWorker class. Imports System.Threading Public Class Form1 Private WithEvents worker As New BackgroundMultiWorker With {.WorkerSupportsCancellation = True} Private ReadOnly results(9) As BackgroundWorkerResult Private ReadOnly rng As New Random Private Sub Form1_Load(sender As Object, e As EventArgs) Handles MyBase.Load 'The NumericUpDown is used to select the index of a BackgroundWorker to cancel. With NumericUpDown1 .DecimalPlaces = 0 .Minimum = 0 .Maximum = results.GetUpperBound(0) End With End Sub Private Sub Button1_Click(sender As Object, e As EventArgs) Handles Button1.Click 'Create 10 BackgroundWorkers and run them. For i = 0 To results.GetUpperBound(0) results(i) = New BackgroundWorkerResult worker.RunWorkerAsync(i) Next End Sub Private Sub Button2_Click(sender As Object, e As EventArgs) Handles Button2.Click Dim index = Convert.ToInt32(NumericUpDown1.Value) If worker.IsBusy(index) Then 'Cancel the BackgroundWorker at the specified index. worker.CancelAsync(index) End If End Sub Private Sub worker_DoWork(sender As Object, e As DoWorkEventArgs) Handles worker.DoWork 'Do work for a random number of seconds between 10 and 20. Dim period = rng.Next(10, 20 + 1) For i = 0 To period If worker.IsCancellationPending(e.Token) Then e.Cancel = True Return End If 'Simulate work. Thread.Sleep(1000) Next 'The work was completed without being cancelled. e.Result = period End Sub Private Sub workers_RunWorkerCompleted(sender As Object, e As RunWorkerCompletedEventArgs) Handles worker.RunWorkerCompleted Dim result = results(CInt(e.Token)) If e.Cancelled Then result.WasCancelled = True Else result.Result = CInt(e.Result) End If If Not worker.IsBusy() Then 'All work has completed so display the results. Dim output As New List(Of String) For i = 0 To results.GetUpperBound(0) result = results(i) output.Add($"Task {i} {If(result.WasCancelled, "was cancelled", $"completed {result.Result} iterations")}.") Next MessageBox.Show(String.Join(Environment.NewLine, output)) End If End Sub End Class Public Class BackgroundWorkerResult Public Property WasCancelled As Boolean Public Property Result As Integer End Class

--- abstract: 'Recently, attention-based encoder-decoder (AED) models have shown state-of-the-art performance in automatic speech recognition (ASR). As the original AED models with global attentions are not capable of online inference, various online attention schemes have been developed to reduce ASR latency for better user experience. However, a common limitation of the conventional softmax-based online attention approaches is that they introduce an additional hyperparameter related to the length of the attention window, requiring multiple trials of model training for tuning the hyperparameter. In order to deal with this problem, we propose a novel softmax-free attention method and its modified formulation for online attention, which does not need any additional hyperparameter at the training phase. Through a number of ASR experiments, we demonstrate the tradeoff between the latency and performance of the proposed online attention technique can be controlled by merely adjusting a threshold at the test phase. Furthermore, the proposed methods showed competitive performance to the conventional global and online attentions in terms of word-error-rates (WERs).' author: - '[^1]' bibliography: - 'IEEEexample.bib' title: | Gated Recurrent Context: Softmax-free Attention\ for Online Encoder-Decoder Speech Recognition --- automatic speech recognition, online speech recognition, attention-based encoder-decoder model Introduction {#sec:introduction} ============ the last few years, the performance of deep learning-based end-to-end automatic speech recognition (ASR) systems has improved significantly through numerous studies mostly on the architecture designs and training schemes of neural networks (NNs). Among many end-to-end ASR systems, attention-based encoder-decoder (AED) models [@LAS; @Bahdanau] have shown better performance than the others, such as the connectionist temporal classification (CTC) [@CTC] and recurrent neural network transducer (RNN-T) [@RNN-T], and even outperformed the conventional DNN-hidden Markov model (HMM) hybrid systems in case a large training set of transcribed speech is available [@SOTA-LAS]. Such successful results of AED models come from the tightly integrated language modeling capability of the label-synchronous decoder, supported by the attention mechanism that provides proper acoustic information at each step [@garg2019improved]. A major drawback of the conventional AED models is that they cannot infer the ASR output in an online fashion, which degrades the user experience due to the large latency [@sainath2019two]. This problem is mainly caused by the following aspects of the AED models. Firstly, the encoders of most high-performance AED models make use of layers with global receptive fields, such as bidirectional long short-term memory (BiLSTM) or self-attention layer. More importantly, a conventional global attention mechanism (e.g., Bahdanau attention) considers the entire utterance to obtain the attention context vector at every step. The former issue can be solved by replacing the global-receptive encoder with an online encoder, where an encoded representation for a particular frame depends on only a limited number of future frames. The online encoder can be built straightforwardly by employing layers with finite future receptive field such as latency-controlled BiLSTM (LC-BiLSTM) [@zhang2016highway] and masked self-attention layers. However, reformulating the global attention methods for an online purpose is still a challenging problem. Conventional techniques for online attentionare usually two-step approaches where the window (i.e., chunk) for the current attention is determined first at each decoder step, then the attention weights are calculated using the softmax function defined over the window. As the softmax function is a common solution for representing discrete probability distributions (i.e., attention weights), existing online attentions mainly differ in how they determine the window. Neural transducers [@jaitly2015neural; @sainath2018improving] divide an encoded sequence into multiple chunks with a fixed length, and the attention-decoder produces an output sequence for each input chunk. In the windowed attention techniques [@hou2017gaussian; @tjandra2017local; @merboldt2019analysis], the position of each fixed-size window is decided by a position prediction algorithm. The window position is monotonically increasing in time, and some approaches employ a trainable position prediction model with a fixed Gaussian window. In MoChA-based approaches [@chiu2018monotonic; @miao2019online; @tsunoo2019towards], a fixed-size chunk is obtained using a monotonic endpoint prediction model, which is jointly trained considering all possible chunk endpoints. A common limitation of the aforementioned approaches is that the fixed-length of the window needs to be tuned according to the training data. Merely choosing a large window of a constant size causes a large latency while setting the window size too small results in degraded performance. Therefore multiple trials of the model training are required to find a proper value of the window length, consuming excessive computational resources. Moreover, the trained model does not guarantee to perform well on an unseen test set, since the window size is fixed for all datasets. Although a few variants of MoChA utilize an adaptive window length to remove the need for tuning the window size, such variants induce other problems. MAtChA [@chiu2018monotonic] regards the previous endpoint as the beginning of the current chunk. Occasionally, the window can be too short to contain enough speech content when two consecutive endpoints are too close, which may degrade the performance. AMoChA [@fan2018online] employs an auxiliary model that predicts the chunk size but also introduces an additional loss term for the prediction model. As the coefficient for the new loss needs tuning, AMoChA still requires repeated training sessions. Besides, several recent approaches [@moritz2019triggered; @dong2019cif] utilize strictly monotonic windows. But these methods have a limitation in that the decoder state is not used for determining the window, which means such algorithms might not fully exploit the advantage of AED models, i.e., the inherent capability of autoregressive language modeling. The aforementioned inefficiency in training the conventional online attentions is essentially caused by the fact that the softmax function needs a predetermined attention window to obtain the attention weights, which results in repetitive tuning process of the window-related hyperparameter. To overcome this drawback, we propose a novel softmax-free global attention method called gated recurrent context (GRC), inspired by the gate-based update in gated recurrent unit (GRU) [@cho2014learning]. Whereas conventional attentions are based on a kernel smoother (e.g. softmax function) [@wasserman2006all; @tsai2019transformer], GRC obtains an attention context vector by recursively aggregating the encoded vectors in a time-synchronous manner, using update gates. GRC can be reformulated for the purpose of online attention, which we refer to decreasing GRC (DecGRC), where the update gates are constrained to be decreasing over time. DecGRC is capable of deciding the attention-endpoint by thresholding the update gate values at the inference phase. DecGRC as well as GRC introduces no hyperparameter to be tuned at the training phase. The main contributions of this paper can be summarized as follows: - We propose a novel softmax-free attention method called **Gated Recurrent Context (GRC)**. To the best of our knowledge, GRC is the first attention method that represents discrete probability distributions without a kernel smoother. - We present a novel online attention method, **Decreasing GRC (DecGRC)**, a constrained variant of GRC. DecGRC does not need any new hyperparameter to be tuned at the training phase. At test time, the tradeoff between performance and latency can be adjusted using a simple thresholding technique. - We experimentally show that GRC and DecGRC perform competitive to the conventional global and online attention methods on the LibriSpeech test set. The remainder of this paper is organized as follows. In Section \[sec:backgrounds\], the general framework of attention-based encoder-decoder ASR is formally described, followed by conventional online attention methods and their common limitation. Section \[sec:proposed\] proposes formulations of both GRC and DecGRC and the algorithm for online inference. The experimental results with various attention methods are given in Section \[sec:experiments\]. Conclusions are presented in Section \[sec:conclusion\]. Backgrounds {#sec:backgrounds} =========== Attention-based Encoder-Decoder for ASR {#AED_based_ASR} --------------------------------------- An attention-based encoder-decoder model consists of two sub-modules $\mathrm{Encoder}(\cdot)$ and $\mathrm{AttentionDecoder}(\cdot)$, and it predicts the posterior probability of the output transcription given the input speech features as follows: $$\mathbf{h} = \mathrm{Encoder}(\mathbf{x}),$$ $$P(\mathbf{y}|\mathbf{x}) = \mathrm{AttentionDecoder}(\mathbf{h},\mathbf{y})%,$$ where $\mathbf{x}=[x_1, x_2, ..., x_{T_{in}} ]$ and $\mathbf{h}=[h_1, h_2, ..., h_{T} ]$ are sequences of input speech features and encoded vectors respectively, and $\mathbf{y}=[y_1, y_2, ..., y_U ]$ is a sequence of output text units. Either the start or end of the text is considered as one of the text units. In general, $\mathrm{Encoder}(\cdot)$ reduces its output length $T$ to be smaller than the input length $T_{in}$, cutting down the memory and computational footprint. A global $\mathrm{Encoder}(\cdot)$ is implemented with NN layers having powerful sequence modeling capacity, e.g., BiLSTM or self-attention layers with subsampling layers. On the other hand, an online $\mathrm{Encoder}(\cdot)$ must only consist of layers with finite future receptive field. $\mathrm{AttentionDecoder}(\cdot)$ operates at each output step recursively, emitting an estimated posterior probability over all possible text units given the outputs produced at the previous step. This procedure can be summarized as follows: $$s_u =\mathrm{RecurrentState}(s_{u-1}, y_{u-1}, c_{u-1}),$$ $$\label{AttentionContext} c_u = \mathrm{AttentionContext}(s_u, \mathbf{h}),$$ $$P(y_u | \mathbf{y}_{<u}, \mathbf{x}) = \mathrm{ReadOut}(s_u, y_{u-1}, c_u)%,$$ where $c_u$ denotes the $u$-th attention context vector and $s_u$ is the $u$-th decoder state. $\mathrm{RecurrentState}(\cdot)$ consists of unidirectional layers, e.g., unidirectional LSTM and masked self-attention layers. $\mathrm{ReadOut}(\cdot)$ usually contains a small NN followed by a softmax activation function. The most popular choice for $\mathrm{AttentionContext}(\cdot)$ is the global soft attention (GSA) [@Bahdanau; @luong2015effective] that includes the softmax function given as follows:$$\label{eq:GSA_context} c_u = \sum_{t=1}^{T}{\alpha_{u,t}} h_t ,$$ $$\label{GSA_weights} \alpha_{u,t} = \frac{\exp(e_{u,t})} {\sum_{j=1}^{T}{\exp(e_{u,j})}},$$ $$\label{GSA_score} e_{u,t} = \mathrm{Score}(s_u, h_t, \alpha_{<u,t})%,$$ in which $\alpha_{u,t}$ is an attention weight on the $t$-th encoded vector $h_t$ at the $u$-th decoder step, and $e_{u,t}$ is a score indicating the relevance of $h_t$ to the $u$-th decoder state. Many different choices are available for the similarity function $\mathrm{Score}(\cdot)$. The whole system is trained to maximize the log posterior probability on a training dataset $\mathbf{D}=\{(\mathbf{x}^{(n)},\mathbf{y}^{(n)}) \}_{n=1}^{N} $, $$\mathrm{max}_{\theta} \,\, \mathrm{E}_{ (\mathbf{x},\mathbf{y}) \sim \mathbf{D}} \Big[ %\sum_{u=1}^{U^{(n)}}{\log}P(y_u^{(n)}| \mathbf{y}^{(n)}_{<u}, \mathbf{x}^{(n)} ;\theta) \Big], %\sum_{u=1}^{U}{\log}P(y_u| \mathbf{y}_{<u}, \mathbf{x} ;\theta) \Big], \sum_{u=1}^{{|\mathbf{y}|}}{\log}P(y_u| \mathbf{y}_{<u}, \mathbf{x} ;\theta) \Big]%,$$ where $\theta$ denotes the set of all trainable parameters, and $|\mathbf{y}|$ is the text sequence length of the sampled data. Inference can be performed by searching the most likely text sequence: $$\mathbf{\hat{y}} = \mathrm{argmax}_{\theta} \,\, {\log}P(\mathbf{y} | \mathbf{x} ;\theta).$$ Online Attention {#sec:online_attention} ---------------- To achieve online attention, the context vector $c_u$ in Eq.  must have local dependency on the encoded vectors $\mathbf{h}$. Windowed attention and MoChA are widely-used online attention methods that show high performance for which only the $\mathrm{AttentionContext}(\cdot)$ function in Eq.  is modified in the general framework. ### Windowed attention Among various formulations of windowed attention, a simple heuristic using $\mathrm{argmax}$ for window boundary prediction [@merboldt2019analysis] has shown the best performance. This method can be described as follows: $$\label{Windowed_att_position} %p_1 = 0, \quad p_u = \mathrm{argmax}_{\tau}(\alpha_{u-1,\tau}), p_1 = 0, \quad p_u = \mathrm{argmax}_{t}(\alpha_{u-1, 1\leq t\leq T}),$$ $$\label{Windowed_att_context} c_u = \sum_{t = p_u}^{p_u+w-1}{\alpha_{u,t}} h_t ,$$ $$\label{Windowed_att_weights} \alpha_{u,t} = \frac{\exp(e_{u,t})} {\sum_{j=p_u}^{p_u+w-1}{\exp(e_{u,j})}}%,$$ where $p_u$ is the start point of the attention window at the $u$-th step, and $w$ is the window size. The windowed attention is online, as the attention context $c_u$ derived through Eqs. - does not depend on the entire encoded vector sequence $\mathbf{h}$. The tradeoff between performance and latency of windowed attention relies on the window length $w$. ### MoChA In MoChA [@chiu2018monotonic], an attention window endpoint is first decided, followed by attention weights calculation within a fixed-size window as follows: $$\label{MoChA_infer_context} c_{u} = \sum_{t=\tau_u-w+1}^{\tau_u}\beta_{u,t} h_t,$$ $$\label{MoChA_infer_beta} \beta_{u,t} = \frac{\exp(e_{u,t})} {\sum_{j=\tau_u-w+1}^{\tau_u}{\exp(e_{u,j})}},$$ $$\label{MoChA_infer_tau} \tau_{u} = \mathrm{MonotonicEndpoint}(\tilde{e}_{u,\geq\tau_{u-1}}) ,$$ $$\label{Monotonic_infer_chunkenergy} \tilde{e}_{u,t} = \mathrm{MonotonicScore}(s_u, h_t, \alpha_{<u,t}) + b%,$$ where $\mathrm{MonotonicScore(\cdot)}$ is a similarity function, $b$ is a trainable bias parameter, $\tilde{e}_{u,t}$ is the monotonic score, and $\mathrm{MonotonicEndpoint(\cdot)}$ is an window end-decision algorithm based on thresholding, and $\beta_{u,t}$ is an attention weight within the window. Note that Eqs. - are substitutes for Eqs. - in GSA. The performance and latency of MoChA are also known to depend on the chunk size $w$. Optimizing an AED model using these formulations is infeasible since they do not fit the backpropagation framework. To solve this problem, an expectation-based formulation is exploited for training [@chiu2018monotonic]: $$\label{MoChA_train_beta} %\beta_{u,t} = \sum_{k=t}^{t+w-1} \Big{(} \alpha_{u,t} \exp(e_{u,k}) \Big{/} \sum_{l=k-w+1}^{k}\exp(e_{u,l}) \Big{)}, \beta_{u,t} = \sum_{k=t}^{t+w-1} \frac{ \alpha_{u,t} \exp(e_{u,k})}{ \sum_{l=k-w+1}^{k}\exp(e_{u,l}) },$$ $$\label{MoChA_train_alpha} \alpha_{u,t} = p_{u,t} \Big( (1-p_{u,t-1})\frac{\alpha_{u,t-1}}{p_{u,t-1} } + \alpha_{u-1,t} \Big),$$ $$\label{MoChA_train_p} p_{u,t} = \sigma(e_{u,t})%,$$ where $p_{u,t}$ is a stopping probability at the $t$-th time step and $\alpha_{u,t}$ is an accumulated selection probability that the window endpoint is $t$. ### A limitation of the conventional methods As mentioned in Sec. \[sec:introduction\], the softmax function in the conventional online attentions (e.g., Eqs. -) requires a predetermined attention window, which induces a limitation in training efficiency since multiple trials of training are inevitable for tuning either the window length or the coefficient of an additional loss term. To overcome this limitation, in the next section, we propose a novel softmax-free global attention approach and its online version which is free from the tuning of hyperparameters in training. Proposed methods {#sec:proposed} ================ Gated Recurrent Context (GRC) ----------------------------- We propose a novel softmax-free global attention method called GRC, which recursively aggregates the information of the encoded sequence into an attention context vector in a time-synchronous manner. Specifically, the following formulas are employed in place of the Eqs. -: $$\label{GRC_context} c_{u} = d_{u,T},$$ $$\label{GRC_recursive} \quad d_{u,t} = (1-z_{u,t})d_{u,t-1} + z_{u,t}h_t,$$ $$\label{GRC_updategate} z_{u,1}=1, \quad z_{u,t} = \sigma(e_{u,t}) = \frac{1}{1+\exp(e_{u,t})},$$ $$\label{GRC_energy} e_{u,t} = \mathrm{Score}(s_u, h_t, \alpha_{<u,t}) + b%,$$ where $z_{u,t}$ and $d_{u,t}$ are the update gate and the intermediate attention context vector for the $t$-th time step at the $u$-th decoder step, respectively. GRC computes an intermediate value for the final context vector recursively in time, inspired by GRU [@cho2014learning]. Note that Eqs. - of GRC do not utilize the softmax function at all, unlike the conventional attentions. Nevertheless, GRC can be interpreted as a global attention method, since it calculates a weighted average of the encoded sequence over the whole time period, as explained in Sec. \[sec:relation\_to\_GSA\]. ### Relation to GSA {#sec:relation_to_GSA} The update gate $z_{u,t}$ of GRC in Eq.  and the attention weight $\alpha_{u,t}$ of GSA in Eq.  have one-to-one correspondence according to the following theorem: \[theorem\] \[thm1\] For arbitrary $n \in \mathbb{N}$, let $Z^n=\{x \in \mathbb{R}^{n} \,|\,x_1=1,\,\, 0 \leq x_j \leq 1 \,\, for \,\, j=2,3,\dots,n \}$ and $A^n=\{x \in \mathbb{R}^{n} \,|\,\sum_{j=1}^{T}x_j=1,\,\, 0 \leq x_j \leq 1 \,\, for \,\, j=1,2,\dots,n \}$. There exists a bijective function $\boldsymbol{\bar{\alpha}} :Z^T \rightarrow A^T$ s.t. for any $\mathbf{h}=[h_1, h_2, \dots, h_T]$ and $\mathbf{z}_{u}=[z_{u,1}, z_{u,2}, \dots, z_{u,T}]$, the following holds: $$\label{thm1_eq} d_{u,T} = \sum_{t=1}^{T} \boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{t}h_t%,$$ where $\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{t}$ denotes the $t$-th element of $\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})$, and $d_{u,T}$ is obtained from $\mathbf{z}_{u}$ and $\mathbf{h}$ according to Eq. . Using the recursive Eq. , $$\label{thm1_proof_eq1} \begin{split} d_{u,T} = &(1-z_{u,T}) d_{u,T-1} + z_{u,T}h_T \\ = &(1-z_{u,T})(1-z_{u,T-1}) d_{u,T-2} \\ &+ (1-z_{u,T})z_{u,T-1} h_{T-1} + z_{u,T}h_T \\ = &\dots \\ = &\sum_{t=1}^T \Big(\prod_{j=t+1}^{T} (1-z_{u,j})\Big)z_{u,t}h_t . \end{split}$$ Therefore the function $\boldsymbol{\bar{\alpha}}$ that satisfies Eq. \[thm1\_eq\] is given by $$\label{GRC_GSA_dual_function} \boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_t:= z_{u,t}\prod_{j=t+1}^{T} (1-z_{u,j}) \quad \text{for $t=1, 2, \dots, T$.} % \begin{dcases} % z_{u,t}\prod_{j=t+1}^{T} (1-z_{u,j}) & \text{if $t \leq T$,} \\ % 0 & \text{otherwise,} \\ % \end{dcases} % \quad \text{for $t=1, 2, \dots, T$.}$$ Given that $\mathbf{z}_u \in Z^T$, the output $\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})$ is an element of $A^T$ because it is trivial to show that $0 \leq \boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_t \leq 1$ for $i = 1, 2, \dots, T$, and also $\sum_{t=1}^{T} \boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_t=1$ holds as follows: $$\begin{split} \sum_{t=1}^{T} \boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_t &= \sum_{t=1}^{T} z_{u,t}\prod_{j=t+1}^{T} (1-z_{u,j}) \\ &= \sum_{t=2}^{T} z_{u,t}\prod_{j=t+1}^{T} (1-z_{u,j}) + \prod_{j=2}^{T} (1-z_{u,j})\\ %&= \sum_{t=2}^{T} z_{u,t}\prod_{j=t+1}^{T} (1-z_{u,j}) + \prod_{j=3}^{T} (1-z_{u,j}) - z_{u,2}\prod_{j=3}^{T} (1-z_{u,j})\\ &= \sum_{t=3}^{T} z_{u,t}\prod_{j=t+1}^{T} (1-z_{u,j}) + \prod_{j=3}^{T} (1-z_{u,j})\\ &= \dots \\ &= z_{u,T} + (1-z_{u,T}) = 1. \end{split}$$ The $\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})$ is a bijective function since the inverse mapping of $\boldsymbol{\bar{\alpha}}$ exists as follows: $$\begin{split} z_{u,T} & = \boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_T, \\ z_{u,T-1} & = \begin{dcases} \frac{\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{T-1}}{\big(1-z_{u,T}\big)} = \frac{\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{T-1}}{1-\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_T} & \text{if $\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_T < 1$;} \\ 0 & \text{otherwise,} \\ \end{dcases} \\ z_{u,T-2} & = \begin{dcases} %\frac{\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{T-2}}{\big(1-z_{u,T}\big) \big(1-z_{u,T-1}\big)} = \frac{\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{T-2}}{1 - \boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_T - \boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{T-1}} & \text{if %$\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{T-1} + \boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{T} < 1$; $\sum_{j=T-1}^{T}\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{j}$; } \\ 0 & \text{otherwise,} \\ \end{dcases} \\ & \vdots\\ \therefore z_{u,t} & = \begin{dcases} \frac{\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{t}}{1 - \sum_{j=t+1}^{T} \boldsymbol{ \bar{\alpha}}(\mathbf{z}_{u})_j} & \text{if $\sum_{t=j+1}^{T} \boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_{T} < 1$;} \\ 0 & \text{otherwise,} \\ \end{dcases} %\quad \text{for $t= 1, 2, \dots, T$.} \\ \end{split}$$ for $t= 1, 2, \dots, T$. It is also trivial to show that $z_{u,1} = 1$ and $0 \leq z_{u,t}\leq 1$ for $i = 2, \dots, T$, given that $\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u}) \in A^T$. Therefore, $\mathbf{z}_u \in Z^T$. +0.1in Note that $\boldsymbol{\bar{\alpha}}(\mathbf{z}_u)_t$ in Eq. corresponds to the attention weight $\alpha_{u,t}$ in Eq.  of GSA. By Thm. \[thm1\], the attention context vector $c_u$ of GRC is capable of expressing all possible weighted averages of the encoded representations over time, as in the GSA. Thus the range of $c_u$ in GRC or GSA is the same. Nonetheless, we empirically showed that GRC performs comparable to or even better than GSA, and the experimental results are given in Sec. \[sec:experiments\]. ### Relation to sMoChA {#relation_sMoChA} The sMoChA [@miao2019online] is a variant of MoChA where Eq.  is replaced by the following formula: $$\label{sMoChA} \alpha_{u,t} = p_{u,t} \prod_{j=1}^{t-1} (1-p_{u,j})%,$$ which enables the optimization process to be more stabilized. Eq.  is almost similar to the function $\boldsymbol{\bar{\alpha}}$ in Eq. , and implies evidence on the stability of GRC training. Despite this fact, sMoChA is an algorithm independent of GRC, as Eq.  is merely used as the selection probability component in the whole training formulas and not even used for inference. Decreasing GRC (DecGRC) ----------------------- The intermediate context $d_{u,t}$ of GRC is a weighted average of the encoded representations over time according to the following corollary: \[coroll1\_thm1\] Let $Z^n$ and $A^n$ be the sets defined in Thm. \[thm1\]. For any $\tau \in \{1, 2, \dots, T\}$, $\mathbf{z}_u \in Z^\tau$, and $\mathbf{h}=[h_1, h_2, \dots, h_T]$ , there exists a function $\boldsymbol{\bar{a}} :Z^\tau \rightarrow A^T$ that satisfies the following equation: $$%\label{thm2_eq} \label{coroll1_thm1_eq} d_{u,\tau} = \sum_{t=1}^{T} \boldsymbol{\bar{a}}(\mathbf{z}_u)_{t}h_{t}%,$$ where $\boldsymbol{\bar{a}}(\mathbf{z}_u)_{t}$ denotes the $t$-th element of $\boldsymbol{\bar{a}}(\mathbf{z}_u)$, and $d_{u,\tau}$ is obtained from $\mathbf{z}_{u}$ and $\mathbf{h}$ according to Eq. . By substituting every $T$ in the proof of Thm. \[thm1\] with $\tau$, there exists a bijective function $\boldsymbol{\bar{\alpha}}: Z^\tau \rightarrow A^\tau$ given by $$\boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_t:= z_{u,t}\prod_{j=t+1}^{\tau} (1-z_{u,j}) \quad \text{for $t=1, 2, \dots, \tau$,}%.}$$ such that $$%\label{thm1_coroll1_proof_eq1} d_{u,\tau} = \sum_{t=1}^\tau \boldsymbol{\bar{\alpha}}(\mathbf{z}_{u})_t h_t.$$ It is trivial to show that the following function $\boldsymbol{\bar{a}}: Z^\tau \rightarrow A^T$ satisfies the equation in Coroll. \[coroll1\_thm1\_eq\]: $$\boldsymbol{\bar{a}}(\mathbf{z}_u)_t = \begin{dcases} \boldsymbol{\bar{\alpha}}(\mathbf{z}_u)_t & \text{if $t \leq \tau$;} \\ 0 & \text{otherwise,} \\ \end{dcases} \quad \text{for $t= 1, 2, \dots, T$.} \\$$ Global attention methods including GSA and GRC cannot compute the attention weights without the entire sequence of the encoded vectors $\mathbf{h}$. However, considering that the attention techniques are methods for calculating the weighted average of the encoded vectors, Coroll. \[coroll1\_thm1\] enables us to treat an intermediate context $d_{u,t}$ as a substitute for the attention context vector $c_u$ in Eq.  of GRC even when the whole encoded sequence is not provided. Inspired by this, we further propose a novel online attention algorithm, namely DecGRC. DecGRC is a modified version of GRC, replacing Eq.  with $$\label{DecGRC} z_{u,1}=1, \quad z_{u,t} = \frac{1}{1+\sum_{j=1}^{t}\exp(e_{u,j})}.$$ Note that the update gate is constrained to be monotonically decreasing over time. Assume that there exists an *endpoint* index $t_{end}$ with which $z_{u,t_{end}}$ has a very small value (e.g. less than 0.001). Considering that $z_{u,t}<z_{u,t_{end}}$ holds for all $t>t_{end}$, the difference between $d_{u,t_{end}}$ and $d_{u,T}$ is small, as the numerical change $|d_{u,t}-d_{u,t-1}|$ for $t>t_{end}$ induced by the recursion rule in Eq.  is negligible if $z_{u,t}$ is small enough. Intuitively, intermediate context vectors roughly converge after the endpoint. DecGRC can operate as an online attention method if such an endpoint index $t_{end}$ exists at each decoder step and the index can be decided by the model. We experimentally observed that DecGRC models adequately learn the alignment between encoded vectors and text output units, and the intermediate context nearly converges after the aligned time index at each decoder step. Relevant experimental results are given in Sec. \[sec:attention\_analysis\] Accordingly, with an online encoder, online inference can be implemented via a well-trained DecGRC model. We describe the online inference technique in Alg. \[alg:example\], where the endpoint index is decided simply by thresholding the update gate values. encoded vectors $\mathbf{h}$ of length $T$, threshold $\nu$ $s_0=\vec{0}$, $u=1$, $y_0=\mathrm{StartOfSequence}$ $d_{u} = h_1$ $e_{u,t} = \mathrm{Score}(s_u, h_t,\alpha_{u,t})+b$ $z_{u,t} = 1 / (1+\sum_{j=1}^{t}\exp(e_{u,j}))$ $d_{u} = (1-z_{u,t}) d_{u} + z_{u,t} h_t$ **break** $s_u =\mathrm{RecurrentState}(s_{u-1}, y_{u-1}, d_{u})$ $\tilde{P}(y_u | \mathbf{y}_{<u}, \mathbf{h}) = \mathrm{ReadOut}(s_u, y_{u-1}, c_u)$ $y_u = \mathrm{Decide}\big(\tilde{P}(y_u | \mathbf{y}_{<u}, \mathbf{h})\big)$ $u=u+1$ Computational efficiency of proposed methods -------------------------------------------- GRC or DecGRC increases negligible amount of memory footprint, since only one trainable parameter $b$ in Eq.  is added to the standard GSA-based AED model. Both proposed methods have computational complexity of $O(TU)$, same as the conventional global attentions. However, in practice, a speech sequence is linearly aligned with the text sequence on average. As Alg. \[alg:example\] only regards to encoded vectors before endpoint indices, the total number of steps in the for loop is typically slightly larger than $TU/2$, if the threshold $\nu$ is set to an appropriate value. Therefore, DecGRC is computationally more efficient than the global attentions such as GRC and GSA. The recursive updating in Eq.  induces negligible amount of computation compared to the whole training or inference process. There still exists a room for faster computation by enabling parallel computation in time. The parallel computation can be implemented by utilizing Eq.  where $\alpha_{u,t}$ is replaced with $\bar{\alpha}(\mathbf{z}_u)$ in Eq. , instead of Eqs. -. ----- ---------------------- ----- -- -- -- ---------- ----------- ---------- ----------- E1 GSA (Bahdanau) - 15.15 E2 GRC - **14.59** E3 Windowed att. (w=11) E1 12.50 23.79 15.27 25.81 E4 Windowed att. (w=20) E1 5.78 14.82 5.71 15.90 E5 MoChA (w=2) - 6.49 17.11 6.17 18.18 E6 MoChA (w=8) - **4.74** 14.20 4.95 15.32 E7 - 4.91 14.85 5.10 15.85 E8 E2 4.97 **14.02** **4.83** **14.90** E9 - 5.54 15.49 5.51 16.91 E10 E1 **5.28** 15.44 **5.17** 16.40 E11 - 6.09 16.05 6.18 16.47 E12 E2 5.48 **15.14** 5.55 **15.88** E13 E10 12.82 24.10 15.14 26.94 E14 E10 5.62 15.86 5.56 16.96 E15 MoChA (w=2) E5 6.48 18.35 6.55 19.33 E16 MoChA (w=8) E6 **5.11** **15.10** **5.15** 16.45 E17 E8 5.77 16.24 5.87 17.04 E18 E12 5.79 15.67 6.04 **16.34** ----- ---------------------- ----- -- -- -- ---------- ----------- ---------- ----------- Most importantly, both proposed methods introduce no hyperparameter at the training phase. Thus the proposed methods do not need to repeat training to find a proper value of such a hyperparameter. Though the DecGRC inference in Alg. \[alg:example\] introduces a new hyperparameter (i.e., threshold $\nu$) at test phase, the threshold searching on development sets does not take a long time, because the size of the development sets are minor compared to the training set. Hence the total time spent to prepare an ASR system can be saved. Furthermore, the tradeoff between latency and performance can be adjusted by resetting the threshold value $\nu$ at inference phase, unlike the conventional online attention methods [@jaitly2015neural; @merboldt2019analysis; @chiu2018monotonic]. In these existing methods, the inference algorithms’ decision rules on the attention endpoints are determined at the training phase, and remains unchanged at the test stage. The experiments on DecGRC with different thresholds are demonstrated in Sec. \[sec:ablation\_study\]. Experiments {#sec:experiments} =========== Configurations -------------- All experiments were conducted on LibriSpeech dataset[^2], which contains 16 kHz read English speech with transcription. The dataset consists of 960 hours of a training set from 2,338 speakers, 10.8 hours of a dev set from 80 speakers, and 10.4 hours of a test set from 66 speakers, with no overlapping speakers between different sets. Both dev and test sets are split in half into clean and other subsets, depending upon the ASR difficulty of each speaker. We randomly chose 1,500 utterances from dev set as a validation set. All experiments [^3] shared the same network architecture and training scheme of a recipe of RETURNN toolkit [@zeyer2018returnn; @zeyer2018comprehensive], except the attention methods. Input features were 40-dimensional mel-frequency cepstral coefficients (MFCCs) extracted with Hanning window of 25 ms length and 10 ms hop size, followed by global mean-variance normalization. Output text units were 10,025 byte-pair encoding (BPE) units extracted from transcription of LibriSpeech training set. The $\mathrm{Encoder}(\cdot)$ consisted of 6 BiLSTM layers of 1,024 units for each direction, and max-pooling layers of stride 3 and 2 were applied after the first two BiLSTM layers respectively. For the online $\mathrm{Encoder}(\cdot)$, 6 LC-BiLSTM layers were employed in place of the BiLSTM layers, where the future context sizes were set to 36, 12, 6, 6, 6, and 6 for each layer from bottom to top and the chunk sizes were twice the future context sizes. Both $\mathrm{Score(\cdot)}$ and $\mathrm{MonotonicScore(\cdot)}$ functions were implemented using Bahdanau score with fertility-based weight feedback and 1,024-dimensional attention key, as in [@zeyer2018improved]. $\mathrm{RecurrentState}(\cdot)$ was implemented with an unidirectional LSTM layer with 1,000 units. $\mathrm{ReadOut(\cdot)}$ consisted of a max-out layer with 2$\times$500 units, followed by a softmax output layer with 10,025 units. Weight parameters were initialized with Glorot uniform method [@glorot2010understanding], and biases were initially set to zero. Optimization techniques were utilized during the training: teacher forcing, Adam optimizer, learning rate scheduling, curriculum learning, and the layer-wise pre-training scheme. Briefly, the models were trained for 13.5 epochs using a learning rate of 8$\times$10$^{-4}$ with a linear warm-up starting from 3$\times$10$^{-4}$ and the Newbob decay rule [@zeyer2017comprehensive]. Only the first two layers of $\mathrm{Encoder(\cdot)}$ with half-width were used at the beginning of a training, then the width and the number of layers gradually increased to the original size at 1.5 epoch. The CTC multi-task learning [@kim2017joint] with a lambda of 0.5 was employed to stabilize the learning, where CTC loss is measured with another 10,025-units softmax layer on the top of $\mathrm{Encoder(\cdot)}$. For the models which began the learning from parameters of a pre-trained model, the layer-wise pre-training was skipped. Every model was regularized by applying dropout rate 0.3 to $\mathrm{Encoder(\cdot)}$ layers and the softmax layer and employing label smoothing of 0.1. For each epoch of the training, both cross-entropy (CE) losses and output error rates were measured 20 times on the validation set with teacher forcing. During the inference phase, model with the lowest WER on the dev-other set among all checkpoints was selected as the final model, and performed beam search once on the dev and test sets with a beam size of 12. We trained MoChA models for 17.5 epochs with five times longer layer-wise pre-training to make them converge. A small learning rate of 1e-5 was used for training windowed attention models as in [@merboldt2019analysis]. Though the numbers of total epochs for different experiments were not the same, each model was optimized to converge and showed negligible improvements after that. Performance comparison between attentions ----------------------------------------- All experimental results are summarized in Tbl. \[LibriSpeechWER\]. For each experiment, we performed two trials of training with the same configuration and chose a model with the lowest word-error-rate (WER), a word-level Levenshtein distance divided by the number of ground-truth words, on dev-other set. In E1 to E2 and E9 to E12, GRC showed better performance than the other attention methods on test-other set, showing 3.7% and 3.2% relative error-reduction rate (RERR) compared to GSA when evaluated on BiLSTM and LC-BiLSTM encoder, respectively. In E3 to E6 and E13 to E16, performances of the conventional online attentions, i.e., windowed attention and MoChA, were shown to be highly dependent on a choice of window size hyperparameter $w$. On the other hand, DecGRC is trained without any additional hyperparameter and only involves a threshold $\nu$ at the inference phase. In E3 to E8 and E13 to E18, DecGRC outperformed the conventional online attention techniques on BiLSTM encoder. With LC-BiLSTM encoder, the performance of DecGRC on test-other set surpassed the conventional attentions including GSA, while the scores on test-clean set were worse than the competitors. The overall performance of GRC and DecGRC is degraded on LC-BiLSTM compared to their preferable performance on BiLSTM, which was conjectured to be caused by the following aspect of the proposed methods; $\boldsymbol{\bar{\alpha}}({\mathbf{z}_u})$ in Eq.  has a dependency on update-gate values of the future time-steps. Therefore using a short future receptive field of LC-BiLSTM may affected the degradation. 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The cross-entropy loss curves on training and dev set in E1, E2, E6, and E7 are depicted in Fig. \[train\_dev\_loss\]. The model based on each attention method was trained from scratch until convergence, with a few spikes in its training loss curve. A spike in the loss curve occurs when the layer-wise pre-training algorithm inserts a new layer and units into the encoder, as the untrained new components make the performance worse right after the insertion. GRC converged later than GSA, and DecGRC converged slightly later than GRC. MoChA showed the slowest optimization speed, which was partly due to the 5 times longer layer-wise pre-training scheduling than the others. Such long pre-training was employed to stabilize the training of MoChA, whereas the both GRC and DecGRC successfully converged with the standard pre-training. Note that the longer pre-training of MoCha was adopted because it had failed to converge with a short pre-training in our initial experiments. The relatively stable learning of the proposed methods over MoChA can be explained in relation to sMoChA, as described in Sec. \[relation\_sMoChA\]; the sMoChA stabilized the training of MoChA by utilizing a modified selection probability formula, which is actually almost similar to the attention weight $\boldsymbol{\bar{\alpha}}({\mathbf{z}_u})$ of GRC in Eq. . Attention analysis {#sec:attention_analysis} ------------------ ![An input spectrogram, attention plots with the output BPE sequence of GSA (E1), GRC (E2), and DecGRC (E8), and the update gates of the DecGRC, from top to bottom. All results were obtained with BiLSTM encoder on an utterance 8254-84205-0009 in dev-other set. The update gates were obtained with teacher forcing, and the attention plots were results of the beam search w/ beam size 12. “\_\_" was inserted after a BPE unit end if it was not a word-end. []{data-label="attention_plot"}](att7.pdf){width="9.25cm"} GRC and DecGRC accurately learned alignments between encoded representations and output text units, as illustrated in Fig. \[attention\_plot\]. An interesting characteristic of GRC was observed that it tended to put much weight on the latter time indices of attention weights, compared to GSA. This can be regarded as an innate behavior of GRC, as the attention weight $\boldsymbol{\bar{\alpha}}({\mathbf{z}_u})$ in Thm. \[thm1\] is designed to weigh the latter indices when the update gates $z_{u,t}$ have similar value over several consecutive time-indices. The latter-time-weighing attribute could be especially effective for a long text unit (e.g., a BPE unit “swinging” in Fig. \[attention\_plot\]), as a long BPE unit often ends with a suffix that might be crucial to distinguish words (e.g., “-ing", “-n’t", or “-est" in English). A piece of statistical evidence is presented in Fig. \[median\_length\_of\_BPE\_units\_to\_WER\]; GRC outperformed GSA when the median length of BPE was larger than or equal to 6, while it showed similar performance for shorter median lengths. Attention weights of DecGRC tended to be much smoother (i.e., focused on longer time) than GRC and GSA. Such smoothness was hypothesized to be caused by the decreasing update gates, which made the model trained to be cautious for a sharp descent of update gate values, as it is irreversible in DecGRC. In addition, DecGRC did not attend on the first time index, unlike GSA and GRC. It is an intrinsic property of DecGRC, as the earliest update gates have values close to 1 and therefore difficult to carry information to later time. As the initial frames of an utterance usually contain helpful information such as background noise, this might cause DecGRC to be degraded compared to the global attentions. The last two plots in Fig. \[attention\_plot\] show that the update gate values of DecGRC mostly changed near the attention region. As the update gates rapidly decreased after the attention region, tight attention endpoints could easily be found by setting the threshold value approximately in a range of \[0.001, 0.2\]. For instance, with an inference threshold $\nu=0.01$ in Fig. \[attention\_plot\], the total number of steps in the for loop in Alg. \[alg:example\] was 459, which was approximately 54% of $TU=13\times65=845$. It implies that insignificant time indices were properly ignored during the inference. coordinates [(2,0.21849929211892402)(3,0.10279748360326596)(4,0.08669469039740035) (5,0.10634648370497427)(6,0.1729957805907173) (7,0.28125) (8,0)]{}; coordinates [(2,0.21755545068428503)(3,0.10001635955323547)(4,0.08326625525444951) (5,0.11492281303602059)(6,0.12658227848101267) (7,0.25) (8,0)]{}; Ablation study on DecGRC inference threshold {#sec:ablation_study} -------------------------------------------- We evaluated WERs of DecGRC models for different threshold values, and the results are summarized in Tbl. \[ablation\]. Setting the threshold to a value larger than 0.2 was found to be detrimental to the performance on the BiLSTM encoder (E8), with larger thresholds giving higher WERs. It means that some encoded vectors in the correct attention region were ignored due to the high threshold, as shown in the last two plots of Fig. \[attention\_plot\]. Impressively, the best performance was obtained with $\nu$ between 0.001 and 0.1, not $\nu=0$. This may be attributed to the fact that the thresholding not only reduced the latency, but also eliminated undesirable updates after the correct attention region. With thresholds higher than the best-performing threshold, the latency could be further reduced by taking the performance penalty, and vice versa. The best-performing threshold on the LC-BiLSTM encoder (E18) was $\nu=0.08$, which means that the optimal threshold for performance depends on the model architecture, thus threshold searching is required before test phase. Nevertheless, as the beam search inference on the dev set took less than 15 minutes using a single GPU, the time spent for the tuning process of the threshold was no more than 2.5 hours, which is much shorter than the model training time; a single epoch of training took 9 hours on average, and the total time for training a model from scratch was more than 5 days. ------- -- ---------- ----------- ---------- ----------- 0 5.03 14.08 4.89 14.83 0.001 4.96 **14.01** 4.86 **14.76** 0.01 4.97 14.02 **4.83** 14.90 0.05 **4.83** 14.02 4.84 14.93 0.2 5.09 14.34 5.10 15.10 0.25 5.85 14.79 5.98 15.64 0.4 10.59 18.35 11.58 19.24 0.6 39.67 39.08 40.42 40.70 0 6.07 15.80 6.30 16.51 0.001 6.08 15.77 6.32 16.50 0.01 6.01 15.75 6.22 16.45 0.05 5.83 **15.63** 6.06 16.35 0.08 5.79 15.67 6.04 **16.34** 0.1 **5.78** 15.66 **6.03** 16.36 0.2 6.41 16.20 6.77 16.93 0.25 7.27 16.78 7.84 17.77 0.4 15.53 21.93 16.76 23.94 0.6 70.54 66.38 71.82 70.20 ------- -- ---------- ----------- ---------- ----------- : Ablation study about the inference threshold of DecGRC on LibriSpeech dataset. []{data-label="ablation"} Conclusion {#sec:conclusion} ========== We proposed a novel softmax-free global attention method called GRC, and its variant for online attention, namely DecGRC. Unlike the conventional online attentions, DecGRC introduces no additional hyperparameter to be tuned at the training phase. Thus DecGRC does not require multiple trials of training, saving time for model preparation. Moreover at the inference of DecGRC, the tradeoff between ASR latency and performance can be controlled by adapting the scalar threshold which is related to the attention endpoint decision, whereas the conventional online attentions are not capable of changing the endpoint decision rule at test phase. Both GRC and DecGRC showed comparable ASR performance to the conventional global attentions. For further research, the proposed attention methods will be investigated in various applications which leverage AED models. We are particularly interested in applying DecGRC to simultaneous machine translation [@arivazhagan2019monotonic] and real-time scene text recognition [@liu2018squeezedtext], where the latency can be reduced by exploiting an online attention method. [^1]: The authors are with the Institute of New Media and Communications, Department of Electrical and Computer Engineering, Seoul National University, Seoul, Republic of Korea (e-mail: hslee@hi.snu.ac.kr; whkang@hi.snu.ac.kr; sjcheon@hi.snu.ac.kr; hjkim@hi.snu.ac.kr; nkim@snu.ac.kr). This work has been submitted to the IEEE for possible publication. Copyright may be transferred without notice, after which this version may no longer be accessible. [^2]: The LibriSpeech dataset can be downloaded from <http://www.openslr.org/12>. [^3]: The scripts for all experiments are available at <https://github.com/GRC-anonymous/GRC>.

Q: sql replication using remote server PI'm trying to do replicate two data bases. DB in LAN network (Publisher) DB in virtual dedicated network (Subscriber) According to my situation, replicate publisher implemented in my server in LAN network.But subscriber is implementing on a virtual dedicated server. i configured router port to my server machine in LAN network.using sql management studio on virtual server, i connected to the db in LAN network.But when i try to create subscriber using virtual server db i can't access to the publisher.(IN LAN network.) it gives errors as below. "SQL Server replication requires the actual server name to make a connection to the server. Connections through a server alias, IP address, or any other alternate name are not supported. Specify the actual server name, 'BESTLIFE\BESTLIFECROWN'. (Replication.Utilities)" Please help me to solve this . A: You didn't say whether you used the GUI or scripts, but somewhere, a call got made to one of the stored procedures (likely sp_addsubscription) with a server name that doesn't match the actual server name. For instance, the error message above says that the server is called BESTLIFE\BESTLIFECROWN. If that's not the name of the server that you put in as hosting the subscriber, it's not going to work. Whether you need to add a DNS alias or whatever, that's the only value that will work for this setup.

Who's Online Guest Users: 15 Saudi Cracks Down on Ethiopian Migrants Friday, November 15 2013 @ 08:30 AM MSK As garbage piled in the Saudi streets, 23,000 Ethiopians have surrendered to Saudi authorities after a clampdown on illegal migrant workers began in the oil-rich kingdom last week, stirring clashes after frustrated workers took to the streets. The clashes “occurred because the illegal workers were frustrated they did not have a way to surrender to the police,” Ambassador Mohammad Hassan Kabiera told the English-language Arab News daily, AFP reported on Thursday. The workers took to the streets to voice their concerns, prompting “clashes with some youths in the neighborhood”, he said. “We have been informed that so far about 23,000 Ethiopians have handed themselves in,” Kabiera said. The Ethiopian workers’ surrender followed clashes earlier this week between police and Ethiopian migrants on Saturday that led to the deaths of three people in the poor Manfuhah neighborhood of Riyadh. On Tuesday, Ethiopia said three of its citizens had died during clashes in the Gulf kingdom, without elaborating. "The act of killing innocent civilians is uncalled for, we condemn that," Foreign Ministry spokesman Dina Mufti told reporters, saying he had been informed of the death of three Ethiopian citizens. The troubles followed the kingdom’s move to round up thousands of illegal workers starting from November 4, following the expiry of a final amnesty for them to formalize their status. Among them were foreigners who overstayed their visas, pilgrims who had sought jobs, and migrants working under one sponsor trying to get jobs elsewhere. Having an official sponsor is a legal requirement in Saudi Arabia and most other Gulf states. Nearly a million migrants — Bangladeshis, Filipinos, Indians, Nepalis, Pakistanis and Yemenis among them — took advantage of the amnesty to leave. Another roughly four million were able to find employers to sponsor them. Expatriates account for a full nine million of the oil-rich kingdom’s population of 27 million. Defended Despite feeling the loss of the everyday work the foreign laborers provided, Saudis largely have cheered the campaign. Al Riyadh daily quoted Prince Khalid as defending the campaign, saying it “does not target a specific group but all illegal” workers and residents. “We will continue these campaigns until we ensure all residents in our country are staying legally,” he said. Residents have taken matters into their own hands on several occasions, despite police calling on the public not to make citizen arrests. Workers from neighboring Yemen also face harassment. Yemeni Nobel Peace Prize Laureate Tawakkol Karman posted a picture last week on her Facebook page of what appeared to be a Saudi man in his car grabbing hold of a Yemeni man for a police officer. Fresh violence erupted in Riyadh’s Manfouha district later on Wednesday, resulting in the death of a Sudanese resident. At least 17 expatriate workers were also reported injured as they clashed with local residents, police said. On Wednesday, Saudi media quoted Riyadh governor Prince Khalid Bin Bandar Bin Abdul Aziz as saying that “casualties and deaths have not surpassed three Saudis and two foreigners”, again without giving details. Saudi columnist Abdul-Rahman al-Rashed cautioned Saudis to remember that without “a strong state and oil revenues” they too may have emigrated in search of work. “Those deprived of the chance of a proper life can understand the feeling of those wanting to seek a better life,” he wrote in the Asharq al-Awsat newspaper. Don't take easy at any stage of your life during that process and work really hard to bring some positive results. That time i am working for one of the best educational network, where students can pay for college essays online and get their products online. Our network also provides money back guarantee on ever service which is really great for all students. A genuine write-up could possibly be rewarding. I really like this original write-up as well as whichever other people make a decision kid ought to be might permit you may be maintaining most current combined with the drastically beneficial, My family and i expected get pleasure from so as to thrust grows such a web sites we've got genuinely gotten to preserve i would authenticate speedily beneath of which likewise has a brand-new established that you have get to completing a unique complete. quick weight loss My wife or husband and we seriously appreciated examining which usually, you could possibly become a outstanding article article author. Prevent meaning that many of us you need to please take a notice with the web page all of which will return sometime rapidly. Access Control System

Q: Log4j and Jboss. How do I get my log.Debug("Debug") messages to display? I'm trying to start my jBoss server (v4.2) to run and display all of my log.debug messages. I need to achieve this by way of editing jboss configurations. Not programmatically through the application. my jboss-log4.xml <?xml version="1.0" encoding="UTF-8"?> <!DOCTYPE log4j:configuration SYSTEM "log4j.dtd"> <!-- ===================================================================== --> <!-- --> <!-- Log4j Configuration --> <!-- --> <!-- ===================================================================== --> <!-- $Id: jboss-log4j.xml 62403 2007-04-18 15:26:43Z dimitris@jboss.org $ --> <!-- | For more configuration infromation and examples see the Jakarta Log4j | owebsite: http://jakarta.apache.org/log4j --> <log4j:configuration xmlns:log4j="http://jakarta.apache.org/log4j/" debug="false"> <!-- ================================= --> <!-- Preserve messages in a local file --> <!-- ================================= --> <!-- A time/date based rolling appender --> <appender name="FILE" class="org.jboss.logging.appender.DailyRollingFileAppender"> <errorHandler class="org.jboss.logging.util.OnlyOnceErrorHandler"/> <param name="File" value="${jboss.server.log.dir}/server.log"/> <param name="Append" value="false"/> <!-- Rollover at midnight each day --> <param name="DatePattern" value="'.'yyyy-MM-dd"/> <!-- Rollover at the top of each hour <param name="DatePattern" value="'.'yyyy-MM-dd-HH"/> --> <layout class="org.apache.log4j.PatternLayout"> <!-- The default pattern: Date Priority [Category] Message\n --> <param name="ConversionPattern" value="%d %-5p [%c] %m%n"/> <!-- The full pattern: Date MS Priority [Category] (Thread:NDC) Message\n <param name="ConversionPattern" value="%d %-5r %-5p [%c] (%t:%x) %m%n"/> --> </layout> </appender> <!-- A size based file rolling appender <appender name="FILE" class="org.jboss.logging.appender.RollingFileAppender"> <errorHandler class="org.jboss.logging.util.OnlyOnceErrorHandler"/> <param name="File" value="${jboss.server.log.dir}/server.log"/> <param name="Append" value="false"/> <param name="MaxFileSize" value="500KB"/> <param name="MaxBackupIndex" value="1"/> <layout class="org.apache.log4j.PatternLayout"> <param name="ConversionPattern" value="%d %-5p [%c] %m%n"/> </layout> </appender> --> <!-- ============================== --> <!-- Append messages to the console --> <!-- ============================== --> <appender name="CONSOLE" class="org.apache.log4j.ConsoleAppender"> <errorHandler class="org.jboss.logging.util.OnlyOnceErrorHandler"/> <param name="Target" value="System.out"/> <param name="Threshold" value="DEBUG"/> <layout class="org.apache.log4j.PatternLayout"> <!-- The default pattern: Date Priority [Category] Message\n --> <param name="ConversionPattern" value="%d{ABSOLUTE} %-5p [%c{1}] %m%n"/> </layout> </appender> <!-- ====================== --> <!-- More Appender examples --> <!-- ====================== --> <!-- Buffer events and log them asynchronously <appender name="ASYNC" class="org.apache.log4j.AsyncAppender"> <errorHandler class="org.jboss.logging.util.OnlyOnceErrorHandler"/> <appender-ref ref="FILE"/> <appender-ref ref="CONSOLE"/> <appender-ref ref="SMTP"/> </appender> --> <!-- EMail events to an administrator <appender name="SMTP" class="org.apache.log4j.net.SMTPAppender"> <errorHandler class="org.jboss.logging.util.OnlyOnceErrorHandler"/> <param name="Threshold" value="ERROR"/> <param name="To" value="admin@myhost.domain.com"/> <param name="From" value="nobody@myhost.domain.com"/> <param name="Subject" value="JBoss Sever Errors"/> <param name="SMTPHost" value="localhost"/> <param name="BufferSize" value="10"/> <layout class="org.apache.log4j.PatternLayout"> <param name="ConversionPattern" value="[%d{ABSOLUTE},%c{1}] %m%n"/> </layout> </appender> --> <!-- Syslog events <appender name="SYSLOG" class="org.apache.log4j.net.SyslogAppender"> <errorHandler class="org.jboss.logging.util.OnlyOnceErrorHandler"/> <param name="Facility" value="LOCAL7"/> <param name="FacilityPrinting" value="true"/> <param name="SyslogHost" value="localhost"/> <layout class="org.apache.log4j.PatternLayout"> <param name="ConversionPattern" value="[%d{ABSOLUTE},%c{1}] %m%n"/> </layout> </appender> --> <!-- Log events to JMS (requires a topic to be created) <appender name="JMS" class="org.apache.log4j.net.JMSAppender"> <errorHandler class="org.jboss.logging.util.OnlyOnceErrorHandler"/> <param name="Threshold" value="ERROR"/> <param name="TopicConnectionFactoryBindingName" value="java:/ConnectionFactory"/> <param name="TopicBindingName" value="topic/MyErrorsTopic"/> </appender> --> <!-- Log events through SNMP <appender name="TRAP_LOG" class="org.apache.log4j.ext.SNMPTrapAppender"> <errorHandler class="org.jboss.logging.util.OnlyOnceErrorHandler"/> <param name="ImplementationClassName" value="org.apache.log4j.ext.JoeSNMPTrapSender"/> <param name="ManagementHost" value="127.0.0.1"/> <param name="ManagementHostTrapListenPort" value="162"/> <param name="EnterpriseOID" value="1.3.6.1.4.1.24.0"/> <param name="LocalIPAddress" value="127.0.0.1"/> <param name="LocalTrapSendPort" value="161"/> <param name="GenericTrapType" value="6"/> <param name="SpecificTrapType" value="12345678"/> <param name="CommunityString" value="public"/> <param name="ForwardStackTraceWithTrap" value="true"/> <param name="Threshold" value="DEBUG"/> <param name="ApplicationTrapOID" value="1.3.6.1.4.1.24.12.10.22.64"/> <layout class="org.apache.log4j.PatternLayout"> <param name="ConversionPattern" value="%d,%p,[%t],[%c],%m%n"/> </layout> </appender> --> <!-- Emit events as JMX notifications <appender name="JMX" class="org.jboss.monitor.services.JMXNotificationAppender"> <errorHandler class="org.jboss.logging.util.OnlyOnceErrorHandler"/> <param name="Threshold" value="WARN"/> <param name="ObjectName" value="jboss.system:service=Logging,type=JMXNotificationAppender"/> <layout class="org.apache.log4j.PatternLayout"> <param name="ConversionPattern" value="%d %-5p [%c] %m"/> </layout> </appender> --> <!-- ================ --> <!-- Limit categories --> <!-- ================ --> <!-- Limit the org.apache category to INFO as its DEBUG is verbose --> <category name="org.apache"> <priority value="DEBUG"/> </category> <!-- Limit the org.jboss.serial (jboss-serialization) to INFO as its DEBUG is verbose --> <category name="org.jboss.serial"> <priority value="DEBUG"/> </category> <!-- Limit the org.jgroups category to WARN as its INFO is verbose --> <category name="org.jgroups"> <priority value="DEBUG"/> </category> <!-- Limit the jacorb category to WARN as its INFO is verbose --> <category name="jacorb"> <priority value="DEBUG"/> </category> <!-- Limit JBoss categories --> <category name="org.jboss"> <priority value="DEBUG"/> </category> <!-- Limit the JSR77 categories --> <category name="org.jboss.management"> <priority value="DEBUG"/> </category> <!-- Enable JBossWS message tracing --> <category name="jbossws.SOAPMessage"> <priority value="TRACE"/> </category> <!-- Decrease the priority threshold for the org.jboss.varia category <category name="org.jboss.varia"> <priority value="DEBUG"/> </category> --> <!-- Show the evolution of the DataSource pool in the logs [inUse/Available/Max] <category name="org.jboss.resource.connectionmanager.JBossManagedConnectionPool"> <priority value="TRACE"/> </category> --> <!-- | An example of enabling the custom TRACE level priority that is used | by the JBoss internals to diagnose low level details. This example | turns on TRACE level msgs for the org.jboss.ejb.plugins package and its | subpackages. This will produce A LOT of logging output. | | Note: since jboss AS 4.2.x, the trace level is supported natively by | log4j, so although the custom org.jboss.logging.XLevel priority will | still work, there is no need to use it. The two examples that follow | will both enable trace logging. <category name="org.jboss.system"> <priority value="TRACE" class="org.jboss.logging.XLevel"/> </category> <category name="org.jboss.ejb.plugins"> <priority value="TRACE"/> </category> --> <!-- | Logs these events to SNMP: - server starts/stops - cluster evolution (node death/startup) - When an EJB archive is deployed (and associated verified messages) - When an EAR archive is deployed <category name="org.jboss.system.server.Server"> <priority value="INFO" /> <appender-ref ref="TRAP_LOG"/> </category> <category name="org.jboss.ha.framework.interfaces.HAPartition.lifecycle"> <priority value="INFO" /> <appender-ref ref="TRAP_LOG"/> </category> <category name="org.jboss.deployment.MainDeployer"> <priority value="ERROR" /> <appender-ref ref="TRAP_LOG"/> </category> <category name="org.jboss.ejb.EJBDeployer"> <priority value="INFO" /> <appender-ref ref="TRAP_LOG"/> </category> <category name="org.jboss.deployment.EARDeployer"> <priority value="INFO" /> <appender-ref ref="TRAP_LOG"/> </category> --> <!-- ======================= --> <!-- Setup the Root category --> <!-- ======================= --> <root> <appender-ref ref="CONSOLE"/> <appender-ref ref="FILE"/> </root> <!-- Clustering logging --> <!-- Uncomment the following to redirect the org.jgroups and org.jboss.ha categories to a cluster.log file. <appender name="CLUSTER" class="org.jboss.logging.appender.RollingFileAppender"> <errorHandler class="org.jboss.logging.util.OnlyOnceErrorHandler"/> <param name="File" value="${jboss.server.log.dir}/cluster.log"/> <param name="Append" value="false"/> <param name="MaxFileSize" value="500KB"/> <param name="MaxBackupIndex" value="1"/> <layout class="org.apache.log4j.PatternLayout"> <param name="ConversionPattern" value="%d %-5p [%c] %m%n"/> </layout> </appender> <category name="org.jgroups"> <priority value="DEBUG" /> <appender-ref ref="CLUSTER"/> </category> <category name="org.jboss.ha"> <priority value="DEBUG" /> <appender-ref ref="CLUSTER"/> </category> --> </log4j:configuration> Page I'm testing private static final Logger log = Logger.getLogger(ServerLogsController.class .getName()); @GET @Path("/testDebug") public String testDebug(@Context final ServletContext context) { log.error("This is an error which always shows!"); log.debug("This is a debug message"); return "Test Debug Page"; } A: There's two ways I can think of to get the debug messages to show here: 1) You can add a new entry in your xml file for ServerLogsController to display DEBUG messages. <category name="package.for.ServerLogsController"> <priority value="DEBUG" /> <appender-ref ref="CONSOLE"/> <appender-ref ref="FILE"/> </category> where you replace package.for.ServerLogsController with the correct package name. Note that you can also set that to just package.for and all files under that directory will log @ DEBUG level. This setting will override the root behavior mentioned in the second bullet (i.e. if root is set to DEBUG but package.for.ServerLogsController is set to ERROR, you will not see DEBUG messages from package.for.ServerLogsController. 2) Set debugging on the root package <root> <priority value="DEBUG"/> <appender-ref ref="CONSOLE"/> <appender-ref ref="FILE"/> </root> This will make all packages log at DEBUG level unless specifically overriden by a package.

djangoappengine - Django backends (DB, email, etc.) for App Engine ================================================================== Djangoappengine contains App Engine backends for Django-nonrel, e.g. the database and email backends. In addition we provide a testapp_ which contains minimal settings for running Django-nonrel on App Engine. Use it as a starting point if you want to use App Engine as your database for Django-nonrel. Take a look at the documentation below and subscribe to our `discussion group`_ for the latest updates. Contents -------- .. toctree:: :maxdepth: 2 :titlesonly: installation db services management admin mapreduce Contribute ------------------------------------------------------ If you want to help with implementing a missing feature or improving something please fork the source_ and send a pull request via Github or a patch to the `discussion group`_. .. _discussion group: http://groups.google.com/group/django-non-relational .. _testapp: https://github.com/django-nonrel/django-testapp .. _source: https://github.com/django-nonrel/djangoappengine

The Carolina Hurricanes will put their four-game winning streak on the line when they host the Philadelphia Flyers in a Metropolitan Division match-up on Thursday. The Canes will ice the same lineup seen in Chicago on Tuesday - and why mess with what's working? - including Petr Mrazek starting in net. GAME PREVIEW Here is the projected lineup for the Hurricanes.

IN THE COURT OF CRIMINAL APPEALS OF TEXAS PD-1374-14 WESLEY ALLEN DOTSON, Appellant v. THE STATE OF TEXAS ON APPELLANT’S PETITION FOR DISCRETIONARY REVIEW FROM THE FOURTH COURT OF APPEALS KARNES COUNTY Per curiam. Richardson, J., not participating. OPINION A jury convicted appellant of aggravated assault of a public servant, and sentenced him to fifty years’ confinement and assessed a $10,000 fine. On appeal, appellant claimed that the trial court erred by allowing the State to impeach a defense witness with prior felony convictions that were more than ten years old. The court of appeals upheld the trial court’s actions by applying the common law tacking doctrine to the remote convictions, and assessing their admissibility under Rule of Evidence 609(a)’s “outweigh” standard rather than Rule of Evidence 609(b)’s  WESLEY ALLEN DOTSON – 2 “substantially outweigh” standard. Dotson v. State, No. 04-13-00858-CR, slip op. at 3-4 (Tex. App.–San Antonio Sept. 10, 2015)(not designated for publication). Applying Rule 609(a), the court of appeals upheld the admission of the prior remote convictions. Id. at 6. Appellant has filed a petition for discretionary review of this decision. We recently addressed this issue in Meadows v. State, PD-0175-14, slip op. at 4 (Tex. Crim. App. Feb. 25, 2015), in which we held that the unambiguous plain language of Rule of Evidence 609 supplants the common-law tacking doctrine. Under Rule 609(b), evidence of a prior conviction is inadmissible to impeach a witness “if more than ten years has elapsed since the later of the date of conviction or release of the witness from confinement imposed for that conviction ‘unless the court determines, in the interests of justice, that the probative value of the conviction supported by specific facts and circumstances substantially outweighs its prejudicial effect.’” Id. at 6. The Court of Appeals in the instant case did not have the benefit of our opinion in Meadows. Accordingly, we grant ground (1) of appellant’s petition for discretionary review, vacate the judgment of the Court of Appeals, and remand this case to the Court of Appeals in light of our opinion in Meadows.1 DELIVERED April 15, 2015 DO NOT PUBLISH 1 Ground (2) of appellant’s petition for discretionary review is refused without prejudice. 

Q: py2neo graph.merge() behaves differently from Cypher MERGE? So, for an empty database MERGE (N1:A {name:"A"})-[:r]->(N2:B {name:"B"}) will create two nodes N1 and N2 with an edge r between them. The following python code however does not do that... but why? Should it not? from py2neo import Graph, authenticate, rel, Node graph = Graph() # set up authentication parameters authenticate("localhost:7474", <user>, <password>) # clear the data base graph.delete_all() graph.merge(rel(Node("A" , name="A"), "r", Node("B" , name="B"))) Running that script results in a still empty database. Why is that and how can I get the Cypher merge behaviour from py2neo without using graph.cypher.execute("MERGE ...")? A: In Py2neo graph.merge matches or creates a single node by label and (optionally) property, where you are wanting to MERGE on the entire pattern (node, relationship, other node). The pattern you are using for the Cypher MERGE statement does not appear to be supported in Py2neo outside of Cypher.

Q: How can I load a sound file into memory using NAudio and use it later? I'm playing the same sound files (randomly choosing between them) 5 times a second, and I'm always loading into memory, so the program uses a lot of memory. How could I load the sound file into memory, and start it from there? I'm using NAudio. Current code: var sound = "sounds/test.mp3"; using (var audioFile = new AudioFileReader(sound)) using (var outputDevice = new WaveOutEvent()) { outputDevice.Init(audioFile); outputDevice.Play(); while (outputDevice.PlaybackState == PlaybackState.Playing) { Thread.Sleep(1000); } threadStop(); } A: If you remove the using blocks then audioFile and outputDevice will not be disposed. You can then retain them in memory, and the same references will be used each time you play the audio. With using blocks, you are repeatedly instantiating NAudio objects whose memory may not be deallocated immediately. var sound = "sounds/test.mp3"; var audioFile = new AudioFileReader(sound); var outputDevice = new WaveOutEvent(); outputDevice.Init(audioFile); outputDevice.Play(); while (outputDevice.PlaybackState == PlaybackState.Playing) { Thread.Sleep(1000); } threadStop(); A: I fixed the whole issue by using the code found in this article. It uses the MixingSampleProvider. I load the sounds into a custom class called: CachedSound. And then I play them using another class called: AudioPlaybackEngine. Which handles the mixer, and I use the CachedSoundSampleProvider class to read the cached sound. The code looks like this: class AudioPlaybackEngine : IDisposable { private readonly IWavePlayer outputDevice; private readonly MixingSampleProvider mixer; public AudioPlaybackEngine(int sampleRate = 44100, int channelCount = 2) { outputDevice = new WaveOutEvent(); mixer = new MixingSampleProvider(WaveFormat.CreateIeeeFloatWaveFormat(sampleRate, channelCount)); mixer.ReadFully = true; outputDevice.Init(mixer); outputDevice.Play(); } public void PlaySound(string fileName) { var input = new AudioFileReader(fileName); AddMixerInput(new AutoDisposeFileReader(input)); } private ISampleProvider ConvertToRightChannelCount(ISampleProvider input) { if (input.WaveFormat.Channels == mixer.WaveFormat.Channels) { return input; } if (input.WaveFormat.Channels == 1 && mixer.WaveFormat.Channels == 2) { return new MonoToStereoSampleProvider(input); } throw new NotImplementedException("Not yet implemented this channel count conversion"); } public void PlaySound(CachedSound sound) { AddMixerInput(new CachedSoundSampleProvider(sound)); } private void AddMixerInput(ISampleProvider input) { mixer.AddMixerInput(ConvertToRightChannelCount(input)); } public void Dispose() { outputDevice.Dispose(); } public static readonly AudioPlaybackEngine Instance = new AudioPlaybackEngine(44100, 2); } class CachedSound { public float[] AudioData { get; private set; } public WaveFormat WaveFormat { get; private set; } public CachedSound(string audioFileName) { using (var audioFileReader = new AudioFileReader(audioFileName)) { // TODO: could add resampling in here if required WaveFormat = audioFileReader.WaveFormat; var wholeFile = new List<float>((int)(audioFileReader.Length / 4)); var readBuffer= new float[audioFileReader.WaveFormat.SampleRate * audioFileReader.WaveFormat.Channels]; int samplesRead; while((samplesRead = audioFileReader.Read(readBuffer,0,readBuffer.Length)) > 0) { wholeFile.AddRange(readBuffer.Take(samplesRead)); } AudioData = wholeFile.ToArray(); } } } class CachedSoundSampleProvider : ISampleProvider { private readonly CachedSound cachedSound; private long position; public CachedSoundSampleProvider(CachedSound cachedSound) { this.cachedSound = cachedSound; } public int Read(float[] buffer, int offset, int count) { var availableSamples = cachedSound.AudioData.Length - position; var samplesToCopy = Math.Min(availableSamples, count); Array.Copy(cachedSound.AudioData, position, buffer, offset, samplesToCopy); position += samplesToCopy; return (int)samplesToCopy; } public WaveFormat WaveFormat { get { return cachedSound.WaveFormat; } } } // This class automatically disposes the file reader that it contains. class AutoDisposeFileReader : ISampleProvider { private readonly AudioFileReader reader; private bool isDisposed; public AutoDisposeFileReader(AudioFileReader reader) { this.reader = reader; this.WaveFormat = reader.WaveFormat; } public int Read(float[] buffer, int offset, int count) { if (isDisposed) return 0; int read = reader.Read(buffer, offset, count); if (read == 0) { reader.Dispose(); isDisposed = true; } return read; } public WaveFormat WaveFormat { get; private set; } }

417 F.3d 715 UNITED STATES of America, Plaintiff-Appellee,v.John LASHAY, Defendant-Appellant. No. 04-3378. United States Court of Appeals, Seventh Circuit. Argued July 6, 2005. Decided August 3, 2005. Tracy M. Johnson (argued), Michelle L. Jacobs, Office of the United States Attorney, Milwaukee, WI, for Plaintiff-Appellee. Michael Holzman (argued), Rosen & Holzman, Waukesha, WI, for Defendant-Appellant. Before COFFEY, RIPPLE, and ROVNER, Circuit Judges. ILANA DIAMOND ROVNER, Circuit Judge. 1 A jury found John LaShay guilty of conspiracy to defraud the United States, 18 U.S.C. § 371, and tampering with a witness, id. § 1512(b)(1). At sentencing, the district court treated the sentencing guidelines as advisory and imposed concurrent terms of 24 months on the conspiracy count and 6 months on the witness-tampering count. LaShay now argues that there was insufficient evidence to support the witness-tampering conviction, and that the district court should have submitted sentencing issues to a jury.1 We affirm the convictions but vacate the sentences and remand for resentencing. 2 Beginning in June 2002, LaShay was involved in a scheme to help Pakistani nationals obtain permanent resident status in the United States by finding United States citizens for them to marry. LaShay's employer at a local gas station, Faryad Hussain, asked him if he knew anyone who would marry an acquaintance who needed a green card, and LaShay suggested that his daughter might do so. LaShay's daughter eventually married one of Hussain's acquaintances and sponsored his application for permanent residency. LaShay afterward approached several other women about marrying Pakistani nationals, including his daughter's mother and a former co-worker. According to Hussain, LaShay was promised $400 or $500 for his role in the conspiracy, but the payments were never made. 3 During the investigation of this scheme, a government agent discovered that LaShay had cashed a $2000 check written out to him by Hussain. This amount matched the sum LaShay's daughter had told authorities she was offered for her marriage. Because of this, and because $2000 was a much larger amount than Hussain typically gave employees for business purposes, the agent considered this check significant and followed up on it in a July 2003 interview with James Clark, LaShay's friend and fellow gas station employee. As Clark recounted that interview at trial, he told the agent that the station did keep cash on hand to cash paychecks for customers, but that $2000 was more than the customary amount. Hussain, however, testified at trial as a government witness that he indeed gave LaShay the check to use for petty cash at the gas station, and that it was not a payment for participation in marriage fraud. 4 According to Clark's trial testimony, LaShay mentioned the $2000 check to him several times in the three days immediately preceding his interview with the government agent. LaShay told Clark that Hussain had given him the check to provide funds for cashing checks for customers, but that he was "worried" about the check because immigration authorities had a copy of it. He asked if Clark remembered Hussain giving him the check, but, according to his testimony, Clark responded that there was no way he could have been present for the event because he and LaShay worked different shifts. Nonetheless, LaShay raised the subject daily for three days, stating that he wanted to make sure Clark remembered that the check had been for petty cash. Clark responded that he wasn't going to lie for anyone. On cross-examination, though, Clark conceded that he did not feel LaShay had been trying to threaten or intimidate him. When asked on redirect if he felt LaShay had been asking him to lie, he responded yes, although on re-cross he also contradicted that statement by agreeing that defense counsel was "correct" in saying that LaShay hadn't really been asking him to lie. 5 After the guilty verdicts, the district court proceeded to sentencing. It stated that, in light of Blakely v. Washington, 542 U.S. 296, 124 S.Ct. 2531, 159 L.Ed.2d 403 (2004), and United States v. Booker, 375 F.3d 508 (7th Cir.2004), it did not believe the sentencing guidelines bound its sentencing determination. Rather, the district court decided to proceed with "[t]he Guidelines used as just that, a guide." Although LaShay had filed objections to the presentence report based on upward adjustments made to his offense level for committing the offense while on pretrial release and having a leadership role in the conspiracy, the district court did not resolve them. Instead, taking into account matters of punishment, deterrence, retribution, rehabilitation, and the safety of the public, the district court accepted the government's recommendation of 24 months' imprisonment. 6 The witness-tampering count alleges that LaShay "did knowingly attempt to corruptly persuade James Clark with the intent to influence his testimony" at LaShay's trial, in violation of 18 U.S.C. § 1512(b)(1). LaShay argues that there was insufficient evidence to support the jury's guilty verdict on this charge. He argues that there was no evidence that he threatened, intimidated, or harassed Clark, or in any way encouraged him to lie. 7 In reviewing for the sufficiency of the evidence, we consider the evidence in the light most favorable to the government and ask whether any rational jury could have found the elements of the offense beyond a reasonable doubt. United States v. Henningsen, 387 F.3d 585, 589 (7th Cir.2004). We neither reweigh the evidence nor substitute our judgment of the facts for that of the factfinder. United States v. Masten, 170 F.3d 790, 794 (7th Cir.1999). 8 In relevant part, § 1512(b)(1) subjects to imprisonment anyone who "knowingly uses intimidation, threatens, or corruptly persuades another, or attempts to do so," with the intent to "influence, delay, or prevent the testimony of any person in an official proceeding." To have convicted LaShay of this offense as alleged in the indictment, the government was required to prove that: 1) Clark was a witness or prospective witness; 2) LaShay attempted to persuade Clark to provide false testimony; and 3) LaShay acted knowingly and with the intent to influence Clark's testimony. United States v. Arocho, 305 F.3d 627, 639 (7th Cir.2002), superseded by statute on other grounds as stated in United States v. Rodriguez-Cardenas, 362 F.3d 958 (7th Cir.2004); United States v. Johnson, 903 F.2d 1084, 1087 (7th Cir.1990). 9 The jury's verdict is supported by sufficient evidence. LaShay focuses on the fact that he never threatened Clark, but a defendant need not use physical force or intimidation to be guilty of witness tampering, so long as he attempts to "corruptly persuade" a witness to testify falsely. United States v. LaFontaine, 210 F.3d 125, 133 (2d Cir.2000); United States v. Pennington, 168 F.3d 1060, 1066 (8th Cir. 1999); United States v. Gabriel, 125 F.3d 89, 102 (2d Cir.1997); see also Arocho, 305 F.3d at 640 (holding that conviction under § 1512(b)(1) was supported by sufficient evidence where defendants never threatened witness but repeatedly urged him to change his story and wrote false statement that witness signed). For instance, "corrupt" persuasion occurs "`where a defendant tells a potential witness a false story as if the story were true, intending that the witness believe the story and testify to it.'" Gabriel, 125 F.3d at 102 (quoting United States v. Rodolitz, 786 F.2d 77, 82 (2d Cir.1986)). In Gabriel, the defendant faxed a witness a false account of a meeting relevant to the government's investigation of whether the defendant made misrepresentations in pursuit of government contracts. Gabriel, 125 F.3d at 93-94. He urged the witness to "think this through" before answering any questions about his memory of that meeting. Id. at 94. The Second Circuit held that this was sufficient to support a conviction for witness tampering. Id. at 105. Here, LaShay similarly placed a story before Clark in the hopes that he would adopt it if interviewed. 10 Similarly, the Second Circuit upheld a district court's finding of witness tampering where the defendant tried to persuade a witness to give a false account that tracked the defendant's position. LaFontaine, 210 F.3d at 132 (affirming revocation of bail based on "practical probability" of witness tampering). The defendant had done nothing more than "remind" the witness that her mother had undergone a hernia operation, when in fact the mother had received cosmetic procedures which the defendant's clinic disguised as a hernia operation when billing the insurance company. Id. at 128. This case presents a similar situation, with LaShay repeatedly urging Clark to "remember" that he saw Hussain hand over the $2000 check for petty cash, when Clark knew he had not actually seen the check change hands. A jury could properly view LaShay's remarks as an unstated invitation to lie. Id. This is true even though the evidence at trial never established that LaShay's account of the check was false; LaShay was suggesting that Clark claim personal knowledge of the transaction when in fact he had none. See id. at 132-33 (practical probability of witness tampering even though defendant had some evidence to suggest that the version of events she proposed to witness could be true). 11 In his opening brief, which he filed before United States v. Booker, ___ U.S. ___, 125 S.Ct. 738, 160 L.Ed.2d 621 (2005), LaShay argues that the district court's use of the sentencing guidelines as a reference violated the Sixth Amendment. He contends that the court should have submitted the question whether he was an organizer or manager in the conspiracy to a sentencing jury. But this position is no longer tenable; Booker holds that application of the sentencing guidelines does not violate the Sixth Amendment so long as the district court treats them as advisory rather than mandatory. 125 S.Ct. at 750. The district court here made clear that it did not consider itself bound by the guidelines, but still found them to be a useful reference. Under those circumstances, LaShay had "no right to a jury determination of the facts that the judge deems relevant." Id. 12 In his reply brief, however, LaShay for the first time argues that the district court erred when it failed to resolve the dispute over the applicable guideline range before sentencing him. Typically, arguments first raised in a reply brief are considered waived. Kelso v. Bayer Corp., 398 F.3d 640, 643 (7th Cir.2005). But LaShay's argument here is based on Booker, which was not decided until after his opening brief had already been filed, meaning he raised the argument as soon as it was reasonably available to him. Accordingly, we will review the district court's sentence for harmless error, since LaShay raised a Blakely objection in the district court. United States v. Schlifer, 403 F.3d 849, 854 (7th Cir.2005). 13 LaShay is correct that, though the guidelines are no longer mandatory, district courts still must consult them and take them into account when sentencing. United States v. Baretz, 411 F.3d 867 (7th Cir.2005). The district court should have calculated the guideline range accurately and then explained any deviation it chose to make in LaShay's case. United States v. George, 403 F.3d 470, 473 (7th Cir.2005). Here, the district court did not bother to calculate a range at all, but simply accepted the government's sentencing recommendation. This was error. Id. 14 Nor can this error can be considered harmless. Although the government conceded at sentencing that LaShay had not committed the offense while on pretrial release, leaving only his purported leadership role in the conspiracy in dispute, this dispute might seriously have impacted LaShay's term of imprisonment. The government contended that the applicable guideline range was 21 to 27 months, but without this three-level increase in the offense level, LaShay's range would have been 12 to 18 months. LaShay's counsel argued for 14 months at sentencing. Under these circumstances, the government cannot demonstrate that the district court's failure to calculate the guideline range did not impact LaShay's sentence. 15 Accordingly, although we AFFIRM LaShay's convictions, we REMAND this case to the district court for resentencing. Notes: 1 Although counsel reported at argument that LaShay has now been released from imprisonment, his appeal is not moot because he is still serving his term of supervised releaseUnited States v. Trotter, 270 F.3d 1150, 1152 (7th Cir. 2001). On remand, the district court could still alter LaShay's overall sentence. Id.

1. Field of the Invention The present invention relates to a lens barrel which holds a zoom lens consisting of multiple lens groups, to a photographic apparatus which takes photographs by capturing light from a subject entering through the zoom lens held by the lens barrel, and to an optical apparatus which has a lens consisting of multiple lens groups. 2. Description of the Related Art Recently, digital cameras have been spreading rapidly, and increasingly higher image quality is demanded together with smaller size and thinner profiles. A thin card-size digital camera equipped with a lens barrel which holds a zoom lens consisting of multiple lens groups has been proposed (see Non-patent Document 1: Internet URL—http://www.business-ijP/sentan/jusyou/2003/pentax/) and introduced commercially as one of digital cameras which meet the above needs. This camera is capable of high image quality zooming using optical zoom whereas earlier thin digital cameras use an electronic zoom function for magnification. One of the trends in user needs is to have higher-powered optical zoom capabilities while achieving smaller size and thinner profiles. Patent Document 1 (Japanese Patent Laid-Open No. 2003-295031) proposes a technique for collapsing a lens barrel equipped with a zoom lens in a thin camera body using an ingenious method for forming cam grooves. An internal configuration of the lens barrel disclosed in Patent Document 1 is described below. FIGS. 1, 2, and 3 are sectional views taken along the optical axis of the lens barrel mounted in a digital camera. Of these, FIGS. 1 and 2 show the lens as it is extended. According to Patent Document 1, FIG. 1 is a diagram showing a telephoto end while FIG. 2 is a diagram showing a wide-angle end. FIG. 3 is a diagram showing the lens barrel as it is collapsed. FIG. 4 is a developed view illustrating cam grooves used to extend and collapse the lens barrel from/into the camera body. A configuration of a lens barrel 100 is described with reference to FIGS. 1 to 4. The lens barrel 100 holds a four-group zoom lens composed of a first lens group 210, second lens group 220, third lens group 230, and fourth lens group 240. Of the four lens groups, the second lens group 220 is moved along the optical axis for adjustment of focal distance while the fourth lens group 240 serving as a focus lens is moved along the optical axis for focus adjustment. The first lens group 210 is held in an inner tube 110. The inner tube 110 is equipped with cam pins 111, which are engaged with cam grooves 121 (see FIG. 4) formed in the inner surface of an outer tube 120. Three cam pins 111 are installed on the outer wall of the inner tube 110 at unequal intervals and three cam grooves 121 are formed on the inner wall of the outer tube 120 at unequal intervals (see FIG. 4) to engage with the cam pins 111. Consequently, when rotation of a zoom motor 270 is transmitted to a gear 124 installed on the inner wall of the outer tube 120 via a coupling gear 271 (see FIG. 2), rotating the outer tube 120, the first lens group 210 extends together with the inner tube 110 following the shape of the cam grooves 121. The second lens group 220 is held by a lens group holding frame 221, on whose circumference three cam pins 222 are installed at unequal intervals. The cam pins 222 are engaged with respective cam grooves 122 formed in the inner wall of the outer tube 120 (see FIG. 4). A guide rod 1132 is passed through a through-hole 221a made in the lens group holding frame 221 of the second lens group 220. Along with rotation of the outer tube 120, the second lens group 220 moves along the optical axis, being guided by the guide rod 1132. The guide rod 1132 is supported by a tip support 1132a while a guide rod 1133 which guides the third lens group 230 is supported by another tip support 1133a. The tip supports 1132a and 1133a support the respective guide rods 1132 and 1133 and are also used as members which support the inner tube 110. The tip supports 1132a and 1133a are equipped with an intermediate frame 1101 and a retainer ring 1102. The intermediate frame 1101 is inserted slidably along the inner wall of the inner tube 110 and the retainer ring 1102 is installed at the rear end of the inner tube 110 to prevent the intermediate frame 1101 from moving backward. The intermediate frame 1101 and retainer ring 1102 are equipped with respective spring pegs 1101a and 1102b. A spring 1103 is bridged between the spring pegs to restrict the movement of the intermediate frame 1101 by urging the intermediate frame 1101 forward along the sliding surface so that the intermediate frame 1101 will not move backward when it is extended together with the inner tube 110. Furthermore, a cam groove 123 (see FIG. 4) is formed between the cam grooves 121 and 122 in the outer tube 120 to engage with a cam pin (not shown) installed on a lens group holding frame 130 of the third lens group 230. Consequently, as the outer tube 120 rotates by receiving the driving force of the zoom motor 270 via the coupling gear 271 and gear 124 (see FIG. 2), the third lens group 230 moves along the optical axis following the shape of the cam groove 123. Incidentally, a shutter unit 131 is linked to the lens group holding frame 130 which holds the third lens group 230. A through-hole 131a is made in the lens group holding frame 130 as in the case of the lens group holding frame 221. The guide rod 1132 is passed through the through-hole 131a. Furthermore, the guide rod 1132 is also passed through a through-hole 141a made in a lens group holding frame 140 which holds the fourth lens group 240 described later. In this way, this example employs a configuration in which the second lens group 220, third lens group 230, and fourth lens group 240 are guided by the common guide rod 1132 to avoid misalignment of optical axes. Extension operation of the lens barrel 100 with this configuration is described in detail with reference to FIG. 4. When the outer tube 120 is rotated by the zoom motor 270, the inner tube 110 extends from a collapsed state to an extended position (B-side end of the area indicated by symbol A) following the shape of the cam grooves 121 (area indicated by symbol A) and held at the extended position (area indicated by symbol B). Until the outer tube 120 is held at the extended position, the second lens group 220 moves along the area indicated by symbol C following the shape of the cam grooves 122 and reaches the end of the area indicated by symbol C when the inner tube 110 is extended to the extended position. As a zoom switch (not shown) is operated at this time, the second lens group 220 enters the area indicated by symbol D, and moves to the end of the area indicated by symbol D if the zoom switch continues to be operated. On the other hand, as the inner tube 110 rotates, the third lens group 230 leaves a collapsed position, moves along the cam groove 123 through an extension area (area indicated by symbol E) and reaches an extended position (intersection of areas indicated by symbols E and F). It remains held at the extended position (area indicated by symbol F) even if the zoom switch is operated. In this way, by arranging cam grooves ingeniously in the inner wall of the outer tube 120, it is possible to move the first lens group, second lens group 220, and third lens group 230 among the four lens groups along the optical axis following the shape of the cam grooves by the rotation of the single tube 120 and move the second lens group along the optical axis by the operation of the zoom switch, and thereby do zooming. In the lens barrel 100 shown in FIGS. 1 to 3, the fourth lens group 240 at the tail of the four lens groups composing the zoom lens is used as a focus lens. The zoom lens held in the lens barrel 100 has a high zoom ratio, and consequently the fourth lens group 240 acting as the focus lens must have a relatively long travel distance. Thus, in this example, a column screw 1131 (see FIG. 1) as long as the long travel distance is installed along the optical axis, a nut 141b is fastened to the lens group holding frame 140 which holds the fourth lens group 240, and the column screw 1131 is screwed into the nut 141b for accurate focus adjustment. Focus is adjusted as the column screw 1131 is rotated by rotational driving force of a focus motor (not shown) transmitted via a gear train (not shown) and a lens group holding frame 141 moves along the optical axis by the distance equivalent to the rotation of the column screw 1131, being guided by the column screw 1131 and guide rods 1132 and 1133. When an image taking lens starts to catch a subject, focus is adjusted by generating image data by means of an image pickup device 280, detecting a focus position based on the image data, and moving the fourth lens group 240 acting as the focus lens to the focus position through rotation of the column screw. After focus adjustment, when a shutter button (not shown) is pressed, the shutter unit 131 provided in the lens group holding frame 130 which holds the third lens group 230 is operated in, synchronization with full depression of the shutter button to take a photograph. Consequently, light from the subject passes through the first lens group 210, second lens group 220, third lens group 230, and fourth lens group 240 (focus lens) and forms an image on a light-receiving surface of the image pickup device 280, which generates an image signal which represents the subject image formed on the light-receiving surface. Even if attempts are made to further reduce the length of the lens barrel, since the lens barrel shown in FIGS. 1 to 4 consists of two tubes, it is not possible to reduce the length sufficiently. It is conceivable to reduce the length of the lens barrel by increasing the number of tubes of the lens barrel to three or four. In that case, however, to arrange lens groups of the collapsed lens barrel along the optical axis, it is necessary to build a safety factor into the length of the lens barrel to allow adjacent lens groups to stay clear of each other. Besides, for high-powered zooming, it is also necessary to increase the length of the extended lens barrel to allow for a longer adjustable distance between lens groups composing the zoom lens. Thus, due to the increase in the length of the extended lens barrel, the length of the collapsed lens barrel cannot be decreased as it ought to be.