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Q: Third party wants to call Salesforce.Can we use named credentials in this case i have a use case where Some code has been written in salesforce and Third party wants to call it.They are calling using rest like this. https://xxx.com/services/oauth2/token?grant_type=password&client_id=12345&client_secret=12345&username=sandbox.username&password=password Can i use Named credentials in this scenario. A: Named Credentials are only relevant for calls made from Salesforce to either Salesforce itself or some other platform. They cannot be used by outside callers into Salesforce. When calling in to Salesforce from a third party, OAuth authentication is required unless you choose to expose an Apex REST service to the unauthenticated world via a Force.com Site. Naturally, doing so has significant security implications. If the third party system is a different Salesforce instance, you can create a Named Credential in that instance and authenticate it via OAuth.

Q: How to launch an activity in a toolkit library from a separate application I have a android toolkit with several Views, Activities, and other useful tools. Then when someone would like to use the toolkit, they create their own application, reference the toolkit and get all the goodies. I've gotten this to work for views, but I'm having trouble launching Activities. Say there is an Activity in the toolkit called BasicHttpServerActivity. How would I launch this activity from a separate application? I've tried using intent filters on the toolkit but I keep getting an error. Here is my current setup. Toolkit MANIFEST <activity android:name=".BasicHttpServerActivity"> <intent-filter> <action android:name="com.fs.BasicHttpServerActivity.LAUNCH" /> </intent-filter> </activity> Separate application activity launch (attempt) Intent serverIntent = new Intent("com.fs.BasicHttpServerActivity.LAUNCH"); startActivity(serverIntent); Logcat says: 04-14 17:16:44.204: ERROR/AndroidRuntime(450): android.content.ActivityNotFoundException: No Activity found to handle Intent { act=com.fs.BasicHttpServerActivity.LAUNCH } A: The other application would need to add the activity to its manifest. There is no "toolkit manifest".

179 Kan. 50 (1956) 292 P.2d 711 LAWRENCE L. MILLER, Appellee, v. FARMERS MUTUAL AUTOMOBILE INSURANCE COMPANY, Appellant. No. 39,864 Supreme Court of Kansas. Opinion filed January 28, 1956. William E. Haney, of Topeka, argued the cause, and Howard A. Jones and Charles L. Davis, Jr., both of Topeka, were with him on the briefs for the appellant. William Hergenreter, of Topeka, argued the cause, and Wendell L. Garlinghouse, Warren W. Shaw, Robert R. Jones and John A. Baush, all of Topeka, were with him on the briefs for the appellee. The opinion of the court was delivered by PRICE, J.: This was an action by an insured against an insurance company for a declaratory judgment to determine the rights and obligations of the parties under an automobile insurance policy. From an adverse judgment defendant has appealed. Plaintiff was the owner of a 1952 Pontiac automobile. The insurance policy in question was purchased by him from defendant and was in effect from February 20, 1953, to August 20, 1953. It was a "standard policy" classified as for "pleasure and business," and insured plaintiff against liability for bodily injury to the extent of $15,000 for each person, and against liability for property damage for each accident to the extent of $10,000. It provided that in the event plaintiff was sued as a result of a collision involving his automobile, or one being driven by him, defendant company would defend such suit. With respect to coverage while driving a vehicle other than the described Pontiac the policy provided: "V. Use of Other Automobiles "If the named insured is an individual who owns the automobile classified `pleasure and business,' ... such insurance as is afforded by this policy for bodily injury liability, for property damage liability ... with respect to said automobile applies with respect to any other automobile, subject to the following provisions: "(a) With respect to the insurance ... the unqualified word `insured' includes (1) such named insured, ..." "(b) This insuring agreement does not apply: "(1) To any automobile ... furnished for regular use to the named insured ... "(2) To any automobile while used in the business or occupation of the named insured ... except a private passenger automobile operated or occupied by such named insured, ..." On April 17, 1953, while driving a 1951 Chevrolet vehicle, commonly known as a "carry-all," and which was owned by the adjutant *52 general's department of the state of Kansas, plaintiff was involved in a collision with a vehicle owned by one D and being driven by D's wife. As a result of this mishap D sued plaintiff to recover for damage to his vehicle in the amount of $500, and D's wife sued plaintiff to recover for her personal injuries in the sum of $5,585. Plaintiff notified defendant insurance company of these actions filed against him, but the company, after making an investigation under a reservation of rights, refused to defend the suits for the asserted reasons that (1) at the time of the collision in question plaintiff was driving a vehicle which was furnished for his regular use by his employer, and (2) that the vehicle being driven by plaintiff at the time in question was other than a private passenger automobile used in the business or occupation of plaintiff, and therefore the exclusionary provisions of the policy, supra, relating to the use of other automobiles, applied, thus relieving defendant company of all obligation to defend the actions. Because of this dispute between the parties as to their respective rights and obligations under the policy plaintiff filed this action for a declaratory judgment. The pleadings raised only two questions. The first was whether the Chevrolet vehicle which plaintiff was driving at the time of the collision was one "furnished for regular use" to him. The second was whether the vehicle was other than "a private passenger automobile." The trial court, after hearing considerable evidence, made findings of fact on the two questions as follow: "9. That the 1951 Chevrolet automobile being driven by the plaintiff on April 17, 1953 was furnished to the plaintiff by the employer of plaintiff, the Adjutant General of the State of Kansas. That plaintiff used said automobile very seldom, probably not more than 2 or 3 times a year and then only for short trips. That said automobile was not furnished to the plaintiff `for regular use.' "10. That the 1951 Chevrolet automobile was called a `carry-all' by the manufacturer, which is similar to the type generally called `station wagon.' That the automobile in question at the time of the accident, before and since has only been used to transport one to seven human beings. That said automobile was and is a private passenger automobile." As a conclusion of law the court held: "1. That the defendant, Farmers Mutual Automobile Insurance Company was obligated under its policy No. 15-021851 to provide the protection to the plaintiff up to the limits set out in the policy declarations for the accident in which the plaintiff was involved on April 17, 1953 while the plaintiff was driving the 1951 Chevrolet described in plaintiff's petition, . .." *53 Judgment was entered accordingly and defendant has appealed, specifying as error the findings quoted above, the conclusion of law, the rendition of judgment thereon, and the denial of its motion for a new trial. Concerning the question whether the Chevrolet vehicle which plaintiff was driving at the time of the collision was one "furnished for regular use" to him, the evidence disclosed the following: Plaintiff had been employed as a civilian employee of the adjutant general's department of Kansas for several years. He was a contracting and purchasing clerk and bought items and supplies for the arsenal located on south Topeka Avenue in Topeka. The major portion of his duties was performed at his desk at the arsenal. His work required him to leave the arsenal very little, but occasionally he would drive from the arsenal to some store in downtown Topeka, and on rare occasions he would drive outside of Topeka. There were thirty or thirty-five employees in plaintiff's office, and a "car pool," consisting of four vehicles, including the Chevrolet in question, was available for use by the employees. These vehicles were owned by the adjutant general's department. The vehicle in question was purchased in 1951, and between then and April 17, 1953, the date of the accident, plaintiff had driven it perhaps four or five times. During the six months following the accident he had driven it approximately five or six times. He and his immediate superior testified that this vehicle was not furnished for his regular use, and that, provided it was not being used by some other employee, it was merely available to him on the very infrequent occasions he had to use a government-owned vehicle in his work. On many occasions, when no vehicle in the "car pool" was available he used his own automobile. Upon this evidence, of which the foregoing is only a brief resume, the trial court found that the vehicle in question was not furnished to plaintiff for his regular use within the meaning of the exclusionary provision of the policy. The evidence concerning whether the vehicle in question was other than "a private passenger automobile" disclosed the following: It is referred to in the "trade" and by the manufacturer as a "carry-all," and is described as being identical to what is commonly known as a "station wagon," except that it lacks many of the "refinements" of the latter. It has the same engine and mechanism as a comparable "station wagon," has two doors, a front seat, middle *54 seat and rear seat. It always had been used to carry persons, not exceeding seven in number. Upon this evidence, of which the foregoing is merely a brief summary, the trial court found that the vehicle was a private passenger automobile within the meaning of the exclusionary provision of the policy, and not a "truck," as contended by defendant. We think there can be no question but that the findings by the trial court on these two controverted issues are amply supported by substantial competent evidence. Such being the case, under the well-established rule, they are not to be disturbed on appellate review. And, if the findings are to be upheld, the conclusion of law made by the court is of a certainty correct and judgment was properly rendered thereon. However, as the precise questions apparently have never been passed upon by this court, we pause briefly to comment on defendant's contentions. In support of them we are cited to a number of decisions from other jurisdictions in which "use of other automobile" provisions in insurance policies are discussed. Each has been examined and considered. A number of them are set out in the annotation found at 173 A.L.R. 901. A study of the authorities discloses that courts have found it difficult to lay down any hard and fast rule, and that, generally speaking, each case has been decided upon its own facts and circumstances. As a matter of practical everyday experience, the average person occasionally drives an automobile other than his own. The purpose and effect of the "use of other automobile" provision in a policy are obvious. It extends the driver's insurance to infrequent or casual driving of other automobiles, but excludes him from coverage with respect to his regular use of an automobile not covered by the policy. And, with respect to the requirement that the "other automobile" be a private passenger automobile, the reason is equally obvious. It is common knowledge that the ordinary risk is greatly increased when an insured is driving a truck, bus, delivery, freight or cargo-hauling vehicle. We agree with the trial court that under the facts of this case the use which plaintiff made of the vehicle in question clearly was so infrequent and casual that it is not to be considered as one furnished to him for his regular use within the meaning of the policy, and that it was not intended for and in fact was not used for any purpose other than transporting not to exceed seven passengers. It clearly *55 was a private passenger automobile within the meaning of the policy. Defendant inferentially contends that inasmuch as the vehicle in question was government-owned it therefore was not a "private" passenger automobile. This contention cannot be sustained. The test to be applied to the word "private" is the type of vehicle and not its ownership. And there is still another reason why we think this case was correctly decided in the court below. Assuming, for the sake of argument, there is some ambiguity or uncertainty in the language of the exclusionary provision in question, defendant company is bound by the universal rule to the effect that where a provision of an insurance policy is susceptible of different constructions it is to be construed most favorably to the insured, and that if the insurer intends to restrict its coverage it should use language clearly stating its purpose. (Evans v. Accident Association, 102 Kan. 556, 171 Pac. 643, L.R.A. 1918D 122; Sebal v. Columbian Nat. Life Ins. Co., 144 Kan. 266, 58 P.2d 1108; Knouse v. Equitable Life Ins. Co., 163 Kan. 213, 181 P.2d 310; and Smith v. Mutual Benefit Health & Acc. Ass'n, 175 Kan. 68, 258 P.2d 993.) The judgment is affirmed.

Sernaglia della Battaglia Sernaglia della Battaglia is a comune (municipality) in the Province of Treviso in the Italian region Veneto, located about northwest of Venice and about northwest of Treviso. Sernaglia della Battaglia borders the following municipalities: Farra di Soligo, Giavera del Montello, Moriago della Battaglia, Nervesa della Battaglia, Pieve di Soligo, Susegana, Volpago del Montello. References Category:Cities and towns in Veneto

Gallery Listing Agent Request more information Thank you for the email, we'll get back to you shortly Name (required)Email Address (required)Questions/Comments Description Very nice building,previously used as a Bar. Bar has a full kitchen/grill. Can be used for many other purposes such as a rental hall, a car dealership, retail store, restaurant, beauty salon, etc. Seller to do no repairs, as is sale. New furnace, water heater and central air. Seller's willing to negotiate, bring all offers. Quit Claim deed. 24 HOUR NOTICE TO SHOW. Possible Land Contract Terms.

Git Large File Storage (LFS) or Rsync for Media Files - AJAlabs Now that Git Large File Storage (LFS) has been announced. What is the general opinion on large file storage syncing best practices? Do you use Git LFS or sync with rsync?<p>Reference: https:&#x2F;&#x2F;github.com&#x2F;blog&#x2F;1986-announcing-git-large-file-storage-lfs ====== detaro Depends on what you want to do. Do you just want to sync in one direction? Between two locations? Or the full git-like randomly between multiple repos thing? There are other options like git-annex as well.

MOS (operating system) MOS signifies 'Mobile Operating System' (). It was a Soviet clone of Unix in the 1980s. Overview This operating system was commonly found on SM EVM minicomputers; it was also ported to ES EVM and Elbrus. MOS was also used in high-end PDP-11 clones. There have been several modifications of MOS named MNOS, DEMOS, etc. See also List of Soviet computer systems References Category:Unix variants Category:Computing in the Soviet Union

Labour's betrayal over Brexit was compared to a Carry On remake of Mutiny On the Bounty by David Lidington as he stood in for Theresa May at Prime Minister's Questions today. The Commons leader accused Jeremy Corbyn's party of 'drifting on Europe' and losing touch with the referendum result, labelling its policy on Brexit as 'rudderless'. Labour - Threat - Government - Legislation - Article And after Labour steps up its threat to amend the Government's legislation to trigger Article 50 - the formal mechanism for leaving the EU - he accused the party of behaving in a 'profoundly undemocratic' manner. To roars of approval from Tory benches, he compared Remain MPs to the low budget Carry On franchise making a film about the crewmen who staged a revolt on HMS Bounty in 1789 and set their captain and 18 loyalists adrift in the south Pacific ocean. Mr - Lidington - Government - Vote Mr Lidington said: 'No other EU government is seeking to reverse or question the vote. 'It shows how distant the Labour party is from any aspiration to be back in government again. Action - Mutiny - Bounty - Reshot - Carry 'We watch them in action - its like quarrelling like Mutiny on the Bounty as reshot by the Carry On team.' He added: 'They are rudderless. They are drifting on Europe as on so many other aspects of policy.' Mr - Lidington - Attack - Labour - Government Mr Lidington's attack on Labour shows the Government stepping up its rhetoric on opponents over Brexit. Yesterday No 10 accused Labour and the Lib Dems of not being on the 'UK team' because of their plans to re-write any legislation needed to start Brexit talks.

Q: How Can I Specify A Minimum Ruby Version in a Gemfile? I know that I can specify a Ruby version in a Gemfile like so: ruby '2.0.0' However, instead of setting the exact Ruby version, I'd like to be able to specify a minimum Ruby version so that my scripts remain compatible with new version of Ruby. A: You could raise an exception instead: raise 'Ruby should be >2.0' unless RUBY_VERSION.to_f > 2.0 A: Already possible since Bundler 1.12, e.g. ruby "~> 2.3.0" see here: https://github.com/bundler/bundler-features/issues/119

Molecular dynamics of hyperbranched polyesters in the confinement of thin films. Broadband Dielectric Spectroscopy is employed to investigate the molecular dynamics in thin films of hyperbranched polyesters (type AB(1)B(2), with -OH and -OCOCH(3) as terminal groups). Three relaxation processes are detected: alpha, beta and gamma. While the latter two are not influenced by the confinement, a pronounced effect is observed on the alpha relaxation: with decreasing film thickness the slower relaxation modes of the dynamic glass transition are gradually suppressed, resulting in an increase of the average relaxation rate and in a linear decrease of the dielectric strength. This is attributed to an immobilization in confinement of the polymeric segments located at the periphery of the hyperbranched macromolecular structures.

New tree-living crab species found in Kerala Thiruvananthapuram: Scientists have discovered a new species of long legged, tree-dwelling crabs in Western Ghats of Kerala. The new species named Kani maranjandu after the Kani tribe in Kerala, are substantially different from other congeners. The characteristic traits of the crab include the structure of its hard upper shell, its male abdominal structure and reproductive parts and diagnostic elongated walking legs, which no other genus has, said researchers from University of Kerala. This is the first report of its kind to offer a record of an arboreal crab - a species that lives in trees. The survey of the freshwater crab fauna started in 2014 in the Westerns Ghats in Kerala. People from the Kani tribe reported sightings of a 'long legged' tree crabs in the area. After a year, researchers were finally able to capture a female specimen and later a large adult male. "As water holding hollows in large trees are essential for the survival of this unique species, the discovery also stress the need for conservation of large trees in the degraded forest ecosystems of the Western Ghats," said Biju Kumar of University of Kerala. "It also highlights how little we know about the actual biodiversity that resides in these forests and the efforts that must still be made to find and study the many undoubted new species that still live there," Kumar said. The finding was published in The Journal of Crustacean Biology. PTI Disclaimer: Kindly avoid objectionable, derogatory, unlawful and lewd comments, while responding to reports. Such comments are punishable under cyber laws. Please keep away from personal attacks. The opinions expressed here are the personal opinions of readers and not that of Mathrubhumi.

Piezoelectric porcelain compositions are utilized in sound generators, vibrators, actuators, etc., as electrical-mechanical conversion elements utilizing the inverse piezoelectric effect, and also in sensors, generators, etc., as mechanical-electrical conversion elements utilizing the inverse piezoelectric effect. They are also utilized as electrical-mechanical-electrical circuit elements and also for mechanical-electrical-mechanical vibration control. Conventional piezoelectric porcelain compositions, normally, are constituted with Pb being the main ingredient. Conventional piezoelectric porcelain compositions are made, for example, of PZT constituted by two ingredients of PbZrO3 and PbTiO3, or of materials obtained by modifying PZT by Pb(Mg⅓Nb⅔)O3, Pb(Zn⅓Nb⅔)O3 or other third ingredient. Since Pb is harmful to the human body, however, efforts are underway to develop Pb-free piezoelectric materials. Ferroelectrics, Vol. 160, P265-276 (1994) (Non-patent Literature 1) reports a Pb-free piezoelectric material made of a composite oxide of tungsten bronze type expressed by the formula Sr2-xCaxNaNb5O15 and, in particular, it reports that the composite oxide of tungsten bronze type has single-crystal piezoelectric characteristics. Also, Japanese Patent Laid-open No. Hei 11-240759 (Patent Literature 1) discloses, as piezoelectric porcelain for actuators, a composite oxide of tungsten bronze type expressed by the formula Sr2NaNb5O15. In Patent Literature 1, compositions that are obtained by partially substituting Nb of the composite oxide of tungsten bronze type with V and Ta, as well as those obtained by partially substituting Sr with at least one of Mg, B and Ca and also partially substituting Na with K, are proposed. Similarly, Japanese Patent Laid-open No. Hei 11-278932 (Patent Literature 2) discloses a composite oxide of tungsten bronze type expressed by the formula Sr2NaNb5O15, where compositions are proposed that are obtained by partially substituting Sr of this oxide with at least one of (Bi1/2Li1/2), (Bi1/2Na1/2) and (Bi1/2Na1/2) or with at least one of Mg, Ba and Ca. Furthermore, Japanese Patent Laid-open No. 2000-169229 (Patent Literature 3) discloses a piezoelectric material produced by adding 0.5 to 3 percent by weight of rare earth oxide Re2O3, as a characteristic improvement component, to a polycrystal piezoelectric compound expressed by the formula Sr2-xCaxNaNb5O15 (x=0.05 to 0.35). Particularly in Patent Literature 3, it is proposed that A in the composition expressed by the formula Sr2-xAxNaNb5O15 (in the formula, x=0.075 to 0.25) represent at least two types of elements selected from Ca, B and Mg. Japanese Patent Laid-open No. Hei 10-297969 (Patent Literature 4) discloses a piezoelectric ceramic material expressed by the formula (1−y)(Ba1-xSrx)Nb2O6-yNaNbO3, whose main ingredient is a porcelain component whose x is in the range of 0≦x≦1, while y is in the range of 0.15≦y<⅓.

A refrigeration system generally requires a special electric control unit, for example, for some large refrigeration systems, the electric control unit may be an inverter starting cabinet. Moreover, electronic devices in the inverter starting cabinet generate more heat, and a greater temperature rise has some influences on the working state thereof. Therefore, it is necessary to cool the electronic devices, to meet performance requirements thereof. At present, there are already several electronic device cooling modes. For example, a plurality of openings is provided on a housing of an electronic control unit, to cool the electronic device through natural convection or forced convection; for another example, a water-cooled heat exchange device is arranged in the housing, to cool the electronic device by introducing cooling water from an external water source. Therefore, the above electronic device cooling mode may have a problem of relatively low efficiency, or may have a problem that the electronic device in the cabinet fails due to improper dehumidification in a high-temperature and high-humidity environment.

SSL on port 8080 and 8081 When I use https on port 8080 every thing is fine, but when I use https on port 8081 I get Code: Secure Connection Failed An error occurred during a connection to XXXX.com.br:8081. SSL received a record that exceeded the maximum permissible length. (Error code: ssl_error_rx_record_too_long) The page you are trying to view cannot be shown because the authenticity of the received data could not be verified. Please contact the website owners to inform them of this problem. Alternatively, use the command found in the help menu to report this broken site. I am able to make it work by adjusting apps.vhost, but whenever I change something in the ISPConfig configuration, it overwrite's apps.vhost defaulting it back to a non-ssl connection. How can I configure it in ISPConfig so that it remains ssl, or if that is not possible, what action should I refrain from doing so it does not rewrite apps.vhost. Thanks, Trixor EDIT: And I figured something out that works: Put this in your Server config -> Web -> Apps-vhost port

Q: How to display all attributes of model subclass on first initialization? Problem When a child model is initialized for the first time, only defaults of the child are set as attributes. When a second(and all subsequent) child is being initialized, the attributes of child display defaults of child and it's parent. Fiddle var Parent = Backbone.Model.extend({ defaults: { name: "john", lname: "smith", age: 30, language: "english", location: "belgium" } }); var Child = Parent.extend({ defaults: { hobby: "doing nothing", age: 24, occupation: "student" }, initialize: function () { this.constructor.__super__.initialize.apply(this, arguments); _.defaults(this.defaults, this.constructor.__super__.defaults); console.log(this.attributes); } }); attributes of child initialized for the first time : var child1 = new Child(); child1.attributes : hobby: "doing nothing" age: 24 occupation: "student" attributes of same Child class, initialized for the second time: var child2 = new Child(); child2 attributes: age: 24 hobby: "doing nothing" language: "english" lname: "smith" location: "belgium" name: "john" occupation: "student" Question Why are not all defaults(child's and parent's) are being set as attributes when a child model is initialized for the first time ? Because i've to display a Backbone.Collection inside a <ul> and every model's attributes are configurable through a html form inside each <li>. But because of this problem, i can't get to all attributes of the first model in the collection. A: You're modifying the Child class's defaults object when the first object is instantiated, during its initialize method. At that point, the Backbone.Model constructor has already used defaults to fill in the attributes for that object, so it will only affect subsequent instantiations. Take a look at Backbone.Model: var Model = Backbone.Model = function(attributes, options) { var defaults; var attrs = attributes || {}; options || (options = {}); this.cid = _.uniqueId('c'); this.attributes = {}; _.extend(this, _.pick(options, modelOptions)); if (options.parse) attrs = this.parse(attrs, options) || {}; if (defaults = _.result(this, 'defaults')) { attrs = _.defaults({}, attrs, defaults); } this.set(attrs, options); this.changed = {}; this.initialize.apply(this, arguments); }; initialize is the very last step, after the defaults have been set, so modifying defaults at that point won't do anything for the current object. To get it to work how you want, modify defaults after you declare the class, rather than during initialize: Child.prototype.defaults = _.defaults(Child.prototype.defaults, Parent.prototype.defaults); Working example

// moment.js language configuration // language : catalan (ca) // author : Juan G. Hurtado : https://github.com/juanghurtado (function (factory) { if (typeof define === 'function' && define.amd) { define(['moment'], factory); // AMD } else if (typeof exports === 'object') { module.exports = factory(require('../moment')); // Node } else { factory(window.moment); // Browser global } }(function (moment) { return moment.lang('ca', { months : "Gener_Febrer_Març_Abril_Maig_Juny_Juliol_Agost_Setembre_Octubre_Novembre_Desembre".split("_"), monthsShort : "Gen._Febr._Mar._Abr._Mai._Jun._Jul._Ag._Set._Oct._Nov._Des.".split("_"), weekdays : "Diumenge_Dilluns_Dimarts_Dimecres_Dijous_Divendres_Dissabte".split("_"), weekdaysShort : "Dg._Dl._Dt._Dc._Dj._Dv._Ds.".split("_"), weekdaysMin : "Dg_Dl_Dt_Dc_Dj_Dv_Ds".split("_"), longDateFormat : { LT : "H:mm", L : "DD/MM/YYYY", LL : "D MMMM YYYY", LLL : "D MMMM YYYY LT", LLLL : "dddd D MMMM YYYY LT" }, calendar : { sameDay : function () { return '[avui a ' + ((this.hours() !== 1) ? 'les' : 'la') + '] LT'; }, nextDay : function () { return '[demà a ' + ((this.hours() !== 1) ? 'les' : 'la') + '] LT'; }, nextWeek : function () { return 'dddd [a ' + ((this.hours() !== 1) ? 'les' : 'la') + '] LT'; }, lastDay : function () { return '[ahir a ' + ((this.hours() !== 1) ? 'les' : 'la') + '] LT'; }, lastWeek : function () { return '[el] dddd [passat a ' + ((this.hours() !== 1) ? 'les' : 'la') + '] LT'; }, sameElse : 'L' }, relativeTime : { future : "en %s", past : "fa %s", s : "uns segons", m : "un minut", mm : "%d minuts", h : "una hora", hh : "%d hores", d : "un dia", dd : "%d dies", M : "un mes", MM : "%d mesos", y : "un any", yy : "%d anys" }, ordinal : '%dº', week : { dow : 1, // Monday is the first day of the week. doy : 4 // The week that contains Jan 4th is the first week of the year. } }); }));

-ifndef(_hadoopfs_types_included). -define(_hadoopfs_types_included, yeah). -record(thriftHandle, {id}). -record(pathname, {pathname}). -record(fileStatus, {path, length, isdir, block_replication, blocksize, modification_time, permission, owner, group}). -record(blockLocation, {hosts, names, offset, length}). -record(malformedInputException, {message}). -record(thriftIOException, {message}). -endif.

Introduction {#Sec1} ============ Somatic cell nuclear transfer (SCNT) consists in injecting a donor somatic nucleus into a recipient oocyte to obtain a clone that carries the genome of the donor animal^[@CR1]--[@CR3]^. This technology allows the restoration of valuable genetic resources from somatic material when both sperm and oocytes, or embryos, are unavailable. This is the case in fish, where the most recognized support for the preservation of genetic resources is solely the cryopreserved sperm^[@CR4]^, and where neither oocytes nor embryos can be cryopreserved^[@CR5]^. In this context, cryopreserved fin cells, which carry the genome of both parents, are particularly beneficial for regenerating a breeder^[@CR6]^. Somatic diploid cells are easily collected from fins by non-invasive methods regardless the characteristics of the fish (age, maturity stage, sex, conservation status). Somatic cells are easy to culture *in vitro* and to cryopreserve even under difficult experimental conditions^[@CR7],[@CR8]^. After SCNT, the production of offsprings based on the genome of the donor only requires that the contribution of the oocyte (maternal) genome is prevented. In mammals, this is achieved by enucleating the recipient oocyte before performing the SCNT. In a majority of fish, the oocyte structure makes enucleation very difficult: oocytes are large and opaque, they contain bulky nutritional reserves (the yolk), a dense cytoplasm (the ooplasm), and a thick protective envelope around the oocyte (the chorion)^[@CR9],[@CR10]^. These characteristics prevent the vizualization of maternal genome by transparency and its aspiration for enucleation. Most authors overcome these difficulties by activating oocytes and taking the second polar body as a guide for putative localization of maternal pronucleus^[@CR11]--[@CR13]^. However, these oocytes are less suitable for donor DNA reprogramming than non-activated oocytes^[@CR6]^, and aspiration of the female pronucleus is associated with loss of essential developmental factors such as maternal mRNAs, mitochondria and proteins. Thanks to highly focused laser irradiation of the non-activated oocyte, the Cibelli group^[@CR14],[@CR15]^ succeeded in inactivating the maternal metaphase at a more appropriate recipient stage, but adaptation of this method to species other than zebrafish was never reported, likely because of the difficult tuning of the laser on different egg types. Overall, in addition to be time consuming, oocyte enucleation in fish is a very problematic issue for the success of nuclear transfer and embryonic development of the clone. For this reason, several authors have attempted to carry out nuclear transfer without any inactivation or elimination of maternal DNA. It is interesting that in goldfish, zebrafish, weatherfish and medaka, such a protocol avoiding the enucleation step still allows the development of clones carrying only the genome of the donor^[@CR16]--[@CR21]^. Understanding the mechanisms responsible for the spontaneous loss of oocyte DNA and/or the possible interference induced by retained maternal DNA during early development would help to promote the development of clones from donor origin only. However, this issue is hampered in fish by the lack of knowledge about cellular events that occur after SCNT. It is not known for example whether meiosis resumes normally, and how the clone ploidy is established. Ovulated oocytes bear a condensed maternal DNA maintained in a metaphase plate (MII stage) up to fertilization, when oocyte activation triggers the second polar body extrusion and maternal genome haploidization^[@CR10]^. Polar body extrusion has never been studied in fish after SCNT, and although few studies explored clone ploidy^[@CR17]--[@CR19],[@CR22]^, remodelling of the maternal and somatic chromatins in the clones during the first cell cycle are not known. In this context, the objective of our study was to understand the fate of maternal DNA and the mechanism of spontaneous enucleation in clones, and to characterize the interplay between somatic and maternal DNA. First, we explored the organization and location of maternal and somatic DNA after donor cell injection into the MII stage oocyte. After oocyte activation, we analyzed the extrusion pattern of the polar body to identify how DNAs were handled by the oocyte environment. Then, we characterized the organization of the blastomere during the first cell division and identified the fate of DNA from both origins at this stage. Finally, we discussed how these mitotic figures can explain the spontaneous neutralization of maternal DNA as well as the many embryonic defects observed in clones. Results {#Sec2} ======= Maternal and somatic DNA fate after injection into the MII oocyte {#Sec3} ----------------------------------------------------------------- Characterization of the various compartments in control oocytes was necessary in order to identify and localize the maternal and somatic DNA in the clones. In goldfish, the opacity of the chorion and light refraction of the oocytes prevented any live analysis of the whole oocytes. Instead, all samples had to be fixed and analyzed on histological sections. Oocyte structure (Fig. [1A,B](#Fig1){ref-type="fig"}) was very consistent: the chorion was observed as a thick membrane with a crenellated shape. We hypothesize that this shape would permit expansion of the chorion upon activation, to allow the formation of the perivitelline space. The micropyle (sperm entry point) was always found as a canal-like invagination of the chorion. By observing the successive oocyte sections, it is possible to identify the beginning of membrane invagination, then the side of the canal (micropylar canal) and finally its bottom. The micropyle depth depended on the section angle, but it always penetrated a homogeneous area that was assigned to the ooplasm of the animal pole. Under the chorion and all around the oocyte, the cortical granules were embedded in a thin cytoplasmic layer. They were distinguished from yolk droplets by their transparency under UV light, while yolk droplets appeared as transparent globules under visible light (Fig. [1A,C](#Fig1){ref-type="fig"}). The density of oocyte yolk droplets increased as the sections deepened towards the vegetative pole. Interestingly, in 100% of control oocytes (n = 18), maternal DNA was not found at the bottom of the micropyle, but against the side of the micropylar canal, in the ooplasm, and it was always organized in a metaphase plate (Fig. [1C](#Fig1){ref-type="fig"}).Figure 1Structure of a non-activated control oocyte and location of the maternal DNA. Control oocytes were fixed, cut into 7 µm sections and DNA was stained with Hoechst 33342. (**A**) Image of an upper section of a non-activated oocyte observed under visible light. (**B**) Schematic representation of the oocyte compartments, validated by the observation of successive sections from 18 oocytes. (**C**) Image of the oocyte observed under UV-light, arrowhead shows the maternal DNA condensed in a metaphase plate (MII). The MII was located against the micropylar canal. Inset represents the MII observed in confocal microscopy. In the clones, maternal DNA was present in every oocytes (100%, n = 28 clones), and it was located against the micropylar canal (Fig. [2A,E](#Fig2){ref-type="fig"}), like in the control oocytes. This DNA was always condensed in a metaphase plate (MII stage) that was not different from the one of non-activated control oocytes. In addition, even if the oocyte membrane was perforated during injection through the micropylar canal, the entire structure of the oocyte was similar to the one of the non-activated control oocytes.Figure 2Maternal and Somatic DNA location into non-activated clones. Non-activated clones after somatic DNA injection were fixed, cut into 7 µm sections and DNA was stained with Hoechst 33342. Images of a section of a clone (Clone A) observed (**A**) under UV- and (E) visible light. The arrow shows the maternal DNA in a metaphase plate (MII), located against the micropylar canal, as in control oocytes. This example (Clone A) is representative of 28 clones. Images of sections of 3 different clones (Clones B to D) observed under (**B**--**D**) UV-light or (**F**--**H**) visible light, showing the various locations of the somatic DNA: (**B**,**F**) into the ooplasm, (**C**,**G**) at the yolk border, and (**D**,**H**) into the yolk reserve. Those three clones are representative of the 16 clones in which the somatic DNA was observed. Arrowheads show the somatic DNA. Insets represent the maternal or somatic DNA observed by confocal microscopy. Such a consistency in location and shape of the maternal DNA allowed us to precisely distinguish it from the somatic DNA. Somatic DNA was observed in 57% of non-activated clones (n = 16/28). Although care was taken to inject the somatic cell just under the plasma membrane at the bottom of the micropylar canal, its DNA was found in different compartments within the oocytes (Fig. [2](#Fig2){ref-type="fig"}): most of the somatic DNA was found in the ooplasm (37.5%) (Fig. [2B,F](#Fig2){ref-type="fig"}), or at the boundary between the ooplasm and the yolk (43.8%) (Fig. [2C,G](#Fig2){ref-type="fig"}). Almost a fifth of them were found deeper in the oocyte (18.8%), among the yolk droplets (Fig. [2D,H](#Fig2){ref-type="fig"}). For the clones whose somatic DNA was not found (n = 12/28), we suspect that it was located deeper in the yolk, beyond the first 8 to 10 sections analyzed in our study, from the animal pole downward. Unlike maternal DNA, the injected somatic DNA exhibited different configurations (Fig. [3](#Fig3){ref-type="fig"}). In 62% of the clones, it was organized in metaphasic chromosomes (Fig. [3B](#Fig3){ref-type="fig"}). In 13% of the clones, a pycnotic pattern was observed (Fig. [3C](#Fig3){ref-type="fig"}). Uncondensed DNA was also present in 25% of the clones (Fig. [3D](#Fig3){ref-type="fig"}). Interestingly, no clear relationship could be established between the DNA structure and its sub-cellular location in the oocyte (Fig. [3](#Fig3){ref-type="fig"}). For example, very well organized metaphasic DNA was unexpectedly observed in the deepest part of the oocyte yolk droplets area, where it should have been less exposed to the MPF-rich ooplasm (Fig. [2D](#Fig2){ref-type="fig"}).Figure 3Maternal and somatic DNA structure in non-activated clones, and their respective location within the oocyte. Clones were fixed, cut into 7 µm sections and DNA was stained with Hoechst 33342. Confocal images and localization of (**A**) maternal DNA condensed into a metaphase plate (MII), (**B**) somatic DNA condensed into a metaphase plate, (**C**) pycnotic somatic DNA, and (**D**) decondensed somatic DNA (interphasic). Those images are representative of 28 clones. Below each image is given the corresponding percentage of DNA found in the ooplasm, at the boundary between the ooplasm and the yolk, and in the yolk. Analysis of polar body extrusion pattern after oocyte activation in clones {#Sec4} -------------------------------------------------------------------------- In control activated oocytes labeled with Hoechst 33342, we observed 3 DNA dots that could be ascribed to the maternal pronucleus, the second polar body and the first polar body (Fig. [4A](#Fig4){ref-type="fig"}). However, neither the shape nor the size of the DNA dots could help us to determine the origin or ploidy of each dot. Therefore removal of the chorion was found to be an efficient way to remove the first polar body as it was no longer attached to the oocyte membrane. Observation of dechorionated samples indeed reduced the DNA dot number to two: the maternal pronucleus and the second polar body. We were able to discriminate between the two dots thanks to the Vybrant Green dye which labeled the second polar body only, while the maternal pronucleus was still labeled with Hoechst (Fig. [4B,C](#Fig4){ref-type="fig"}).Figure 4Maternal pronucleus and polar body differential staining in control oocytes after activation. (**A**) Top view image of a non-dechorionated oocyte: Hoechst 33342 staining did not allow discriminating the maternal pronucleus from the first and second polar body. (**B**) Top view image of a dechorionated oocyte: the first polar body was eliminated during dechorionation. Vybrant Green dye stained only one of the two DNA dots. (**C**) Side view image of a dechorionated oocyte: this orientation shows that the second polar body is stained by both dyes, Hoechst 33342 and Vybrant Green, while the maternal pronucleus is only stained by Hoechst 33342. Arrowheads show the second polar body. Arrows show the maternal pronucleus. After activation, most of the dechorionated control oocytes exhibited only one second polar body, which indicates normal DNA fate in untreated oocytes (Fig. [5A](#Fig5){ref-type="fig"}). A similar trend was observed in injected control oocytes, which received the carrier medium but no donor cell. This indicates that perforation of the membrane through the micropyle and injection of the carrier medium did not adversely affect oocyte activation and polar body extrusion. On the contrary, the rate of extrusion of a single polar body was significantly lower in clones (p = 0.001 and p = 0.013 in comparison to control and injected control oocytes, respectively), although it still involved up to 67% of the clones. This result in clones was not correlated with the initial spawn quality estimated from the 24 hours development rate of fertilized controls (Fig. [5B](#Fig5){ref-type="fig"}). Surprisingly, although we have shown that all clones had a normal maternal DNA organized into a regular metaphase plate before activation (see above), almost 20% of them did not extrude any polar body (Fig. [5A](#Fig5){ref-type="fig"}). While all clones underwent a cortical reaction and chorion expansion similar to that of the controls (not shown), such polar body retention means that SCNT induced a disruption of this specific step of oocyte activation. Last, we observed expulsion of two polar bodies in some clones, recognizable by the visualization of two green DNA dots. Surprisingly, this was observed in the control groups as well (control and injected control oocytes), despite the absence of injected DNA. In clones, the proportion of two extruded polar bodies was significantly higher than in control oocytes (p = 0.002).Figure 5Polar body extrusion after somatic cell nuclear transfer. (**A**) Graph showing the percentage of activated oocytes which expelled 0, 1 or 2 polar bodies (PB) in control oocytes (from 9 females), injected control oocytes (from 7 females) and clones (from 8 females). Injected control oocytes correspond to oocytes injected with the carrier medium, but without the donor cell. Per female, at least 17 oocytes or clones have been analyzed. NS = Not significant; \*p \< 0.05; \*\*p \< 0.01. Inset pictures represent one or two polar bodies stained by Vybrant green and observed in clones (bar = 20 µm). (**B**) Graph showing the relation between the rate of one polar body extrusion in clones and spawn quality assessed from development rate at 24 h post-fertilization. No correlation was observed (r^2^ = 0.06, n = 8 spawns, p \> 0.05). Characterization of DNA fate and blastomeres morphology during the first cell division in clones {#Sec5} ------------------------------------------------------------------------------------------------ The blastomeres morphology during this first cell cycle was characterized in 3 experiments involving a total of 120 developing clones. Two symmetric blastomeres similar to those of fertilized embryos (Fig. [6A](#Fig6){ref-type="fig"}) were observed in 41% of clones, while 11% had 2 cells of asymmetric size (Fig. [6B](#Fig6){ref-type="fig"}). Up to 8% exhibited 3 or more cell-like structures containing DNA (data not shown) without having gone through an initial 2-cells stage (Fig. [6C,D](#Fig6){ref-type="fig"}). The 3-cell clones always had two symmetric cells and a much smaller one (Fig. [6C](#Fig6){ref-type="fig"}). Up to 40% of the clones remained in a unicellular state during the observation period (Fig. [6E](#Fig6){ref-type="fig"}). They were not different from the controls that were either activated in water without spermatozoa, or activated in water after injection with the carrier medium without donor cell. However, although the controls collapsed within 2 hours, all the apparently arrested clones resumed cell division and reached the mid-blastula stage (5 hours post-fertilization, hpf). At the hatching stage (5 days post-fertilization, dpf), 21% of the clones were still alive. It is interesting to note that almost all these pre-hatched embryos (81%) derived from clones that had shown symmetric blastomeres after the first cleavage.Figure 6Blastomeres morphology of the clones at the 2 cells stage. Clones were observed 1 h post activation. Images of (**A**) a non-dechorionated clone with two symmetric blastomeres, (**B**) a non-dechorionated clone with two asymmetric blastomeres, (**C**,**D**) two dechorionated clones with a multicellular configuration, and (**E**) a non-dechorionated clone which presents no cellular division although it will develop later on. Clones were observed under visible light. Morphologies were established on a set of 120 clones. This better survival of the symmetric clones led us to focus on how the DNA was organized in their blastomeres at the 2 cells stage. We observed in clones and in controls (fertilized oocytes) that when the first 2 cells were being formed, the mitosis of the second cell cycle had already begun. As summarized Fig. [7A](#Fig7){ref-type="fig"}, despite their correct morphology and cell number, only half the clones with two symmetric blastomeres presented 2 normal mitotic spindles, i.e. a symmetric microtubule spindle bearing DNA in each cell (Fig. [7B,a,b](#Fig7){ref-type="fig"}). Almost a quarter of the symmetric clones presented only one normal spindle in one of the two blastomeres and the remaining clones had only abnormal spindles in their blastomeres. The pattern of these abnormal mitotic spindles was variable: multipolar spindle (Fig. [7B,c](#Fig7){ref-type="fig"}), chromosomal misalignments on the metaphase plate (Fig. [7B,d](#Fig7){ref-type="fig"}), spindle with random DNA location (Fig. [7B,e](#Fig7){ref-type="fig"}), bent spindles (Fig. [7B,f](#Fig7){ref-type="fig"}), and lagging chromosomes resulting from a defect during the first mitosis (Fig. [7B,g,h](#Fig7){ref-type="fig"}). None of these figures were observed in the control embryos.Figure 7Spindle and DNA structures in symmetric blastomeres of 2 cells stage clones. (**A**) Graph showing the percentage of clones exhibiting a normal mitotic spindle in both blastomeres (2 normal spindles), only one normal spindle in one of the two cells (1 normal spindle), or only abnormal spindles (0 normal spindle) (n = 7 control embryos from fertilized oocytes, n = 14 symmetric clones). (**B**) Confocal images of normal and abnormal spindles in clones. Embryos were fixed, and cut into 7 µm sections. Microtubules were immunolabeled with an anti-α-tubulin antibody (green) and DNA was stained with Hoechst 33342 (magenta). Images of (a) a normal figure with duplicated centrosome at each side of the prometaphasic DNA, (b) a normal spindle with condensed metaphasic DNA, (c) an abnormal tripolar spindle with anaphasic DNA, (d) an abnormal multipolar spindle with metaphasic DNA, (e) an abnormal spindle with unidentified DNA stage and localization, (f) an abnormally bent spindle with metaphasic DNA, (g--h) lagging chromosomes (arrow heads) spanning accross the cleavage furrow of the first cell division. Strikingly, almost two-thirds of the symmetric clones (11/14; 78%) showed fragmented DNA under the cleavage furrow separating the first two blastomeres (Fig. [8](#Fig8){ref-type="fig"}), while no such figure was observed in control embryos (0/7). This fragmented DNA presented no clear condensed chromosomes, nor centrosomes or a microtubules network.Figure 8Identification of fragmented DNA on the cleavage furrow of the clones. Embryos were fixed, and cut into 7 µm sections. Microtubules were immunolabeled with an anti-α-tubulin antibody (green) and DNA was stained with Hoechst 33342 (blue or magenta). Reconstitution of several section images of two clones at 2-cells stage (Clone A and B). White circles: fragmented DNA (blue) located on the cleavage furrow. Insets and clone C: images of the fragmented DNA (magenta) observed in by confocal microscopy, dotted lines show the cleavage furrow. Those images are representative of 11 clones. Discussion {#Sec6} ========== The question of chromatin fate after SCNT has always been a matter of acute concern in all studied species, although the complexity of most fish eggs hindered the access to such knowledge to date. In our study, we provide the first information on the behavior of the maternal and somatic chromatins in a system where the oocyte (maternal) DNA was not removed prior to SCNT. Fate of the maternal DNA after SCNT {#Sec7} ----------------------------------- This study showed that prior to activation of embryonic development, the maternal DNA at MII stage remained undisturbed by the injection procedure of SCNT. Its location against the micropylar canal probably protected the maternal DNA from the injection needle and its integrity was not compromised by nuclear transfer. Finding this chromatin against the canal and not at its bottom, at the sperm entry site, may also explain why successful enucleation by aspiration at this oocyte stage has never been reported in fish. This sheltered position also rules out the hypothesis that the maternal DNA could be stripped off or damaged during the somatic cell injection through the micropyle. Our results indeed demonstrated that maternal DNA loss did not occur at this step of the process. Moreover, this homogeneity of maternal DNA structure and location in clones cannot account for the variability in the embryo fate observed later on during development. Our finding that the maternal DNA metaphase was undisturbed by SCNT was making it likely that extrusion of a second polar body of maternal origin would be maintained in our system. As thoroughly studied in mouse, polar body extrusion requires several conditions including chromosome condensation in a metaphasic plate and its location close to the plasma membrane where interaction with the cortical cytoskeleton will trigger asymmetric cleavage^[@CR23],[@CR24]^. And indeed, polar body extrusion was maintained in most clones, so we infer that the maternal DNA was always involved. Therefore, the microcapillary penetration or the TCF carrier medium injection did not alter substantially the integrity of the cortical cytoskeleton that is necessary for the maternal polar body formation. The extrusion of an additional polar body (two extruded polar bodies) that was observed in some cases can be ascribed to the somatic DNA, as will be discussed later. It was surprising however that a small part of the control oocytes would also extrude two polar bodies, although no somatic DNA was present. This phenomenon could be explained by an incorrect positioning of the meiotic spindle at the plasma membrane upon oocyte activation, leading to the total expulsion of maternal DNA in two distinct globules, as already described in mouse after the microtubules network had been deliberately destabilized^[@CR23]^. If this defect was to occur in clones as well, it may be responsible for a small number of embryos undergoing spontaneous loss of maternal DNA upon oocyte activation. To date, we did not identify the genetic origin of the polar bodies to develop further this hypothesis. Last, the rate of clones with no polar body extrusion was higher than in control groups, although this was not statistically significant because of high variability between cloning series. It means that in some series, the somatic cell injection was deleterious and prevented the polar body extrusion process. The hypothesis of an intracellular signaling defect, such as a disturbance of the intracellular concentration of calcium, could be a reason for polar body extrusion failure in some cases as reported previously in mouse^[@CR25]^. Since we injected a whole somatic cell, its own cytoplasmic cargo was injected as well, which could have disrupted the activation signaling pathway, but we have no clue about why this alteration would occur in some cloning series and not in others, as this observation was not related to spawn quality. Fate of the somatic DNA after SCNT {#Sec8} ---------------------------------- Contrarily to the stability demonstrated for maternal DNA before oocyte activation, the structure of somatic DNA was more variable, although it still adopted a metaphasic pattern in two third of the clones. It has been previously shown that even though the whole cell is injected, its plasma membrane is disrupted within the first few seconds following SCNT^[@CR21]^. Therefore, the somatic DNA is readily exposed to the high MPF levels of the oocyte. It was therefore expected that the chromatin would adopt a metaphasic stage, despite the fact that the injected nuclei in G0/G1 phase had not undergone its own S phase (DNA synthesis) and that the somatic DNA had not been duplicated. Such condensation pattern upon injection into a non-activated oocyte resembles the so called Premature Chromatin Condensation (PCC) phenomenon described in mammals, whose favorable or unfavorable somatic reprogramming efficiency and contribution to the success of embryonic development is still a matter of debate^[@CR26]--[@CR32]^. But the similarity ends up there, because in mammals, extrusion of a second polar body that would halve clone ploidy is prevented by cytochalasin B^[@CR33],[@CR34]^. This procedure has never been used in fish, as penetration and release of chemicals in the highly amphiphilic fish eggs is difficult to achieve^[@CR35]^, and cytochalasin B trapped in the egg is deleterious for ooplasmic segregation at the onset of embryonic development^[@CR36]^. At this point, two scenarios can be proposed in fish clones: for those clones whose condensed somatic DNA was close enough to the oocyte plasma membrane prior to activation, their chromosomes may have been able to interact with the cortical cytoskeleton, resulting in the extrusion of an additional polar body from somatic origin. We reported that 31% of the clones had a condensed somatic DNA localized into the ooplasm. Some of them could count among those which expelled two polar bodies, supposedly from both DNA origins. In this case, the clones would end up with a haploid somatic DNA and a haploid maternal DNA, resulting in a diploid hybrid. This was not assessed in the present study, but such diploid hybrids were reported in medaka^[@CR17]^ and in goldfish (Depincé *et al*., personal communication). The second scenario is when the somatic DNA was too far from the plasma membrane to be able to contribute to polar body extrusion. The odds for this scenario are favorable in fish when considering the huge size of the oocyte and the low surface/volume ratio at the animal pole. This hypothesis is strikingly supported by a study on mouse oocyte^[@CR27]^ in which injected DNA beads underwent ectopic polar body extrusion only when they were close enough to the cortex, showing a distance-dependent induction of polar body extrusion. At this point, the fate of the somatic DNA upon activation is difficult to ascertain from our data. Somatic chromosomes could undergo a pseudo-anaphase that would lead to the formation of two haploid nuclei in the clones, or the pseudo-mitosis would not operate on the somatic nucleus, despite the loss in MPF, and a single diploid nucleus would reform thereafter. We believe that these options are the roots for the high variability observed in mitotic figures during early development. But we also reported that not all clones bore somatic DNA in a metaphase stage, as almost one fourth of them was found uncondensed in the oocyte. It means that this DNA did not sense the MPF signal. Therefore, we infer that these clones would escape the oocyte activation signaling which would have led to haploidization. We believe that this DNA may then catch up the embryonic cell cycle leading to regular somatic DNA replication and first mitosis. Those clones may account for the successful diploid clones reported in several studies^[@CR17]--[@CR19]^. However, we could wonder if the clones whose somatic DNA location is deeper in the oocyte will be able to develop. Indeed, the somatic DNA was sometimes observed among the yolk droplets. If this DNA was to contribute to the embryo development, it would have to migrate towards the animal pole, possibly within the powerful cytoplasmic streams observed^[@CR37]^ during the first cell formation. Although not precisely assessed here, this hypothesis may be one explanation for those clones showing one seemingly stalled blastodisc at the 2 cells stage but which developed later on and reached at least the mid-blastula stage. In these, the somatic DNA would be delayed at reaching the ooplasm where embryonic mitosis could finally resume. Fate of the maternal DNA upon first cell cleavage {#Sec9} ------------------------------------------------- From the above discussion, several clones should still possess the entire diploid somatic DNA, either because it was uncondensed, or because it was condensed but far from the plasma membrane. And because of the successful maternal polar body extrusion, a high majority of the clones should still possess half the maternal DNA as well. This raises the question of how this maternal DNA behaved during clone development, especially during the first mitosis, and whether it interfered with the somatic DNA. It has been proposed in medaka that the presence of maternal DNA is beneficial for the cellular reprogramming of the somatic cell, by decreasing cleavage asynchronies and ploidy mosaicism in clones^[@CR18],[@CR38]^. However, no study provided any hint about how this would operate in the first embryonic cells. One striking observation in the present study is that most symmetric clones displayed a fragmented DNA that was located under the cleavage furrow of the first cell division. It is known that the position of the cleavage furrow is determined by the positioning of the mitotic apparatus, the latter being accurately centered in the fish egg blastodisc by dynein-associated pulling forces^[@CR39],[@CR40]^. Polar body extrusion also takes place in a centered position, at the apex of the animal pole^[@CR39],[@CR41]^. It means that in our system, the cleavage furrow is a landmark of where half the maternal DNA was extruded and half remained in the embryo. The fact that some DNA was found at the bottom of the cleavage groove strongly suggests that it is of maternal origin and that it remained at its original location in the absence of any capture by some microtubular apparatus before the first embryonic cleavage. In mutant zebrafish where male centrosome was made unable to attach the maternal pronucleus, the later did not undergo any migration either, and it stayed at its original location close to the polar body^[@CR42]^. In other mutants, ectopic masses of DNA at early stage, that can be compared to the maternal DNA in our clones, subsequently became fragmented or got lost^[@CR43]^. Due to the meroblastic cleavage of embryonic fish cells, the fragmented DNA observed in our clones could be left in the yolk area, without affecting the integrity of the cellular cleavages. However, it cannot be excluded that this DNA may be sequestered into micronuclei. Some chromosomes or DNA fragments could be scattered in the cytoplasm or integrated into the genome of some blastomeres, leading to aneuploid cells that should be eliminated during embryonic apoptotic waves at mid-blastula stage. In all, this could explain how in some fish clones, the maternal DNA was sequestered and eliminated during subsequent mitosis. Fate of the clones during embryonic development {#Sec10} ----------------------------------------------- Even if DNA of maternal origin was excluded during development in some clones, embryonic development still stayed vulnerable when considering the wide set of alterations reported here during the first cell cycle. Symmetry defects could be due to a miscentering of the first mitotic spindle, because of altered interactions of the somatic mitotic spindle with the microfilament network of the blastodisc in the clones. But even when clones successfully underwent a first symmetric cleavage, we report that spindle defects and chromosome lagging and misalignments persisted in many of them. Because an entire somatic cell was injected, its own centrosome (centrioles and pericentriolar material) and its own cytoplasmic cargo (proteins and RNA) were incorporated and could have induced a protein or RNA imbalance of the oocyte cargo. One nagging question remains about the interaction between the somatic centrosomal apparatus and maternal pericentriolar material. The broad time window (\>40 min) of this event that is taking place before the first cleavage impeded our ability to explore it in the present study. We believe nevertheless that the injected somatic centrosome may have contributed to successfully replace the missing spermatic one. Conclusion {#Sec11} ========== To summarize (Table [1](#Tab1){ref-type="table"}), we demonstrated that the maternal metaphasic DNA was undisturbed after SNCT and that microinjection of a somatic cell through the micropyle was not impeding the oocyte plasma membrane ability to support polar body extrusion. Moreover, we provide strong indications that during mitosis, the maternal DNA remained at its original location, resulting in its positioning under the first cleavage furrow of the clones and its likely dispersion later on at the interface between yolk and embryonic cells. We also reported a high variability in somatic DNA structure and location which may account for the high variability in clone ploidy and blastomeres morphology during development. We also proposed some hypothesis about how clone ploidy could be maintained in some cases in relation to the somatic DNA structure and location upon injection, and despite the fact that no cytochalasin B is used in fish SCNT. This is the first time that some information on the cellular events taking place after SCNT is provided in such a specific model that is fish oocyte and embryo. Materials and Methods {#Sec12} ===================== Gametes collection {#Sec13} ------------------ Two years old mature goldfish (*Carassius auratus*), originating from outdoor ponds at INRA U3E experimental facility (Rennes, France), were used as breeders. Male and female were kept in separated 1 m² tanks, at a constant temperature of 14 °C, under spring photoperiod (16 h light and 8 h dark cycle). They were transferred at 20 °C few days prior to hormonal induction by intra-peritoneal injection of 0.5 mL/kg Ovaprim^TM^ (Syndel Laboratories, Canada). Sixteen hours later, gametes were collected by stripping. Oocytes were maintained at 12 °C for up to 5 hours in their own coelomic fluid. Sperm was diluted in SFMM (NaCl 110 mM, KCl 28.3 mM, MgSO~4~ 2H~2~O 1.1 mM, CaCl~2~ 2H~2~O 1.8 mM, Bicine 10 mM, Na Hepes 10 mM, pH 7.8, 290 mOsm/kg) and stored on ice for up to 24 h. Fish handling and sampling was carried out in strict accordance with the welfare guiding principles of the French regulation on laboratory animals, under the French and European regulations on animal welfare (Authorization N° 005239 level 1; C. Labbé), and under the supervision of staff of the animal facilities possessing an agreement level (C35-238-6). The experimental protocol was approved by the welfare committee from the Fish Physiology and Genomics department at Institut National de la Recherche Agronomique (registration C-2018-01-CL-AD) in accordance with the French guidelines on broodstock handling, gamete collection and embryo rearing. Nuclear transfer procedure {#Sec14} -------------------------- Nuclear transfer was carried out as described previously^[@CR21]^. Donor somatic cells were obtained from caudal fin after explant culture and cell cryopreservation^[@CR6]^. After thawing, mesenchymal cells in G0/G1 stage were washed in the cell culture medium with antibiotics (2.5 µg/mL amphotericin B, 50 µg/mL gentamicin) and stored on ice for up to 2 hours. Nuclear transfer was performed at 20 °C with a Cell Tram Vario injector (Eppendorf) connected to a micromanipulator (Transferman NK2, Eppendorf) under a stereomicroscope (Olympus SZX 12). Recipient oocytes were placed into Trout Coelomic Fluid (TCF) to prevent oocyte activation^[@CR44]^. Donor cells were isolated in TCF as well. After localization of micropyle at the animal pole (sperm entry point), oocytes were held by gentle depression of the holding microcapillary (iD 100 µm). A single donor cell was aspirated in a glass microcapillary (iD 15 µm, custom Tip Type IV, Eppendorf) and injected with about 10 pL of TCF into the recipient oocyte through the micropyle, just under the oocyte plasma membrane. After nuclear transfer, oocytes were incubated for 30 min in TCF to improve success rate of the nuclear transfer^[@CR21]^. They were then either fixed for analysis, or activated with tap water to trigger embryo development. Embryos were incubated at 20 °C in dechlorinated tap water. When specified, the chorion was enzymatically removed by incubation of the embryos with 4 mg/mL protease from *Streptomyces griseus* (SIGMA, P8811) diluted in Holfreter 2.2 (NaCl 60 mM, CaCl~2~ 2H~2~O 68 µM, KCl 67 µM, D-Glucose 12 mM, PVP 40 000 62.5 µM, Hepes 5 mM, pH 7.4, 140 mOsm/kg). Dechorionated embryos were incubated in Holfreter 2.2 at 20 °C up to fixation and analysis. In analyzes devoted to the clone fate, several development stages were specifically observed: the 2 cells stage (about 1 hpf), when a scission grove appeared on the top of the single blastodisc, the mid-blastula stage (5 hpf) when the control embryos reached the 1000 cells stage and began embryonic layers differentiation, and the hatching stage (4--5 days post fertilization, dpf), when the control embryos were released from the chorion. At the end of each SCNT session, oocyte quality was checked by an *in vitro* fertilization test. About 100 oocytes from each of the spawns used for nuclear transfer were fertilized in dechlorinated tap water with 10 µL diluted sperm. The number of live embryos was assessed at 24 hpf (6--9 somite stage) and at hatching, and expressed as a percentage of the initial oocyte number. Oocytes were graded as good quality when the development rate was above 90% at 24 hpf. Nevertheless, all experiments whose control rates were below 60% were discarded. Fixation and immunofluorescence analysis after nuclear transfer {#Sec15} --------------------------------------------------------------- After nuclear transfer, non-activated oocytes and embryos (2 cells stage) had to be orientated with the animal pole up, to ensure identification of the DNA on sections during histological analysis. Oocytes were orientated prior to methanol fixation, when the micropyle used to identify the animal pole was still visible. To prevent activation, oocytes were held in 2% gelose (agar-agar, PROLABO 20768.235) cupules prepared in Goldfish Ringer medium (GFR: NaCl 125 mM, CaCl~2~ 2H~2~O 2.4 mM, KCl 2.4 mM, MgSO~4~ 7H~2~O 0.3 mM, MgCl~2~ 6H~2~O 0.9 mM, D-glucose 6 mM, Hepes 4 mM, pH 7.3, 256 mOsm/kg) supplemented with Soybean Trypsin Inhibitor Type II-S (SIGMA, P9128), and orientated under binocular with the micropyle up. They were then covered with melted 2% agar-agar gelose, cooled, and fixed with cold methanol overnight. Dechorionated embryos at 2 cells stages were directly fixed with cold methanol overnight and all samples were stored at −20 °C until gelose embedding. Methanol prevented blastodisc and blastomeres deformation and was mandatory for immunofluorescence specificity. After fixation, early embryos were transferred in 70% ethanol to limit methanol toxicity, orientated with the embryonic cells up, and embedded in a 2% agar-agar gelose prepared in distilled water. For paraffin embedding, oocytes and embryos in their agar cushion were transferred in 100% ethanol (at least 2 h), 96% ethanol (2 × 30 min), butanol-1 (3 × 3 h and 1 × 1 h) and melted paraffin (60 °C, 2 × 2 h). Samples were then embedded with the animal pole up in paraffin cassettes and cut into 7 µm sections. Only the first one fourth of the sample height was cut for histological analysis (approximatively 250 µm). This area corresponds to the ooplasm. Sections were then mounted on slides with ovalbumin 0.5% (PROLABO, 20771.236). Paraffin removal and rehydration of the slides was carried on in successive bath of toluene 100% (10 min), ethanol (100%, 96% and 70%, 5 min each), and stored in PBS (SIGMA, P4417). For fluorescence immunolabeling, all slides were saturated in PBS with 2% bovine serum albumin (BSA, SIGMA, A2153) and 0.5% Triton X-100 (SIGMA, T8787)(1.5 h, 20 °C) and incubated with mouse anti-tubulin-α antibody (SIGMA, T9026)(1.5 h, 30 °C). After washing in PBS-BSA 0.2%, samples were incubated with the goat anti-mouse antibody coupled with Alexa-Fluor 488 (SIGMA, A11001) (1.5 h at 30 °C). After washing, samples were stained with Hoechst 33342 (SIGMA, B2261) (2.5 µg/mL, 15 min, 20 °C). Slides were mounted with PBS-Glycerol solution and stored at 4 °C until analysis. Fluorescence observation and images were taken under a fluorescent microscope (Nikon 90i) and a SP8 confocal microscope (Leica microsystems) to characterize the DNA structure and localization. *In vivo* study of polar body extrusion {#Sec16} --------------------------------------- In order to visualize the polar body extrusion, oocytes were stained with two live DNA markers: Hoechst 33342 labeled both the maternal pronucleus and the extruded polar body, while Vybrant Green dye (Invitrogen, V35004) labeled only the extruded polar body. We believe that the amphiphilic Vybrant dye penetrated the oocyte well, but the composition of the ooplasm prevented this dye from specifically binding the maternal DNA. Instead, the entire ooplasm displayed a very weakly non-specific green fluorescence. This bias was used for our purposes because only the DNA incorporated into the tiny cell that is the polar body could be labeled with Vybrant Green, while the maternal pronucleus was only labeled with Hoechst. Non-activated oocytes were incubated with 100 µg/mL of Hoechst 33342 in TCF for 30 min at 20 °C, and rinsed twice with TCF to prevent non-specific Hoechst signal. After oocyte activation in dechlorinated tap water for 1 min, chorions were removed as described above within 10 min to ensure polar body visualization. Dechorionated oocytes were incubated with 10 µM Vybrant green dye in Holfreter 2.2 medium, before and during the polar body extrusion (around 13 min post-activation at 20 °C). To prevent the loss of the polar body, oocytes were no longer manipulated from this time on. As a consequence, the oocytes had a random orientation. Only the oocytes spontaneously oriented with the animal pole upwards, identified thanks to oocyte DNA labelling with Hoechst, were included in the analysis. Multiplane observations of the oocytes were carried on under a stereomicroscope for up to 40 min post-activation, to observe all possible polar bodies extrusions. Statistical analysis {#Sec17} -------------------- Data were expressed as mean ± standard deviation. Kruskal-Wallis test (non-parametric test) was performed using IBM SPSS Statistics, Version 24.0. Armonk, NY:IBM Corps (Table [1](#Tab1){ref-type="table"}).Table 1Summary of the results regarding the fate of the maternal DNA prior oocyte activation, after oocyte activation and after the first mitosis (MII: oocyte metaphase 2). +++ : \> 90%; ++ : \> 50%; + : \> 10%; + /−: \> 0%; \*mostly (81%) from symmetric cleavage.ControlsClonesMaintenance of maternal MII+++ +++ **Oocyte activation**1 PB extrusion+++ ++ 2 PB extrusion+/−+ **Mitosis**Symmetric cleavage++++Survival at hatching++++\* **Publisher's note:** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The authors thank the staff from INRA U3E (Rennes) for providing goldfish breeders. F. Borel, A. Patinote, J.- M. Aubry, C. Duret and P.-L. Sudan took great care of the goldfish at the INRA LPGP experimental facility (Rennes). The members of the INRA LPGP histology service, A. Branthonne and B. Porcon are also acknowledged for training C.R. and for technical support. G. Halet, from the Institute of Genetics and Development (IGDR Rennes), contributed to the reflection and results deciphering thanks to his fundamental knowledge of the meiotic and mitotic divisions. N. Beaujean (INRA-INSERM SBRI, Lyon) also helped us to deepen our interpretations thanks to her knowledge on cellular events after nuclear transfer. The other members of the thesis committee are also thanked for their kind help and support. Audrey Laurent (INRA LPGP Rennes) provided valuable comments on the manuscript and interpretation of the data. This work has benefited from the Tefor Fish Phenotyping Platform at the INRA LPGP, Rennes (ANR-II-INBS-0014) for confocal analysis where the expertise of V. Thermes and M. Thomas is gratefully acknowledged. This work was funded by the French CRB Anim project, ANR-11-INBS-0003. C.R. was recipient of an INRA PHASE and Région Bretagne PhD fellowship. C.R. organized and carried out the study, analyzed and interpreted the data and drafted the manuscript. A.D. performed the nuclear transfer experiments and contributed to the coordination of the study. N.C. provided the donor somatic cell culture, initiated the immunofluorescence protocols and participated to the clone fate experiment. P.Y.L.B. and C.L. conceived and designed the study. C.L. supervised the experiments and the manuscript writing. All authors read, improved and approved the final manuscript. The authors declare no competing interests.

NOT PRECEDENTIAL UNITED STATES COURT OF APPEALS FOR THE THIRD CIRCUIT _____________ No. 16-1660 _____________ JANICE HAAGENSEN, PERSONAL REPRESENTATIVE OF THE ESTATE OF MYRTLE SHELBURNE HAAGENSEN, Appellant v. BETTY MAY REED; EDWARD ABERSOLD; ANNIE AND RUFUS K. HERSHBERGER; RICHARD RAPONE, TAX COLLECTOR OF LAWRENCE COUNTY; J.R HARDESTER, DIRECTOR OF ASSESMENTS OF LAWRENCE COUNTY; KAREN MAGNONE, PROPERTY TAX COLLECTOR OF NORTH BEAVER TOWNSHIP, IN AN INDIVIDUAL AND OFFICIAL CAPACITY *Caption Amended Per Clerk’s Order of 04/14/2016 _____________ On Appeal from the United States District Court for the Western District of Pennsylvania District Court No. 2-14-cv-00495 District Judge: The Honorable Arthur J. Schwab Submitted Pursuant to Third Circuit L.A.R. 34.1(a) November 9, 2016 Before: SMITH, Chief Judge, McKEE, and RESTREPO, Circuit Judges  (Filed: November 15, 2016) _____________________ OPINION1 _____________________ SMITH, Chief Judge. In 2006, Janice Haagensen, as personal representative of her mother’s estate, initiated a quiet title action in the Court of Common Pleas of Lawrence County, Pennsylvania. The state court ruled against her in March 2011, concluding that she failed to establish a “right to immediate exclusive possession” as required to succeed in her quiet title action. Her untimely appeal to the Pennsylvania Commonwealth Court was unsuccessful. In December 2011, the Pennsylvania Supreme Court denied her petition for allowance of appeal. In 2014, Haagensen turned to the federal courts and filed this pro se civil rights action against the neighbor defendants in her state court quiet title action, the state court trial judge who presided over that action, and the tax assessment office and tax collector (tax entities). A district judge in the United States District Court for the Western District of Pennsylvania dismissed her action. He concluded that the Rooker-Feldman doctrine2 barred her action against the neighbor defendants 1 This disposition is not an opinion of the full court and pursuant to I.O.P. 5.7 does not constitute binding precedent. 2 See Rooker v. Fidelity Trust Co., 263 U.S. 413 (1923), and District of Columbia Court of Appeals v. Feldman, 460 U.S. 462 (1983). 2 and the state court judge, and that the statute of limitations barred the claims against the tax entities. Haagensen sought reconsideration, which the District Court denied. Within days, the neighbor defendants moved for sanctions pursuant to the court’s inherent power to levy sanctions, claiming that Haagensen initiated this action to “harass her neighbors.” See Roadway Express, Inc. v. Piper, 447 U.S. 752, 765-66 (1980) (acknowledging that a court may impose sanctions pursuant to its inherent power when a losing party has acted, inter alia, vexatiously or for oppressive reasons) (citation omitted). Immediately thereafter, Haagensen filed a notice of appeal. Acknowledging that appeal, the District Court entered a text-only entry on the docket stating: “In light of the appeal filed by Plaintiff, said Motions for Sanctions . . . are dismissed without prejudice pending the resolution of the appeal.” We affirmed the dismissal of Haagensen’s claims in their entirety. Haagensen v. Wherry, 610 F. App’x 210 (3d Cir. 2015). Relevant to the appeal we now consider, we agreed that Rooker-Feldman barred the claims against the neighbor defendants. After our mandate issued, Haagensen filed a petition for a writ of certiorari. Following the Supreme Court’s denial of that request, the case returned to the District Court. The neighbor defendants filed their second motion for sanctions asking the court to exercise its inherent power. Haagensen opposed the motion, contending only that the District Court lacked jurisdiction to consider 3 that motion. The Court disagreed and awarded monetary sanctions in the amount of $4,298.40 in attorney’s fees and costs. The Court declined, though, to enjoin Haagensen from filing any further pro se pleadings. Haagensen next filed a timely motion for reconsideration, which the District Court denied. This timely appeal followed. Haagensen does not take issue with the amount of the attorney’s fees or the propriety of the sanctions being imposed pursuant to the inherent power of the court. Rather, she contends that the District Court’s dismissal under Rooker-Feldman for lack of subject matter jurisdiction, as well as our affirmance, deprives the District Court of authority to do anything further in the case.3 Despite Haagensen’s prolix brief in support of her argument, we are not persuaded. The District Court had federal question jurisdiction over Haagensen’s civil rights claims under 42 U.S.C. § 1983 against the neighbor defendants, the state court judge and the tax entities. 28 U.S.C. § 1331. Thereafter, the neighbor defendants raised the Rooker-Feldman doctrine in their motion to dismiss. That doctrine bars the District Court from reviewing and rejecting an unfavorable state 3 Ordinarily, we review an award of sanctions for abuse of discretion. Lazorko v. Pa. Hosp., 237 F.3d 242, 248 (3d Cir. 2000). Because Haagensen challenges only the District Court’s jurisdiction to award the sanctions, and not the decision to assess the sanctions or the amount, our review is de novo. See Great W. Mining & Mineral Co. v. Fox Rothschild LLP, 615 F.3d 159, 163 (3d Cir. 2010). Inasmuch as the order awarded sanctions in a specific amount, it is a final order, and we exercise appellate jurisdiction under 28 U.S.C. § 1291. Lazorko, 237 F.3d at 248. 4 court judgment. See Exxon-Mobil Corp. v. Saudi Basic Indus., 544 U.S. 280, 284 (2005). Rooker-Feldman’s application, however, is limited to those cases “brought by state-court losers complaining of injuries caused by state-court judgments rendered before the district court proceedings commenced and inviting district court review and rejections of those judgments.” Id. Thus, Rooker-Feldman does not apply “simply because a party attempts to litigate in federal court a matter previously litigated in state court.” Id. at 293. As a result, courts must scrutinize a plaintiff’s federal complaint to determine if the claim at issue is barred by Rooker- Feldman or is viable because it is actually “an independent, non-barred claim.” Great W. Mining & Mineral, 615 F.3d at 166. Having determined that Haagensen’s claim against the neighbor defendants complained of an injury from the state court judgment in the quiet title action, the District Court properly ended its analysis of the merits of her § 1983 claim at that point under the Rooker-Feldman doctrine.4 Haagensen, 610 F. App’x at 211. Although barred from reviewing the merits of that claim, see Exxon-Mobil Corp., 544 U.S. at 284, the District Court appropriately exercised its federal question jurisdiction over Haagensen’s other § 1983 claims against the tax entities and 4 One of the neighbor defendants was Edward W. Abersold. According to a suggestion of death, Abersold died on July 13, 2016 and no estate has yet to be opened. Under all the circumstances, Haagensen’s motion for substitution is denied. Furthermore, because we will affirm the order granting the motion for sanctions, the motion to amend the caption is moot. Haagensen’s other motions are denied. 5 managed other matters separate and distinct from the merits of the claim barred by the Rooker-Feldman doctrine, such as the neighbor defendants’ motion for sanctions. In light of Haagensen’s appeal, the District Court permissibly denied the motion for sanctions without prejudice, thereby allowing the neighbor defendants to renew their request following the conclusion of the appeal. See Fed. R. Civ. P. 54(d)(2)(B), (E) (providing that, when the sanctions requested are neither for violation of the rules or under 28 U.S.C. § 1927, a court order may establish when a motion for attorney’s fees may be filed). Our mandate affirming the District Court’s judgment on the first appeal returned the case to the District Court for whatever additional proceedings were appropriate or necessary. See Ostrer v. United States, 584 F.2d 594, 598 (2d Cir. 1978) (“The effect of the mandate is to bring the proceedings in a case on appeal in our Court to a close and to remove it from the jurisdiction of this Court, returning it to the forum whence it came.”). In the absence of a renewed motion for sanctions, the District Court’s action would have been to close the civil action in accordance with the mandate as there was nothing more for the court to do. The renewed motion for sanctions, however, raised an issue that the District Court was authorized to resolve. We conclude that the District Court had the authority under § 1331 to resolve this motion for sanctions. See Willy v. Coastal Corp., 503 U.S. 131, 138 (1992) (reiterating that “‘[i]t is well established that a federal court may 6 consider collateral issues after an action is no longer pending’ . . .[and] therefore does not raise the issue of a district court adjudicating the merits of a ‘case or controversy’ over which it lacks jurisdiction”) (quoting Cooter & Gell v. Hartmarx Corp., 496 U.S. 384, 395 (1990); Cooter & Gell, 496 U.S. at 396 (concluding that “the imposition of a Rule 11 sanction is not a judgment on the merits of the action” and that it “require[d] the determination of a collateral issue: whether the attorney has abused the judicial process,” which “may be made after the principal suit has been terminated”). For that reason, we will affirm the District Court’s judgment. 7 

Baldy (Jackson County, Oregon) Baldy is a mountain located north-northeast of Talent and east-northeast of Phoenix in Jackson County, Oregon. It forms part of the eastern edge of the Rogue Valley, and is about west-northwest of Grizzly Peak and south-southeast of Roxy Ann Peak. References Category:Mountains of Jackson County, Oregon Category:Mountains of Oregon

Train Like Your An Elf With Some Dwarves To Save Racerback Tank ${{ currentBasePrice.toFixed(2) }} Don't just run because you have to when you workout, hit that gym and run like you're running through the forest of mirkwood. You better run fast, because you got some dwarves to save. Maybe even a hobbit too. You better get buff too, because you're going to have some orcs to kill. Also Available On {{ firstRelatedProduct.defaults.style_description }} {{ style.description }} {{ relatedProduct.defaults.style_description }} View All Styles Product Story Don't just run because you have to when you workout, hit that gym and run like you're running through the forest of mirkwood. You better run fast, because you got some dwarves to save. Maybe even a hobbit too. You better get buff too, because you're going to have some orcs to kill.

Metastatic thyroid carcinoma causing superior vena caval obstruction diagnosed on I-131 scan. An 80-year-old woman was referred for a painless mass arising in right side of her neck of 4 months' duration. Ultrasound revealed a multinodular goiter, but cytology confirmed a follicular carcinoma. Thyroid function was normal. Total thyroidectomy was performed with evidence of tumor infiltration into the strap muscles extending up to the right submandibular gland and right internal jugular vein, which was completely occluded. Radioiodine was considered as the treatment of choice postoperatively. This is an unusual case of SVC obstruction caused by tumor embolus diagnosed on I-131 scan.

[Localization of mitral valve prolapse zones with multiplane transesophageal echocardiography]. There are few literature data on the localization and extent of mitral valve prolapse zones with transesophageal echocardiography (TEE). To assess a standardized imaging technique for the localization and extent determination of prolapse zones, based on 3 easily reproducible views with multiplane TEE. Seventy patients with severe mitral regurgitation due to valve prolapse requiring a multiplane TEE prior to surgery (valve repair or replacement) have been retrospectively assessed. Data of TEE on the localization and extent of prolapse zones have been confronted to per-operative anatomical observations (gold standard). The sensitivity of TEE for the identification of isolated P2 prolapse, prolapse with commisural extension, isolated rupture of the posterior commisure and bi-valvular prolapses were respectively at 96%, 88%, 86% and 80%. The corresponding specificities were from 98% to 100%. The use of a standardized technique with the use of 3 easily reproducible incidences with multiplane TEE allows a precise definition of the localization and extent of mitral valve prolapse zones, in order to potentially indicate valve repair.

Bush vs. the trial lawyers. Bush vs. the trial lawyers. Trial Balloon Edwards blames big business; Bush blames lawyers. Thursday, President Bush went to North Carolina to blame rising health care costs on malpractice lawyers. In a conference call with reporters and in Senate floor speeches Thursday and Friday, Sen. John Edwards, D-N.C., fired back. The 2002 elections are heating up, the 2004 presidential race is underway, and Bush has made his first risky wager: He's trying to counter the Democrats' two-sided issues with a three-sided issue. Advertisement A one-sided issue is one on which the country overwhelmingly agrees. Terrorism is a one-sided issue. So is education funding. So is supporting charities, religious or not. A two-sided issue is one on which each party clearly defends one side and attacks the other. Tax cuts are usually a two-sided issue. So is environmental regulation. So is privatizing Social Security. A three-sided issue is a two-sided issue into which a third viewpoint has been injected. The debate between cutting taxes, spending more on programs, and maintaining taxes in order to pay off public debt is a three-sided issue. So is the debate between censorship, free speech, and parental control of what children can see. Will Saletan writes about politics, science, technology, and other stuff for Slate. He’s the author of Bearing Right. A one-sided issue is what you reach for when you want peace. A two-sided issue is what you reach for when you have the advantage and you want a fight. A three-sided issue is what you reach for when your opponent has the advantage and you want to seize it from him. In the summer of 2001, Bush was getting hammered on a bunch of two-sided issues. From tax cuts to health care to the environment, Democrats painted him as a servant of big business. Then came Sept. 11. All the two-sided issues were wiped out by a one-sided issue, just the kind at which Bush excels. His dad was sheepish and clumsy about voicing collective values. Bill Clinton looked as though he was lying even when he was telling the truth. Not Bush 43. He jumped on the terrorism issue and rode it to stratospheric approval ratings. Along the way, he mixed in one-sided classics such as leaving no child behind and loving a neighbor like you'd like to be loved yourself. Now things have gotten sticky again. The terrorism debate has advanced from fighting al-Qaida to thornier questions of resource allocation and bureaucratic reorganization. The economy is shaky, the stock market is in the toilet, and Democrats are pounding Bush over corporate corruption. This time, he isn't just pleading for unity. He's fighting back. Advertisement The issue Bush has seized on—twice in Alabama on July 15, and twice again in North Carolina Thursday—is tort reform. He has sworn up and down that he's getting tough on corporate cheaters, but polls show most Americans don't believe him. He needs a new culprit to attack, one that is as unpopular as thieving executives, more plausible as a target of Republican wrath, and capable of absorbing some blame for the country's economic troubles. That target is lawyers. "This is a way to change the subject of the economic debate from what's going wrong in the markets and at corporations to what the president is doing to fix things," a Bush adviser told the Washington Post. The beauty of attacking plaintiffs' attorneys—"trial lawyers," as Bush likes to call them—is that they oppose the GOP on issue after issue (environmental litigation, terrorism insurance, investor lawsuits) but are hired guns. They lack the populist resonance of their clients. If you've been cheated by a CEO or refused treatment by an HMO or exposed to carcinogens by a polluter, people feel sorry for you, but nobody feels sorry for your lawyer. In his speech, Bush exploited this gap, distinguishing the interests of malpractice attorneys from the interests of policyholders, taxpayers, and plaintiffs. "You pay either as a patient or you pay as a taxpayer," said the president. "Frivolous lawsuits drive up the cost of government health programs by over $25 billion every year. … What we want is quality health care, not rich trial lawyers." These attorneys don't really represent ordinary people, Bush suggested: They just "fish" for clients, and "the current system often doesn't serve the patient. … Sometimes the lawyers take up to 40 percent of the verdict—40 percent." If trial lawyers don't fight for anyone, whom do they fight against? Not big business. They persecute "small business owners," says the president. In the context of medicine, they persecute the "good men" who cure the sick. "We want to help doctors to heal, not encourage lawyers to sue," Bush argued earlier this year. On this view, the malpractice attorney isn't just a hired gun. He's inherently the bad guy. Advertisement How do Democrats answer this attack? They don't. They simply take the lawyer out of the picture. You'd think this would be particularly hard for Edwards, since he is a malpractice lawyer, and a rich one at that. Surely that's one reason why Bush went to Edwards' state and complained about its liability insurance rates. But Edwards is an expert at taking himself out of the picture, because that's what an artful plaintiff's lawyer does. He focuses relentlessly on his client, forcing the jury—or in this case, the electorate—to choose between a poor plaintiff and a deep-pocketed defendant. He reduces the cast of characters from three to two. Edwards' technique was on display on the Senate floor and in his conference call. He described "families whose children can no longer walk" or "have been blinded for life." Better yet, he let one of his clients do the talking. Christopher Griffin, whose daughter recently died after Edwards won a huge damage award for her family in a medical error case, excoriated the Bush administration's suggestion that plaintiffs such as he were "lottery winners." "Every time I go to my daughter's grave, it's hard to feel that way," said Griffin. If Edwards can reduce tort reform to a two-sided issue, he can add it to the Democrats' populist arsenal. Bush's speech "fits a pattern with [this] administration when it comes to the interests of regular people competing with the interests of big corporations, insurance companies, HMOs, and energy companies," Edwards told reporters. To his colleagues, he lamented, "At a time when Americans are demanding more corporate responsibility … the president has gone to North Carolina today to ask for less corporate responsibility, to make it easier on insurance companies, and to make it harder on victims." This isn't what Bush had in mind when he started this fight. But that's what you get for arguing with a lawyer.

Purchase a teacher's guide and student text together in this Educator's Package and save $75.50. With 24 solutions-oriented chapters, Exploring Global Issues: Social, Economic, and Environmental Interconnections demonstrates how individual decisions have global impacts and promotes student engagement through hands-on activities, real-world examples, and student-in-action profiles. This teacher-tested resource is correlated to Common Core and national standards, and is designed to support learning in a variety of courses including social studies, human geography, environmental science, and more! Table of Contents Introduction and Table of Contents Unit 1: Introduction to Global Issues and Sustainability Chapter 1. Global Issues Day 1 Reading: Introduction to Global Issues Activity: From Issue to Opportunity Students develop criteria for determining what makes an issue global in scope, brainstorm and list global issues, group and prioritize the issues into categories to highlight interconnections, and explore solutions. Day 2 Reading: Global Issues and Sustainability Activity: Making Global Connections Students demonstrate the interconnectedness of global issues and solutions through a kinesthetic exercise using global issues cards and a ball of yarn. Day 3 Reading: Global Issues Today Activity: What’s in the News? In this media literacy activity, students use an “iceberg model” to analyze the global patterns and underlying structural causes that drive events in the news. Unit 2: Essential Human Needs Activity: What Causes Hunger? Students will each read about the drought that affected the Horn of Africa in 2011 and identify root causes of famine. In small groups, they will share what they learned about causes and consequences of famine. Day 2 Reading: Background on Food Activity: What to Eat? Students brainstorm around the meaning of malnutrition and possible root causes of malnutrition. In pairs, they construct an ideal diet for a day, considering how many calories and which nutrients are important to include in their meals. Day 3 Reading: Food Today Activity: What the World Eats In a matching exercise, students work to connect countries’ food availability with information about each country’s geographic, economic, and sociopolitical features. Students identify factors that may contribute to food availability or scarcity within a particular country. By examining a map of world hunger, students see for themselves where hunger is most prevalent in the world and discuss possible root causes. Day 4 Reading: Food Today Activity: Food Fight Students will research and debate the question of whether a vegetarian lifestyle is advisable, considering both environmental resources and human health. Chapter 4. Water Day 1 Reading: Introduction to Water Activity: Water Carry Simulating the situation in many places around the world, students must complete a schoolwork assignment while carrying water from a distant source to their “home” reservoir. Students then consider solutions to this issue of gathering water. They analyze the connection between these solutions and sustainable development. Day 2 Reading: Background on Water Activity: River to the Sea? Students explore the differing ideas of water as a right and water as a commodity. After learning about the Colorado River and its place in the hydrology of the western United States, students brainstorm reasons for why the river no longer reaches the sea. After learning about the various uses of water in the region, they make recommendations for water use in the future. Days 3 & 4 Reading: Water Today Activity: A Personal Water Audit Students imagine how they would use only 5 gallons of water per day. They then explore their own water footprint by conducting a personal water audit of their direct water use over the next 24-hour period. On day 2, students are introduced to the idea of virtual, or embodied, water and estimate the amount of virtual water they consume. Days 5 & 6 Reading: Pathways to Progress: Water Activity: Water, Water Everywhere? Students take on perspectives of different stakeholder groups involved in determining how to deal with increasing demands on a waterway. Stakeholder groups are encouraged to form alliances in order to reach consensus on the plan that will be best for everyone involved. Chapter 5. Air Day 1 Reading: Introduction to Air Activity: Valuing Clean Air Students consider the economic benefits of clean air alongside the costs of pollution control. In small groups, students will perform a cost-benefit analysis of implementing congestion pricing to reduce vehicle traffic, bearing in mind monetary costs alongside environmental and social externalities. ​ Days 2 & 3 Reading: Background on Air; Air Today: Indoor Air Pollution Activity: What’s Your IAQ Students research 1 type of indoor air pollution, later investigating whether this source is present in their home or school. Students will create a public service announcement (in poster form) about the potentially harmful health effects of this particular pollutant and ways we can safeguard ourselves and our family and friends from exposure. ​ Day 4 Reading: Air Today: Outdoor Air Pollution Activity: Taking Air Pollution to Court Students learn about common sources of outdoor air pollutants and their effects on human health through a mock trial, whereby a group of citizens is suing a local steel mill over air pollution concerns. Taking on the roles of plaintiffs, defendants, lawyers, and jurors, students will grapple with the difficulty of connecting air pollution to a single source. ​ Day 5 Reading: Pathways to Progress: Air Activity: Capping Pollution In a cap-and-trade exercise, students take on the roles of electric utility companies tasked with making a profit while remaining below a government-mandated cap on air pollutants. The exercise concludes with a discussion of the effects—good, bad, intended, and unintended—of this market-based approach to pollution control. Chapter 6. Energy Days 1 & 2 Reading: Introduction to Energy Activity: Energy Access for All Students categorize the different uses of energy into 3 different levels of necessity. Students then receive an energy profile for different youth around the world and identify their most pressing energy needs. After, they will learn about the UN Sustainable Energy for All initiative and work together in small groups to create a public service announcement that encourages people and governments around the world to work toward these goals. Days 3 & 4 Reading: Background on Energy Activity: A Personal History of Energy Students will analyze a graph of crude oil prices from 1861 to 2011 and then suggest factors that could impact the price of oil. Students will conduct an interview outside of class with a member of an older generation to learn how changes in energy prices or availability have personal impacts. Day 5 Reading: Energy Today Activity: Power to the People! Students identify an activity they do that requires electricity. Working backwards from this activity, they diagram the path this electricity travels as far as they can. Small groups then research a primary energy source used to generate electricity and identify its benefits and trade-offs. Days 6 & 7 Reading: Pathways to Progress: Energy Activity: Powerful Arguments Students begin by participating in a sides debate in which each person either agrees or disagrees with a statement about energy use and then supports their opinion with reasoning. Small groups then research the main arguments for and against different energy debates to prepare for a class debate. Activity: Dividing the Pie A pie or cake is used to represent the world’s resources. As the population of a group of students clustered in the middle of the classroom grows, similar to the pattern of global population growth, each student is able to contemplate how his or her slice of the pie may be shrinking. ​ Day 2 Reading: Background on Population Activity: Modeling Growth Students consider different patterns of population growth by graphing multiple scenarios. Graphing the patterns, students are able to visualize how a population is affected when it exceeds the carrying capacity of its environment. ​ Day 3 Reading: Population Today Activity: Reading the Pyramids Students learn how to read and interpret population pyramids. While investigating age-sex structures of several national populations, students use this skill to determine what might cause different age distributions and what challenges might arise from each age distribution. ​ Day 4 Reading: Population Today, continued Activity: Room for More? Each student uses an online calculator to estimate his or her individual ecological footprint. Students then investigate the interconnections between population size and the collective ecological footprint of a region. ​ Day 5 Reading: Pathways to Progress: Population Activity: Population Connections Students are introduced to the relationship between increased life expectancy and reduced fertility rates. Students investigate 10 additional factors that correlate with fertility rates, either positively or negatively, and contemplate which factors could be focused on to slow global population growth. Activity: Watch Where You Step Students create a web diagram to illustrate impacts associated with everyday items. This activity builds on the concept of “ecological footprint” to consider the mark that consumption leaves on the environment, along with impacts on people and societies. Students then develop ideas to reduce the ecological footprint and associated impacts related to an everyday item. ​ Day 2 Reading: Background on Consumption Activity: The Cost of Production Students consider where most of our imported material goods are assembled and the environmental and social impacts of production. In small groups, students develop policies that a company might use in working with foreign manufacturers, considering pros and cons of each policy. ​ Day 3 Reading: Consumption Today Activity: Why Buy? Students begin by considering the purpose of advertising. Each student critically analyzes an advertisement that appeals to him or her, weighing advertising techniques against personal consumption values/ideals. Students discuss whether additional information should be included in product advertisements and how advertising links to consumption choices. ​ Day 4 Reading: Consumption Today Activity: Cashmere Connections Students use information from an engaging video to learn about how environmental concerns, economic forces, and social behaviors are connected to the cashmere clothing industry. They then construct a “connection circle” to identify relationships among variables in the system of cashmere production and consumption. Chapter 9. Climate Change Day 1 Reading: Introduction to Climate Change Activity: Changes All Around In small groups, students examine the climate of 6 distinct locations. Students will then predict what might happen to the climate of a particular region as Earth continues to warm and share these predictions with the rest of the class. ​ Day 2 Reading: Background on Climate Change Activity: Determining Trends In small groups, students will learn about different environmental and societal changes that have occurred since the Industrial Revolution. Each group will share trends they discern from their assigned variable with the rest of the class. The class will then work together to see how all of the variables might be related to one another and how each of them could relate to climate change. ​ Day 3 Reading: Climate Change Today Activity: It All Adds Up Students gather information about their personal energy use to calculate their carbon footprint using an online carbon calculator. Each student will compare their personal result with the carbon footprint of an average person living in the United States as well as other countries around the world. To close, students will discover ways to reduce their carbon emissions. ​ Day 4 Reading: Pathways to Progress: Climate Change Activity: So Many Solutions! Students consider the costs and benefits of a variety of responses to climate change to determine which solutions might be the most sustainable. Chapter 10. Biodiversity Day 1 Reading: Introduction to Biodiversity Activity: What Is Nature Worth? Working in small groups, students brainstorm the services different ecosystems provide and critically analyze how ecosystem services support environmental, social, or economic systems. Students then explore the idea of determining an economic value for ecosystem services. ​ Day 2 Reading: Background on Biodiversity Activity: Seeking Refuge Students are presented with 4 different conservation efforts that currently exist in the United States. After determining the pros and cons of each approach, students must decide which is the best use of conservation funding and articulate their reasoning. ​ Day 3 Reading: Biodiversity Today Activity: Endangered Species Investigation Students individually research an endangered species to learn about activities that threaten the survival of the species and what actions have been taken to reverse the species’ decline. As a class, students make conclusions about the human activities that have the greatest impact on endangered species. Students then work to develop their own policies that address the decline in biodiversity. ​ Day 4 Reading: Pathways to Progress: Biodiversity Activity: Designing Community-based Conservation Programs Students experience the process of community-based conservation firsthand as they work in small groups to develop solutions that support both human and wildlife communities. In a jigsaw activity, students develop conservation strategies designed to meet different goals, ultimately collaborating to come up with solutions that achieve multiple goals. Chapter 11. Oceans Day 1 Reading: Introduction to Oceans Activity: Bounty of the Oceans Students explore the variety of and interconnections between marine species. In small groups, students research one marine species. As a class, students work together to create a visual representation of each species’ use of the oceans and the relationships between this small sample of marine life. ​ Day 2 Reading: Background on Oceans Activity: Van to the Ocean Floor Students learn about the use of underwater remote operated vehicles (ROVs) to explore the oceans as well as uncover a unique ecosystem that scientists are just beginning to learn about themselves, deep-water corals. Students use data and images collected from Lophelia II, an expedition undertaken by the National Oceanic and Atmospheric Administration, to perform their own scientific exploration from a classroom setting. ​ Day 3 Reading: Oceans Today Activity: Nonpoint Source Pollution Students learn to distinguish point source pollutants from nonpoint source pollutants. They discover how nutrient pollution is affecting the oceans. Students then develop research questions and strategies for addressing the problem of low dissolved oxygen in one region, the Puget Sound. ​ Day 4 Reading: Pathways to Progress: Oceans Activity: Who Cares about Marine Protected Areas? Students take on perspectives of different stakeholder groups involved in the creation of a Marine Protected Area (MPA) along the coast of their city. Stakeholder groups are encouraged to form alliances, contemplate compromise, and seek consensus. Their efforts will, hopefully, result in a final proposal for an MPA along their coastline, potentially with sections portioned off for specific uses and a list of regulations to be applied to the MPA. Unit 4: Human Health, Security, & Well-being Chapter 12. Quality of Life Day 1 Reading: Introduction to Quality of Life Activity: Livin’ the Good Life Students develop indicators to measure quality of life and conduct a survey of peers and adults to obtain data for their indicators. They analyze the survey data using spreadsheet software and produce charts to demonstrate their results. Students compare their own performance as measured by the quality of life indicators against averages determined by the survey results. ​ Day 2 Reading: Background on Quality of Life Activity: Defining Happiness Students individually decide what types of things positively contribute to their quality of life. They compare their ideas about quality of life to national statistics related to how Americans spend their time and determine how Americans could restructure their time to improve quality of life. ​ Day 3 Reading: Quality of Life Today Activity: What’s Your Rank? Students are divided into groups to research regions around the world. Based on the United Nations Human Development Index Indicators and rankings, students will analyze statistics for 5 countries within their assigned region. They will then consider regional differences in rankings and possible roots causes of these differences. ​ Day 4 Reading: Pathways to Progress: Quality of Life Activity: In the Pursuit of Happiness Students will interpret the Declaration of Independence and a number of different quotes from historical figures related to happiness. They will then write a personal essay that speaks to their philosophy on the pursuit of happiness. ​ Chapter 13. Governance Day 1 Reading: Introduction to Governance Activity: Three Faces of Governance Students create a national energy policy via cooperation and negotiation among the three faces of governance: the state (government), civic organizations, and the private sector. In groups representing each of these areas, students work to accomplish their individual policy goals while negotiating and forming coalitions with other groups to strengthen their overall energy policy. Policy proposals are presented, and one plan is selected to become a national energy policy. ​ Day 2 Reading: Background on Governance Activity: Uncursing Resources? After reading about the “resource curse” in the accompanying text, students consider two case studies of oil-rich countries: Norway and Angola. They then form groups and discuss whether or not these countries are “cursed” by their own natural resource wealth. Students analyze what has led the countries to where they are today. ​ Days 3-4 Reading: Governance Today Activity: Governance in the Classroom Students examine the connections between governance and outcomes by changing a rule in their classroom for one week and monitoring the outcome. After experiencing the modified rules, they reflect on how the rule change was made and whether it affected the classroom in the way they thought it would. ​ Day 5 Reading: Pathways to Progress: Governance Activity: The Tip of the Iceberg Students research an uprising or revolution, selecting from a list prepared by the teacher. After finding several news articles, students use an “iceberg model” to analyze the patterns and underlying governance structures that underlay the event. ​ Chapter 14. Health Days 1 & 2 Reading: Introduction to Health Activity: Changing Minds Students examine personal habits in an effort to improve health. Using the example of handwashing, they take on the role of public health planners and design a blueprint for changing the habits of their school. Students discuss the challenges that people face trying to change habits related to health and the sources of their own health habits, such as upbringing, choices, and environment. ​ Day 3 Reading: Background on Health Activity: Rural vs. Urban Health Students consider the health concerns of communities in urban and rural settings, specifically after a migration from a rural to urban setting, which often occurs during the industrialization of a nation. Ultimately, students begin to place health within a social, economic, and geographic context. ​ Day 4 Reading: Background on Health continued Activity: Pandemic! Students are introduced to the history of global pandemics and evaluate the possible public health responses to a flu pandemic today. Based on the World Health Organization’s handling of the 2009 swine flu pandemic, students design a response to a rapidly spreading, deadly flu. This activity gives perspective on one of the biggest accomplishments of modern public health, the ability to mitigate the effects of pandemic disease, as well as revealing the limitations of the modern global health system. ​ Chapter 15. Conflict Day 1 Reading: Introduction to Peace and Conflict Activity: Conflict Watch Students watch a world news report from any major television channel. They take note of a conflict mentioned, the bias in which it is presented, and research other media sources to get all sides of the story. They then present the information they learned to their classmates. ​ Day 2 Reading: Background on Peace and Conflict Activity: To Fight or Not to Fight? Students examine a variety of interstate and intrastate conflicts through a role-playing activity. They learn to identify root causes of conflict, how to separate positions from interests in a conflict, and experience mediating a conflict. ​ Day 3 Reading: Peace and Conflict Today Activity: Increasing the Peace Students read several scenarios related to different types of conflicts. They critically analyze what types of actions would escalate the conflict and what types of actions would resolve the conflict. ​ Day 4 Reading: Pathways to Progress: Peace and Conflict Activity: Peaceful Solutions, Day 1 Student take on the role of peace diplomats who offer specific ideas for developing greater security and stability within a given country. ​ Day 5 Reading: Pathways to Progress: Peace and Conflict Activity: Peaceful Solutions, Day 2 Student take on the role of peace diplomats who offer specific ideas for developing greater security and stability. ​ Chapter 16. Human Rights Day 1 Reading: Introduction to Human Rights Activity: Current Events and Human Rights Students explore a number of current events related to human rights issues. After researching and responding to specific questions about a specific current event, they will present information back to their peers about the issue, the rights that were violated, and what solutions have been offered. ​ Day 2 Reading: Background on Human Rights Activity: Defending Civil Rights Students examine a variety of historic civil rights court cases in the United States. Students will analyze these cases in pairs and create compelling opening statements to present to their peers to advocate for the rights these court cases sought to protect. The activity will culminate in creating a timeline of these cases to see how far the Civil Rights Movement has come in the United States. ​ Day 3 Reading: Human Rights Today Activity: The Power to Change Students brainstorm different types of human rights. After reviewing the Universal Declaration of Human Rights, they are provided a specific article from the Declaration. In groups, they create 2 skits: one that presents how an individual or group is not allowed to exercise a particular right and one that presents an individual or group able to exercise this right because of a personal or structural solution. Students will act out these skits to their classmates. ​ Day 4 Reading: Pathways to Progress: Human Rights Activity: Creating Our Future Students consider what they can personally do to create solutions to human rights issues. Students will identify what human rights issues they want to work on. Using an action-planning model, they visualize solutions to this specific issue, identify objectives, develop a plan, and implement their vision through action and service learning. ​ Chapter 17. Gender Day 1 Reading: Introduction to Gender Activity: Gender in MediaStudents begin by acknowledging some individual beliefs they have related to gender. They then analyze an advertisement that portrays different genders and consider stereotypes and impacts of media on society. They generate ideas about how the ad could be modified so that it does not promote stereotypes about gender.​​ ​ Day 2 Reading: Background on Gender Activity: Women’s Movements Around the World Students research different women’s rights movements around the world. In small groups, they learn about a specific women’s movement and share this information with their classmates. The class then identifies different types of gender-related issues and analyzes impacts of these issues on sustainability. ​ Day 3 Reading: Gender Today Activity: Everyone Does Better When Women Do Better Students enact the roles of citizens and government representatives from various countries at a “town meeting” forum. Citizens address their local government representative with concerns about the status of women and girls in their country and potential solutions. With input from the citizens, the leaders prioritize the concerns voiced at the meeting and decide on the most effective way to take action and improve the situation in each of the countries. ​ Day 4 Reading: Pathways to Progress: Gender Activity: Closing the Gender Gap Students analyze what the typical girl in a developing country will experience from birth until adulthood. They will then brainstorm points of intervention in order to consider ways to reform the cycle of gender inequality that persists today. They will work in pairs to determine ways to change the course of this girl’s life and examine possible unintended consequences of these interventions. ​ Chapter 18. Human Migration Day 1 Reading: Introduction to Human Migration Activity: What’s in the News? In this media literacy activity, students read the news and use an iceberg model to analyze the global patterns and underlying structural causes that drive migration patterns. ​ Day 2 Reading: Background on Human Migration Activity: Seeking Asylum Through a simulation, students experience the difficult choice and struggles facing refugees and internally displaced persons (IDPs) when they are forced to leave their homes. Students learn about the root causes of refugee and IDP crises, and the options and obstacles each group faces. ​ Day 3 Reading: Human Migration Today Activity: Policy Analysis Students analyze a time line of U.S. Policy on Immigration and Naturalization, observing trends and patterns during the last 200 years. After reviewing this information, they suggest immigration policies based on projections for the next several decades. ​ Day 4 Reading: Pathways to Progress: Human Migration Activity: To Move or Not to Move? Students analyze different scenarios and in groups, recommend whether an individual should migrate from a specific country or not based on a variety of factors. In addition to the scenario they receive, students will research information to make an informed decision on this migration. Groups will present their recommendations to the class. Unit 5: The Global Economy: Economics & Development Chapter 19. Economics Day 1 Reading: Introduction to Economics Activity: The Costs of Education After researching information provided to them, students analyze the economic costs of dropping out of school. After gathering this information, students will individually write argumentative essays on the long-term economic consequences of dropping out and pose solutions that would encourage more students to graduate. ​ Day 2 Reading: Background on Economics Activity: What’s Up with the GDP? In this economics simulation, students graph changes in the personal incomes of different community residents and in the community’s proportion of the gross domestic product (GDP) following an oil spill. The lesson explores the effect of an environmental disaster on the GDP, and the accuracy of GDP as a measurement of a community’s overall health. ​ Day 3 Reading: Economics Today Activity: Pondering Economic Policies Students take on roles of different world leaders tasked with reviewing real-world economic policies before deciding whether to move forward with them or not. After drawing their own conclusions, they learn about the real results of these economic policies. ​ Day 4 Reading: Pathways to Progress: Economics Activity: The Choice Is Yours Students take a closer look into the benefits and consequences of purchasing certain kinds of food. They determine which food is the best choice based on information they are provided and share their reasoning with the class. ​ Chapter 20. Poverty & Development Day 1 Reading: Introduction to Poverty Activity: Take a Step for Equity Students are randomly assigned an economic class, and then hear poverty and wealth statistics describing their economic class as they step forward in a line. Ultimately, a distance is created between the wealthiest and the poorest, illustrating the economic gap between the rich and poor. Students then brainstorm and discuss ways to alleviate poverty and hunger. ​ Day 2 Reading: Background on Poverty Activity: Shop Till You Drop Students experience how resources are distributed and used by different people based on access to wealth. Students discuss and work toward personal and structural solutions to address the environmental impacts of resource consumption, and to help alleviate poverty. ​ Day 3 Reading: Poverty Today Activity: What’s Debt Got to Do with It? Students model the impact of debt on the social and economic health of developing countries. Working in “very poor country” groups, students choose how to allocate limited funds to different sectors of their country’s economy. The groups take on loans to help their country develop and experience what happens when their funds are diverted to debt repayment and away from investment. ​ Day 4 Reading: Pathways to Progress: Poverty Activity: Microcredit for Sustainable Development Students research a developing country and then apply for a $100 microcredit grant to start a small business, as if they were a person living in that country. A business plan and an illustrated poster are presented to a “sustainable development panel of experts” (students) who determine whether or not the business plan is economically, socially, and environmentally sustainable. ​ Chapter 21. Globalization Days 1 and 2 Reading: Introduction to Globalization Activity: Globalizing My World As an introductory activity, students spend a day analyzing how trade has impacted their daily lives. As they spend time analyzing products, food, and media they consume, they can start to identify potential trends and patterns that connect directly to globalization. ​ Day 3 Reading: Background on Globalization Activity: Do You Want Fries with That? Students take on perspectives of different stakeholder groups involved in determining whether or not a fast-food chain should be allowed within a community located in France. Stakeholder groups share their point of view to a panel who will ultimately decide whether a fast-food chain should be allowed within this given community. ​ Day 4 Reading: Globalization Today Activity: To Trade or Not to Trade Students are introduced to the North American Free Trade Agreement (NAFTA) and its stated goals. In small groups, they will research either the pros or cons of NAFTA from the point of view of the United States, Mexico, or Canada. After researching this information, the pro and con groups for each country will join together to share and listen to both sides of the argument. As a country group, they will decide whether NAFTA has overall been a worthwhile effort to improve their country’s economy. If not, they will analyze what provisions need to be met to meet is original goals. Each country group will present their position to the entire class. Unit 6: Creating Sustainable Communities Chapter 22. Community Development Days 1–3 Reading: Introduction to Community Development Activity: Social Capital Youth Summit Students are placed into groups based on common interests. Each group then works together to find what about their common interest draws them all to it, before planning and hosting a mini-event sharing their interest with the rest of the class. Through this process, students build social capital both within groups (bonding capital) and between groups (bridging capital), then discuss how these sorts of relationships could help them work together to address common problems. ​ Days 4 & 5 Reading: Background on Community Development Activity: Putting Our Community on the Map In groups, students create representational maps of their school and the surrounding community to conceptualize and understand interrelations among neighborhood resources, the environment, community, and sustainability. Students then brainstorm specific ways to make the school’s neighborhood more sustainable through improvements to the physical environment and revise their maps to reflect these enhancements. A homework assignment asks students to assess the availability of important resources near their homes. In an extension activity, students present their ideas to community stakeholders. ​ Day 6 Reading: Community Development Today Activity: Fixing Up the Neighborhood In groups, students consider common challenges to community well-being. After identifying underlying problems, considering solutions, and determining available resources, they determine solutions to put their hypothetical community on a course to sustained well-being. Students will consider both positive and negative repercussions for their proposed community development schemes. ​ Chapter 23. Sustainable Design Day 1 Reading: Introduction to Sustainable Design Activity: A Sense of Place Students visit 1 of their favorite places and make observations. In small groups, students will share with classmates, and look for patterns in their observations. Together, the group will name the 3 characteristics it feels are most important for a place to possess, and relate these characteristics to sustainable design. ​ Day 2 Reading: Background on Sustainable Design Activity: Green Products Consultants As a class, students generate a list of products used to construct the built environment. In pairs, students assume the role of a Life Cycle Assessment expert and perform a Life Cycle Assessment for 2 different versions of a product. In pairs, students present their results to an “architectural firm” in a written report and to the class with a verbal report. ​ Days 3 and 4 Reading: Sustainable Design Today Activity: Nature Knows Best Students will observe something in nature and identify characteristics that could be used as a model for design. They will then design a sustainable material, product, or place. Students will showcase their designs and be able to explain what makes them sustainable. ​ Days 5 and 6 Reading: Pathways to Progress: Sustainable Design Activity: (re)Designing a Better World In small groups, students will define revitalization, resiliency, and restoration and consider why these concepts are used in the design world. The class views a video documenting 1 architect’s effort to build a community center for a community affected by a tsunami. Students will use the story to learn the steps of the design process. Students will then demonstrate their understanding of the design process by identifying the steps in another real-world example. ​ Chapter 24. Taking Action Day 1 Reading: Introduction to Taking Action Activity: Bio-poem Students create a concept map that illustrates their strengths, interests, and the factors that have encouraged these strengths and gifts. Students then create a bio-poem that describes who they are and the future they desire. ​ Day 2 Reading: Background on Taking Action Activity: The Fight to Help Haiti Students discover what makes for effective action by investigating the work of 4 disaster relief organizations in Haiti after the country experienced a devastating earthquake in 2010. In small groups, students examine the accomplishments and limitations of 1 of these organizations. As a class, students will present their findings as well as brainstorm how they would choose to run a disaster relief organization based upon lessons learned in Haiti. ​ Day 3 Reading: Taking Action Today Activity: Thirty Days for Change Students identify a personal action or habit they can create to lead a more sustainable lifestyle. The class will then participate in a 30-day Sustainability Challenge in which they will try to make this personal action a habit. Each week of the challenge, students will meet with group members for encouragement and accountability. ​ Day 4 Reading: Pathways to Progress: Taking Action Activity: Creating Our Future How do we create a just and humane world for ourselves and for future generations? Students identify and plan what they want their future to look like. Using an action planning model, students visualize their desired future, identify objectives, develop a plan to address local and global issues, and implement their vision through action and service learning. Preview Videos See what the developers of Exploring Global Issues have to say about the book. This video describes the EGI student text and corresponding teacher's guide; a foundational text for social studies and science courses alike. Introduction Have you ever thought about how a teenager in Vietnam could be linked to the pair of jeans you wear? You are connected to the world in countless ways. Where did tomatoes for the ketchup in your school cafeteria come from? Where were the cars in your school parking lot manufactured? In which country was the computer code for your cellphone written? You might be thinking, "Why should I care?" In a world where two people 7,000 miles apart can connect with just a click of the mouse, knowledge of different cultures and customs can prove useful. In a world where we rely more and more on goods and services from other countries, knowledge of international trade and economics is essential. In a world where the air you breathe can be affected by a factory outside your nation's borders, knowledge of wind cycles and international enforcement of environmental standards can be crucial to creating solutions to issues that impact us all. Everyone benefits from an understanding of global issues. It is the nature of the world in which we live that connections—whether social, economic, or environmental—now occur on a global scale. Global issues, such as poverty, climate change, conflict, and population growth are interrelated and affect the lives of all people around the world. The good news is while these issues can be challenging, they have interconnected solutions that we can develop to create long-lasting, positive change. By thinking of global solutions to global issues, we can begin to create a truly sustainable world. Exploring Global Issues: Social, Economic, and Environmental Interconnections provides you the opportunity to learn about 24 topics related to global issues and sustainable ways to address these issues. You will learn about the background of the topic, examine how it impacts the world today, draw personal and community connections, and devise solutions to address the issue. Each chapter features young people who are doing work related to the topic. Each chapter also features case studies that present issues in context. For example, the chapter on air includes a case study of pollution in Mexico City. These case studies allow you to see an issue in real life and perhaps from a perspective that you had not considered before. They also provide you with the opportunity to connect your personal experiences and knowledge about an issue with a different part of the world. As you learn about these topics, you will also participate in activities related to each chapter. These resources are designed to: enhance your ability to think critically improve your problem-solving abilities expand your global perspective increase your knowledge of global issues and sustainable solutions This text will provide you with the foundational knowledge and skills to understand what's happening in the world around you and prepare you to be an engaged citizen capable of creating change locally and globally. State Standards Educator Quotes The Exploring Global Issues textbook is the ultimate one-stop shop for all things global. Whether you’re looking to teach an entire course on sustainability or the environment, for example, or you want to add engaging curriculum to core classes like social studies or science, this book is the one to get the job done. Students in my Global Issues classes agree: they’ve called the book 'informative, topical, engaging, thought-provoking, and user-friendly.' Exploring Global Issues is unique in that it thoughtfully examines global issues that might otherwise fall “between the cracks” of the average high school curriculum. It also objectively guides students to a genuine understanding of these issues, encouraging them to form their own well-supported opinions along the way. - Rick Malmstrom, Social Studies Teacher, The Ellis School, PA Exploring Global Issues is an excellent way to teach about complex, modern issues with great supporting resources that save a lot of time when trying to imagine how to delve into the many facets of modern global and ecological issues. The curriculum is flexible, adaptive and user friendly, but does not compromise on the depth and detail of the issue even though it is extremely accessible to students. - Bridgette McGoldrick, History Teacher, The Annie Wright School, WA Curriculum Funding Toolkit Use this toolkit to help find funds to purchase Facing the Future curriculum for your classroom. The funding opportunities listed below have been screened by Facing the Future staff to ensure that they are easy to apply to and that funds from these sources can be used to purchase our curriculum. Adopt-A-Classroom partners donors with teachers so you can have funds to purchase critical resources and materials for your classroom. By registering, your classroom will be posted on the Adopt-A-Classroom website available for donors to select. When adopted, you will have full discretion to purchase items that meet your unique classroom needs. FAQs Teachers can post a project or curriculum they would like to fund. Donors can make an online donation for any amount toward the cost of the project or curriculum. When the item is fully funded, DonorsChoose purchases the item and sends it and a thank you kit to the teacher. Eligibility: Local Educational Agencies, public or private schools, nonprofits, and higher education institutions Amount: Varies by state | Deadline: Varies by state Do you have an idea for a service-learning project that will impact your community? Learn and Serve America provides grant support annually (primarily through intermediaries) to diverse partnerships to develop and sustain service-learning projects. Generally, grants are for a period of three years, renewable annually contingent upon performance and the availability of funds. Note: Funds are allocated to each State by a formula that considers each State’s school-age population and Title I allotment. Grants are awarded on a non-competitive basis to States through State Education Agencies (SEAs) that then provide sub-grants to Local Educational Agencies, public or private schools, nonprofits, and higher education institutions that implement programs. As the largest volunteer child advocacy association in the nation, Parent Teacher Association (PTA) reminds our country of its obligations to children and provides parents and families with a powerful voice to speak on behalf of every child while providing the best tools for parents to help their children be successful students. Eligibility: Applicants must be practicing U.S public school teachers in grades PreK–12, public school education support professionals, or faculty and staff at public higher education institutions Amount: $5,000 | Deadline: Open The NEA Foundation Student Achievement Grants aim to improve the academic achievement of students in U.S. public schools and public higher education institutions in any subject area(s). The proposed work should engage students in critical thinking and problem solving that deepen their knowledge of standards-based subject matter. The work should also improve students’ habits of inquiry, self-directed learning, and critical reflection. Amount: Grants average between $5,000 and $10,000 | Deadline: January 1 and October 31 The Verizon Foundation seeks to improve literacy, knowledge, and readiness for the twenty-first century. Its four core areas are education, literacy, Internet safety, and domestic violence. Eligible organizations seeking grants from the Verizon Foundation must be prepared to track and report program outcomes and specific results that demonstrate measurable human impact. In the grant application, organizations must indicate what outcomes are targeted through programming and what results, as specified on the grant application, the organization will measure. Federal funds tend to be large grant awards and most often are open to schools, districts, or state governments. Individual teachers are not typically awarded small grants through Federal Grant Programs. You can search all federal funding opportunities at grants.gov or Department of Education funding opportunities at their Discretionary Grant Application Packages page. Information About Programs Use the Guide to Education Programs to learn about federally funded programs. Below are direct links to specific programs for which funding opportunities may arise or may be available through your state: We equip and motivate students to develop critical thinking skills, build global awareness, and engage in positive solutions for a sustainable future through hands-on curricula and professional learning.

Teacher adopts 7th grader in need of kidney transplant AURORA, Colorado -- A 7th grader is one step closer to getting a kidney transplant thanks to his teacher. He's given the boy a home so that he can be added to the transplant list. Damien was diagnosed with a disease called focal segmental glomerulosclerosis that's taken a toll on his organs, leaving him in need of a kidney transplant. Damien and his math teacher Finn Lanning met at the start of the school year. Within weeks the 13-year-old was being pulled from school to live in a hospital because another foster family couldn't care for him. "Over the course of the years, I ended up in foster homes because of my medical needs," explained Damien. Lanning went on to explain that, "When you're living in the hospital, you're not able to be on the transplant list because folks who don't have stable housing are considered high risk for their organ to not work."

Bachelor or Master Thesis Optics (m/f/d) – LiDAR Optics Development Description Your Topic LiDAR systems measure distances by stopping the time a laser pulse needs to travel from the sensor to an object and back. By conducting more than 1 Million distance measurements per second, a 3D point cloud of the surroundings of the sensor can be created in real time. At the heart of the sensor lies the optical system containing an ultra-fast pulsed laser diode, collimating optics and a single photon detector. If you are interested in Optics and want to learn about cutting edge LiDAR technology then get in touch with us. We always have interesting topics to work on. Blickfeld is a Munich-based startup company founded in 2017 with the vision to provide autonomous systems the eyes to see the world: We develop revolutionary scanning LiDAR systems and detection software for environment perception. Our unique solution enables countless scenarios like autonomous transportation, mapping, robotics, and smart and safe cities. Tasks: Get acquainted with the working principle of our lidar optics Help us to model and improve our optical system See your work included in a working prototype and validate the results of your work Skills: You are pursuing a Bachelor or Master degree in a technical field such as Physics, Electrical Engineering, Optics or similar You have basic knowledge in either Optics, Electronics or Semiconductor Physics

Martin Luther Cathedral, Daugavpils The Evangelical Lutheran Church of Martin Luther () or Martin Luther Cathedral is an Evangelical Lutheran cathedral in Daugavpils, Latvia. Design The cathedral was designed by Wilhelm Neumann, one of the most influential architects in the current landscape of Daugavpils. It is built is the brick gothic style, and was completed in 1893. Diocese of Daugavpils The cathedral is the seat of the Lutheran Bishop of Daugavpils in the Evangelical Lutheran Church of Latvia. The current bishop is Einārs Alpe, born 11 November 1963, who was ordained in the Lutheran Church in 1991, and was consecrated and enthroned as Bishop of Daugavpils on 13 October 2007. Gallery References See also Ss. Boris and Gleb Cathedral, Daugavpils Category:Cathedrals in Latvia Category:Daugavpils

Category Archives: Scaled Agile Two of the questions I’m frequently asked these days “Do we need the Scaled Agile Framework (SAFe)?” as well as “CAN we (safely) implement SAFe?”. I recently published a self-assessment based on the questions I typically help organizations answer when they’re looking at this. Continue reading → Last week I gave a deep dive workshop in the Agile Games New England conference about the NEED for engagement and participation when implementing agile at scale using an approach like SAFe as well as how I use online games like Kahoot and Socrative and various points throughout the implementation to increase engagement and participation especially when working with big groups beyond the team. Here’s my slide deck from the talk: Earlier this evening I delivered a talk at Agile Boston named “The Art of SAFe ART/Value Stream Design” where I tried to explain the different layers of SAFe and how they apply in a variety of real-world situations. We discussed Telco and Financial Services systems of systems as well as some examples brought up by the audience. I had lots of fun although my Wacom tablet didn’t play along nicely. Need to figure out what that was about. PS If you’re interested to learn about SAFe, ART, Value Streams, my next Leading SAFe 4.0 workshop is in the Boston area on March 9-10th. If you move REALLY fast you can take advantage of early bird pricing. In any case as readers of my blog you can get a 10% discount. Just use YYBLOG on checkout. SAFe (The Scaled Agile Framework) uses Story Points throughout the various levels as its estimation currency. This is covered in the “Story” article on the SAFe site. This is a pretty standard practice in organizations scaling agile these days. If you dive a bit deeper into how this is done in SAFe you will see that actually the story points used in SAFe are quite similar to “Ideal Developer Day” as this helps the teams align to a common baseline and support a rational economic ROI discussion at the level of Features/Capabilities that require effort from more than one team or haven’t even been mapped to a specific team yet. An alternative to using Story Points at the team level that is interesting to look at especially as Kanban is becoming a first-class citizen of the SAFe world is to use NoEstimates. What is the connection between Uncertainty and the Scaled Agile Framework? Uncertainty is one of the core reasons we need to be agile. Different modes of Business/Requirements/Technology uncertainties impact our economic costs in product development – especially the potential impact of risk. The first principle of SAFe™ is “Take an economic view”. I frequently use my “uncertainty filter glasses” to take an alternative economic view. I find it helps Scaled Agile/SAFe™ practitioners/leaders understand both the need for Agility as well as examine various work system design considerations. In this article I introduce the Stacey Matrix which is one of my favorite models for understanding the uncertainty landscape as well as implications of uncertainty on various specific SAFe™ design decisions. Making it Concrete – The Stacey Uncertainty Matrix and its relation to the Scaled Agile Framework As I wrote about at some length in Risk-Aware Product Development (a.k.a Agile) explaining the concept of Requirement/Business/Technology uncertainty is one of the first things I do with most audiences I meet for the first time. On a Leading SAFe/SPC class this typically takes place in the first module when we go over the need for SAFe. This is not a core part of the materials but I take the time to explain it anyhow and then find myself referring back to it throughout the workshop. The first layer of realization is that our problem with the classic approaches to product development is that they were built for complicated endeavors but not complex ones. Then we layer on more interesting realizations like the fact that for some endeavors like those approaching the “Anarchy”/”Chaos” domains probably the best approach would be a “Skunkworks” style cross-functional co-located fully empowered small team. As you grow a bit farther from Anarchy you can scale agility using an approach like the Scaled Agile Framework. At these levels of uncertainty/risk the trade-off of distributed teams, distributed PI Planning, system team, component teams, shared architects/UX MIGHT make sense and are worth considering. As you approach the simpler domain sometimes even the alignment rationale for “whole train” PI Planning can be reconsidered. Is that SAFe™ heresy? maybe. But I find that telling people “Whole ART PI Planning” is mandatory is less effective than showing them WHEN it has a better economic impact. (BTW as you grow in complexity/uncertainty you also need better people that are more engaged – which the Whole ART PI Planning helps with as well) In general, this thinking helps leaders at these workshops grasp the various economic levers that go into tailoring a SAFe™ implementation. I find this disarms some of the resistance you get when people feel something is “a must”. Using this approach they typically go out with a stronger conviction to avoid some compromises and a better feeling about the compromises that do make sense. To take another example of how I use the uncertainty matrix during SAFe™ training/implementation discussions – SAFe™ talks about a hierarchy between ART Product Management and the Product Owners working with the teams. A typical and sensible question people have is “Who should wear the Product Owner hat?”. Using the uncertainty matrix, we realize that in some cases the Product Owner should be a Product Manager (probably the top two quadrants of the matrix) and in some other cases he can also be a more technical leader (Especially on the far right side of the matrix). As the typical organization I work with is struggling to fill those Product Owner roles, this realization helps them deploy their people more effectively in a way that minimizes the risk of ineffective feedback loops due to the wrong individuals being in the tight Product Owner loop. In summary Understanding uncertainty and its attributes and implications is in my view and experience a critical step of buying into the need for agile as well as gaining the ability to design an effective agile approach for your context. Presenting the Stacey Matrix and trying to map it to your reality is one technique I used to help people gain this understanding. Using it as a decision filter/design criteria for further SAFe™ tailoring questions complements this initial presentation/exposure and grounds it. If you are teaching Leading SAFe™/SPC classes, explaining the need for agile to leaders/executives, or working with an organization to implement a scaled agile approach, I believe you will see improved results if you add this technique to your toolbox. I know I have.

Infinite Loop — From Karateka to Cubasis, 8 new iOS apps worth a try Check out these apps, including one from a longtime Ars reader. The App Store has over 700,000 options available, with dozens of new apps released every week. As we noted last Friday, we can't always take a deep dive into every app that comes across our desks. But sometimes we hear about apps that sound quite promising and feel like they deserve to be highlighted. Here are several new or updated apps that you might give a try this weekend. (All links are for the US App Store.) Famed game designer Jordan Mechner has teamed up with The Batman artist Jeff Matsuda to create a throughly modern, 3D remake of his classic Apple II game Karateka. The new version is available on Xbox Live, PSN, and Steam, and an iOS version was released this week. You have a chance to play three different heroes, all vying for the heart of a kidnapped princess in feudal Japan. The game might be fun for those of us who played the original on an Apple II, Commodore 64, or even an NES, but younger gamers will still appreciate the unique style and easy-to-learn gameplay. Steinberg, makers of the Cubase sequencer, have released an adapted version called Cubasis for iPad. At $49.99, the app is no casual purchase, but for serious musicians the app is worth considering as part of a mobile music-making toolbox. Cubasis can record dozens of audio or MIDI tracks (it's compatible with Core MIDI). It can also add studio-quailty effects and mix everything down for export to SoundCloud, Dropbox, and more. Projects can also be shared with the desktop Cubase app for further editing. For live performances and recording sessions alike, the app also comes complete with 70 virtual instruments based on the HALion Sonic workstation and 300 MIDI and audio loops to get you started. This little mobile photography gem is a one-trick pony, but the trick is an extremely clever one. Select two photos; the app analyzes them and then applies the color scheme from one photo to the other. (See a video of how it works here.) You can make some crazy color changes, but this primarily helps you match the look of photos shot under different lighting conditions. Once you save the edited versions, you can later combine them into albums, galleries, or collages with an overall harmonious color palette. If you like retro styles but are looking for a break from Instagram and its many clones, you might like Retromatic. It includes a simple and effective masking tool which allows you to pull your subject out of a photo and put it into a unique, retro-inspired graphic. You can add other elements like sunbursts, borders, and more, resulting in something far more original than the usual "lo-fi" filtered photo. Redbox Instant is a new streaming video service from Redbox and Verizon, meant to compete with the likes of Netflix and Amazon Instant Video. If you are not already a Redbox user, you can add $8-per-month movie streaming to your iOS devices with this new app. The service itself is currently in beta, but you can sign up to join the beta now. Longtime Ars forum member vafarmboy recently published his first iOS app. It's rather simple and straightforward, but Strengthiness Interval Timer is designed to help you set up and follow an interval training regimen, such as Tabata protocol, Super-8, or VO2max/Viking Warrior Conditioning. (I personally like to use custom intervals when building speed for 5K runs.) Just set a time, how many rounds you want to repeat, and go. The current $0.99 price is good through December, after which it will go to its regular $1.99 price. Tumblr has revamped its iOS app with a native iPad user interface. The now-universal app is optimized for Retina displays and also includes Markdown support for posting and a new Explore tab for finding new tumblogs to follow. Dropbox can be an indispensable tool for syncing and accessing files from your iPhone or iPad; in fact, many apps rely on Dropbox for remote file access over Apple's own iCloud. The new 2.0 version of the iOS app adds a ton of UI polish but also includes easier file uploading to specific folders as well as a completely new photo viewer which lets you interact with your synced photos. Promoted Comments I'm trying to use Color Thief on iPad, but it says photo permissions are denied, and when I go to settings, privacy, photos, it's not listed as an app I can enable. This bug comes up if you have Restrictions turned on. If in General->Restrictions->Location Services you have "Don't Allow Changes" turned on, Color Thief never even gets the chance to add the app to the Photos Privacy permissions list. Please temporarily turn off Location services restrictions. Sorry about this bug; we'll fix it in the next update. Does the new Karateka have a mirror image mode? The original Apple II version had a mirror image version of the game written on the back of the floppy as I recall, so if you booted up with the floppy upside down the game was reversed. Good stuff, though the appearance of Cubasis would have been more impressive had not Music Studio (formerly Xewton Music Studio) for the past year been doing most, if not nearly all, of what Cubasis can, for less than 20 dollars, with iPhone support, and with a similar number of sampled instruments (which, surprisingly, are of a similar quality, even to the trained ear). I have little doubt Cubasis will quickly become a standard for mobile musicians, regardless. And I am surprised Karateka has gained this much traction, partially because of the mediocre reviews of the console version, and partially because of all the massive App Store releases over the past days and weeks (Ravensword: Shadowlands, Vice City, Modern Combat 4, Jet Set Radio, Bastion, Autumn Dynasty Universal, FFIV (a game which port even a FF-skeptic like me can realize the importance of ;-) ), etc). I'm trying to use Color Thief on iPad, but it says photo permissions are denied, and when I go to settings, privacy, photos, it's not listed as an app I can enable. You might need to enable access to location data. If you tag your photos with location data, any app that gets access to those photos gets access to that location data. So no access to location data means no access to photos. I'm trying to use Color Thief on iPad, but it says photo permissions are denied, and when I go to settings, privacy, photos, it's not listed as an app I can enable. This bug comes up if you have Restrictions turned on. If in General->Restrictions->Location Services you have "Don't Allow Changes" turned on, Color Thief never even gets the chance to add the app to the Photos Privacy permissions list. Please temporarily turn off Location services restrictions. Sorry about this bug; we'll fix it in the next update. This Strengthiness Interval Timer is a shame! Repeat Timer Pro (or even Free) is so-o much better for that. I'm using it for my circuit training and I know what I'm talking about. I think you should really have reviewed Repeat Timer instead of this. This Strengthiness Interval Timer is a shame! Repeat Timer Pro (or even Free) is so-o much better for that. I'm using it for my circuit training and I know what I'm talking about. I think you should really have reviewed Repeat Timer instead of this. Gonna have to disagree with you on that. The Strengthiness Interval Timer has louder beeps, easier setup (try setting an interval for 100 seconds on a picker), a countdown timer, can count rounds up instead of just down, and has a much bigger, easier to read display (especially for iPad, considering Repeat Timer doesn't have an iPad version). Repeat Timer is a good app and has some nice polish. I have it and I like it. It just doesn't work as well as a training app, which is what the Strengthiness Interval Timer was designed for. Much like a kettlebell, it may not be pretty, but it's simple, functional, and is the best tool for its intended purpose. I don't use the Strengthiness Interval Timer just for my own personal training, either; I and my friends, who are professional trainers, use it training our clients. Thanks for trying, though. Gonna have to disagree with you on that. The Strengthiness Interval Timer has louder beeps, easier setup (try setting an interval for 100 seconds on a picker), a countdown timer, can count rounds up instead of just down, and has a much bigger, easier to read display (especially for iPad, considering Repeat Timer doesn't have an iPad version). Well, if you don't bother about graphics so much, Repeat Timer does work well on iPad in 2x mode. ;-) I don't think counting rounds up is of any value. I always have this setting at 99, and I have no problem realizing whether I'm doing circuit 1, 2, or 3. You might have other use cases though. I agree that it's hard to hear the beeps when loud music is on but I use earphones and my own music, so it's never a problem (Repeat Timer supports earphones, btw, which is cool . vafarmboy wrote: Repeat Timer is a good app and has some nice polish. I have it and I like it. It just doesn't work as well as a training app, which is what the Strengthiness Interval Timer was designed for. Much like a kettlebell, it may not be pretty, but it's simple, functional, and is the best tool for its intended purpose. I don't use the Strengthiness Interval Timer just for my own personal training, either; I and my friends, who are professional trainers, use it training our clients. Thanks for trying, though. See, your use cases differ from those of individual athletes. You need to enter intervals frequently (not once a week like me, for instance) and you can't use earbuds… but your professional/personal opinion is much appreciated. ;-) I'm amazed that one of the MOST important apps for iOS music, AudioBus, got no press, and Cubasis did. Like others have said, "DAW" apps (simplistic, walled garden sketch pads, not true DAWS, let's not fool ourselves) for iOS have been around for some time. AudioBus acts like a mixer, and enables users to allow different apps to communicate with each other, which, before its development, was either impossible, or a major PITA. Again, one of the most important music apps for iOS to let them be more than toys... I'm trying to use Color Thief on iPad, but it says photo permissions are denied, and when I go to settings, privacy, photos, it's not listed as an app I can enable. This bug comes up if you have Restrictions turned on. If in General->Restrictions->Location Services you have "Don't Allow Changes" turned on, Color Thief never even gets the chance to add the app to the Photos Privacy permissions list. Please temporarily turn off Location services restrictions. Sorry about this bug; we'll fix it in the next update. Honestly - I couldn't care less. I bought the app, tried to start it, reported it and asked for a refund. I don't care if it's iOS that won't give you access to photos unless I allow you to track where I use the app and where I'm going while it's running (In the background? How should I know?) or if it's your app that just doesn't allow me the option to manipulate photos while losing location information I don't care about. Those settings are under "privacy" for a reason. I just hope I get my money back. This requirement should be noted in the description in the app store (where I just rated it with one star because of this). EDIT: Bought it for the iPhone. Location services were turned off when I tried to start it and it wouldn't get past the "abandon your privacy NOW" screen. Unacceptable.

battlestar galactica For those unfamiliar with the brilliance of 'Battlestar Galactica,' "frakking" sounds like just another silly word to look up on Urban Dictionary. However, for fans of sci-fi, it's a very specific reference. In the alternate universe where 'Battlestar' is set, saying "frak" is the equivalent to dropping the F-bomb. At first, it sounds absurd and just an obvious way to curse without the FCC crawling up the network's "ack." But after watching a few episodes, most viewers accept "frak" and even start to like it. Break Media just released a music video entitled, 'Tonight, I'm Frakking You.' The dance-worthy R&B song spoofs the sci-fi terminology and fanboy culture as the singer, dressed as a Vulcan, courts ladies at a cosplay club. The current "Golden Age" of television has been accompanied by some terrific music. It's impossible to imagine 'Lost' without Michael Giacchino's distinctive score, or '24' without Sean Callery's pulse-pounding music. The best scores not only add emotion and tension to good stories, they are thoughtful, creative endeavors well worth listening to on their own. Bear McCreary created a percussive, evocative and operatic score for Syfy's late, great 'Battlestar Galactica.' If you watched the show, you no doubt recall its infamous "poundy drums," its poignant themes and its distinctive rendition of 'All Along the Watchtower,' which became a major thematic element in the show's final season. The iconic commander of the 'Battlestar Galactica' fleet, who was played by Edward James Olmos in the Syfy series of the same name, will be played in the upcoming 'Blood and Chrome' prequel by Luke Pasqualino from the U.K. version of 'Skins,' according to EW. 'Battlestar Galactica: Blood and Chrome,' a backdoor pilot for a possible young Adama series, chronicles the character's entry into the ongoing Cylon War. 'Husker' Adama is itching to get in the fight, but in 'Blood and Chrome,' he'll be paired with Coker, an officer who has served on the front lines and wants nothing more than to be done with fighting. Coker will be played by Ben Cotton, EW reports. As I reported in this October story about 'Blood and Chrome,' the pilot, which was written by 'BSG' writer Michael Taylor, will go into production this year, but it's not clear if it will air in 2011 or in early 2012. Casting the role of a young William Adama is no easy task, so let's help Syfy out. The casting notices for the new 'Battlestar Galactica' prequel series, 'Battlestar Galactica: Blood & Chrome' has gone out and there are three main characters in need of actors. Besides the 20-something, cocky, yet inexperienced Adama, TV Guide reports the series is casting one male and one female lead. It's the 10th year of the Cylon war and Adama's risky behavior leads to conflict with Electronic Countermeasures Officer, Coker Fasjovik. Coker Fasjovik is in his late 20s/mid-30s and "is weary after a long mission serving on Adama's first ship, a less-than-impressive Raptor called the Weasel." The female lead, Beka, appears to have a nefarious plan; Coker Fasjovik suspects her, but Adama is on her side. Due to low ratings, Syfy has cancelled the 'Battlestar Galactica' prequel 'Caprica.' Syfy is pulling the show from its broadcast rotation immediately, and the remaining five episodes of the show's first season will air some time in the first few months of 2011, according to the network. A few months ago, the Syfy network commissioned an online series called 'Battlestar Galactica: Blood & Chrome,' a chronicle of the war experiences of young William Adama. The network liked Michael Taylor's script for the project so much that Syfy will air 'Battlestar Galactica: Blood & Chrome' on the network as the pilot for a possible young Adama TV series. Mark Stern, Syfy's executive vice president of original programming and the co-head of original content for Universal Cable Productions, said the network hoped to begin production on the pilot in Vancouver in early 2011. "When we read Michael's script, it was so clearly a full-blown pilot for a series," Stern said in a Thursday interview. "The scope is fantastic and bigger, I think, than anticipated, so we said, 'Let's do it as a 2-hour backdoor pilot.' ... We're trying to get up and running as soon as possible." Was there a more a disappointing moment in childhood than the Sunday-morning realization that the only thing on TV was televangelists and 'The 700 Club'? You came looking for 'He-Man,' instead you got Pat Robertson. For some reason Ron Moore and the 'Caprica' team seem to want us to relive that moment every Tuesday night as we tune in for new episodes of the 'Battlestar Galactica' spin-off. As other critics have noted, 'Caprica' has turned away from some of the deliciously-enticing ideas the show started to examine in the first half of the first season -- things like the potential origins of true artificial intelligence or completely virtual worlds -- and now, instead, we're getting a primer on the intricacies of a religion that doesn't even exist. When we last left 'Caprica' (which seems like ages ago), things were descending into chaos. At the center of the madness – the suicide attempt by Amanda, Zoe's rebellious escape, the U-187 – sits one lynchpin of a character: Lacy Rand. Played by Canadian actor Magda Apanowicz, Lacy has grown from a background character into a crucial game-changer. Nearly every plotline hinges on her actions. TV Squad caught up with the ever-gregarious Apanowicz right before the finale of season 1, and she is nothing at all like the subservient, malleable Lacy. She spoke with us about the upcoming season 1.5, how in love with 'Battlestar Galactica' she is, and what it's like to hug a Cylon. Most ambitious cable dramas attempt to craft season-long narrative arcs in addition to telling more contained weekly stories. The unfortunate thing about 'Caprica' (10PM ET Tuesday, Syfy) is that the 'Battlestar Galactica' prequel still isn't demonstrating consistent focus on either of those fronts. 'Caprica's' first two fall episodes are frustrating, despite the obvious attempts to revive the sporadic momentum that the show's spring run had. The thing is, for the dramatic stakes to matter, the audience has to care about the characters, but it's often difficult to invest in their journeys for any number of reasons. Of all the 'Stargate Universe' characters struggling aboard the Destiny, David Blue's Eli is arguably the person who's changed the most. Over the course of the first season, we watched him grow from introverted computer geek into one of the more vital members of the ship's crew. We left Eli at the end of last season's cliffhanger finale as he and injured shipmate Chloe were stranded in an undiscovered part of the Destiny. TV Squad caught up with Blue – who's actually a lot taller (and slimmer) than he looks on TV – and chatted about season 2 of 'Stargate Universe,' what's in store for Eli, and what he thinks about the constant comparisons to 'Battlestar Galactica.' Michelle Forbes is a rare breed of actor; ever the chameleon, she nomadically jumps from show to show, giving us just a taste of her ability. She then moves on to her next role to stun us once again. Most recently, Forbes played a maenad on vampire hit 'True Blood' and the icy Admiral Cain on 'Battlestar Galactica.' One role that Forbes treasures is one you probably don't know her for, which is as demented psychologist Dr. Penelope Verrity in the second season of Canadian-made-and-produced 'Durham County.' It's a dark, dark role in an avant-garde show, and it mostly went under the radar. TV Squad sat down with Forbes to discuss why she's done talking about 'Star Trek,' how she stays a TV nomad and why she wishes everyone knew about 'Durham County.' Well, we were promised answers. And we didn't really get them. This was the two-hour season finale of 'Persons Unknown' (Sat., 9PM ET on NBC). Considering that the show has gotten incredibly low ratings, it seems highly doubtful that it will be back next year. Thus, this is essentially our series finale as well. So, were all the loose ends tied up? Before Johnny Depp was Edward Scissorhands, Don Juan DeMarco or even Jack Sparrow for that matter -- he was Officer Tom Hanson on '21 Jump Street.' For anyone who remembers or wants to remember vintage Johnny Depp at his finest, pick up the complete third season of '21 Jump Street' on DVD and in stores today. Today is a big day for new releases as there is literally something for everyone. For the rest of new titles, including new 'Stargate Universe' and 'Battlestar Galactica' DVD's, find the entire list after the jump. We've entered the third installment of The TV Squad TV Club's 'Battlestar Galactica' viewing marathon. This week, we talk about Season 1, episodes 9-13, including the shocking season finale. In a vidcast, I discuss the assignment with AOL TV editor extraordinaire Kelly Woo. And, via the magic of Skype, TV Squad writer Jason Hughes chimes in on the how Col. Tigh is more than just a cantankerous drunk, and Sandie Angulo Chen discusses the finale, and how shocking it is even now. Below, Jason, Sandie and myself furthered the discussion in an e-mail exchange from earlier in the week. Stay tuned for what we'll be covering during the next club meeting, which we're hoping to schedule for later in August. Questions and discussion points can be directed to us on Twitter (@aoltv, use the hashtag #tvsquadtvclub), on our Facebook fan page or by e-mail at tvsquadtvclub AT gmail DOT com.

Aldo-keto reductase and alcohol dehydrogenase contribute to benznidazole natural resistance in Trypanosoma cruzi. The improvement of Chagas disease treatment is focused not only on the development of new drugs but also in understanding mechanisms of action and resistance to drugs conventionally used. Thus, some strategies aim to detect specific changes in proteins between sensitive and resistant parasites and to evaluate the role played in these processes by functional genomics. In this work, we used a natural Trypanosoma cruzi population resistant to benznidazole, which has clones with different susceptibilities to this drug without alterations in the NTR I gene. Using 2DE-gel electrophoresis, the aldo-keto reductase and the alcohol dehydrogenase proteins were found up regulated in the natural resistant clone and therefore their possible role in the resistance to benznidazole and glyoxal was investigated. Both genes were overexpressed in a drug sensitive T. cruzi clone and the biological changes in response to these compounds were evaluated. The results showed that the overexpression of these proteins enhances resistance to benznidazole and glyoxal in T. cruzi. Moreover, a decrease in mitochondrial and cell membrane damage was observed, accompanied by a drop in the intracellular concentration of reactive oxygen species after treatment. Our results suggest that these proteins are involved in the mechanism of action of benznidazole.

New excised-leaf assay method to test inoculativity of Asian citrus psyllid (Hemiptera: Psyllidae) with Candidatus Liberibacter asiaticus associated with citrus huanglongbing disease. The Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Psyllidae), is the primary vector of Candidatus Liberibacter asiaticus (Las) associated with huanglongbing, or citrus greening, the most devastating citrus (Citrus spp.) disease worldwide. Here, we developed a new "excised-leaf assay" that can speed up Las-inoculativity tests on Asian citrus psyllid from the current 3-12 mo (when using whole citrus seedlings for inoculation) to only 2-3 wk. Young adults of Asian citrus psyllid that had been reared on Las-infected plants were caged on excised healthy sweet orange [Citrus sinensis (L.) Osbeck] leaves for a 1-2-wk inoculation access periods (IAP), and then both psyllids and leaves were tested later by quantitative polymerase chain reaction (PCR). When single adults were tested per leaf, percentages of Las-positive leaves averaged 2-6% by using HLBaspr primers and 10-20% by using the more sensitive LJ900 primers. Higher proportions of Las-positive leaves were obtained with 1) higher densities of inoculating psyllids (5-10 adults per leaf), 2) longer IAPs, and 3) incubation of leaves for 1 wk postinoculation before PCR. Logistic regression analysis indicated a positive correlation between Las titer in Asian citrus psyllid adults tested singly and the probability of detecting Las in the inoculated leaves, correlations that can be very useful in epidemiological studies. Comparison between excised leaves and whole seedlings, inoculated consecutively for 1 wk each by one or a group of psyllids, indicated no significant difference between Las detection in excised leaves or whole plants. This new excised-leaf assay method saves considerable time, materials, and greenhouse space, and it may enhance vector relation and epidemiological studies on Las and potentially other Liberibacter spp. associated with huanglongbing disease.

Q: ImportError: No module named PyQt4 I installed pyqt4 by using Homebrew. But when I import PyQt4 in python interpreter, It said that "No module named PyQt4". Can somebody help me with that? A: After brew install pyqt, you can brew test pyqt which will use the python you have got in your PATH in oder to do the test (show a Qt window). For non-brewed Python, you'll have to set your PYTHONPATH as brew info pyqt will tell. Sometimes it is necessary to open a new shell or tap in order to use the freshly brewed binaries. I frequently check these issues by printing the sys.path from inside of python: python -c "import sys; print(sys.path)" The $(brew --prefix)/lib/pythonX.Y/site-packages have to be in the sys.path in order to be able to import stuff. As said, for brewed python, this is default but for any other python, you will have to set the PYTHONPATH. A: You have to check which Python you are using. I had the same problem because the Python I was using was not the same one that brew was using. In your command line: which python output: /usr/bin/python which brew output: /usr/local/bin/brew     //so they are different cd /usr/local/lib/python2.7/site-packages ls   //you can see PyQt4 and sip are here Now you need to add usr/local/lib/python2.7/site-packages to your python path. open ~/.bash_profile   //you will open your bash_profile file in your editor Add 'export PYTHONPATH=/usr/local/lib/python2.7/site-packages:$PYTHONPATH' to your bash file and save it Close your terminal and restart it to reload the shell python import PyQt4    // it is ok now A: If you're using Anaconda to manage Python on your system, you can install it with: $ conda install pyqt=4 Omit the =4 to install the most current version. Answer from How to install PyQt4 in anaconda?

Evolutionary transformations of fetal membranes and reproductive strategies. Fetal membranes (such as the chorioallantois and yolk sac) are essential to embryonic development, and have contributed importantly to the evolutionary and ecological diversity of vertebrates. Since the mid-19th century, many scientific careers have been devoted to investigations of their structure, function, and development. However, significant gaps remain in our understanding of the diversity and evolution of fetal membranes. This symposium volume focuses on the use of cladistic principles and phylogenetic relationships to reconstruct the evolutionary morphology of fetal membranes. The main goal of the present paper is to introduce the application of such methods to the evolution of vertebrate fetal membranes, as well as to provide the reader with background information on relevant concepts and terminology. Contributions within this journal issue draw upon studies of metatherian and eutherian mammals, as well as sauropsid reptiles (notably squamates). Particular attention is given to historical transformations of fetal membranes associated with the evolution of such phenomena as placentation and matrotrophy, and reproductive strategies such as viviparity. What emerges from the contributed papers is a broad sampling of contemporary research on fetal membranes, and an overview of how these membranes have evolved to support embryonic life in diverse terrestrial and intra-uterine environments.

Q: PHP files can't be executed after enabling HTTPS on Nginx/php-fpm I am enabling HTTPS on Nginx/php-fpm server, the server still running well but i can't access php file, it'll be downloaded instead of running it, and if i disabling HTTPS block then the php files can be accessible. I'm new to HTTPS and this is the first time i have an SSL certificate so i want to setup to my server. any idea ? My /etc/nginx/nginx.conf: user www-data; worker_processes 1; pid /run/nginx.pid; worker_rlimit_nofile 10240; events { use epoll; worker_connections 10240; # multi_accept on; } timer_resolution 500ms; http { ## # Basic Settings ## sendfile on; tcp_nopush on; tcp_nodelay on; keepalive_timeout 65; types_hash_max_size 2048; server_tokens off; client_header_buffer_size 64; client_max_body_size 6m; server_names_hash_bucket_size 64; server_name_in_redirect off; include /etc/nginx/mime.types; default_type application/octet-stream; log_format main '$remote_addr - $remote_user [$time_local] "$request" ' '$status $body_bytes_sent "$http_referer" ' '"$http_user_agent" "$http_x_forwarded_for"'; ## # Logging Settings ## access_log /var/log/nginx/access.log; error_log /var/log/nginx/error.log; output_buffers 1 32k; postpone_output 1460; open_file_cache max=1000 inactive=20s; open_file_cache_valid 30s; open_file_cache_min_uses 2; open_file_cache_errors on; fastcgi_connect_timeout 300; fastcgi_send_timeout 300; fastcgi_read_timeout 300; fastcgi_buffer_size 32k; fastcgi_buffers 4 32k; fastcgi_busy_buffers_size 32k; fastcgi_temp_file_write_size 32k; ## # Gzip Settings ## gzip on; gzip_disable "MSIE [1-6]\.(?!.*SV1)"; gzip_proxied expired no-cache no-store private auth; gzip_min_length 0; gzip_comp_level 2; gzip_buffers 4 16k; gzip_http_version 1.1; gzip_types text/plain text/css application/json application/x-javascript text/xml application/xml application/xml+rss text/javascript; proxy_cache_path /var/lib/nginx/cache levels=1:2 keys_zone=staticfilecache:80m inactive=1d max_size=2500m; proxy_temp_path /var/lib/nginx/proxy; proxy_connect_timeout 300; proxy_read_timeout 120; proxy_send_timeout 120; proxy_buffer_size 16k; proxy_buffers 4 16k; ## # Virtual Host Configs ## include /etc/nginx/conf.d/*.conf; include /etc/nginx/sites-enabled/*; } This is my /etc/nginx/sites-available/default: server { listen 80 default_server; # listen [::]:80 default_server ipv6only=on; root /usr/share/nginx/html; index index.php index.html index.htm; # Make site accessible from http://localhost/ server_name repodev.com; return 301 https://$host$request_uri; #rewrite http to https location / { try_files $uri $uri/ =404; } error_page 404 /404.html; # redirect server error pages to the static page /50x.html error_page 500 502 503 504 /50x.html; location = /50x.html { root /usr/share/nginx/html; } # pass the PHP scripts to FastCGI server listening on 127.0.0.1:9000 location ~ \.php$ { try_files $uri =404; # fastcgi_split_path_info ^(.+\.php)(/.+)$; # # NOTE: You should have "cgi.fix_pathinfo = 0;" in php.ini # # # With php5-cgi alone: # fastcgi_pass 127.0.0.1:9000; # # With php5-fpm: fastcgi_pass unix:/var/run/php5-fpm.sock; fastcgi_index index.php; fastcgi_param SCRIPT_FILENAME $document_root$fastcgi_script_name; include fastcgi_params; } location ~ /\.ht { deny all; } } cgi.fix_pathinfo = 0 has been set on /etc/php5/fpm/php.ini, and this is my SSL configuration file, /etc/nginx/conf.d/ssl.conf: server { listen 443 default_server ssl; server_name repodev.com; ssl_certificate /etc/ssl/unified.crt; ssl_certificate_key /etc/ssl/my-private-decrypted.key; ssl_session_cache shared:SSL:10m; ssl_session_timeout 10m; keepalive_timeout 70; ssl_prefer_server_ciphers on; ssl_ciphers "EECDH+ECDSA+AESGCM EECDH+aRSA+AESGCM EECDH+ECDSA+SHA384 EECDH+ECDSA+SHA256 EECDH+aRSA+SHA384 EECDH+aRSA+SHA256 EECDH+aRSA+RC4 EECDH EDH+aRSA RC4 !aNU$ ssl_protocols TLSv1 TLSv1.1 TLSv1.2; location / { root /usr/share/nginx/html; index index.php index.html index.htm; } } A: Please understand, that the SSL server is a completely separate object from the non-SSL one. This means, that you have to add the location ~ \.php$ { ... } block to the SSL version, if you want it to use PHP, it is not inherited from the non-SSL server. EDIT THis is ofcourse also true for your error_page and everything else.

--- author: - | [ $\mbox{\bf Seiichiro Tani}^{\ast\dagger}$ ]{}\ [tani@theory.brl.ntt.co.jp]{} - | [ $\mbox{\bf Hirotada Kobayashi}^{\ddagger}$ ]{}\ [hirotada@nii.ac.jp]{} - | [ $\mbox{\bf Keiji Matsumoto}^{\ddagger \dagger}$ ]{}\ [keiji@nii.ac.jp]{} title: | Exact Quantum Algorithms\ for the Leader Election Problem[^1] --- ${}^{\ast}$NTT Communication Science Laboratories, NTT Corporation\ ${}^{\dagger}$Quantum Computation and Information Project, ERATO-SORST, JST\ ${}^{\ddagger}$Principles of Informatics Research Division, National Institute of Informatics [10]{} Yehuda Afek and Yossi Matias. Elections in anonymous networks. , 113(2):312–330, 1994. Masami Amano and Kazuo Iwama. Undecidability on quantum finite automata. In [*Proceedings of the Thirty-First Annual ACM Symposium on Theory of Computing*]{}, pages 368–375, 1999. Andris Ambainis. A new protocol and lower bounds for quantum coin flipping. , 68(2):398–416, 2004. Andris Ambainis. 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Q: What's wrong with the syntax of this batch script? I'm trying to autoload Putty Pageant with some SSH-keys with a batch script, but because I want to bypass the error message of Pageant that it is already running, I placed it in an IF-statement. For some reason however, it doesn't work: tasklist /FI "IMAGENAME eq pageant.exe" 2>NUL | find /I /N "pageant.exe">NUL if %ERRORLEVEL%==1 ( :: checks whether pageant.exe is running or not :: set the SSH-keys if exist "C:\SSH keys\key1.ppk" (set KEYS="C:\SSH keys\key1.ppk") if exist "C:\SSH keys\key2.ppk" (set KEYS=%KEYS% "C:\SSH keys\key2.ppk") if not defined KEYS ( msg * A SSH-key is propably missing. ) :: Start pageant with the defined SSH-keys start /d"C:\Program Files (x86)\PuTTY" pageant.exe %KEYS% ) While they do work separately: (1) tasklist /FI "IMAGENAME eq pageant.exe" 2>NUL | find /I /N "pageant.exe">NUL if %ERRORLEVEL%==1 ( :: checks whether pageant.exe is running or not :: This works! start /d"C:\Program Files (x86)\PuTTY" pageant.exe ) (2) :: set the SSH-keys if exist "C:\SSH keys\key1.ppk" (set KEYS="C:\SSH keys\key1.ppk") if exist "C:\SSH keys\key2.ppk" (set KEYS=%KEYS% "C:\SSH keys\key2.ppk") if not defined KEYS ( msg * A SSH-key is propably missing. ) This works as well! start /d"C:\Program Files (x86)\PuTTY" pageant.exe %KEYS% Is it a syntax problem? A: Without an error message I can only guess. Do you have delayed expansion enabled? See setlocal /?. Add this to the beggining of your script setlocal EnableExtensions EnableDelayedExpansion and endlocal to the end of your script. This allows the KEYS variable to evaluate the the actual value. Delayed expansion allows the value to be set immediately to the variable not just when the scope of the if statement has ended. Also don't forget to use ! instead of % for the variables set inside the if statement. Example: (Run this in a .bat once with the EnableDepayedExpansion and once without and you will see the difference.) setlocal EnableExtensions EnableDelayedExpansion set "Value=Hello World" echo %Value% if 1==1 ( set "Value=Goodbye World" echo %Value% echo !Value! ) echo %Value% endlocal

Tathavade Tathawade (Marathi: तथावडे) is a census town in Pune district in the Indian state of Maharashtra. Tathawade is an emerging suburb of Pune. Many educational institutes like JSPM Institutes, Indira College, Balaji Institutes, Orchids International School, Blossom Public School are located here. Being at a close proximity to Hinjawadi IT Park & Expressway, the real estate has flourished here. Notable business coming up here are: Panchshil Business Park World Trade Center Decathlon Dmart near Indira College Demographics India census, Tathavade had a population of 7975. Males constitute 54% of the population and females 46%. Tathavade has an average literacy rate of 54%, lower than the national average of 59.5%: male literacy is 63%, and female literacy is 44%. In Tathavade, 17% of the population is under 6 years of age. References Category:Cities and towns in Pune district

Phase II trial of acivicin versus etoposide-cisplatin in non-small cell lung cancer. An Eastern Cooperative Oncology Group study. Identification of effective new chemotherapeutic agents is a major objective of clinical research efforts in patients who have metastatic non-small cell lung cancer (NSCLC). Canadian investigators observed responses in NSCLC when acivicin was given as a daily IV bolus for 5 consecutive days. Based on these results the Eastern Cooperative Oncology Group tested acivicin as a continuous infusion in patients with advanced NSCLC. A total of 82 patients were entered on a Phase II trial in which patients have randomized either to acivicin 60 mg/m2 given as a continuous intravenous infusion over 72 hours repeated every 28 days or to the reference regimen which consisted of cisplatin 60 mg/m2 intravenously on day 1 and etoposide 120 mg/m2 daily on days 1, 2, and 3 repeated every 28 days. Five partial remissions (11%) were observed in 42 patients treated with etoposide-cisplatin, and no responses were observed in 40 patients treated with acivicin. Median survival durations for etoposide cisplatin and for acivicin were 29.7 and 21.1 weeks, respectively. Based on these results, acivicin appears to be inactive in NSCLC.

73/((-308936)/414))? -23/3 Calculate (-36)/48*-2*8816/(-228). -58 What is 3/9*49/294*-2? -1/9 -18*161/(-966)*(-56)/3 -56 Evaluate ((-938)/(-77))/((-476)/2618). -67 Calculate (-297)/15*13130/(-2626). 99 (237391/17739582)/((-22)/(-8)) 2/411 What is the value of ((406/21)/((-580)/87))/(4/(140/(-21)))? 29/6 Calculate ((38/(-4))/(-2*3/(-72)))/(37870/(-18935)). 57 What is the value of (-1)/(((-375)/(-390))/(-25)*-2)? -13 Evaluate 6/20*270/648*(-32)/12. -1/3 ((-5)/(-90))/((-36)/((-360)/(-5))) -1/9 What is (-1944)/135*20/32*-4? 36 What is the value of ((-176)/(-33)*(-21)/((-672)/8))/((-10)/(-48))? 32/5 (-60)/9*548/(-28496) 5/39 418/3*2148/3938 76 Calculate (((-12712)/(-336))/(-227))/(-4*(-4)/48*4). -1/8 What is (9/90)/(7/5)*34/119? 1/49 Calculate 15*(-28)/(-24)*(-888)/777. -20 Calculate ((-720)/15)/12*(-4)/(264/11). 2/3 What is the value of ((-88)/(-8228))/(126/(-693))? -1/17 What is the value of ((7/(-21))/(-1))/((-30)/((-154980)/(-41)))? -42 (3*-12)/((-8874)/((-11016)/(-108))) 12/29 Calculate -2*((-44)/(-264))/((28/(-7))/(-56)). -14/3 What is the value of (132*22/(-330))/(8/20)? -22 Evaluate (-88)/(-78)*11921/3668. 11/3 Evaluate (30/(-11))/(2/((-22)/5)*(-2529)/(-12645)). 30 Evaluate (-1)/2*((-102)/75)/17. 1/25 Evaluate (2752/8256)/(((-86)/(-10))/(24/(-10))). -4/43 Calculate ((-2744)/2401*(-21)/66)/((-18)/33). -2/3 What is ((-290)/(-783)*-90)/(((-25)/(-12))/(-5))? 80 (24/1088*-34)/((-3)/36) 9 What is the value of 345/(5*(-39)/(-13))? 23 Calculate (6844/(-2006))/((-6)/(-51)). -29 Calculate (253/(23023/(-1092)))/((-8)/(-2)). -3 What is the value of ((-20)/140)/(783/189)? -1/29 (-1)/(5/(30/(-6)))*81/(-3) -27 What is (18/45)/((-171)/(-684)*4/7)? 14/5 Calculate (-6)/16*((-20)/15)/((-129)/(-43))*114. 19 Evaluate ((-1557)/692*24/(-27))/((-2)/(-33)). 33 What is the value of 8*(-21)/(-2184)*(-2)/(-2)? 1/13 Calculate 326556/(-1995620)*((-1)/1)/((-9)/390). -78/11 Calculate 21/((-210)/(-100))*(-56)/56*(-5)/35. 10/7 What is the value of ((2496/182)/12)/((-6)/105)? -20 What is the value of ((3944/17)/29)/(16/148)? 74 Evaluate (-105)/28*(-12672)/(-6600)*(-3)/((-99)/5). -12/11 Evaluate 6/(-15)*(-6)/(72/15)*7004/(-206). -17 Calculate (-2758)/(-985)*(-80)/(-7). 32 What is ((-8092)/85)/(-17)*(-12)/(-9)*4950/(-240)? -154 What is the value of 21/(7371/18)*(-783)/174? -3/13 What is (120/(-200))/((-10)/(2000/(-1380)))? -2/23 20*(-324)/(-2880)*4*3/450*5 3/10 Evaluate (384/(-320))/(114/(-20)*-1)*4/24. -2/57 Calculate ((-1)/(-2))/(1259/188850). 75 Evaluate 2472/(-13184)*(-2)/(-12)*4. -1/8 Evaluate (((-263)/(-17884))/((-7)/8))/((-2)/(-28)). -4/17 Calculate ((85/(-238))/(50/(-70)))/(2/(-44)). -11 44/((-11616)/24)*(-4)/4 1/11 What is ((3/1)/3)/((-29)/(-5278)*-7)? -26 Calculate (17/(867/(-6)))/((-27)/(-918)). -4 Calculate -67*252/(-5628)*(-14)/2331. -2/111 Evaluate (-3840)/(-288)*2/5*105/(-14). -40 What is the value of ((-34328)/30037)/(26/42)? -24/13 What is the value of 1112/834*7/((-1400)/45)? -3/10 (((-6)/(-22))/(-1))/((360/264)/(-15)) 3 What is the value of 84210/(-60150)*10/(-9)? 14/9 Evaluate (28/1*-1)/((208/(-8))/(-13)). -14 Calculate (2/(16/(-2)))/(84/(-2112)*(-332)/(-1743)). 33 What is 16/16*28/(-10)*5? -14 Evaluate ((-740)/(-15))/((-2)/6)*(7315/(-154))/95. 74 (1760/(-50))/(-11)*(-31)/62 -8/5 Evaluate ((-7)/(49/21))/(2/30*5). -9 ((-1)/(-1))/((588/42532)/(3/(-7))) -31 What is the value of ((33/(-286)*13)/6)/((-5)/(-8))*105? -42 ((-2)/(-16))/((-92)/(-552))*5/9*-2 -5/6 Calculate ((-5841)/(-1593))/(44*11/528). 4 What is (-196*10/(-560))/((-1)/(24/4))? -21 What is ((-6)/(-4))/(31383/(-355674))? -17 Evaluate ((-1505)/(-35))/(-731)*-3*17. 3 Calculate (636/21147)/((-4)/(-28)). 4/19 Evaluate (127743/(-924))/(-14*4/(-32)). -79 (-4*5/40)/(-26*38/(-148200)) -75 Evaluate ((-4520)/1695*150/56)/(18/(-189)). 75 What is 1*((-96)/(-16))/54*18/4*34? 17 Calculate (-4715)/23*(-10)/25*(-7)/14. -41 What is 11/10*-2*3*(-60)/756*-21? -11 What is (56/20)/(244/6710*5/(15/(-3)))? -77 What is the value of ((-70)/35)/(35/45)? -18/7 What is the value of ((-42)/2625*25/40)/(13/(-1872)*9)? 4/25 Calculate ((175/(-50))/(-1))/(-14). -1/4 Evaluate ((-79704)/(-615))/(-162)*5/56. -1/14 Calculate ((-24)/294)/(286/2002). -4/7 What is 255657/(-32988)*-4*3? 93 What is the value of ((-10)/(-50)*(-1485)/(-363))/(-15)? -3/55 (3605/7931)/((-30)/(-627)) 19/2 Evaluate 35*45/(-34650)*902. -41 Calculate 10/22*(-214434)/(-2565). 38 What is 54/(31/((-9052)/219))? -72 Evaluate (-11)/(132/180)*(-10)/(-6). -25 625/(-75)*((-1428)/(-70))/17 -10 What is the value of ((-186)/(-4557)*1)/(11/(-154))? -4/7 ((-1833)/(-1222))/(2/(160/(-3))) -40 Calculate ((49680/60180)/(-138))/(2/(-17)). 3/59 Calculate ((-10)/4)/((-990)/72*138/253). 1/3 What is the value of ((-196)/(-14))/(138/(-345))? -35 (78*636/3445)/((-6)/15) -36 What is the value of (((-92)/(-897))/(192/(-1248)))/((-43)/(-3))? -2/43 Calculate (115*112/141680)/((9/(-3))/3). -1/11 Calculate (90/570)/((-186)/(-5890)). 5 What is ((108/48)/3)/(104/32)? 3/13 Calculate ((40/45)/(204/(-12)))/(508/(-1143)). 2/17 (-5824)/(-126)*((-32)/16)/(-16) 52/9 Calculate -1*((-10)/1)/(-10)*3/((-3)/52). 52 What is the value of ((-4)/(32/(-3)))/(11403/364896)? 12 Calculate -165*53/10017*-63. 55 What is the value of (-64)/(16/(-4))*(-15)/(-30)*-1? -8 What is the value of ((-3000)/3600)/((-9)/3)? 5/18 (3/(-3))/(160/2816)*(-25)/30*-3 -44 (772/(-579))/((12/4)/(-54)) 24 Evaluate (-32)/(-6)*1050158/250784. 67/3 What is ((8/(-40))/((425/25)/(-85)))/((-1)/107)? -107 What is (29400/(-61250))/(8/170)? -51/5 What is 12/((-10)/(-3)*-1)*2890/1156? -9 Evaluate (-162)/(-63)*((-30)/40)/(27/(-336)). 24 What is the value of (-188)/(-1)*4424/(-17696)? -47 What is the value of (-64)/(-9)*(-3)/(-8)*12? 32 Evaluate ((-5)/(-87))/((-90445)/651204). -12/29 What is the value of (-15)/(-68)*(8/(-12))/((-1715)/2058)? 3/17 What is the value of (570/(-741))/((-1)/78*5)? 12 429/13*((-112)/126)/(10/15) -44 What is (-304)/(-608)*-3*2*(-1)/(-9)*-42? 14 ((-21)/9*(-5)/245)/((-85)/(-1275)) 5/7 What is 407/(-74)*63/(-77)? 9/2 Calculate (171630/(-11442))/(2/(-6)). 45 What is the value of 975/(-146510)*-46*126/30? 9/7 What is (7680/(-144))/16*1134/45? -84 ((-15)/(-10))/(((-108)/(-3024))/((-16)/12)) -56 Calculate (6/3)/(((-6149)/(-572))/(3/12*-2)). -4/43 ((-3)/45)/(28/2870)*(544/17)/16 -41/3 Calculate (1230/(-451))/(((-40)/(-110))/1). -15/2 What is 1050/126*(-336)/(-1400)? 2 What is (-4)/(3*42/(-5796))*1/(-2)? -92 What is ((-2)/(-7)*-20)/(15278/267365)? -100 Calculate (24*31/(-3224))/(27/(-6)). 2/39 Evaluate 24/(-46)*(-1)/(-2)*6195/(-12390). 3/23 ((-103)/(6798/77))/((-301)/(-3)) -1/86 What is the value of 10*(35/((-5775)/(-44)))/20? 2/15 What is the value of -180*(-259)/(-83916)*2/(-2)*-3? -5/3 Evaluate ((-2)/5)/(21/1435)*3996/888. -123 What is the value of (136/(-204))/((-56)/(-84))? -1 What is ((-198)/(-8))/(15/(-560)*-56)*4/(-6)? -11 ((-7)/3)/(85/((-29835)/234)) 7/2 Calculate 4*3/(-24)*1*7*(-150)/(-150). -7/2 77/(-22)*((-48)/(-15))/4*(-770)/1666 22/17 (3/(-9)*-3)/((1/3)/((-734)/(-58353))) 2/53 Calculate (7392/(-176))/(3/(4/4)). -14 What is the value of 1/(10/((-4)/(-2))*149424/13584)? 1/55 What is the value of (-54)/21*(-322)/552? 3/2 Calculate (-75)/2*(1010/5555)/(3/11). -25 Calculate 566/(-2547)*(-2871)/(-22). -29 (2/26)/(6/13)*-46 -23/3 Evaluate ((63/(-336))/((-18)/(-1)))/((-1094)/3282). 1/32 (-1808)/226*((-4)/(-2))/(-2)*39/(-2652) -2/17 What is (-47100)/2512*(-3)/45? 5/4 Calculate (-27)/(-57)*(-17974)/(-5676). 3/2 33/(-44)*(-368)/9*8/(96/(-18)) -46 What is the value of 35442/(-716)*(-16)/(-44)? -18 What is ((-18)/(-3))/(26/(-208))? -48 49*1269/(-1974)*4/(-6) 21 Calculate 27816/4941*((-81)/(-12))/9. 38/9 Calculate ((((-39)/(-3))/(-13))/(4/(-60)))/(6/10). 25 What is ((-14)/3)/((5588/(-330))/127)? 35 Calculate 280/(-49)*(-97944)/(-5830). -96 (-2)/136*(-7980)/3990 1/34 What is the value of 6*330/1232*14*(-6)/(-5)? 27 -2*6/276*1380/276 -5/23 What is (5/(-975))/((-291)/(-194)*1/(-9))? 2/65 1*(-14)/(-132)*(-52840)/(-92470) 2/33 What is the value of (54/(-8))/((-34)/((-10880)/48))? -45 What is the value of -1*(29/((-2552)/32)*7/(-7))/(-2)? 2/11 Evaluate ((-11322)/340)/37*12*(-20)/6. 36 Evaluate (3/(-9))/(60051/(-9738)). 2/37 Calculate (-2)/(259/222*1080/56)*10*-7. 56/9 (-24*66/8712)/(1/187) -34 What is the value of (-2)/131*-4*5/(-30)*276

1. Introduction {#sec1-viruses-12-00261} =============== The innate immune system is the first defense line that recognizes pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) against microbial pathogen invasion \[[@B1-viruses-12-00261]\]. Retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs), comprised of RIG-I, melanoma differentiation--associated gene (MDA) 5, and laboratory of genetics and physiology (LGP) 2, recognize non-self-signatures of viral RNAs in the cytosol of cells and activate their downstream signal transduction to trigger host interferon (IFN) responses and eliminate invading viruses by induction of a wide range of IFN-stimulated genes (ISGs) \[[@B2-viruses-12-00261]\]. However, hosts and viruses have developed a variety of mechanisms to modulate the RLRs signaling pathway to avoid excessive IFN production and antagonize such innate antiviral responses via targeting multiple steps in the RLRs signaling pathway, respectively. For instance, west Nile virus non-structural protein 1 protein antagonized IFN β production by targeting RIG-I and MDA5 \[[@B3-viruses-12-00261]\]. Ring finger protein (RNF) 122 targeted RIG-I for proteasomal degradation to inhibit RLRs-mediated IFN production \[[@B4-viruses-12-00261]\]. Nervous necrosis virus (NNV) is one of the major pathogens that infects fresh and marine fish and causes serious economic losses worldwide \[[@B5-viruses-12-00261]\]. Increasing evidences showed that the RLRs signaling pathway was involved in NNV infection. For example, zebrafish RIG-I plays an essential role in group II type I IFN induction during NNV infection \[[@B6-viruses-12-00261]\]. Our previous studies also suggested that the RLRs signaling pathway is activated during red spotted grouper nervous necrosis virus (RGNNV) infection in sea perch (*Lateolabrax japonicus*) and its key components possessed anti-RGNNV activities \[[@B7-viruses-12-00261],[@B8-viruses-12-00261]\]. It has been known that viruses can escape from host recognition by degradation of RLRs or interference with the RLRs signaling to establish persistent infections \[[@B9-viruses-12-00261]\]. Several studies have addressed NNV persistent infections in many fish including zebrafish, grouper, and barramundi \[[@B10-viruses-12-00261],[@B11-viruses-12-00261]\] despite the IFN response being induced in the persistent infection individuals, indicating NNV could evade or counteract the host IFN system. However, the molecular mechanisms through which NNV evade or inactivate the complex signaling pathway of host innate immunity are not completely understood. It has been known that some viruses utilize their encoded proteins to evade the restriction of RLRs signaling pathway and even hijack host factors to facilitate their infections in mammals \[[@B2-viruses-12-00261]\]. MicroRNAs (miRNAs), as post-transcriptional regulators, play critical roles in various biological processes, such as cell proliferation and differentiation, cell cycle and apoptosis, and immunoregulation \[[@B12-viruses-12-00261],[@B13-viruses-12-00261],[@B14-viruses-12-00261]\]. Increasing evidence has revealed that miRNAs are implicated in numerous viral infections as negative or positive factors of antiviral innate immunity pathways, including RLRs signaling pathway. MiRNA-146a inhibits RIG-I-dependent type I IFN production by targeting TNFR-associated factor (TRAF) 6, IL-1Rassociated kinase (IRAK) 1, and IRAK2 \[[@B15-viruses-12-00261]\]. MiRNA-3570 negatively regulates the RIG-I-dependent innate immune response to rhabdovirus in miiuy croaker (*Miichthys miiuy*) by targeting mitochondrial antiviral signaling protein (MAVS) \[[@B16-viruses-12-00261]\]. However, how RGNNV utilizes miRNAs for immune evasion remains unknown. In this study, we identified miR-202-5p as a new negative regulator of RLRs signaling pathway and defined a novel function for miR-202-5p to facilitate RGNNV infection. Our findings reveal a novel mechanism of RGNNV to inhibit RLRs signaling pathway by miR-202-5p and will help to develop new treatments for viral nervous necrosis disease. 2. Materials and Methods {#sec2-viruses-12-00261} ======================== 2.1. Ethics Statement {#sec2dot1-viruses-12-00261} --------------------- All procedures with zebrafish were approved by the Ethics Committee of Sun Yat-Sen University (protocol no. 20200110008, approval date: 11 October 2019) and the methods were carried out following the approved guidelines. 2.2. Fish Strains, Cell Lines, and Reagents {#sec2dot2-viruses-12-00261} ------------------------------------------- Zebrafish wild type AB line was purchased from the China zebrafish resource center. MiR-202-5p^-/-^ zebrafish were generated in our laboratory previously \[[@B17-viruses-12-00261]\]. Fish were raised at 28 °C with 10 h darkness and 14 h light and were fed with commercial pellets twice a day. All embryos were collected after natural spawning and staged as previously reported \[[@B18-viruses-12-00261]\]. ZBE3 cells derived from zebrafish embryos were cultured at 28 °C as previously described \[[@B19-viruses-12-00261]\]. HEK 293T cells were maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with heat inactivated 10% FBS (Invitrogen, California, USA), pyruvate glucose, and L-glutamine (Gibco, California, USA), at 37 °C under a humidified atmosphere of air containing 5% CO~2~. The anti-Flag (M20008) and anti-HA antibodies (M20013) were purchased from Abmart (Guangzhou, China). Anti-α-Tubulin (ab15246) and anti-GFP antibodies (G1544) were purchased from Abcam (London, Britain) and Sigma (Missouri, USA), respectively. The secondary antibodies goat anti-rabbit IgG-HRP and goat anti-mouse IgG-HRP were purchased from Invitrogen. miRNA mimics for miR-202-5p, hsa-miR-202-5p, and negative controls of miRNA mimics (Ctrl-m) were purchased from Ribobio (Guangzhou, China). 2.3. Viral Challenge {#sec2dot3-viruses-12-00261} -------------------- For in vitro infection, ZBE3 cells were infected with RGNNV at a multiplicity of infection (MOI) of 1 for 12 h and 24 h, respectively. Then, the infected cells were collected for RNA isolation. To detect the expression of miR-202-5p in vivo, 1 nL of RGNNV (10^8^ TCID~50~/mL) was injected into 1-cell stage embryos of wild type (WT) zebrafish with a microinjection machine (ZGBPCO1500). An equal number (40 embryos) of control or infected embryos were collected for RNA isolation at 24 and 48 h post fertilization (hpf). Fish were divided into experimental and control groups (30 per group). Adult wild type and miR-202-5p^-/-^ zebrafish were infected intraperitoneally with 50 μL of RGNNV (10^6^ TCID~50~/mL) or PBS, respectively. Randomly, three fish from challenged wild type and miR-202-5p^-/-^ groups were collected at 24 and 48 h post injection, respectively. Subsequently, RNA from these fish was extracted to detect the expression of antiviral genes and *RNA-dependent RNA polymerase* (*RDRP*) by quantitative real-time PCR (qRT-PCR). 2.4. Prediction of MiR-202-5p Target Genes {#sec2dot4-viruses-12-00261} ------------------------------------------ Target genes of miR-202-5p (5′-UUCCUAUGCAUAUACCUCUUUG-3′) and Hsa-miR-202-5p (5′-UUCCUAUGCAUAUACUUCUUUG-3′) were analyzed for sites complementary to the miR-202-5p seed sequence (UUCCUAUG) by using both PITA (<http://genie.weizmann.ac.il/pubs/mir07/mir07_data.html>) and miRanda (<http://www.microrna.org/microrna/home>). Genes predicted by both PITA and miRanda were considered as potential target genes of miR-202-5p. 2.5. Plasmid Construction {#sec2dot5-viruses-12-00261} ------------------------- The cDNA fragment of zebrafish tripartite motif-containing protein 25 (zbTRIM25) (GenBank accession no. NM200175.1) including the sequences of ORF and partial 3′UTR, was cloned into pCMV-Flag vector (Invitrogen). The ORF of zbTRIM25 was sub-cloned into pCMV-Flag vector (Invitrogen) to generate recombinant plasmid pCMV-Flag-zbTRIM25. Full-length zbRIG-I and zbRIG-I deletion mutant zbRIG-I-2CARD and zbRIG-I-RD were constructed in our laboratory \[[@B20-viruses-12-00261]\]. HA-K63Ub plasmid was purchased from Rebio (Shanghai, China). To construct 3′-UTR luciferase reporter plasmid of zbTRIM25, zbTRIM25 3′-UTR fragment (300 bp) containing the putative miR-202-5p binding site was amplified and cloned into psiCHECK2 vector (Promega, Wisconsin, USA). To construct the mutant 3′-UTR luciferase reporter plasmid of zbTRIM25, we used an over-lap PCR approach to introduce five base pair mutants in the seed region of miR-202-5p binding site. The wild or mutant 3′-UTR luciferase reporter plasmids of human tripartite motif-containing protein 25 (TRIM25) were constructed as described above. The primer sequences were listed in [Table S1](#app1-viruses-12-00261){ref-type="app"}. All plasmids were sequenced to verify integrity. The zebrafish IFN1 promoter plasmid (*pGL3-DrIFN 1-pro-Luc*) was kindly provided by Prof. Yibing Zhang at the Institute of Hydrobiology, Chinese Academy of Sciences. 2.6. RNA Isolation and qRT-PCR {#sec2dot6-viruses-12-00261} ------------------------------ ZBE3 cells in 6-well plates were transfected with miR-202-5p mimics or Ctrl-m (700 ng) by Lipofectamine 3000 (Invitrogen) for 24 h, then infected with RGNNV at a MOI of 1 for 24 h. The cells were collected for RNA isolation. Total RNA was isolated using Trizol reagent (Invitrogen) according to the manufacturer's instructions. The first-strand cDNA was synthesized using PrimeScript™ 1st Strand cDNA Synthesis Kit (Takara, Dalian, China) and was diluted 6 folds before qRT-PCR analysis. The efficiencies for all primers were greater than 95%. QRT-PCR analyses of *zbTRIM25*, *zbRIG-I*, *RDRP*, RLRs signaling pathway related genes (*MAVS*, *TRAF3*, *IRF3*, and *IFN 1*) and ISGs (\[*Myxovirus resistant a*\] *MXa*, \[*dsRNA-dependent protein kinase*\] *PKR*, and *ISG15*) were performed as previously described \[[@B21-viruses-12-00261]\]. The relative gene expression was normalized with *18s rRNA* using 2^-ΔΔCt^ methods. Expression analysis of miR-202-5p was performed using Mir-XTM miRNA First Strand Synthesis Kit (Takara) as previously described \[[@B22-viruses-12-00261]\]. Data were shown as mean ± SD from three independent experiments in triplicate. The primer sequences were listed in [Table S1](#app1-viruses-12-00261){ref-type="app"}. 2.7. Dual Luciferase Reporter Assay {#sec2dot7-viruses-12-00261} ----------------------------------- For the miR-202-5p target efficiency assay, HEK 293T cells in 24-well plates were transiently co-transfected with plasmids (wild-type or mutant psiCHECK2-3′UTR-zbTRIM25) (10 ng) and miR-202-5p mimics or Ctrl-m (175 ng) using Lipofectamine 3000 according to the manufacturer's instructions. Cells were lysed at 48 h post transfection, and the luciferase activities were measured by a dual-luciferase reporter assay system (Promega). The relative luciferase activities were determined by normalizing firefly activity to renilla activity. Data were shown as mean ± SD from three independent experiments in triplicate. To detect the effect of hsa-miR-202-5p (a homologous miRNA to miR-202-5p) on human TRIM25 promoter, HEK 293T cells were co-transfected with hsa-miR-202-5p mimic or Ctrl-m (175 ng) in combination with wild-type or mutant *psiCHECK2-3′UTR-hsTRIM25* (10 ng) for 48 h. The relative luciferase activities were measured as described above. To test zebrafish IFN 1 promoter activity, HEK 293T cells seeded in 24-well plate were transfected with *pCMV-Flag* or *pCMV-Flag-zbTRIM25* plasmids (100 ng) together with miR-202-5p mimics or Ctrl-m (175 ng) as well as *pGL3-DrIFN 1-pro-Luc* (100 ng) and *pRL-TK* (25 ng) vectors for 24 h. After treatment with poly I:C (5 mg/mL) for 24 h, the relative luciferase activities were measured as described above. HEK 293T cells in 24-well plates were transfected with 250 ng of *pGL3-DrIFN1-pro-Luc* plasmid or pGL3-Basic empty vector with 25 ng of *pRL-TK* vector (Promega). In addition, the following plasmids were co-transfected: 125 ng of *pCMV-Flag-zbTRIM25*, 125 ng of mutant zbRIG-I or empty control plasmids, 175 ng of miR-202-5p mimics or Ctrl-m. Then, the cells were treated with poly I:C (5 mg/mL) and lysed for luciferase assay as described above. At least three independent experiments were performed. 2.8. Co-Immunoprecipitations (Co-IP) and Ubiquitination Assays {#sec2dot8-viruses-12-00261} -------------------------------------------------------------- Co-IP and ubiquitination assays were performed as described previously \[[@B20-viruses-12-00261],[@B23-viruses-12-00261]\]. HEK 293T cells in 10-cm plates were co-transfected with 10 μg of different plasmid combinations (4 μg of Flag-zbTRIM25, 4 μg of pEGFP-RIG-I, and 2 μg of HA-K63Ub) and 3.5 μg of miR-202-5p mimics or Ctrl-m. Then, the cells were lysed on ice with lysis buffer for 15 min at 48 h after transfection. The cell lysates were then immunoprecipitated with anti-GFP antibodies. Immunoprecipitates or whole-cell lysates were immunoblotted with anti-HA, anti-GFP, anti-Flag, and anti-Tubulin antibodies, respectively. 2.9. Statistics Analysis {#sec2dot9-viruses-12-00261} ------------------------ All statistics were calculated using SPSS version 20. Differences between control and treatment groups were assessed by one-way ANOVA. *p* \< 0.05 was considered a statistically significantly difference. 3. Results {#sec3-viruses-12-00261} ========== 3.1. MiR-202-5p Expression is Up-Regulated Post RGNNV Infection In Vivo and In Vitro {#sec3dot1-viruses-12-00261} ------------------------------------------------------------------------------------ Our previous study demonstrated that ZBE3 cells were susceptible to RGNNV infection \[[@B19-viruses-12-00261]\]. To investigate the roles of host miRNAs during RGNNV infection, a miRNA profile was obtained from the mock and RGNNV infected ZBE3 cells to analyze the relationship between miRNAs and RGNNV infection. MiR-202-5p, which is on the list of the top 10 most up-regulated miRNAs post RGNNV infection (its fold change was 5.32), was selected for further study. To further confirm the up-regulation of miR-202-5p during RGNNV infection, qRT-PCR analysis was performed in RGNNV-infected ZBE3 cells. Results showed that miR-202-5p was significantly increased upon RGNNV infection in a time dependent manner in vitro ([Figure 1](#viruses-12-00261-f001){ref-type="fig"}A). Meanwhile, we also investigated the expression of miR-202-5p in RGNNV infected zebrafish embryos at 24 h, and the results were concordant with ZBE3 cells ([Figure 1](#viruses-12-00261-f001){ref-type="fig"}B). 3.2. MiR-202-5p Suppresses the Expression of Antiviral Genes and Promotes RGNNV Replication {#sec3dot2-viruses-12-00261} ------------------------------------------------------------------------------------------- To clarify the role of miR-202-5p during RGNNV infection, we examined the effects of miR-202-5p on the immune response to RGNNV in ZBE3 cells. As shown in [Figure 2](#viruses-12-00261-f002){ref-type="fig"}A, RGNNV inhibited the expression of *IFN 1*, *PKR*, *MXa*, and *ISG15* in ZBE3 cells. The transfection of miR-202-5p mimics increased miR-202-5p expression about 4.6-fold (B), whereas miR-202-5p inhibitor significantly decreased its expression level (C). Furthermore, the expression levels of *IFN 1*, *PKR*, *MXa*, and *ISG15* were significantly downregulated and upregulated by miR-202-5p mimics or miR-202-5p inhibitor in ZBE3 cells compared to the control group post RGNNV infection, respectively ([Figure 2](#viruses-12-00261-f002){ref-type="fig"}D,E). Meanwhile, miR-202-5p mimics promoted RGNNV replication, whereas miR-202-5p inhibitors suppressed RGNNV replication ([Figure 2](#viruses-12-00261-f002){ref-type="fig"}F). To further determine the role of miR-202-5p in vivo, we performed RGNNV challenge experiments in miR-202-5p^-/-^ and wild type zebrafish, respectively. As shown in [Figure 3](#viruses-12-00261-f003){ref-type="fig"}A,B, the mRNA levels of *IFN 1* and its downstream antiviral genes (*PKR*, *ISG15*, and *MXa*) were mildly upregulated in miR-202-5p knockout zebrafish (KO) compared to that in wild type zebrafish (WT) without RGNNV infection. Upon RGNNV infection, the expression levels of these genes increased markedly in both wild type and miR-202-5p^-/^ zebrafish, and their expression levels were significantly higher in miR-202-5p^-/-^ zebrafish than that in wild type zebrafish at 24 and 48 hpi, respectively. Correspondingly, the viral replication levels were significantly lower in miR-202-5p^-/-^ zebrafish than that in wild type zebrafish ([Figure 3](#viruses-12-00261-f003){ref-type="fig"}C), suggesting miR-202-5p deletion suppressed RGNNV replication. Taken together, all the evidence strongly demonstrates that miR-202-5p suppresses the expression of antiviral genes and promotes RGNNV replication. 3.3. MiR-202-5p Targets zbTRIM25 {#sec3dot3-viruses-12-00261} -------------------------------- To ascertain the mechanism through which miR-202-5p exerts the promotion role of RGNNV infection, the functional target genes of miR-202-5p were predicted with miRanda and Targetscan databases. Interestingly, zbTRIM25, which has been reported as a positive regulatory factor of RLRs signaling pathway \[[@B20-viruses-12-00261]\], was predicted as a potential target of miR-202-5p ([Figure 4](#viruses-12-00261-f004){ref-type="fig"}A). Then, luciferase reporter assay was performed to confirm the possibility that zbTRIM25 was regulated post-transcriptionally by miR-202-5p. The relative activity of luciferase significantly decreased in zbTRIM25-3′UTR-WT and miR-202-5p mimics co-transfection group compared with that in the zbTRIM25-3′UTR-WT and Ctrl-m co-transfection group. However, no difference was found between the relative luciferase activities of zbTRIM25-3′UTR-mut and miR-202-5p mimics con-transfection group and zbTRIM25-3′UTR-WT and Ctrl-m co-transfection group ([Figure 4](#viruses-12-00261-f004){ref-type="fig"}B). To further validate zbTRIM25 as a target of miR-202-5p, its expression was examined in ZBE3 cells transfected with miR-202-5p mimics or Ctrl-m. As expected, the expression of zbTRIM25 was decreased significantly in miR-202-5p mimics transfected cells ([Figure 4](#viruses-12-00261-f004){ref-type="fig"}C). Moreover, in zbTRIM25 overexpressing HEK 293T cells, the zbTRIM25 protein level was also decreased by co-transfecting with miR-202-5p mimics ([Figure 4](#viruses-12-00261-f004){ref-type="fig"}D). Taken together, our results demonstrate that zbTRIM25 is an actual target of miR-202-5p. Interestingly, we found that the 3′UTR of human TRIM25 (HsTRIM25) contains two human miR-202-5p (hsa-miR-202-5p) binding sites ([Figure 5](#viruses-12-00261-f005){ref-type="fig"}A). Furthermore, endogenous *HsTRIM25* expression was significantly downregulated by hsa-miR-202-5p overexpression ([Figure 5](#viruses-12-00261-f005){ref-type="fig"}B), and the luciferase reporter assay demonstrated that hsa-miR-202-5p had a significant regulatory effect on the luciferase activity in hsa-miR-202-5p mimics and *HsTRIM25* co-transfected HEK 293T cells ([Figure 5](#viruses-12-00261-f005){ref-type="fig"}C). All these results demonstrated that hsa-miR-202-5p could target HsTRIM25. 3.4. MiR-202-5p Negatively Regulates zbTRIM25-Mediated RLRs Signaling Pathway {#sec3dot4-viruses-12-00261} ----------------------------------------------------------------------------- Given that miR-202-5p targets zbTRIM25 and negatively regulates its expression, we examined whether miR-202-5p could suppress zbTRIM25-mediated RLRs signaling pathway. As shown in [Figure 5](#viruses-12-00261-f005){ref-type="fig"}, the expression levels of *zbTRIM25* and its downstream genes, *RIG-I*, *MAVS*, *TRAF3*, *IRF3*, and *IFN 1* decreased to some different extent at 24 h post RGNNV infection in miR-202-5p mimics transfected ZBE3 cells ([Figure 6](#viruses-12-00261-f006){ref-type="fig"}A). In addition, reporter gene analyses showed that miR-202-5p mimics significantly inhibited zbTRIM25 mediated IFN activities ([Figure 6](#viruses-12-00261-f006){ref-type="fig"}B). These findings suggested that miR-202-5p suppressed zbTRIM25-mediated RLRs signaling pathway. 3.5. MiR-202-5p Suppresses zbTRIM25-Mediated zbRIG-I Activation {#sec3dot5-viruses-12-00261} --------------------------------------------------------------- We have confirmed that zbTRIM25 promoted K63 ubiquitination of zbRIG-I and enhanced zbRIG-I's IFN-inducing activities \[[@B20-viruses-12-00261]\]. Given zbTRIM25 was a miR-202-5p target gene, we hypothesized that miR-202-5p might suppress zbTRIM25 mediated zbRIG-I activities to negatively regulate RLRs signaling pathway. To test this hypothesis, we first examined the effect of miR-202-5p on zbTRIM25-mediated zbRIG-I ubiquitination. As expected, the level of ubiquitination of zbRIG-I was inhibited by miR-202-5p mimics transfection ([Figure 7](#viruses-12-00261-f007){ref-type="fig"}A). Subsequently, reporter gene analyses showed that zbTRIM25 mediated zbRIG-I-2CARD and zbRIG-I-RD's IFN-inducing activities were significantly reduced by miR-202-5p mimics ([Figure 7](#viruses-12-00261-f007){ref-type="fig"}B,C). Therefore, miR-202-5p inhibited RLRs signaling through targeting zbTRIM25. 4. Discussion {#sec4-viruses-12-00261} ============= The RLRs signaling pathway plays pivotal roles in virus recognition and initiation of the antiviral immune response. To survive in host cells, various viruses have developed different strategies for their evading and subverting of the immune responses. Previous reports have demonstrated that NNV can evade host innate immunity and causes persistent infection in many fish species, including zebrafish \[[@B11-viruses-12-00261]\]. However, to date, knowledge about the immune evasion strategies of NNV is very limited. Increasing evidence has shown that viruses have evolved a wide variety of mechanisms to evade the host immune systems through interfering with the RLR signaling \[[@B3-viruses-12-00261],[@B24-viruses-12-00261]\]. Several studies have exhibited the relationship between viral infection-induced miRNAs and RLRs signaling pathway, and demonstrated many miRNAs functioned as negative regulators of RLRs signaling pathway during viral infection. For example, miR-3570 inhibited the RIG-I-dependent innate immune response to rhabdovirus by targeting MAVS in miiuy croaker \[[@B16-viruses-12-00261]\]. MiR-22 negatively regulated type I IFN production by targeting MAVS \[[@B25-viruses-12-00261]\]. A previous study has shown that miRNAs were associated with RGNNV infection \[[@B26-viruses-12-00261]\], but the exact functions and regulation mechanisms of miRNAs during RGNNV infection are poorly understood. Herein, miR-202-5p expression was up-regulated in vivo and in vitro during RGNNV infection, suggesting its close association with RGNNV infection. Many studies have demonstrated that miR-202-5p is an evolutionarily conserved miRNA associating with gonad development in vertebrates \[[@B22-viruses-12-00261],[@B27-viruses-12-00261],[@B28-viruses-12-00261]\]. Recently, we reported that miR-202-5p regulated primordial germ cell migration by directly targeting Cdc42se1 \[[@B17-viruses-12-00261]\]. In this study, we investigated a novel role of miR-202-5p in the immune response to RGNNV infection. Firstly, we examined the effect of miR-202-5p on host antiviral signaling. Our results showed that miR-202-5p promoted IFN and ISGs inhibition caused by RGNNV infection in vitro. Furthermore, in vitro and in vivo experiments corroborated that downregulation of miR-202-5p could inhibit RGNNV replication. All these data confirmed miR-202-5p was a positive mediator of immunosuppression and had an enhanced effect on RGNNV replication in zebrafish. To the best of our knowledge, this is the first study to describe the role of miR-202-5p during virus infection. To gain an insight into the precise mechanisms by which miR-202-5p regulated immune response during RGNNV infection, its target genes were predicted by using the bioinformatics tool. zbTRIM25 was predicted as one of its target genes, and subsequently was confirmed by a series of experiments. Moreover, we further confirmed that hsa-miR-202-5p also targeted human TRIM25, demonstrating the universality of our findings. In this study, we found that miR-202-5p could suppress zbTRIM25-mediated RLRs signaling pathway, indicating that miR-202-5p might negatively regulate zbTRIM25 expression, thereby promoted RGNNV infection. Increasing evidence indicates a crucial role of post-translational modifications in modulating TRIM25/RIG-I signaling. TRIM25 has been shown to positively regulate innate antiviral response by inducing the K63-linked ubiquitination of RIG-I \[[@B29-viruses-12-00261]\]. Similar to other TRIM proteins, both gene expression and protein abundance of TRIM25 are tightly regulated and some factors that regulated its expression have been reported. For instance, the C-terminal zinc-fingers of ZCCHC3 interacted with the C-terminal SPRY domain of TRIM25 and was important for K63-linked polyubiquitination and activation of RIG-I and MDA5 mediated by TRIM25 \[[@B30-viruses-12-00261]\]. Ubiquitin-specific protease 15 interacted with and deubiquitylated TRIM25, thereby promoting RIG-I-mediated antiviral signaling during viral infection \[[@B31-viruses-12-00261]\]. C-Src induced TRIM25 tyrosine phosphorylation which facilitated TRIM25-mediated RIG-I ubiquitination \[[@B32-viruses-12-00261]\]. Influenza A virus nonstructural protein 1 (NS1) specifically inhibits TRIM25-mediated RIG-I-CARD ubiquitination through its interaction with the coiled-coil domain of TRIM25, thereby suppressing RIG-I signal transduction \[[@B33-viruses-12-00261]\]. Here, miR-202-5p was identified as a negative regulator of zbTRIM25, which will contribute to the understanding of the regulation mechanism underlying TRIM25-dependent innate immunity. MiRNAs are well known for their post-transcriptional regulation of gene expression, and accumulated information has revealed that several miRNAs are involved in immune regulation via targeting the key components of intracellular pathogen sensing pathways \[[@B34-viruses-12-00261]\]. In our current study, zbTRIM25 was proven to be a target gene of miR-202-5p and miR-202-5p inhibited zbTRIM25-mediated IFN 1 promoter activation and K63-linked ubiquitination of zbRIG-I. Thus, we speculated that miR-202-5p attenuated the K63-linked ubiquitination of zbRIG-I by targeting zbTRIM25, which subsequently might hinder zbRIG-I and MAVS interaction, and thereby inhibited the antiviral signaling ([Figure 8](#viruses-12-00261-f008){ref-type="fig"}). It has been reported that viral infections can modulate the expression of several miRNAs, which in turn regulate RLRs-mediated IFN activation. For example, Enterovirus 71 3C protein inhibited the expression of miR-526a, leading to the upregulation of cylindromatosis, which negatively regulates RLRs-mediated IFN production \[[@B35-viruses-12-00261]\]. Here, we reported that RGNNV infection induced the expression of miR-202-5p, however, the mechanism underlying miR-202-5p transcription activation by RGNNV remains unknown. Whether and how RGNNV proteins participate in miR-202-5p induction needs to be further studied. In summary, miR-202-5p was identified as a mediator of RLRs signaling pathway and promoted RGNNV infection by directly targeting zbTRIM25, with subsequent inhibition of zbTRIM25-mediated zbRIG-I ubiquitination and activation of IFN production ([Figure 8](#viruses-12-00261-f008){ref-type="fig"}). These findings represent a new mechanism underlying RGNNV evasion of the host innate immune system. We thank Yibing Zhang for the careful preparation of the manuscript. The following are available online at <https://www.mdpi.com/1999-4915/12/3/261/s1>, Table S1: Primers used in this study. ###### Click here for additional data file. Conceptualization, K.J. and M.Y.; investigation, W.L., P.J., W.Z., Y.X. and Y.J.; validation, W.Z. and Y.X.; writing---original draft preparation, K.J. and W.L.; writing---review and editing, K.J. and M.Y.; funding acquisition, K.J., W.L. and M.Y. All authors have read and agreed to the published version of the manuscript. This research was supported by the Pearl River S&T Nova Program of Guangzhou (201806010047), the National Natural Science Foundation of China (31771587 and 31970535), Fundamental Research Funds for the Central Universities (17lgpy61), and the Natural Science Foundation of Guangdong Province (2015A030308012). The authors declare no conflict of interest. {#viruses-12-00261-f001} {#viruses-12-00261-f002} {#viruses-12-00261-f003} {#viruses-12-00261-f004} {#viruses-12-00261-f005} {#viruses-12-00261-f006} {#viruses-12-00261-f007} {#viruses-12-00261-f008}

HP Officejet 4630 Troubleshooting 学生贡献的维基 Will Not Print If your device is refusing to print jobs in queue, use the following troubleshooting solutions. No Connection to Printer Make sure your device is either connected to your network or connected by USB. Drivers are out of Date It is always good practice to keep drivers updated. Download the most recent drivers here, select the appropriate operating system and version for your computer and download the driver installer. Run the executable and follow the onscreen instructions. Be sure to restart your computer after installing fresh drivers. Power Cord Connected Insecurely Make sure the power cord is securely plugged into both the outlet and the printer. If it is secure and the problem still persists, follow this guide to replace the power supply in your device. Display is Unresponsive If the display will not respond to input or appears frozen, check the following problems. Drivers are out of Date It is always good practice to keep drivers updated. Download the most recent drivers here, select the appropriate operating system and version for your computer and download the driver installer. Run the executable and follow the onscreen instructions. Be sure to restart your computer after installing fresh drivers. Device Requires Reset Press the power button to turn off the printer. Wait 60 seconds and power the device back on. Power Cord Connected Unsecurely Make sure the power cord is securely plugged into both the outlet and the printer. If it is secure and the problem still persists, follow this guide to replace the power supply in your device. Making Loud Noises If your printer sounds louder than normal or is making a clicking or crunching sound, check the following. Printer is Jammed See if any pieces of paper are stuck in the feed tray. If there is paper stuck in the tray, turn the printer off and remove the jam. Broken Internal Pieces If there are any broken or rattling parts, see this guide on replacing the paper tray and check for any loose pieces in the printer. Will Not Turn On If your printer will not power on, or is completely unresponsive check the following potential problems. Printer is Not Plugged In Plug the printer into a standard wall outlet, then press the power button on the front of the printer. Outlet is Bad The outlet that the printer is plugged into is not working. Plug the printer into a different outlet. If the printer is plugged into a power strip, try plugging directly into a grounded wall socket. Press the power button on the front of the printer once you have ensured an electrical connection. Power Cord is Bad Check the power cord for sharp bends and exposed wire. Replace the power cord if any signs of damage are present. Power Supply is Broken Replace the power supply on the printer. Follow this guide to see how to replace the power supply. Print Quality is Poor If print jobs are not coming out as expected, is blurry, or contains vertical stripes, check the following symptoms for potential problems. Printer is Out of Ink Replace the ink cartridges for your printer. To see this done, visit this guide. Ink cartridges are inncorrect Replace the ink cartridges with hp approved ink cartridges. To see how to replace the ink cartridges, visit this guide.

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Hakkeijima Station Hakkeijima Station (八景島駅) is a station on the Kanazawa Seaside Line, located in Kanazawa-ku, Yokohama, Japan. It opened on 5 July 1989. Station Layout This elevated station consists of a single island platform serving two tracks. Adjacent stations Surrounding area Yokohama Hakkeijima Sea Paradise Category:Railway stations in Kanagawa Prefecture Category:Kanazawa Seaside Line Category:Railway stations opened in 1989 Category:1989 establishments in Japan

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Psychological determinants of idolatry in adolescents. The self-esteem and fear of negative evaluation of 77 fan-club members age 16 or below and 128 age-equivalent secondary school students who had never joined a fan club were investigated. Consistent with common observations, fan-club respondents were mostly females. Significant differences were found between the two samples. Logistic regression analysis showed that being a fan-club member was associated with poor self-esteem and strong fear of negative evaluation, while the bias toward females in the fan-club sample could be attributed to the effects of these two variables.

Brand new: lowest price The lowest-priced brand-new, unused, unopened, undamaged item in its original packaging (where packaging is applicable).Packaging should be the same as what is found in a retail store, unless the item is handmade or was packaged by the manufacturer in non-retail packaging, such as an unprinted box or plastic bag.See details for additional description. About this product Description Description Kirsty and Rachel are in for a surprise when their fairy friends whisk them off to the Fairyland Music Festival, only for Jack Frost and his goblins to strut onto the stage! The naughty gang have stolen the Pop Star Fairies' magical clef necklaces, and Jack Frost intends to use them to become the biggest star in the world.In this third book of the magical series, the girls must help Vanessa the Dance Steps Fairy get her clef back, or dancers everywhere will be more graceful than an elephant on stage!

Q: Nativescript Actionbar drop-down list navigation I'm trying to implement a drop-down list navigation in the Actionbar with Nativescript but can't seem to find any info about it whatsoever. Similar to this and this. I currently have a simple ActionBar: <Page.actionBar> <Page.actionBar> <ActionBar> <ActionBar.actionItems> <ActionItem android.position="actionBar" icon="res://icon" ios.position="right" /> </ActionBar.actionItems> </ActionBar> </Page.actionBar> </Page.actionBar> Any tips? A: You can create the ActionBar in your first example image like this: <Page.actionBar> <ActionBar> <ActionBar.actionItems> <ActionItem android.position="popup" text="Add contact" /> <ActionItem android.position="popup" text="About" /> </ActionBar.actionItems> </ActionBar> </Page.actionBar> That will look right on Android. I have no idea how to make it work for iOS.

List of scientific publications by Vladimir Shlapentokh REDIRECT Vladimir Shlapentokh

--- abstract: 'In this paper, we investigate the coexistence of two technologies that have been put forward for the fifth generation (5G) of cellular networks, namely, network-assisted device-to-device (D2D) communications and massive MIMO (multiple-input multiple-output). Potential benefits of both technologies are known individually, but the tradeoffs resulting from their coexistence have not been adequately addressed. To this end, we assume that D2D users reuse the downlink resources of cellular networks in an underlay fashion. In addition, multiple antennas at the BS are used in order to obtain precoding gains and simultaneously support multiple cellular users using multiuser or massive MIMO technique. Two metrics are considered, namely the average sum rate (ASR) and energy efficiency (EE). We derive tractable and directly computable expressions and study the tradeoffs between the ASR and EE as functions of the number of BS antennas, the number of cellular users and the density of D2D users within a given coverage area. Our results show that both the ASR and EE behave differently in scenarios with low and high density of D2D users, and that coexistence of underlay D2D communications and massive MIMO is mainly beneficial in low densities of D2D users.' author: - 'Serveh Shalmashi, , Emil Björnson, , Marios Kountouris, , Ki Won Sung, , and Mérouane Debbah,  [^1] [^2] [^3] [^4]' bibliography: - 'IEEEabrv.bib' - 'refs.bib' - 'serveh.bib' title: 'Energy Efficiency and Sum Rate Tradeoffs for Massive MIMO Systems with Underlaid Device-to-Device Communications' --- D2D communications, massive MIMO, coexistence, energy efficiency, stochastic geometry. Introduction ============ The research on future mobile broadband networks, referred to as the fifth generation (5G), has started in the past few years. In particular, stringent key performance indicators (KPIs) and tight requirements have been introduced in order to handle higher mobile data volumes, reduce latency, increase the number of connected devices and at the same time increase the energy efficiency (EE) [@Osseiran-2014-COMM; @Bjornson-2014-b-SPM]. The current network and infrastructure cannot cope with 5G requirements—fundamental changes are needed to handle future non-homogeneous deployments as well as new trends in user behavior such as high quality video streaming and future applications like augmented reality. 5G technology is supposed to evolve existing networks and at the same time integrate new dedicated solutions to meet the KPIs [@Bjornson-2014-b-SPM]. The new key concepts for 5G include massive MIMO (multiple-input multiple-output), ultra dense networks (UDN), device-to-device (D2D) communications, and huge number of connected devices, known as machine-type communications (MTC). The potential gains and properties of these different solutions have been studied individually, but the practical gains when they coexist and share network resources are not very clear so far. In this paper, we study the coexistence of two of these main concepts, namely massive MIMO and D2D communication. Massive MIMO is a type of multiuser MIMO (MU-MIMO) technology where the base station (BS) uses an array with hundreds of active antennas to serve tens of users on the same time/frequency resources by coherent transmission processing [@Marzetta2010a; @Rusek-2013-SPM]. Massive MIMO techniques are particularly known to be very spectral efficient, in the sense of delivering high sum rates for a given amount of spectrum [@Bjornson2016a]. This comes at the price of deploying more transceiver hardware, but the solution is still likely to improve the energy efficiency of networks [@Ngo2013a; @Bjornson-2014-arxiv]. On the other hand, in a D2D communication, user devices can communicate directly with each other and the user plane data is not sent through the BS [@Doppler-2009-COMM]. D2D communications are considered for close proximity applications which have the potential to achieve high data rates with little amount of transmission energy, if interference is well-managed. In addition, D2D communications can be used to decrease the load of the core network. D2D users either have their own dedicated time/frequency resources (overlay approach) which in turn leads to elimination of the cross-tier interference between the two types of users (i.e., cellular and D2D users), or they transmit simultaneously with cellular users in the same resource (underlay approach). We consider two network performance metrics in this work: The average sum rate (ASR) in $\mathrm{bit/s}$ and the EE which is defined as the number of bits transmitted per Joule of energy consumed by the transmitted signals and the transceiver hardware. It is well-known that these metrics depend on the network infrastructure, radio interface, and underlying system assumptions [@Tombaz-2011-WCM; @Bjornson-2014-arxiv; @Auer-2013-WCM]. The motivation behind our work is to study how the additional degrees of freedom resulting from high number of antennas in the BS can affect the ASR and EE of a multi-tier network where a D2D tier is bypassing the BS, and how a system with massive MIMO is affected by adding a D2D tier. We focus on the downlink since majority of the payload data and network energy consumption are coupled to the downlink [@Tombaz-2011-WCM]. We assume that each D2D pair is transmitting simultaneously with the BS in an underlay fashion. In addition, we assume that the communication mode of each user (i.e., D2D or cellular mode) has already been decided by higher layers. Related Work ------------ The relation between the number of BS antennas, ASR and EE in cellular networks has been studied in [@Ngo2013a; @Yang-2013-OnlineGreenCom; @Bjornson-2014-arxiv; @Bjornson-2013-ICT] among others. The tradeoff between ASR and EE was described in [@Ngo2013a] for massive MIMO systems with negligible circuit power consumption. This work was continued in [@Yang-2013-OnlineGreenCom] where radiated power and circuit power were considered. In [@Bjornson-2014-arxiv], joint downlink and uplink design of a cellular network was studied in order to maximize EE for a given coverage area. The maximal EE was achieved by having a hundred BS antennas and serving tens of users in parallel, which matches well with the massive MIMO concept. Furthermore, the study [@Bjornson-2013-ICT] considered a downlink scenario in which a cellular network has been overlaid by small cells. It was shown that by increasing the number of BS antennas, the array gain allows for decreasing the radiated signal energy while maintaining the same ASR. However, the energy consumed by the transceiver chains increases. Maximizing the EE is thus a complicated problem where several counteracting factors need to be balanced. This stands in contrast to maximization of the ASR, which is relatively straightforward since the sum capacity is the fundamental upper bound. There are only a few works in the D2D communication literature where the base stations have multiple antennas [@Min-2011-TWC-b; @Yu-2012-GLOBECOM; @Fodor-2011-GLOBECOM; @Shalmashi-2014a-WCNC; @Xingqin-2014-arxiv]. In [@Min-2011-TWC-b], uplink MU-MIMO with one D2D pair was considered. Cellular user equipments (CUEs) were scheduled if they are not in the interference-limited zone of the D2D user. The study [@Yu-2012-GLOBECOM] compared different multi-antenna transmission schemes. In [@Fodor-2011-GLOBECOM], two power control schemes were proposed for a multi-cell MIMO network. Two works that are more related to our work are [@Shalmashi-2014a-WCNC] and [@Xingqin-2014-arxiv]. The former investigates the mode selection problem in the uplink of a network with potentially many antennas at the BS. The impact of the number of antennas on the quality-of-service and transmit power was studied when users need to decide their mode of operation (i.e., D2D or cellular). The latter study, [@Xingqin-2014-arxiv], only employs extra antennas in the network to protect the CUEs from interference of D2D users in the uplink. The ASR in D2D communications is mostly studied in the context of interference and radio resource management [@Shalmashi-2013-PIMRC; @Zulhasnine-2010-WiMob]. There are a few works that consider EE in D2D communications, but only for single antenna BSs, e.g., [@Yaacoub-2012-GCW; @Mumtaz-2014-ICC], and [@Wang-2013-ICC], where the first one proposed a coalition formation method, the second one designed a resource allocation scheme, and the third one aimed at prolonging the battery life of user devices. The spatial degrees of freedom offered by having multiple antennas at BSs are very useful in the design of future mobile networks, because the spatial precoding enables dense multiplexing of users while keeping the inter-user interference under control. In particular, the performance for cell edge users, which have almost equal signal-to-noise ratios (SNRs) to several BSs, can be greatly improved since only the desired signals are amplified by the transmit precoding [@Baldemair-2013-VTM; @Bjornson2013d; @Gesbert-2007-SPM]. In order to model the random number of users and random user positions, we use mathematical tools from stochastic geometry [@Haenggi-Stochastic] which are powerful in analytically quantifying certain metrics in closed-form. Contributions ------------- Our main contributions in this paper can be summarized as follows: - *A tractable model for underlaid D2D communication in massive MIMO systems*: We model a two-tier network with two different user types. The first tier users, i.e., CUEs, are served in the downlink by a BS using massive multiuser MIMO precoding to cancel interference. The second tier users, i.e., D2D users, exploit their close proximity and transmit simultaneously with the downlink cellular transmissions bypassing the BS. The number of D2D transmitters and their locations are modeled according to a homogeneous Poisson point process (PPP) while a fixed number of CUEs are randomly distributed in the network. - *Tractable and directly computable expressions*: We derive tightly approximated expressions for the coverage probability of D2D users and CUEs. These expressions are directly used to compute our main performance metrics, namely, the ASR and EE. We verify the tightness of these approximations by Monte-Carlo simulations. Furthermore, we provide analytical insights on the behavior of these metrics for both CUEs and D2D users. To the best of our knowledge, the energy efficiency analysis for underlay D2D communications in a network with large number of BS antennas has not been carried out before. - *Performance analysis*: Based on extensive simulations, we characterize the typical relation between the ASR and EE metrics in terms of the number of BS antennas, the number of CUEs, and the D2D user density for a given coverage area and study the incurred tradeoffs in two different scenarios. System Model {#sec:Sys_Mod} ============ ![System model where a multi-antenna BS communicates in the downlink with multiple CUEs, while multiple user pairs communicate in D2D mode. The CUEs are distributed uniformly in the coverage area and the D2D users are distributed according to a PPP. The D2D users that are outside the coverage area are only considered as interferers.[]{data-label="figure:sysMod_massiveMIMO_D2D"}](./figures/sysMod_massiveMIMO_D2D){width="0.6\columnwidth"} We consider a single-cell scenario where the BS is located in the center of the cell and its coverage area is a disc of radius $R$. The BS serves $U_c$ single-antenna CUEs which are uniformly distributed in the coverage area. These are simultaneously served in the downlink using an array of $T_c$ antennas located at the BS. It is assumed that $1 \leq U_c \leq T_c$ so that the precoding can be used to control the interference caused among the CUEs [@Bjornson-2014-a-SPM]. In addition to the CUEs, there are other single-antenna users that bypass the BS and communicate pairwise with each other using a D2D communication mode. The locations of the D2D transmitters (D2D Tx) are modeled by a homogeneous PPP $\Phi$ with density $\lambda_d$ in $\mathbb{R}^2$.[^5] This means that the average number of D2D Tx per unit area is $\lambda_d$ and these users are uniformly distributed in that area. The D2D receiver (D2D Rx) is randomly located in an isotropic direction with a fixed distance away from its corresponding D2D Tx—a model that is similar to the one considered in [@Lee-2014-JSAC]. The system setup is illustrated in Fig. \[figure:sysMod\_massiveMIMO\_D2D\]. Let $R_{k,j}$ denote the distance between the $j$-th D2D Tx to the $k$-th D2D Rx. The performance analysis for D2D users is carried out for a typical D2D user, which is denoted by the index $0$. The typical D2D user is an arbitrary D2D user located in the cell and its corresponding receiver is positioned in the origin. The results for a typical user show the statistical average performance of the network [@Haenggi-Stochastic]. Therefore, for any performance metric derivation, the D2D users inside the cell are considered and the ones outside the cell are only taken into account as sources of interference. Note that we neglect potential interference from other BSs and leave the multi-cell case for future work. This is because the interference from D2D transmissions is likely to be much stronger than the interference from other BSs. We assume equal power allocation for both CUEs and D2D users. Let $P_c$ denote the total transmit power of the BS, then the transmit power per CUE is $\frac{P_c}{U_c}$. The transmit power of the D2D Tx is denoted by $P_d$. Let ${\mathbf{h}}_j \in \mathbb{C}^{T_c \times 1}$ be the normalized channel response between the BS and the $j$-th CUE, for $j \in \{0, \dots, U_c-1 \}$. These channels are modeled as Rayleigh fading such that ${\mathbf{h}}_j \sim\mathcal{CN}(\mathbf{0},\mathbf{I})$, where $\mathcal{CN}(\cdot,\cdot)$ denotes a circularly symmetric complex Gaussian distribution. Perfect instantaneous channel state information (CSI) is assumed in this work for analytic tractability, but imperfect CSI is a relevant extension. Linear downlink precoding is considered at the BS based on the zero-forcing (ZF) scheme that cancels the interference between the CUEs [@Bjornson-2014-a-SPM]. The precoding matrix is denoted by $\mathbf{V}=[{\mathbf{v}}_0, \dots, {\mathbf{v}}_{Uc-1}]\in \mathbb{C}^{T_c \times U_c}$ in which each column ${\mathbf{v}}_j$ is the normalized transmit precoding vector assigned to the CUE $j$. Let ${\mathbf{f}}_{0,\textrm{BS}} \in \mathbb{C}^{T_c \times 1}$ be the channel response from the BS to D2D Rx and let it be Rayleigh fading as ${\mathbf{f}}_{0,\textrm{BS}} \sim \mathcal{CN}(\mathbf{0},\mathbf{I})$. Moreover, let $r_j \in \mathbb{C}$ and ${\mathbf{s}} \in \mathbb{C}^{U_c \times 1}$ denote the transmitted data signals intended for a D2D Rx and the CUEs, respectively. Since each user requests different data, the transmitted signals can be modeled as zero-mean and uncorrelated with $\mathbb{E}\big[|r_j|^2\big]=P_d$ and $\mathbb{E}\big[||{\mathbf{s}}||^2\big]=P_c$. The fading channel response between the $j$-th D2D Tx and the $k$-th D2D Rx is denoted by $g_{k,j} \in \mathbb{C}$ where $g_{k,j} \sim\mathcal{CN}(0,1)$. Moreover, $R_{0,\textrm{BS}}$ denotes the random distance between the typical D2D Rx and the BS. The pathloss is modeled as $A_i d^{-\alpha_i}$ with $i \in \{c,d\}$, where index $c$ indicates the pathloss between a user and the BS and index $d$ gives the pathloss between any two users. $A_i$ and $\alpha_i$ are the pathloss coefficient and exponent, respectively, where we assume $\alpha_i>2$. The received signal at the typical D2D Rx is $$\begin{aligned} y_{d,0} &= \sqrt{A_d } R_{0,0}^{-\alpha_d/2} g_{0,0} r_0 +\underbrace{ \sqrt{A_c } R_{0,\textrm{BS}}^{-\alpha_c/2} {\mathbf{f}}_{0,\textrm{BS}}^H \mathbf{V} {\mathbf{s}} }_{\textrm{Interference from the BS}} + \underbrace{\sqrt{A_d } \sum_{j\neq 0} R_{0,j}^{-\alpha_d/2} g_{0,j} r_j}_{\textrm{Interference from other D2D users}} + \eta_d,\end{aligned}$$ where $\eta_d$ is zero-mean additive white Gaussian noise with power $N_0 = \tilde{N}_0 B_w$, $\tilde{N}_0$ is the power spectral density of the white Gaussian noise, and $B_w$ is the channel bandwidth. For given channel realizations, the signal-to-interference-plus-noise ratio (SINR) at the typical D2D Rx is $$\begin{aligned} \label{eq:SINR_d2d} \mathrm{SINR}_d = \frac{P_d R_{0,0}^{-\alpha_d}|g_{0,0}|^2}{I_{\textrm{BS},0} + I_{d,0} + \frac{N_0}{A_d}},\end{aligned}$$ in which both the numerator and the denominator have been normalized by $A_d$. $I_{\textrm{BS},0}$ is the received interference power from the BS and $I_{d,0}$ is the received interference power from other D2D users that transmit simultaneously which are defined as $$\begin{aligned} I_{\textrm{BS},0} &\triangleq \frac{\zeta R_{0,\textrm{BS}}^{-\alpha_c}}{A_d}\|{\mathbf{f}}_{0,\textrm{BS}}^H \mathbf{V}\|^2, \label{eq:I_BS0} \\ I_{d,0} &\triangleq \sum_{j\neq 0} P_d R_{0,j}^{-\alpha_d} |g_{0,j}|^2, \label{eq:I_d0}\end{aligned}$$ where $$\zeta \triangleq A_c \frac{P_c}{U_c}. \label{eq:zeta-def}$$ Let $D_{0,k}$ and $e_{0,k}\in \mathbb{C}$ with $e_{0,k}\sim\mathcal{CN}(0,1)$ be the distance and fading channel response between a typical CUE and the $k$-th D2D Tx, respectively, and let $D_{0,\textrm{BS}}$ denote the distance between a typical CUE and the BS. Then, the received signal at the typical CUE is $$\begin{aligned} y_{c,0} &= \sqrt{A_c} D_{0,\textrm{BS}}^{-\alpha_c/2} {\mathbf{h}}_{0}^H \mathbf{V} {\mathbf{s}} + \underbrace{\sqrt{A_d } \sum_{j} D_{0,j}^{-\alpha_d/2} e_{0,j} r_j}_{\textrm{Interference from all D2D users}} + \eta_c,\end{aligned}$$ where $\eta_c$ is zero-mean additive white Gaussian noise with power $N_0$. Then, the corresponding SINR for the typical CUE is $$\begin{aligned} \mathrm{SINR}_c = \frac{|{\mathbf{h}}_{0}^H {\mathbf{v}}_{0}|^2}{\frac{A_d }{\zeta} D_{0,\textrm{BS}}^{\alpha_c}(I_{d,c} + \frac{N_0}{A_d })}, \label{eq:SINR_CUE}\end{aligned}$$ where $$\label{eq:inf_dc} I_{d,c} \triangleq \sum_{j} P_d D_{0,j}^{-\alpha_d} |e_{0,j}|^2$$ is the received interference power from all D2D users (normalized by $A_d$). Performance Analysis {#sec:performance_analysis} ==================== In this section, we first introduce the performance metrics that are considered in this paper. Then we proceed to derive the coverage probability for both CUEs and D2D users which are needed to compute these metrics. Performance Metrics {#sec:metrics} ------------------- In this paper, two main performance metrics for the network are considered: the average sum rate (ASR) and energy efficiency (EE). The ASR is obtained from total rates of both D2D users and CUEs as $$\text{ASR}= U_c \bar{R}_c + \pi R^2 \lambda_d \bar{R}_d, \label{eq:ASR}$$ where $\pi R^2 \lambda_d$ is the average number of D2D users in the cell and $\bar{R}_t$ with $t\in\{c,d\}$ denotes the average rates of the CUEs and D2D users, respectively. $\bar{R}_t$ for both cellular and D2D users is computed as the successful transmission rate by $$\label{eq:Avg_Rate1} \bar{R}_t = \underset{\beta_t \geq 0}{\mathrm{sup}}~B_w \log_{2}(1 + \beta_t) \mathrm{P}^t_{\mathrm{cov}} (\beta_t)$$ where $$\label{eq:PsuccDef} \mathrm{P}^t_{\mathrm{cov}} (\beta_t) = \mathrm{Pr}\big\{\mathrm{SINR}_{t} \geq \beta_t \big\}$$ is the coverage probability when the received SINR is higher than a specified threshold $\beta_t$ needed for successful reception. Note that $\mathrm{SINR}_{t}$ contains random channel fading and random user locations. Finding the supremum guarantees the best constant rate for the D2D users and the CUEs. If we know the coverage probability ($\mathrm{P}^t_{\mathrm{cov}} (\beta_t)$), can easily be computed by using line search for each user type independently. Moreover, is easily achievable in practice since the modulation and coding is performed without requiring that every transmitter knows the interference characteristics at its receiver. Energy efficiency is defined as the benefit-cost ratio between the ASR and the total consumed power: $$\text{EE} = \frac{\text{ASR}}{\text{Total power}}. \label{eq:EE}$$ For the total power consumption, we consider a detailed model described in [@Bjornson-2014-arxiv]: $$\begin{aligned} \text{Total power}&=\frac{1}{\eta} \big(P_c +\lambda_d \pi R^2 P_d\big) + C_0 + T_c C_1 + \big(U_c + 2 \lambda_d \pi R^2\big)C_2,\label{eq:P_tot}\end{aligned}$$ where $P_c +\lambda_d \pi R^2 P_d$ is the total transmission power averaged over the number of D2D users, $\eta$ is the amplifier efficiency ($0 < \eta \leq 1$), $C_0$ is the load independent power consumption at the BS, $C_1$ is the power consumption per BS antenna, $C_2$ is the power consumption per user device, and $U_c + 2 \lambda_d \pi R^2$ is the average number of active users. In order to calculate the ASR and EE, we need to derive the coverage probability for both cellular and D2D users. The analytic derivation of these expressions is one of the main contributions of this paper. Coverage Probability of D2D Users --------------------------------- We first derive the expression for the coverage probability of D2D users. \[proposition:P\_succ\_d2d\] The approximate coverage probability for a typical D2D user is given by $$\begin{aligned} \mathrm{P}^d_{\mathrm{cov}}(\beta_d) &= \frac{ (\kappa\beta_d)^{2/\alpha_c}}{R^2}\left(y^{U_c + \frac{2}{\alpha_c}-1} (1-y)^{- \frac{2}{\alpha_c}} - \Big(U_c + \frac{2}{\alpha_c}-1\Big) \mathcal{B}\Big(y; U_c + \frac{2}{\alpha_c}-1, 1-\frac{2}{\alpha_c}\Big) \right) \notag \\ &\;\quad \cdot \exp\bigg(- \frac{\pi \lambda_d R_{0,0}^2}{\mathrm{sinc}(\frac{2}{\alpha_d})} \beta_d^{2/\alpha_d}\bigg) \exp\bigg(-\frac{\beta_d} {\bar{\gamma}_d}\bigg), \label{eq:P_succ_d2d}\end{aligned}$$ where $\kappa \triangleq \frac{\zeta}{P_d A_d R_{0,0}^{-\alpha_d}}$ with $\zeta$ defined in , $y \triangleq \frac{1}{\kappa \beta_d R^{-\alpha_c} + 1}$, $\mathrm{sinc}(x) = \frac{\sin(\pi x)}{\pi x}$, $\bar{\gamma}_d = \frac{A_d R_{0,0}^{-\alpha_d}P_d}{N_0}$ is the average D2D SNR, and $\mathcal{B}(x;a,b)$ is the incomplete Beta function. The proof is given in Appendix \[sec:proof\_Pcov\_d2d\]. The coverage probability expression in Proposition \[proposition:P\_succ\_d2d\] allows us to compute the average data rate of a typical D2D user in . We note that is actually a tight approximation and its tightness is evaluated in Section \[sec:results\]. From the expression in , we make several observations as listed below. \[remark:P\_succ\_d2d\_highSNR\] In the high-SNR regime for the D2D users where $\bar{\gamma}_d \gg \beta_d$, the last term in converges to one, i.e., $\exp\left(- \frac{\beta_d} {\bar{\gamma}_d}\right) \to 1$, and we have $$\begin{aligned} \mathrm{P}^d_{\mathrm{cov}}(\beta_d) &= \frac{ (\kappa\beta_d)^{2/\alpha_c}}{R^2}\left(y^{U_c + \frac{2}{\alpha_c}-1} (1-y)^{- \frac{2}{\alpha_c}} - \Big(U_c + \frac{2}{\alpha_c}-1\Big) \mathcal{B}\Big(y; U_c + \frac{2}{\alpha_c}-1, 1-\frac{2}{\alpha_c}\Big) \right) \notag \\ &\;\quad \cdot \exp\bigg(- \frac{\pi \lambda_d R_{0,0}^2}{\mathrm{sinc}(\frac{2}{\alpha_d})} \beta_d^{2/\alpha_d}\bigg). \label{eq:P_succ_d2d_highSNR}\end{aligned}$$ This can also be referred to as the interference-limited regime. \[remark:P\_succ\_d2d\_lambda\_d\] The coverage probability of a typical D2D user is a decreasing function of the D2D density $\lambda_d$. Because higher $\lambda_d$ results in more interference among D2D users. In particular, it can be seen that $\mathrm{P}^d_{\mathrm{cov}}$ in is a function of $\lambda_d$ through $\exp(-C\lambda_d)$ with $C\triangleq\frac{\pi R_{0,0}^2 \beta_d^{2/\alpha_d}}{\mathrm{sinc}(\frac{2}{\alpha_d})} > 0$. Thus, if $\lambda_d \to \infty$, $\mathrm{P}^d_{\mathrm{cov}} \to 0$. Recall that in our model, the D2D Rx is associated to the D2D Tx which is located at a fixed distance away. However, if we had assumed that the D2D Rx’s association to a D2D Tx is based on, for example, the shortest distance or the maximum SINR, then the $\mathrm{P}^d_{\mathrm{cov}}$ would have been unaffected by the D2D density (in the high-interference regime). Now, considering the number of BS antennas or the number of CUEs as variables, we have the following behavior of the D2D coverage probability. \[remark:P\_succ\_d2d\_Tc\_Uc\] $\mathrm{P}^d_{\mathrm{cov}}$ is not affected by the number of BS antennas $T_c$. The BS antennas are used to cancel out the interference among CUEs and they do not have any impact on D2D users’ performance as long as the number of CUEs $U_c$ is constant and does not vary with the number of BS antennas $T_c$. The coverage probability of a typical D2D user $\mathrm{P}^d_{\mathrm{cov}}$ is a decreasing function of $U_c$. However, increasing the number of CUEs have a small effect on D2D users’ performance. This is due to the fact that the resulting interference from the BS to D2D users does not change significantly by increasing the number of CUEs as the transmit power of the BS is the same irrespective of the number of users and the precoding is independent of the D2D channels. Thus, a change of $U_c$ will only change the distribution of the interference but not its average. Next we comment on how changes in the transmit powers of the BS and D2D Tx as well as the distance between D2D user pairs affect the coverage probability of D2D users. \[remark:P\_succ\_d2d\_PcPd\] $\mathrm{P}^d_{\mathrm{cov}}$ is a decreasing function of the ratio between the transmit power of the BS and of the D2D users, i.e., $\frac{P_c}{P_d}$, which is part of the first term in and corresponds to the interference from the BS. For instance, if we fix $P_c$ and decrease $P_d$, the coverage probability for D2D users decreases as the interference from the BS would be the dominating factor. At the same time, if we decrease $P_c$, it would improve the coverage of D2D users. \[remark:P\_succ\_d2d\_Uc\] $\mathrm{P}^d_{\mathrm{cov}}$ is a decreasing function of the distance between D2D Tx-Rx pairs $R_{0,0}$ and the cell radius $R$. Increasing the cell radius with the same D2D user density reduces the effect of the interference from the BS. Also by decreasing the distance between D2D Tx-Rx pairs, it is evident that a better performance for D2D users can be obtained. Using Proposition \[proposition:P\_succ\_d2d\], the following corollary provides the optimal D2D user density that maximizes the D2D ASR, i.e., $\pi R^2 \lambda_d \bar{R}_d$, where $\bar{R}_d$ is given in . \[corollary:ASR\_d2d\_lambda\_d\_max\] For a given SINR threshold $\beta_d$, the optimal density of D2D users $\lambda_d^*$ that maximizes the D2D ASR is $$\begin{aligned} \lambda_d^*(\beta_d) = \frac{\mathrm{sinc}(\frac{2}{\alpha_d})}{\pi R_{0,0}^2}\beta_d^{-2/\alpha_d}. \label{eq:lambda_max}\end{aligned}$$ Given the SINR threshold $\beta_d$ and using –, the D2D ASR is $$\pi R^2 \lambda_d B_w\log_2 (1+\beta_d) \mathrm{P}^d_{\mathrm{cov}}(\beta_d), \label{eq:D2D_ASR_optLambda_d}$$ where $\mathrm{P}^d_{\mathrm{cov}}(\beta_d)$ is given in and depends on $\lambda_d$ through an exponential function. Taking the derivative of with respect to $\lambda_d$ and setting it to zero yields the optimal D2D user density $\lambda_d^*(\beta_d)$ given in that maximizes the D2D ASR. Coverage Probability of Cellular Users -------------------------------------- Next, we compute the coverage probability for CUEs. \[proposition:P\_succ\_cue\] The coverage probability for a typical cellular user is given by $$\begin{aligned} \mathrm{P}^c_{\mathrm{cov}}(\beta_c) &= \mathbb{E}_{D_{0,\textrm{BS}}}\left[e^{-\frac{N_0}{A_d}s} \sum_{k=0}^{T_c - U_c} \frac{s^k}{k!} \sum_{i=0}^{k} \binom{k}{i} \left(\frac{N_0}{A_d }\right)^{k-i}(-1)^i \;\Upsilon(\lambda_d,s,i)\right], \label{eq:P_succ_cue}\end{aligned}$$ with $$\begin{aligned} \Upsilon(\lambda_d,s,i) &= \exp\left(-C_d \lambda_d s^{2/\alpha_d} \right) \sum_{(j_1,\ldots,j_i)\in\mathcal{J}} i! \prod_{\ell=1}^i\frac{1}{j_\ell!(\ell!)^{j_\ell}}\left(-C_d \lambda_d s^{\frac{2}{\alpha_d}-\ell}\prod_{q=0}^{\ell-1}\Big(\frac{2}{\alpha_d}-q\Big)\right)^{j_\ell}, \label{eq:Upsilon}\end{aligned}$$ where $s\triangleq \frac{A_d}{\zeta} D_{0,\textrm{BS}}^{\alpha_c}\beta_c$ with $\zeta$ defined in , $C_d \triangleq \frac{\pi P_d^{2/\alpha_d}}{\mathrm{sinc}(\frac{2}{\alpha_d})}$, and $$\mathcal{J}\triangleq \bigg\{(j_1,\ldots,j_i): j_\ell \in \mathbb{Z}_{\geq 0}, \; \sum_{\ell=1}^i \ell j_\ell = i \bigg\}.$$ The proof is given in Appendix \[sec:proof\_Pcov\_cue\]. This proposition gives an expression for the coverage probability of CUEs in which there is only one random variable left. The expectation in with respect to $D_{0,\textrm{BS}}$ is intractable to derive analytically but can be computed numerically. The analytical results of Proposition \[proposition:P\_succ\_d2d\] and Proposition \[proposition:P\_succ\_cue\] have been verified by Monte-Carlo simulations in Section \[sec:results\]. A main benefit of the analytic expressions (as compared to pure Monte-Carlo simulations with respect to all sources of randomness) is that they can be computed much more efficiently, which basically is a prerequisite for the multi-variable system analysis carried out in Section \[sec:results\]. Next, we present some observations from the result in Proposition \[proposition:P\_succ\_cue\] as follows. \[remark:P\_succ\_cue\_inflim\] In the interference-limited regime where where $I_{d,c}\gg N_0$, the coverage probability in for a typical cellular user is simplified to $$\begin{aligned} \mathrm{P}^c_{\mathrm{cov}}(\beta_c) &= \mathbb{E}_{D_{0,\textrm{BS}}}\left[\sum_{k=0}^{T_c - U_c} \frac{(-s)^k}{k!}\Upsilon(\lambda_d,s,k)\right]. \label{eq:P_succ_cue_inflim}\end{aligned}$$ The result obtained in Remark \[remark:P\_succ\_cue\_inflim\] has a lower computational complexity compared to the expression in Proposition \[proposition:P\_succ\_cue\] and at the same time it is a tight approximation for Proposition \[proposition:P\_succ\_cue\]. This can be observed from the denominator of the where the term $\frac{N_0}{A_d }\approx 0$. \[remark:P\_succ\_cue\_lambda\_dinf\] The coverage probability of a typical CUE $\mathrm{P}^c_{\mathrm{cov}}(\beta_c)$ is a decreasing function of the D2D user density $\lambda_d$. From Proposition \[proposition:P\_succ\_cue\], only $\Upsilon(\lambda_d,s,i)$ is a function of $\lambda_d$ which is composed of an exponential term in $\lambda_d$ multiplied by a polynomial term in $\lambda_d$. Thus, if $\lambda_d \to \infty$, the exponential term which has a negative growth dominates the polynomial term and $\mathrm{P}^c_{\mathrm{cov}}(\beta_c) \to 0$. We proceed to analyze the behavior of Proposition \[proposition:P\_succ\_cue\] by considering a number of special cases. \[corollary:col\_P\_succ\_cue\_TcequalUc\] If $T_c = U_c$, the coverage probability for a typical cellular user is given by $$\begin{aligned} \mathrm{P}^c_{\mathrm{cov}}(\beta_c) &= \mathbb{E}_{D_{0,\textrm{BS}}}\left[\exp\bigg(-\frac{N_0}{A_d}s - C_d \lambda_d s^{2/\alpha_d}\bigg)\right], \label{eq:P_succ_cue_TcequalUc}\end{aligned}$$ where $s = \frac{A_d}{\zeta} D_{0,\textrm{BS}}^{\alpha_c} \beta_c$ and $C_d=\frac{\pi P_d^{2/\alpha_d}}{\mathrm{sinc}(\frac{2}{\alpha_d})}$. follows directly from by setting $T_c-U_c = 0$. \[corollary:P\_succ\_cue\_TcUcinf\] If $(T_c - U_c) \to \infty$, the coverage probability for a typical cellular user tends to one, that is, $$\begin{aligned} \lim_{(T_c - U_c) \to \infty}~\mathrm{P}^c_{\mathrm{cov}}(\beta_c) = 1. \label{eq:P_succ_cue_TcUcinf}\end{aligned}$$ Let $m=T_c - U_c$. Substituting $\mathrm{SINR}_c$ from into , we have $$\begin{aligned} \lim_{m \to \infty}~\mathrm{P}^c_{\mathrm{cov}}(\beta_c) &= \lim_{m \to \infty}~\mathrm{Pr}\left\{ |{\mathbf{h}}_{0}^H {\mathbf{v}}_{0}|^2 \geq \frac{A_d}{\zeta} D_{0,\textrm{BS}}^{\alpha_c}\Big(I_{d,c} + \frac{N_0}{A_d}\Big)\beta_c \right\} \\ &{\overset{(a)}{=}} \lim_{m \to \infty}~\mathbb{E}_{D_{0,\textrm{BS}}, I_{d,c}}\left[e^{-\frac{A_d}{\zeta} D_{0,\textrm{BS}}^{\alpha_c}(I_{d,c} + \frac{N_0}{A_d})\beta_c } \sum_{k=0}^{m} \frac{1}{k!}\bigg(\frac{A_d}{\zeta} D_{0,\textrm{BS}}^{\alpha_c}\Big(I_{d,c} + \frac{N_0}{A_d}\Big)\beta_c\bigg)^k\right] \\ &{\overset{(b)}{=}} \lim_{m \to \infty}~\mathbb{E}_{D_{0,\textrm{BS}}, I_{d,c}}\left[e^{-z} \sum_{k=0}^{m} \frac{z^k}{k!}\right] \\ &{\overset{(c)}{=}} \mathbb{E}_{D_{0,\textrm{BS}}, I_{d,c}}\left[\lim_{m \to \infty} e^{-z} \sum_{k=0}^{m} \frac{z^k}{k!}\right] \\ &{\overset{(d)}{=}} \mathbb{E}_{D_{0,\textrm{BS}}, I_{d,c}}\left[e^{-z} e^{z} \right] = 1,\end{aligned}$$ where $(a)$ follows from the CCDF of $|{\mathbf{h}}_{0}^H {\mathbf{v}}_{0}|^2$ with $2|{\mathbf{h}}_{0}^H {\mathbf{v}}_{0}|^2 \sim \chi^2_{2}$ given $D_{0,\textrm{BS}}$ and $I_{d,c}$. Step $(b)$ follows from setting $z = \frac{A_d}{\zeta} D_{0,\textrm{BS}}^{\alpha_c}(I_{d,c} + \frac{N_0}{A_d})\beta_c$. Step $(c)$ is obtained from the dominated convergence theorem which allows for an interchange of limit and expectation and step $(d)$ is due to the fact that $\sum_{k=0}^{\infty} \frac{z^k}{k!} = e^z$. In the results so far, we have discussed the case where there exist some D2D users as underlay to the cellular network, that is, $\lambda_d \neq 0$, However, it is interesting to see what can be achieved without D2D users. \[corollary:col\_P\_succ\_cue\_lambda\_dzero\] If $\lambda_d= 0$, the coverage probability for a typical cellular user is given by $$\begin{aligned} \mathrm{P}^c_{\mathrm{cov}}(\beta_c) &= \frac{2}{\alpha_c R^2}\Gamma\left(\frac{2}{\alpha_c}\right)\left(\frac{N_0}{\zeta} \beta_c \right)^{-2/\alpha_c} \sum_{k=0}^{T_c-U_c}\binom{\frac{2}{\alpha_c}+k-1}{k}, \label{eq:P_succ_cue_lambda_dzero}\end{aligned}$$ where $\Gamma(\cdot)$ is the Gamma function and $\zeta$ is defined in . Substituting $\mathrm{SINR}_c$ from into and setting $\lambda_d= 0$, we have $$\begin{aligned} \mathrm{P}^c_{\mathrm{cov}}(\beta_c) &= \mathrm{Pr}\left\{ |{\mathbf{h}}_{0}^H {\mathbf{v}}_{0}|^2 \geq \frac{D_{0,\textrm{BS}}^{\alpha_c}}{\zeta} N_0 \beta_c \right\} \nonumber\\ &{\overset{(a)}{=}} \mathbb{E}_{z}\Bigg[\sum_{k=0}^{T_c-U_c}\frac{l^k}{k!}z^k e^{-lz} \Bigg] \nonumber\\ &{\overset{(b)}{=}}\frac{2}{\alpha_c R^2}\Gamma\left(\frac{2}{\alpha_c}\right) \sum_{k=0}^{T_c-U_c}\frac{(-l)^k}{k!} ~\frac{\mathrm{d}^k}{{\mathrm{d}l}^k} ~l^{-2/\alpha_c},\end{aligned}$$ where $(a)$ follows from the CCDF of $|{\mathbf{h}}_{0}^H {\mathbf{v}}_{0}|^2$ with $2|{\mathbf{h}}_{0}^H {\mathbf{v}}_{0}|^2 \sim \chi^2_{2}$ given $D_{0,\textrm{BS}}$ and setting $l= \frac{N_0}{\zeta} \beta_c$ and $z = D_{0,\textrm{BS}}^{\alpha_c}$ with PDF $f(z)=\frac{2}{\alpha_cR^2}z^{\frac{2}{\alpha_c}-1}$. Step $(b)$ follows from taking the expectation with respect to $z$ which is similar to the expression in with the Laplace transform $ \mathcal{L}_{z}(l) = \frac{2}{\alpha_c R^2}\Gamma\big(\frac{2}{\alpha_c}\big)l^{-2/\alpha_c}$. Simplifying the $k$-th derivative to $\frac{\mathrm{d}^k}{\mathrm{d}l^k} ~l^{-2/\alpha_c} = (-1)^k l^{-\frac{2}{\alpha_c}-k} \prod_{i=0}^{k-1}\big(\frac{2}{\alpha_c}+i\big)$ and using the identity $\frac{1}{k!}\prod_{i=0}^{k-1}\big(\frac{2}{\alpha_c}+i\big) = \binom{\frac{2}{\alpha_c}+k-1}{k}$, follows. The closed-form results in Corollary \[corollary:col\_P\_succ\_cue\_lambda\_dzero\] for $\lambda_d= 0$ depends only on noise rather than interference and perhaps can result in higher ASR for CUEs. The ASR for $\lambda_d>0$ also depends on noise but its impact is much smaller. However, we note that this result is obtained for a single cell scenario. Thus, comparing Proposition \[proposition:P\_succ\_cue\] and Corollary \[corollary:col\_P\_succ\_cue\_lambda\_dzero\] and evaluating the potential performance gain/loss due to introducing D2D communications would make more sense in a multi-cell scenario. Using the results from Proposition \[proposition:P\_succ\_d2d\] and Proposition \[proposition:P\_succ\_cue\], we proceed to evaluate the network performance in terms of the ASR and EE from and , respectively. Numerical Results {#sec:results} ================= Description Parameter Value -------------------------------------- ------------ ------------ D2D TX power $P_d$ $6$ dBm BS TX power $P_c$ $30$ dBm Cell radius $R$ $500$ m Bandwidth $B_w$ $20$ MHz Thermal noise power $N_0$ $-131$ dBm Noise figure in UE $F$ $5$ dB Carrier frequency $f_c$ $2$ GHz D2D pair distance $R_{0,0}$ $35$ m Pathloss exponent betw. devices $\alpha_d$ $3$ Pathloss exponent betw. BS–device $\alpha_c$ $3.67$ Pathloss coefficient betw. devices $A_d$ $38.84$ dB Pathloss coefficient betw. BS–device $A_c$ $30.55$ dB Amplifier efficiency $\eta$ $0.3$ Load-independent power in BS $C_0$ $5$ W Power per BS antenna $C_1$ $0.5$ W Power per UE handset $C_2$ $0.1$ W Monte-Carlo runs MC $5000$ : System and simulation parameters.[]{data-label="table:Sim_param"} In this section, we assess the performance of the setup in Fig. \[figure:sysMod\_massiveMIMO\_D2D\] in terms of ASR and EE using numerical evaluations. As we pointed out in , many parameters affect these performance metrics. Initially, we consider the EE and the ASR as functions of three key parameters, namely, the number of BS antennas $T_c$, the density of D2D users $\lambda_d$, and the number of cellular users $U_c$. We show the individual effect of these system parameters on the two performance metrics while other parameters such as BS transmit power $P_c$, D2D transmit power $P_d$, and distance between D2D Tx-Rx pair $R_{0,0}$ are fixed. Later on, we also comment on the choice of these fixed parameters. The system and simulation parameters are given in Table \[table:Sim\_param\]. Before we proceed to the performance evaluation, we verify the analytical results of Proposition \[proposition:P\_succ\_d2d\] and Proposition \[proposition:P\_succ\_cue\] by Monte-Carlo simulations. As depicted in , simulation results closely follow the analytical derivations. The small gap in Fig. \[fig:P\_cov\_d2d\] is due to the spatial interference correlation resulting from the fact that multiple interfering streams are coming from the same location, hence, the Chi-squared distribution in is an approximation. This is a quite standard approximation in analyzing MIMO systems [@Dhillon-2013-TWC]. Moreover, in the simulations, the locations of the D2D Tx are generated in an area with radius $10R$ according to the PPP as opposed to our analytical assumption that they are located in the whole $\mathbb{R}^2$ region. This assumption reduces the interference as compared to our analytical results and thus improves the coverage probability as can be seen in Fig. \[fig:P\_cov\_d2d\]. We consider two scenarios corresponding to the number of CUEs $U_c$ in our evaluations. First, we assume that $U_c$ is chosen as a function of the number of BS antennas $T_c$. Then, we move on to the case where we fix the number of CUEs and study the tradeoffs among other parameters. Both scenarios are relevant in the design of massive MIMO systems. In order to speed up the numerical computations, we neglected the terms that are very small. Number of CUEs as a Function of the Number of BS Antennas --------------------------------------------------------- In this scenario, we assume that there is a fixed ratio between the number of CUEs $U_c$ and the number of BS antennas $T_c$. We assume this ratio to be $\frac{T_c}{U_c}=5$. Simply put, to serve one additional user, we add five more antennas at the BS since the main gains from massive MIMO come from multiplexing of many users rather than only having many antennas. shows the ASR as a function of the density of D2D users $\lambda_d$ and the number of CUEs $U_c$, which is scaled by $T_c$. It is observed that increasing $U_c$, or equivalently $T_c$, always increases the ASR. In contrast, there is an optimal value of $\lambda_d$ as derived in Corollary \[corollary:ASR\_d2d\_lambda\_d\_max\] which results in the maximum ASR for all values of $U_c$ and appears approximately at $\lambda_d = 10^{-4}$. However, there is a difference in the shape of the ASR between the lower and higher values of $U_c$. In order to clarify this effect, we plot the ASR versus $\lambda_d$ in a 2-D plot with $U_c \in \{1,14\}$ equivalent to $T_c \in \{5,70\}$ in . ![ASR $\mathrm{[Mbit/s]}$ as a function of the number of CUEs $U_c$ and the D2D user density $\lambda_d$ for a fixed ratio $\frac{T_c}{U_c}= 5$.[]{data-label="fig:ASR_ld_uc_phi5"}](ASR_ld_uc_phi5){width="0.65\columnwidth"} As seen in , for $U_c = 1$ user and $T_c =5$ antennas, the rate contributed from the CUEs to the sum rate is low as there is only one CUE. This rate is in a comparable level as the contribution of D2D users sum rate to the total ASR. Adding D2D users to the network (i.e., increasing $\lambda_d$), which may cause interference, will nevertheless leads to an increase in the ASR. This increase in the ASR continues until reaching a certain density that gives the maximum ASR. By further increasing $\lambda_d$, the interference between D2D users reduces their coverage probability as previously observed in Remark \[remark:P\_succ\_d2d\_lambda\_d\]. This limits the per link data rate and even a high number of D2D users cannot compensate for the D2D rate loss. At the same time, increasing $\lambda_d$ tremendously affects the CUEs sum rate (cf. Remark \[remark:P\_succ\_cue\_lambda\_dinf\]). Consequently, as $\lambda_d$ increases, the ASR decreases. By increasing the number of CUEs and BS antennas to $U_c = 14$ users and $T_c = 70$ antennas, respectively, in , the average rates of the CUEs become higher than the case with $U_c = 1$ user and $T_c =5$ antennas as expected from Corollary \[corollary:P\_succ\_cue\_TcUcinf\] and the multiplexing gain from having many CUEs. However, by introducing a small number of D2D users, there is a substantial probability that the interference from the D2D users reduces the CUEs’ rates per link as observed in Remark \[remark:P\_succ\_cue\_lambda\_dinf\]. The reduction in these rates are not compensated in the ASR by the contribution of the D2D users’ rates. Note that, as we stated in Remark \[remark:P\_succ\_d2d\_Tc\_Uc\], when $U_c$ is scaled with $T_c$, it impacts the D2D coverage probability, but the decrease in the performance of D2D users is not significant. Furthermore, if we keep increasing $\lambda_d$, even though the rate per link decreases for both CUEs and D2D users, there is a local minima after which the aggregate D2D rate over all D2D users becomes higher and the ASR increases again. The second turning point follows from the same reasoning as for the case of $U_c=1$ user and $T_c = 5$ antennas, i.e., in higher D2D densities, the interference from D2D users are the limiting factor for the ASR. This effect can also be observed in where the ASR performance is depicted versus different number of CUEs (and BS antennas) for two D2D densities. At the lower density, the ASR is linearly increasing with $U_c$ (and $T_c)$, however, in the interference-limited regime (higher $\lambda_d$), increasing the number of CUEs and BS antennas do not impact the network ASR performance. The reasoning in and can be well understood from which explains the tradeoff between the ASR of CUEs and D2D users in the network. In the scenario in which we have $T_c = 70$ antennas and $U_c =14$ users, the cellular network contributes more to the total ASR for the low D2D density regime (e.g., $\lambda_d=10^{-6}$) due to high number of CUEs and BS antennas. In this region, the ASR gains from massive MIMO is large. By increasing $\lambda_d$, the gain from massive MIMO vanishes as the interference added by the D2D users dominates and degrades the performance that was achieved by interference cancellation between CUEs. Therefore, with medium D2D user density, if there is a fixed rate constraint for CUEs, the network can still benefit (from the ASR perspective) from underlay D2D communications. However, in the high D2D density regime (e.g., $\lambda_d = 10^{-4}$), the cellular ASR is too small and it is better that the cellular and D2D tiers use the overlay approach for communication instead of the underlay approach. In , we show the network performance in terms of the EE as a function of the parameters $\lambda_d$ and $U_c$ with $\frac{T_c}{U_c}= 5$. It is observed that the EE is a decreasing function of $U_c$ and $T_c$. In contrast, there is a maximum point in the EE based on different values of $\lambda_d$. To study this result further, similar to the ASR, we first plot the EE versus $\lambda_d$ for $U_c \in \{1,14\}$ and $T_c \in \{4,70\}$ in . We can see that the pattern for both low and high number of BS antennas are similar to . The higher EE is achieved with $U_c =1$ user and $T_c=5$ antennas as opposed to $U_c =14$ users and $T_c=70$ antennas. This is because the extra circuit power of the cellular tier with $U_c =14$ users and $T_c=70$ antennas does not bring any substantial ASR improvement over the case with $U_c =1$ user and $T_c=5$ antennas. ![Cellular ASR vs. D2D ASR $\mathrm{[Mbit/s]}$ for a fixed ratio $\frac{T_c}{U_c}= 5$. The curves are obtained by varying the value of $\lambda_d$ from $10^{-6}$ to $10^{-2}$.[]{data-label="fig:asrC_asrD_ld"}](asrC_asrD_ld_phi5){width="0.65\columnwidth"} Furthermore, if we plot the EE versus $U_c$, we see a different behavior for low and high D2D densities. illustrates that in the low D2D density regime ($\lambda_d=10^{-6}$), even though the ASR increases linearly, the EE almost stays the same as the number of CUEs, and correspondingly the number of BS antennas, increases. From , we can observe that for a fixed $\lambda_d$, only the circuit power is changed by increasing $U_c$ and $T_c$. At the same time, the circuit power dominates the the total power consumption and increases almost linearly leading to an (almost) constant EE. The network performance in terms of the EE is poor with high density of D2D users ($\lambda_d=10^{-4}$). This is due to the fact that the sum rate contributed by the CUEs is already degraded by the interference from high number of D2D users, and additionally, increasing $U_c$ (and accordingly $T_c$) increases the circuit power without any gain in the total ASR. Consequently, the EE decreases. Thus, massive MIMO can only improve the EE if the D2D user density is small, otherwise dedicated resources or underlaying with fewer BS antennas is beneficial. ![EE $\mathrm{[Mbit/Joule]}$ as a function of the number of CUEs $U_c$ and the D2D user density $\lambda_d$ for a fixed ratio $\frac{T_c}{U_c}= 5$.[]{data-label="fig:EE_ld_uc_phi5"}](EE_ld_uc_phi5){width="0.65\columnwidth"} Fixed Number of CUEs -------------------- In this section, we evaluate the system performance when the number of CUEs is fixed with $U_c = 4$ users. The general trend of the network performance is the same as the case with $\frac{T_c}{U_c} =5$ in the previous section. However, there are some differences which are highlighted in and for the ASR and EE, respectively. As it is shown in , in the low D2D user density regime (i.e., $\lambda_d=10^{-6}$) the ASR is increasing in $T_c$, however, with a lower slope as compared to the case of $\frac{T_c}{U_c} =5$. By increasing the number of BS antennas for the fixed number of CUEs, better performance per user can be achieved, however in this case, as the number of CUEs is not high, the ASR increases with a small slope. For high D2D user density (i.e., $\lambda_d = 10^{-4}$), the ASR is almost flat. illustrates that when the D2D user density is low, the EE benefits from adding extra BS antennas until the sum of the circuit power consumption of all antennas dominates the performance and leads to a gradual decrease in the EE. As the figure implies, there exists an optimal number of BS antennas which is relatively small since the main massive MIMO gains come from multiplexing rather than just having many antennas. However, in high density D2D scenario, which is the interference-limited scenario, the EE decreases monotonically with $T_c$. Increasing the number of BS antennas in this region cannot improve the ASR significantly, as shown in ; at the same time the circuit power consumption increases as a result of the higher number of BS antennas, which in turn leads to decreasing network EE. The conclusion is that the D2D user density has a very high impact on a network that employs the massive MIMO technology. In the downlink, these two technologies can only coexist in low density of D2D users with careful interference coordination. The number of CUEs should be a function of the number of BS antennas in order to benefit from high number of BS antennas in terms of the ASR and EE. Otherwise, in high density of D2D users, the D2D communication should use the overlay approach rather than the underlay, that is, dedicated time/frequency resources should be allocated to the D2D tier. The Effect of Other System Parameters ------------------------------------- So far, we have discussed the results based on constant transmit power $P_c$, D2D transmit power $P_d$, and distance between D2D Tx-Rx pairs $R_{0,0}$ given in Table \[table:Sim\_param\]. Now we comment on the choice of these parameters and study their effects on the system performance. From Proposition \[proposition:P\_succ\_d2d\], Proposition \[proposition:P\_succ\_cue\], and Remark \[remark:P\_succ\_d2d\_PcPd\], it is evident that the coverage probability for both D2D and cellular tiers, and consequently the network ASR and EE, depend on the ratio of $P_d$ and $P_c$. Therefore, we fix $P_c$ and vary $P_d$. shows the ASR as function of $\lambda_d$ under two different power levels, i.e., $P_d = 6~\mathrm{dBm}$ and $P_d = 13~\mathrm{dBm}$ in a scenario where the number of CUEs $U_c$ is scaled by $T_c$. We see that higher $P_d$ degrades the ASR at higher number of CUEs (and BS antennas) when the D2D user density is low, but has negligible impact at lower number of CUEs. The reason is that increasing $P_d$, on the one hand, boosts the D2D user rates, and on the other hand, causes more interference to CUEs which deteriorates their rates. Consequently, at low D2D user densities and high number of CUEs and BS antennas where the cellular sum rate is the main contributer to the total ASR, the interference caused by higher D2D transmit power is the dominant factor leading to lower total ASR. However, as $\lambda_d$ increases, the contribution of the D2D sum rate to the total ASR increases, and thus with higher $P_d$, the increase in the D2D sum rates compensates the decrease in CUEs sum rate and the difference in terms of the total ASR between the different power levels vanishes. When the number of CUEs is small, i.e., $U_c=1$ user and $T_c=5$ antennas, the CUE and D2D users have almost the same contributions to the ASR and increasing $P_d$ has negligible impact on the performance. depicts the EE as a function of $\lambda_d$ under the same two levels of D2D transmit power. It is observed that lower $P_d$ is more beneficial in terms of the EE in both cases of $U_c = 1$ user and $U_c=14$ users. This is particularly visible in higher density of D2D users (e.g., $\lambda_d=3\times 10^{-5}$) with $U_c = 1$ user and $T_c=5$ antennas when the interference is the limiting factor. With $U_c = 14$ users and $T_c=70$ antennas, the CUEs have higher impact on the ASR, and as a consequence, the system benefits from lower transmit power of D2D users in terms of the EE. Therefore, we have chosen $P_d = 6~\mathrm{dBm}$ in the previous performance evaluation, as it has a better impact on the ASR as well as EE, especially in higher number of BS antennas. Another important parameter that impacts the ASR is the distance between D2D Tx-Rx pairs, i.e., $R_{0,0}$. The effect of this parameter is only on the coverage probability of D2D users as seen in Proposition \[proposition:P\_succ\_d2d\] and Proposition \[proposition:P\_succ\_cue\]. illustrates the cellular ASR versus the D2D ASR for different values of $\lambda_d$ and $R_{0,0}$. The figure verifies that by decreasing $R_{0,0}$ only the ASR of D2D tier increases and as Remark \[remark:P\_succ\_d2d\_Uc\] implies increasing $R_{0,0}$ decreases the coverage probability of D2D users leading to lower ASR and EE. Since D2D communications are mostly meant for close proximity applications, we have chosen $R_{0,0} =35~\mathrm{m}$ in our performance study. Moreover, by decreasing the distance between D2D users, more D2D users can coexist simultaneously. This is observed in that with $R_{0,0} =35~\mathrm{m}$ the maximum ASR (of the D2D tier as well as the network) is achieved at the D2D density $\lambda_d=10^{-4}$ while with $R_{0,0} =50~\mathrm{m}$, it is achieved at the D2D density $\lambda_d=3.98 \times 10^{-5}$. ![Cellular ASR vs. D2D ASR $\mathrm{[Mbit/s]}$ for different distances between D2D Tx and D2D Rx with $U_c=4$ users and $T_c=70$ antennas. The curves are obtained by varying the value of $\lambda_d$ from $10^{-6}$ to $10^{-2}$.[]{data-label="fig:asrC_asrD_diff-d2d-distance"}](asrC-asrD-Uc4-Tc70-diff-d2d-distance){width="0.65\columnwidth"} Conclusions {#sec:conclusion} =========== We studied the coexistence of two key 5G concepts: device-to-device (D2D) communication and massive MIMO. We considered two performance metrics, namely, the average sum rate in $\mathrm{bit/s}$ and the energy efficiency in $\mathrm{bit/Joule}$. We considered a setup with a number of uniformly distributed cellular users in the cell, while the D2D transmitters are distributed according to a Poisson point process. We derived tractable expressions for the coverage probabilities of both cellular and D2D users which led to computation of the average sum rate and energy efficiency. We then studied the tradeoff between the number of base station antennas, the number of cellular users, and the density of D2D users for a given coverage area in the downlink. Our results showed that both the average sum rate and energy efficiency behave differently in scenarios with low and high density of D2D users. Underlay D2D communications and massive MIMO can only coexist in low densities of D2D users with careful interference coordination, because the massive MIMO gains vanish when the interference from the D2D tier becomes too large. The number of cellular users should be a function of the number of base station antennas in order to benefit from high number of base station antennas in terms of the average sum rate and energy efficiency. If there is a high density of D2D users, the D2D communication should use the overlay approach rather than the underlay or the network should only allow a subset of the D2D transmissions to be active at a time. Proof of Proposition \[proposition:P\_succ\_d2d\] {#sec:proof_Pcov_d2d} ================================================= The proof follows by substituting the definition of $\mathrm{SINR}_d$ from into where we obtain $$\begin{aligned} \mathrm{P}^d_{\mathrm{cov}}(\beta_d) &= \mathrm{Pr}\big\{\mathrm{SINR}_d \geq \beta_d \big\} \nonumber \\ &= \mathrm{Pr} \left\{ P_{d} R_{0,0}^{-\alpha_d} |g_{0,0}|^2 \geq \beta_d \Big(I_{\textrm{BS},0} + I_{d,0} + \frac{N_0}{A_d }\Big) \right\} \nonumber \\ &= \mathrm{Pr} \left\{ |g_{0,0}|^2 \geq \frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}} \Big(I_{\textrm{BS},0} + I_{d,0} + \frac{N_0}{A_d }\Big) \right\} \nonumber \\ &{\overset{(a)}{=}} \mathbb{E}_{I_{\textrm{BS},0}, I_{d,0}} \left[\exp\bigg(- \frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}} \Big(I_{\textrm{BS},0} + I_{d,0} + \frac{N_0}{A_d }\Big)\bigg)\right]\nonumber \\ &{\overset{(b)}{=}} \mathbb{E}_{I_{\textrm{BS},0}}\left[\exp\bigg(- \frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}} I_{\textrm{BS},0}\bigg)\right] \mathbb{E}_{I_{d,0}}\left[\exp\bigg(- \frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}} I_{d,0}\bigg)\right] \exp\bigg(-\frac{\beta_d }{\bar{\gamma}_d}\bigg) \nonumber \\ &{\overset{(c)}{=}} \mathcal{L}_{I_{\textrm{BS},0}}\bigg(\frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}}\bigg)\mathcal{L}_{I_{d,0}}\bigg(\frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}}\bigg) \exp\bigg(-\frac{\beta_d}{\bar{\gamma}_d}\bigg). \label{eq:Pd2dProof}\end{aligned}$$ Step $(a)$ comes from the fact that $|g_{0,0}|^2 \sim \exp(1)$ and $(b)$ follows since the noise and interference terms are mutually independent. In step $(c)$, the Laplace transform defined as $\mathcal{L}_{x}(s) = \mathbb{E}_{x}\big[e^{- sx}\big]$ is identified. The first Laplace transform in is with respect to $I_{\textrm{BS},0}$ in which is a function of two random variables, namely $\|{\mathbf{f}}_{0,\textrm{BS}}^H \mathbf{V}\|^2$ and $R_{0,\textrm{BS}}$. This Laplace transform is calculated as $$\begin{aligned} \mathcal{L}_{I_{\textrm{BS},0}}&\bigg(\frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}}\bigg) = \mathbb{E}_{I_{\textrm{BS},0}} \left[\exp\bigg( - \frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}} I_{\textrm{BS},0}\bigg)\right]\nonumber \\ &= \mathbb{E}_{R_{0,\textrm{BS}}} \left[\mathbb{E}_{\|{\mathbf{f}}_{0,\textrm{BS}}^H \mathbf{V}\|^2}\bigg[\exp\bigg(- \frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}} \frac{\zeta R_{0,\textrm{BS}}^{-\alpha_c}}{A_d}\|{\mathbf{f}}_{0,\textrm{BS}}^H \mathbf{V}\|^2 \bigg) \Big| R_{0,\textrm{BS}}\bigg] \right] \nonumber \\ &=\mathbb{E}_{R_{0,\textrm{BS}}} \left[ \mathcal{L}_{\|{\mathbf{f}}_{0,\textrm{BS}}^H \mathbf{V}\|^2}\bigg(\frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}} \frac{\zeta R_{0,\textrm{BS}}^{-\alpha_c}}{A_d}\bigg)\right]\nonumber \\ &{\overset{(a)}{=}} \mathbb{E}_{R_{0,\textrm{BS}}} \left[\frac{1}{(\kappa \beta_d R_{0,\textrm{BS}}^{-\alpha_c} + 1)^{U_c}}\right]\nonumber \\ &{\overset{(b)}{=}} \int_0^R \frac{2r}{R^2(\kappa \beta_d r^{-\alpha_c}+1)^{U_c}} \mathrm{d}r\nonumber \\ &{\overset{(c)}{=}} \frac{2(\kappa\beta_d)^{2/\alpha_c}}{\alpha_c R^2}\int_0^{y} \frac{t^{U_c+\frac{2}{\alpha_c}-1}}{(1-t)^{\frac{2}{\alpha_c}+1}}\mathrm{d}t \nonumber \\ &{\overset{(d)}{=}} \frac{ (\kappa\beta_d)^{2/\alpha_c}}{R^2}\left(y^{U_c + \frac{2}{\alpha_c}-1} (1-y)^{- \frac{2}{\alpha_c}}- \Big(U_c + \frac{2}{\alpha_c}-1\Big) \mathcal{B}\Big(y; U_c + \frac{2}{\alpha_c}-1, 1-\frac{2}{\alpha_c}\Big) \right) \label{eq:LT_I_BS0}\end{aligned}$$ for $\alpha_c>2$, where $(a)$ follows by introducing the notation $$\kappa = \frac{\zeta}{P_d A_d R_{0,0}^{-\alpha_d}}$$ and from the Laplace transform of the probability density function (PDF) of $\|{\mathbf{f}}_{0,\textrm{BS}}^H \mathbf{V}\|^2$ which, by neglecting the spatial correlation, is tightly approximated by a Chi-squared distribution as $2\|{\mathbf{f}}_{0,\textrm{BS}}^H \mathbf{V}\|^2 \sim \chi^2_{2U_c}$ [@Dhillon-2013-TWC]. Note that $$\begin{aligned} \label{eq:normfHv} \big\|{\mathbf{f}}_{0,\textrm{BS}}^H \mathbf{V}\big\|^2 &= \big\|{\mathbf{f}}_{0,\textrm{BS}}^H [{\mathbf{v}}_{0},\ldots,{\mathbf{v}}_{{U_c}-1}]\big\|^2 \nonumber\\ &=\sum_{i=0}^{U_c-1} |{\mathbf{f}}_{0,\textrm{BS}}^H{\mathbf{v}}_{i}|^2,\end{aligned}$$ where ${\mathbf{f}}_{0,\textrm{BS}}^H{\mathbf{v}}_{i}$, $i = \{0, \ldots, U_c-1\}$, are zero-mean circular symmetric complex Gaussian random variables with unit variance. Therefore, $\sum_{i=0}^{U_c-1} |{\mathbf{f}}_{0,\textrm{BS}}^H{\mathbf{v}}_{i}|^2$ is the summation of $U_c$ i.i.d. exponential random variables which has an $\mathrm{Erlang}(U_c,1)$ distribution. Equivalently, the sum scaled down by $\frac{\sigma^2}{2}$ (i.e., multiplied by $\frac{2}{\sigma^2}$) has a (standard) Chi-squared distribution with $2U_c$ degrees of freedom. Hence, the PDF of $\|{\mathbf{f}}_{0,\textrm{BS}}^H \mathbf{V}\|^2$ is $$\label{eq:pdf_IBS0} f_{\|{\mathbf{f}}_{0,\textrm{BS}}^H \mathbf{V}\|^2} (x) = \frac{x^{Uc-1}e^{-x}}{(U_c-1)!}.$$ From Laplace transform theory we know that $\mathcal{L}\big[t^n e^{-\alpha t}\big] = \frac{n!}{(s+\alpha)^{n+1}}$ and with some simplifications, we obtain the result in step $(a)$. Step $(b)$ in follows from the PDF of $R_{0,\textrm{BS}}$ which is $$f_{R_{0,\textrm{BS}}}(r) = \left\{\begin{array}{ll} \frac{2r}{R^2}, & \textrm{if } 0\leq r \leq R,\\ 0, & \textrm{otherwise}, \end{array} \right.$$ as the typical D2D Rx is uniformly distributed over the cell area and the BS is located in the cell center. Step $(c)$ in is obtained by the change of variable $\frac{1}{\kappa \beta_d r^{-\alpha_c} + 1}\rightarrow t$ which leads to the integral boundary $y \triangleq \frac{1}{\kappa \beta_d R^{-\alpha_c} + 1} $. Finally, $(d)$ follows by integration by part where $\mathcal{B}(x;a,b)$ is the incomplete Beta function defined as $$\label{eq:beta_func} \mathcal{B}(x;a,b) = \int_0^x t^{a-1} (1-t)^{b-1} \mathrm{d}t,$$ for $a,b>0$. Next, we proceed to calculate the second Laplace transform in . This transform is with respect to $I_{d,0}$ in which is a function of two random variables, that is $|g_{0,j}|^2$ and $R_{0,j}$. Therefore, we have $$\begin{aligned} \mathcal{L}_{I_{d,0}} \bigg(\frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}}\bigg) &= \mathbb{E}_{I_{d,0}}\left[\exp\Big(- \frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}} I_{d,0}\Big)\right]\nonumber \\ &= \mathbb{E}_{R_{0,j},|g_{0,j}|^2} \left[\exp\Big(- \frac{\beta_d}{P_dR_{0,0}^{-\alpha_d}} \sum_{j\neq 0} P_d R_{0,j}^{-\alpha_d} |g_{0,j}|^2\Big)\right] \nonumber \\ &= \mathbb{E}_{R_{0,j}} \left[\prod_j \mathbb{E}_{|g_{0,j}|^2}\bigg[\exp\Big(-\frac{\beta_d}{R_{0,0}^{-\alpha_d}} R_{0,j}^{-\alpha_d} |g_{0,j}|^2\Big)\bigg]\right]\nonumber \\ &{\overset{(a)}{=}} \exp\left( -2 \pi \lambda_d \int_0^{\infty} \bigg(1-\mathbb{E}_{G}\bigg[\exp\Big(-\frac{\beta_d}{R_{0,0}^{-\alpha_d}} r^{-\alpha_d} G\Big)\bigg]\bigg)r\,\mathrm{d}r \right) \nonumber \\ &{\overset{(b)}{=}}\exp\left(-2 \pi \lambda_d \int_0^{\infty} \frac{r}{\frac{R_{0,0}^{\alpha_d}}{\beta_d} r^{\alpha_d}+1}\mathrm{d}r \right)\nonumber \\ &{\overset{(c)}{=}} \exp\left(-\frac{\pi \lambda_d}{\mathrm{sinc}(\frac{2}{\alpha_d})}\Big(\frac{\beta_d}{R_{0,0}^{-\alpha_d}}\Big)^{2/\alpha_d}\right), \label{eq:LT_I_d0}\end{aligned}$$ where $(a)$ is based on the probability generating functional (PGFL) [@NET-032], and $(b)$ follows from the fact that $G \sim \exp(1)$ and $\mathcal{L}\big[e^{-t}\big] = \frac{1}{s+1}$. Step $(c)$ follows by solving the integral in step $(b)$ and using $\mathrm{sinc}(x) = \frac{\sin(\pi x)}{\pi x}$. Substituting and in concludes the proof of Proposition \[proposition:P\_succ\_d2d\]. Proof of Proposition \[proposition:P\_succ\_cue\] {#sec:proof_Pcov_cue} ================================================= Substituting $\mathrm{SINR}_c$ from into , we get $$\begin{aligned} \mathrm{P}^c_{\mathrm{cov}}(\beta_c) &= \mathrm{Pr}\left\{ |{\mathbf{h}}_{0}^H {\mathbf{v}}_{0}|^2 \geq \frac{A_d}{\zeta} D_{0,\textrm{BS}}^{\alpha_c}\Big(I_{d,c} + \frac{N_0}{A_d }\Big)\beta_c \right\} \nonumber\\ &{\overset{(a)}{=}} \mathbb{E}_{D_{0,\textrm{BS}}, I_{d,c}}\left[e^{-\frac{A_d}{\zeta} D_{0,\textrm{BS}}^{\alpha_c}(I_{d,c} + \frac{N_0}{A_d})\beta_c } \sum_{k=0}^{T_c - U_c} \frac{1}{k!}\bigg(\frac{A_d}{\zeta} D_{0,\textrm{BS}}^{\alpha_c}\Big(I_{d,c} + \frac{N_0}{A_d}\Big)\beta_c\bigg)^k\right] \nonumber \\ &{\overset{(b)}{=}} \mathbb{E}_{D_{0,\textrm{BS}}, I_{d,c}}\left[e^{-\frac{N_0}{A_d}s} \sum_{k=0}^{T_c - U_c} \frac{s^k}{k!} \sum_{i=0}^{k} \binom{k}{i} \left(\frac{N_0}{A_d }\right)^{k-i} I_{d,c}^i e^{-s I_{d,c}} \right] \nonumber \\ &{\overset{(c)}{=}} \mathbb{E}_{D_{0,\textrm{BS}}}\left[e^{-\frac{N_0}{A_d}s} \sum_{k=0}^{T_c - U_c} \frac{s^k}{k!} \sum_{i=0}^{k} \binom{k}{i} \left(\frac{N_0}{A_d }\right)^{k-i} \mathbb{E}_{I_{d,c}}\Big[I_{d,c}^i e^{-s I_{d,c}} \Big] \right]\nonumber\\ &{\overset{(d)}{=}} \mathbb{E}_{D_{0,\textrm{BS}}}\Bigg[e^{-\frac{N_0}{A_d}s} \sum_{k=0}^{T_c - U_c} \frac{s^k}{k!} \sum_{i=0}^{k} \binom{k}{i} \left(\frac{N_0}{A_d }\right)^{k-i} (-1)^i\frac{\mathrm{d}^i}{{\mathrm{d}s}^i}\mathcal{L}_{I_{d,c}}(s)\Bigg], \label{eq:proof_Prob_cov_CUE}\end{aligned}$$ where $(a)$ follows from the CCDF of $|{\mathbf{h}}_{0}^H {\mathbf{v}}_{0}|^2$ with $2|{\mathbf{h}}_{0}^H {\mathbf{v}}_{0}|^2 \sim \chi^2_{2(T_c-U_c+1)}$ given $D_{0,\textrm{BS}}$ and $I_{d,c}$. In $(b)$, we use Binomial expansion as $$\begin{aligned} \Big(I_{d,c} + \frac{N_0}{A_d}\Big)^k &= \sum_{i=0}^k \binom{k}{i} \left(\frac{N_0}{A_d}\right)^{k-i} I_{d,c}^i,\end{aligned}$$ and $(c)$ follows by taking the expectation with respect to the interference $I_{d,c}$. Step $(d)$ follows from $$\begin{aligned} \mathbb{E}_{I_{d,c}}\Big[I_{d,c}^i e^{-s I_{d,c}} \Big] = (-1)^i \frac{\mathrm{d}^i}{{\mathrm{d}s}^i} \mathcal{L}_{I_{d,c}}(s),\label{eq:E_Idc}\end{aligned}$$ where $\mathcal{L}_{I_{d,c}}(s)$ is obtained using similar steps as in the derivation of $\mathcal{L}_{I_{d,0}}$ in : $$\begin{aligned} \mathcal{L}_{I_{d,c}}(s) = \exp\left(-\frac{\pi \lambda_d P_d^{2/\alpha_d}}{\mathrm{sinc}(\frac{2}{\alpha_d})} s^{2/\alpha_d}\right).\label{eq:L_dc}\end{aligned}$$ Substituting in and using the Faà di Bruno’s formula for the $i$-th derivative of a composite function $f(g(s))$ with $f(s) = e^s$ and $g(s) = - \frac{\pi \lambda_d P_d^{2/\alpha_d}}{\mathrm{sinc}(\frac{2}{\alpha_d})} s^{2/\alpha_d}$, Proposition \[proposition:P\_succ\_cue\] follows.   [^1]: Serveh Shalmashi and Ki Won Sung are with the Dept. of Communication Systems, KTH Royal Institute of Technology, Stockholm, Sweden (emails: {serveh,sungkw}@kth.se). [^2]: Emil Björnson is with the Dept. of Electrical Engineering (ISY), Linköping University, Linköping, Sweden, (email: emil.bjornson@liu.se). [^3]: Marios Kountouris and Mérouane Debbah are with the Mathematical and Algorithmic Sciences Lab, France Research Center, Huawei Technologies Co. Ltd. (emails: {marios.kountouris,merouane.debbah}@huawei.com). [^4]: Part of the material in this paper will be presented at IEEE International Conference on Communications (ICC) Workshop on Device-to-Device Communication for Cellular and Wireless Networks, London, UK, June 2015 [@Shalmashi-2015-ICC]. [^5]: The assumption that the D2D Tx are distributed in the whole $\mathbb{R}^2$ plane removes any concern about the boundary effects and makes the model more mathematically tractable. The boundary effects are local effects in which users at the network boundary experience less interference than the ones closer to the center, because they have fewer neighbors.

Dressmaking project: the evening reception glam LBD I was trying to decide on the material to use for my evening reception dress, I came across the silver and gold lace fabric with the black undertones. I was swithering between them only because I’m partial to silver, but eventually a work friend of mine convinced me to go with the gold and I couldn’t agree more. The next issue I had though was deciding what coloured fabric to use underneath. The type of lace I bought for the evening reception dress is technically same as what I used for the Chinese and white wedding dresses. The only difference between them is they’re in different colours which give the dresses a completely different look and feel when complemented with the different designs. That, my friends, is the versatility and beauty of dressmaking and designing your own garments! My white wedding dress Close up of the lace used for my Chinese wedding dress With the gold lace, there’s a slight black undertone underneath the gold colour accents on the main pattern. I wasn’t sure what the best colour to use underneath. I tried looking for dresses which used the same lace and managed to find a couple, but both used black fabric. I wasn’t sure if black would be too somber a colour for a wedding, but I also wasn’t sure how a nude/peach coloured fabric would look with the black gold lace. It also gives it quite an elegant look too. After looking at various evening and wedding dresses, I decided I liked the subtle contrast of the black background. It looks very elegant, with the matte black fabric complimenting the bright beauty of the metallic gold shimmer. It seems that other designers have the right idea too, just looking for ‘black gold lace dresses’ came up with some pretty beautiful black dresses with gold lace. I’ll be going fabric shopping (again) soon for some black lining and backing fabric now that I’ve decided what colour to use underneath! I’ve already decided that for the evening, I need a dress that I can move and dance in without the restriction of a pencil skirt or a dress I would need to wear heels with. Armed with my Vogue V8667 pattern, I intend to make the sleeveless version of the dress. The funnel neckline means that I can wear a shorter necklace if I wanted to, but if not the lace neckline will also mean that I don’t necessarily need to wear one. We have hired a ceilidh band for the evening, so I will need to make sure I get plenty of air and without sleeves, it’ll certainly help keep my body temperature down! The A-line skirt will allow for movement and will also look quite nice with flats too. The gold of the lace will also go nicely with the gold jewellery I’ve bought to go with my Chinese wedding dress. I’m still working on the bridesmaid dresses at the moment, but hope to have an update with photos for you soon! What do you think of the gold lace and how this will work out for the evening reception dress?

Q: CSS Background-Position not working in .class Recentley tried to make a spritesheet with css and classes for some icons. and found that the css class doesn't work with background-position but ID does now can someone explain me why it does that. My Actual code. I typed the my question to fast and made some mistakes sorry for that. This doesnt work .male { height: 286px; width: 110px; background-position: 0px 0px; } .defender { background: url('../images/classes/human_defender.png'); } <div class="male defender"></div> But when i change the icon1 to an id like so it does work #male { height: 286px; width: 110px; background-position: 0px 0px; } .defender { background: url('../images/classes/human_defender.png'); } <div class="defender" id="male"></div> A: .class { url('backgroundimageurl'); } should be .class {background-image:url(backgroundimageurl);}

Q: how to show tab of view pager on click of navigation drawer item without overlaping? There are three fragments in my app.I showed them in the tabs successfully.Now i want to show fragment of tab1 on the click of navigationdrawer item1 and same for the rest.But there is a problem of overlapping.Can anyone guide me to get rid of this problem? MainActivity.java protected void onCreate(Bundle savedInstanceState) { super.onCreate(savedInstanceState); setContentView(R.layout.activity_main); Toolbar toolbar = (Toolbar) findViewById(R.id.toolbar); setSupportActionBar(toolbar); ViewPager viewPager = (ViewPager) findViewById(R.id.pager); // Set the ViewPagerAdapter into ViewPager viewPager.setAdapter(new ViewPagerAdapter(getSupportFragmentManager())); DrawerLayout drawer = (DrawerLayout) findViewById(R.id.drawer_layout); ActionBarDrawerToggle toggle = new ActionBarDrawerToggle( this, drawer, toolbar, R.string.navigation_drawer_open, R.string.navigation_drawer_close); drawer.setDrawerListener(toggle); toggle.syncState(); NavigationView navigationView = (NavigationView) findViewById(R.id.nav_view); navigationView.setNavigationItemSelectedListener(this); } @Override public void onBackPressed() { DrawerLayout drawer = (DrawerLayout) findViewById(R.id.drawer_layout); if (drawer.isDrawerOpen(GravityCompat.START)) { drawer.closeDrawer(GravityCompat.START); } else { super.onBackPressed(); } } @SuppressWarnings("StatementWithEmptyBody") @Override public boolean onNavigationItemSelected(MenuItem item) { FragmentManager fragmentManager = getSupportFragmentManager(); FragmentTransaction fragmentTransaction = fragmentManager.beginTransaction(); // Handle navigation view item clicks here. int id = item.getItemId(); if (id == R.id.nav_camera) { fragmentOne f1 = new fragmentOne(); fragmentTransaction.replace(R.id.fragment_container,f1); fragmentTransaction.addToBackStack(null); fragmentTransaction.commit(); getSupportActionBar().setTitle("Camera"); } else if (id == R.id.nav_gallery) { fragmentTwo f2 = new fragmentTwo(); fragmentTransaction.replace(R.id.fragment_container,f2); fragmentTransaction.addToBackStack(null); fragmentTransaction.commit(); getSupportActionBar().setTitle("Gallery"); } else if (id == R.id.nav_slideshow) { MenuFragment f3 = new MenuFragment(); fragmentTransaction.replace(R.id.fragment_container,f3); fragmentTransaction.addToBackStack(null); fragmentTransaction.commit(); getSupportActionBar().setTitle("List"); } else if (id == R.id.nav_manage) { } else if (id == R.id.nav_share) { } else if (id == R.id.nav_send) { } DrawerLayout drawer = (DrawerLayout) findViewById(R.id.drawer_layout); drawer.closeDrawer(GravityCompat.START); return true; } } FragmentOne.java public class fragmentOne extends Fragment { TextView t1; public fragmentOne(){ } @Override public View onCreateView(LayoutInflater inflater, ViewGroup container, Bundle savedInstanceState) { // TODO Auto-generated method stub return inflater.inflate(R.layout.fragment_one_layout,container, false); } } ViewPagerAdapter.java public class ViewPagerAdapter extends FragmentPagerAdapter { final int PAGE_COUNT = 3; // Tab Titles private String tabtitles[] = new String[] { "Tab1", "Tab2", "Tab3" }; Context context; public ViewPagerAdapter(FragmentManager fm) { super(fm); } @Override public int getCount() { return PAGE_COUNT; } @Override public Fragment getItem(int position) { switch (position) { // Open FragmentTab1.java case 0: fragmentOne fragmenttab1 = new fragmentOne(); return fragmenttab1; // Open FragmentTab2.java case 1: fragmentTwo fragmenttab2 = new fragmentTwo(); return fragmenttab2; // Open FragmentTab3.java case 2: MenuFragment fragmenttab3 = new MenuFragment(); return fragmenttab3; } return null; } @Override public CharSequence getPageTitle(int position) { return tabtitles[position]; } } MainActivity.xml <?xml version="1.0" encoding="utf-8"?> <RelativeLayout xmlns:android= "http://schemas.android.com/apk/res/android" xmlns:app="http://schemas.android.com/apk/res-auto" xmlns:tools="http://schemas.android.com/tools" android:id="@+id/content_main" android:layout_width="match_parent" android:layout_height="match_parent" android:paddingBottom="@dimen/activity_vertical_margin" android:paddingLeft="@dimen/activity_horizontal_margin" android:paddingRight="@dimen/activity_horizontal_margin" android:paddingTop="@dimen/activity_vertical_margin" app:layout_behavior="@string/appbar_scrolling_view_behavior" tools:context="com.example.chaitanya.navbar.MainActivity" tools:showIn="@layout/app_bar_main"> <android.support.v4.view.ViewPager xmlns:android="http://schemas.android.com/apk/res/android" android:id="@+id/pager" android:layout_width="match_parent" android:layout_height="match_parent" > <android.support.v4.view.PagerTabStrip android:layout_width="match_parent" android:layout_height="wrap_content" android:layout_gravity="top" android:paddingBottom="10dp" android:paddingTop="10dp" android:textColor="#000000" /> </android.support.v4.view.ViewPager> <RelativeLayout android:id="@+id/fragment_container" android:layout_width="match_parent" android:layout_height="wrap_content" android:gravity="center|center_horizontal" ></RelativeLayout> A: Is there a reason you are using a FragmentTransaction? You could call viewPager.setCurrentItem(0); The argument you pass (0 or 1 or 2 or ...) is based on which action you click in the NavigationView. The tabs should update automatically when the ViewPager changes.

4. Is 0 at least as big as b? True Let t be (-3 - -2)*(-4)/(-4). Which is smaller: -3/14 or t? t Suppose l = -0 + 1. Let w = -4 - -2. Let b = w - -4. Do b and l have different values? True Suppose -t + 2 = -0*t. Suppose 5*g - 26 = -11. Let c = g - t. Is -2/5 > c? False Let j be 15/20 + 0 - (-1)/(-2). Let b be 3/12*(-10)/2. Is b > j? False Suppose 5*k + 17 + 23 = 0. Suppose -6 = -3*o - 24. Let r be o/k - (-26)/8. Is r < 2? False Let o = -97 + 52. Let n be (-12)/10*o/36. Is n greater than 2? False Let n = -0.6 - 0.4. Let g = 2/29535 + -561349/2717220. Let m = g - 1/23. Which is bigger: n or m? m Let x = -3/4 + 5/4. Which is smaller: 7 or x? x Suppose -4*j = -7*j + 6. Which is smaller: j or 10/7? 10/7 Let j be (-18)/(-20)*5820/(-16). Let b = j - -327. Is 1 >= b? True Let i = 1703/7866 + -11/171. Let a = i - 463/322. Is -1 > a? True Let s = 5 + -5.4. Let v = s - 0.6. Is -0.1 > v? True Let p be ((-5)/(-2) + -4)*(-4)/(-6). Let x be (-8)/6*3/(-14). Which is bigger: p or x? x Suppose 4*j + 2*r - 12 = -2*r, 2*j = -r + 7. Suppose 4*m = -5*a + 3 + 11, 3*m = 3. Suppose -i + 2*y = a*i + 7, -2 = j*i + y. Are -1/2 and i nonequal? True Let y be (-10)/1*(-4)/(-10). Let j(k) = 3*k + 3 - 2*k + 4. Let s be j(y). Which is bigger: 2 or s? s Suppose 3*v = v. Let l be 10/(-33) - 26/(-39). Is v bigger than l? False Suppose -5*t + 5 = -5*w, 2*t + 1 = w + 3. Let j = 100 - 699/7. Is w <= j? True Suppose -o = l + 5, 36 = -3*o - 3*l + 7*l. Is o bigger than -10? True Let x be (14/(-21))/(5/3). Which is bigger: x or -12? x Let r = 0.2 - -13.8. Let f = r + -16. Which is smaller: 2 or f? f Let y = 88 - -7. Let v be 1/4 - y/(-20). Let b = 1 - v. Which is bigger: -3 or b? -3 Let r be 1*3/(0 + -3). Which is bigger: r or 2/15? 2/15 Let v = -24 + 24.1. Is 5/7 less than v? False Let x(m) = 6*m**2 - 3*m. Let h be x(2). Let p = h - 10. Suppose p*j + 8 = 3*j - o, 4*j = 3*o + 5. Is j at most 1/3? True Let l(d) = d. Let u be l(5). Suppose 0*w - u*w - 55 = 0. Which is smaller: -12 or w? -12 Suppose 3*w - 4 = -2*z + 5*w, 0 = 2*z + 5*w - 32. Let c be -1 - (-2)/(z/9). Let k = 2 - c. Which is greater: -2/11 or k? k Let w be (0 - -2)*(-11)/2. Let t = 15 + w. Suppose 4*q - t = -0*q. Is q less than 3/7? False Let d = 17/57 + -2171/399. Which is smaller: d or -6? -6 Suppose -2*p + v = 4*v + 11, -3*p = -2*v - 16. Let j = -5 - -6. Let s be (j/(-2))/(3/(-18)). Is s bigger than p? True Suppose 0 = b + 2*b + 12, 5*w = -4*b - 16. Suppose w = -3*z - z + 36. Let f = z - 4. Is f bigger than 3? True Let l be (-4)/(-18) + 4/(-18). Let o(q) be the third derivative of -q**5/60 - q**4/24 - q**3/6 + q**2. Let s be o(l). Do s and 1/9 have different values? True Let s = 83 + -84. Is s at least 2/81? False Let c = 82 + -84.8. Which is smaller: 0.1 or c? c Let a be (255/(-102))/(5/4). Let u be 2/1 - (2 - -3). Is u greater than or equal to a? False Let p be (-6)/((-2)/2 - -3). Let a be 2/p*(-3)/(-4). Is 0.2 greater than or equal to a? True Let j = 0.1 - 0.35. Let m = -0.3 - -0.35. Let f = m - j. Which is bigger: f or 1? 1 Suppose p = -2*s + 10, 3*s - 2*p - 26 = 2*p. Is s at least 1? True Let b = 244 + -244. Let z = -39/9707 + 34557427/126191. Let n = -274 + z. Is b >= n? True Let n(h) = -h - 10. Let k(i) = -i**3 - 10*i**2 + i. Let m be k(-10). Let j be n(m). Is j smaller than -1/2? False Let v(j) = j - 4. Let h be v(5). Let o = 17.3 - 15.3. Which is greater: o or h? o Let g(p) = -5*p**2 + p + 3. Let b be g(-2). Which is bigger: b or -18? -18 Suppose 2*f = z + 4*z + 24, z + 2 = -f. Let w be (4/(-3))/(2/6). Is w not equal to z? False Let z = 0.6 - 1.3. Let n = 16 + -15.5. Let d = z + n. Is d < -1? False Let r = 88097811/1549 - 56874. Let k = r - -661498/7745. Let i = k - 85. Are i and -1 unequal? True Let l be (-1)/(-36) + (-6 - -4). Let p = -7/4 - l. Let s be 0/1 - 1*-1. Is p > s? False Let d(z) be the third derivative of z**5/60 + z**3/3 - 4*z**2. Let g be d(3). Which is smaller: g or 10? 10 Let h be 73/(-3)*3/2. Let z = -35 - h. Suppose 6 = 7*a - 1. Is a at least z? False Let h = 25 - 22. Suppose -r + h = 5. Are r and -2 nonequal? False Let l(d) = -d**3 - 6*d**2 - 4*d + 5. Let c be l(-5). Suppose c = 5*j + 4 + 6. Which is smaller: j or -3? -3 Let c(d) = -d**2 - 6*d - 5. Let x = -14 - -11. Let z be c(x). Are z and 4 equal? True Suppose 0 = -7*g + 2*g - 45. Let f = g + 7. Suppose a = -2 - 0. Is f at least a? True Let z be 45/10*(-20)/6. Let q = 44/3 + z. Are q and 1 non-equal? True Suppose -t + 4 = -4*h, -3*h = -4*t - t + 3. Let b = -54/49 - -2204/1911. Which is greater: b or h? b Suppose 4*m = -4*c - 4, 0*c - 3*c + 5*m + 5 = 0. Is -4 != c? True Let g = 9 - 2. Let z = g + -5. Let o = -4 + z. Which is smaller: -1 or o? o Let o = 0 - -10. Let b be o/(-8)*(-10)/(-15). Suppose -3*t = -t. Is t not equal to b? True Suppose 5*r - 14 = -4. Which is bigger: 5/3 or r? r Let g be ((-16)/6)/(1/(-3)). Let z(s) = -14*s - 16 + 2*s**2 + 2*s**2 - s**3 + 7*s**2 + 2*s**3. Let b be z(-12). Is b > g? False Let q(s) = -4*s - 5. Let i be q(-3). Let a = -9 + i. Let n = 2 + -5/2. Which is greater: n or a? n Suppose 0 = t - 0*t. Suppose m - 5*i = 8, t + 1 = -m - 4*i. Let f = 5 - m. Is f smaller than 1? False Let r = 7 - -1. Let u = r + -10. Let a(p) = p + 3. Let q be a(-6). Which is smaller: q or u? q Let u be (5/1)/(1 - 0). Suppose -3*d - 17 = u*o - 0*o, -17 = 4*d + o. Let b be (-1)/6*6/d. Which is greater: b or -0.1? b Let k(x) = x**2 + 5*x + 2. Let w be k(-5). Let u be ((-6)/(-8))/(w/(-8)). Let t be u/(-2)*4/(-3). Are t and -2 unequal? False Suppose 0 = -5*j + 2*t + 18 + 68, 4*j + t - 61 = 0. Suppose r - 5*r = -j. Which is greater: 5 or r? 5 Suppose 0 = -o + 4*o + r - 8, -2*r = -2*o - 8. Which is smaller: 0 or o? 0 Let y = 7.02 - 0.02. Let x = y - 6.8. Are x and 2/3 equal? False Suppose 0 = -4*x + 3*x + 14. Suppose -11*b = -x*b. Which is greater: -2/23 or b? b Let l be 6/(-4) - (-186)/12. Which is smaller: 11 or l? 11 Let l = -5 - -2. Is l greater than or equal to -3? True Let p be 1 + 2*(-971)/9. Let q be 215/(-3)*(1 - -2). Let r = q - p. Is r bigger than 1? False Let t = 5 - 2. Suppose n + 5 = 0, -3*n = -5*y - 4*n + 10. Suppose -1 - 11 = -y*q. Which is greater: t or q? q Let k = -0.06 + -0.52. Let r = k + 0.6. Are r and -2/9 unequal? True Let h = -0.04 - -0.04. Let y = 0.1 - h. Is 0.3 <= y? False Let p = -11 - -5. Let z = 5 + p. Does z = 0? False Let q be (-10)/848 - (-2)/16. Which is smaller: q or 0? 0 Let j be 10/16*2/5. Let s = 6.1 + 0.9. Which is smaller: j or s? j Let d = 8 + -13. Let m = 5 + d. Let z = 4.02 + -0.02. Is z at most as big as m? False Suppose -4*o = -10 - 2. Which is smaller: -1 or o? -1 Let u = 5.04 + -0.04. Let i = u - 6. Is 0 smaller than i? False Suppose x = -1 + 4. Are x and 5 nonequal? True Let w = -7 - 1. Let l = 20 - 27. Which is greater: w or l? l Suppose -3*a + 10 = 2*w - a, 4*w - 4*a + 12 = 0. Suppose -12 = -3*c - c. Let o be c/(w - 1/(-2)). Is 1 >= o? False Let q = 13/109 + -4931/218. Let w = -22 - q. Is w less than or equal to 2? True Suppose 5*n + 2*v + 21 = -v, -v + 4 = -2*n. Which is smaller: n or -8/3? n Let w(t) = -t + 3. Let v be w(4). Let c = -7 + -1. Let x be (c/4)/(19*1). Which is smaller: v or x? v Suppose -4*o - u + 5 = -4, 3 = 3*o - 3*u. Let s be -6*((-76)/(-40) - o). Suppose -6*w = -w. Which is bigger: s or w? s Let m = -4 - -6. Let a = 27 + -46. Let j = -15 - a. Is m at least as big as j? False Let m be (2/6)/((-77)/(-66)). Let f be (-3)/12 + (-1)/(-4). Are m and f equal? False Suppose 3*y - x - 4 = 12, -x - 4 = 0. Is 3 less than or equal to y? True Let s(t) = 3*t**2 - 10*t - 16. Let b(u) = -2*u**2 + 7*u + 11. Let y(q) = -8*b(q) - 5*s(q). Let p be y(7). Is p greater than -1? False Let n be 4/(-339)*9*(-4)/(-24). Do n and -1 have the same value? False Let y = 49/272 - 2/17. Let q = y + 7/16. Are -0.1 and q equal? False Let n(u) = -u - 4*u - 8 + 4*u + 2*u. Let p be n(5). Is p at most -6? False Let g be 7/5*1 + -1. Let f be (-2)/(-8)*(-3 - -1). Is g less than or equal to f? False Suppose -3*i + 12 = -6*i. Let c = -28/93 - 1/31. Which is bigger: i or c? c Let u be 2/(-8) + (-776840)/(-3104). Let m = 250 - u. Which is smaller: m or 0? m Suppose -3*c = 4*b + 4 + 10, -3*c + b - 4 = 0. Let t = 124 + -124. Which is smaller: c or t? c Suppose 4*k - 3*k + 24 = 0. Let t be 18/k - (-2 + 2). Is t grea

Q: Virtual machine and virus on Host The answer should be obvious but I ask anyway. If the host is virus infected with a keylogger and you do sensitive stuff on a virtual linux client, that information is being logged by the keylogger. So if the Host is infected, using a VM is useless, right? What options do I have, beside an anti virus/malware, a new partition with another OS on it and a completely different computer? A: If the host is infected, it's game over. The host O/S sees everything, and even if it's told to ignore things (i.e., redirecting a USB device to the VM), the host can still monitor/log that data. Your options are: use another computer, reinstall your OS, use A/V software, or use a LiveCD. You can try to remove the virus/malware with A/V or another program to clean the system (possibly from a live CD), but to be completely honest it is virtually impossible to guarantee any sort of security after a system has been compromised. There are just too many places and ways for malicious code to hide in a system where A/V and other tools can't detect or clean them out. If this is a business environment where you have security liabilities, or a personal computer with banking details, facebook login cookies or other fun things that a hacker would like to have, then back up your files (make sure they're clean, or you'll just get the virus again) and format and start over.

Ellerker Ellerker is a village and civil parish in the East Riding of Yorkshire, England. It is situated approximately west of Hull city centre and east of the market town of Howden. It lies south of the A63 road junction with the A1034 road. According to the 2011 UK Census, Ellerker parish had a population of 307, a decrease on the 2001 UK Census figure of 320. Ellerker lies within the Parliamentary constituency of Haltemprice and Howden an area that mainly consists of middle class suburbs, towns and villages. The area is affluent and has one of the highest proportions of owner-occupiers in the country. 'Ellerker' means a "marsh where alder trees grow", from Old English alor or aler "alder" and Old Norse kjarr "marsh". The name was recorded as Alrecher in the 11th century and Alekirr in 1139. Same name as Orcher (Normandy, Aurichier 12th century). In 1823 Ellerker was in the parish of Brantingham and the Wapentake of Howdenshire. Village population was 249, including eight farmers, a corn miller, a shopkeeper, a tailor, a shoemaker, and a carpenter. Also listed in directories were three yeomen and a curate of the village church. Once a week a carrier operated from the village to Hull and Wilton. The village church is dedicated to St Anne and is designated as a Grade II listed building. Sir Rafe Ellerker is cited in Part 1 of title 'The Last Years of a Frontier' - DLW Tough, concerning his survey of the Border Marches 1541. References External links Ellerker Parish website Category:Villages in the East Riding of Yorkshire Category:Civil parishes in the East Riding of Yorkshire

Savor This – 48 Hour Film Project 2016 Here is the short film we entered into the 2016 48 Hour Film Project competition in Denver: The competition took place from July 22-24, 2016. Our specifics were: Character: Malik or Malia Simmons Occupation: Architect Line of dialogue: “You’ve got a little something on your shirt.” Prop: Lollipop Genre: Horror OR Buddy Film There was initially some confusion around the name, as we thought it was Malaia, pronounced “muh lay uh.” Though it was clarified Friday night or Saturday morning relatively early, it bled into our actor’s performances. Paul was there to capture the behind-the-scenes video. It’s 30 minutes long, and you can see it right here: Finally, the outtakes. Usually we have quite a few moments we can share, but apparently we were all business when we were on the set for this competition, because there was not a lot to choose from. At least, not a lot that was captured on the cameras we used. (Paul got some good stuff, but you knew that already since you watched the “Making of” above.) On to the outtakes! We did not make it into the “best of” show for Denver this year, but we’re pretty proud of our entry. The team has zero professional filmmakers or actors, but we have a good time and like what we come up with!

Q: Is Blowfish strong enough for VPN encryption? I'm looking at an OpenVPN connection between two sites configured to use 128 bit Blowfish in CBC mode, and trying to figure out how to assess the strength, but I just don't know enough of the maths. I could ask this over on Sec.SE, but there I think the focus might be on whether it should use 3DES instead of Blowfish – here I guess I'm hoping for guidance as to relative strength of the algorithm, and whether a break is realistic when used this way. A: Thomas mentioned some "theoretical weaknesses" that can happen with $2^{32}$ blocks of data with CBC mode and an 8 byte block cipher; I will explore more about what that weakness is, and its practical relevance. In CBC mode, we effectively send randomized data through the block cipher. However, there is a chance that it happens to encrypt the exact same data twice with the same key; this results in the exact same ciphertext block appearing in the encrypted output twice. If an attacker finds this, then he can deduce the exclusive or of the corresponding plaintext blocks. How likely is this to happen? Well, after about $2^{32}$ blocks of data ($2^{35} = 34$ Gigabytes of data), the expected number of times for it to happen is about 1 (it might not happen at all, or it might happen 2 or 3 times); if you encrypt more data, it's expected to happen more often; if you encrypt less, it can still happen (but with a reduced probability of happening). How much effort will an attacker have to go through to find those colliding pairs? Well, not very much; the biggest difficulty that the attacker would have is just dealing with the multigigabytes of data, and that's quite feasible for a determined attacker. How much is this information leakage a security concern? Well, that depends entirely on the nature of the plaintext. The attacker will see the exclusive or of pairs of 8 byte segments, however he has no control over where they might appear. 8 bytes might be enough for him to guess the underlying plaintexts (and then, it might not), and even if he did, we might not care if he can deduce 16 bytes of data out of 34 Gigabytes. On the other hand, maybe we do care -- that's really up to the application. Now, block ciphers with 16 byte blocks (such as AES and Twofish) don't have these concerns (this same weakness can be expected to take place after $2^{68}$ bytes of encrypted data; we will never need to encrypt that much data with a single key). This is one of the reasons we advise people to use more modern ciphers; this observation might not be a concern for a particular user, but with a modern cipher, we know it's not a concern for anyone. A: Both 3DES and Blowfish are from the same pre-2000 era. They both offer adequate security, in the sense of "have been around for some time, no known weakness". Yet, they also both operate on 64-bit blocks. This implies some issues when you begin to encrypt more than about $2^{32}$ blocks of data -- that's 32 gigabytes, a somewhat large but not at all huge amount of data with today's networks. The issues are mostly theoretical (especially with CBC), but an awful lot can hide in a "mostly" (especially with CBC). For the AES competition, NIST required that candidates use 128-bit blocks, for precisely that reason. Twofish is a 128-bit block cipher, designed by the same Bruce Schneier than Blowfish, and is claimed to be "related" to Blowfish, although the lineage is not totally obvious when you look at the algorithms. There is a theoretical attack on 3DES which has cost about $2^{112}$ invocations of DES, along with a storage requirement of $2^{59}$ bytes (half a million terabytes)(if you go to a full million of terabytes, the storage can be hard disks and not RAM, which makes it slightly less unrealistic). That's totally undoable in practice, by a large amount, so no worry here. 3DES and Blowfish mostly differ administratively (3DES is a product of federal bureaucracy, so of course NIST approves of 3DES; whereas Blowfish is from a private individual) and on performance: on a PC, Blowfish is vastly faster than 3DES, whereas with dedicated hardware (FPGA, ASIC) the reverse is true. With a basic PC, the relative slowness of 3DES will not be a problem (or even be detectable) unless you run your VPN over fast links (you could get issues with 100 MBits/s links). A: Triple DES has 168 bit keys, but due to the meet-in-the-middle attack only provides 112 bits of security. Blowfish supports up to 448-bit security. As neither cipher has published practical weaknesses, you are best off looking at key sizes to help you judge strength. Given that, if strength of cipher is your only metric in deciding which cipher to use, it would seem that Blowfish is the better choice. That said, there are probably other things to consider. For example, if this is on the server end, which cipher is more computationally intensive? That would affect how many simultaneous connections you can handle. Furthermore, if your server has a crypto accelerator, the algorithms that the accelerator supports would be important to look into. Other things to find out is what configurations the clients support, etc. Edit: Not sure why I read twofish originally, updated to be more applicable to blowfish.

Boushaki Boushaki (, ) means : Patronym Mohamed Seghir Boushaki (1869-1959), Algerian politician Place Yahia Boushaki, neighbourhood in Algiers

Search This Blog All-U-Can-Eat Hell. World Buffet is a Weird Buffet. West Covina, CA. There are basically two types of people who go to all-you-can-eat buffets. One is the individual who enjoys a lot of variety. She nibbles on a little bit of garden salad, snacks on some mac n’ cheese, samples small servings of shrimp scampi and Salisbury steak until satisfied, then she wipes the corners of her mouth and is off. The other kind views the all-you-can-eat buffet as a challenge, a dare, a double-dog dare with free refills. This diner enjoys pushing the limits of his stomach and esophagus to the point of risking serious injury to gut and gullet such as internal hemorrhaging from overloading on ambrosia fruit salad. This diner (and we all know someone like this or maybe you are this person) views any establishment offering an all-you-can-eat buffet as a sort of mountain that must be summitted or, for the more belligerent eaters, an enemy that must be disemboweled. Eating the buffet out of business is a common joke with these types, but the way and amount they eat wouldn’t make a single buffet owner chuckle. On the contrary, some owners get so angry that they kick out these buffet bingers. Getting ejected from an all-you-can-eat buffet, however, is the ultimate badge of honor for these beasties. It doesn’t happen often, but when it does, it’s a story for their future grandkids around a warm hearth. I hail from the second camp of buffet eaters. Dining at all-you-can-eat buffets was like a competitive sport to me. I hit all genres of buffets from the ubiquitous Chinese buffet to the down home American buffet to the Mexican happy hours to the specialty places that offered a specific item as the all-you-can-eat selection. I’d approach each of these buffets with a different tactic like a pro tennis player going from a grass court to clay. And, yes, I’ve been “kicked out” of all-you-can-eat places: a hot wing joint and a hot pot restaurant. There was no physical grabbing of my collar and tossing me to the curb by some dome-headed buffet bouncer. In both cases the technique was much subtler, like taking more time to bring to the table the next round of hot wings, each time with fewer wings on the plate until none was brought out altogether. But encounters like that only fueled me to do more damage the next time I visited. Must. Eat. More. That was my mantra. At least it was when I was younger, angrier, hungrier. Then, the wear and tear on my belly caught up with me. So gradually and gently, I’ve switched sides and am appreciating the benefits of variety sans gluttony. I’ve learned to graze instead of gorge. Now I taste rather than choke down. Most importantly, I know when to walk away so I can buffet another day. In all honesty, other than the semi-regular trips to the semi-healthy Soup Plantation, I rarely go to buffets anymore. Cutting back on buffets wasn’t just for the sake of my physical health. It was for my mental soundness too. Buffets, especially the Chinese mom and pop ones, depress me. My parents used to own one. It was called the Hong Kong Café. It offered generic, albeit very well made, Americanized Chinese food. It doesn’t exist anymore. It went out of business in two years, and two years of pure hell it was. I was supposed to manage the place but instead I became a glorified busboy. I was also supposed to use my freshly imbibed marketing education from Cal State Fullerton to attract new customers. None of this happened. What did happen were: 14-hour workdays, a steady decrease in our core customer (the fickle business luncher), daily shouting matches between my parents, mounting debts and losses, fat cat investors opening up a bigger buffet across the street, health code violations that ended up on the local television news, deterioration of my mother’s health, and my unraveling sanity. But, boy, somehow we still managed to serve up the best hot and sour soup this side of the Yangtze River with the most tender strips of pork. Eventually, this traumatic family venture would help me lose my taste for the Chinese all-you-can-eat buffet forever. But forever can be a terribly long time. Not long ago my parents came back to the U.S. from another trip to China. I always make sure to pick them up at the airport. “Have you eaten yet?” asks Mama. “Nope,” I reply. I also make sure not to eat before picking my parents up at the airport because they usually want a bite before I bring them back home. “Where do you want to eat?” I ask, knowing already the answer. “Daddy wants Chinese,” Mama answers. Weirdly, whenever they come back from one of their China trips, the first thing they crave is Chinese food — which I suppose is a huge endorsement for authentic Chinese cuisine in Southern California. “Buffet,” my father elaborates. As he made this request, flashbacks of our restaurant failure came at me fast and hard and played in my head with vicious vividity. I couldn’t believe my ears. The particular all-you-can-eat Chinese feed trough my parents decided on was World Buffet in the city of West Covina. This buffet is self-proclaimed as “West Covina’s Best”. This rather modest claim earned instant respect from me and I was curious to see whether it could live up to the boast. Though still reeling from my parents’ lunch choice, I entered the buffet with them anyway. Bright, clean, well staffed and overflowing with food, World Buffet is not a mom n’ pop buffet. World Buffet is big in the Las Vegas buffet tradition. With several generously stocked and enormous, stainless-steel buffet stations from which you can get your glut on, it is very easy to abandon restraint and over do it. My aversion to Chinese buffet was alleviated a bit since there was very little of this place to remind me of the Hong Kong Café. The little angel on my right shoulder suddenly appeared. “Don’t do it.” Soon followed a small puff of smoke and the distinct smell of rotten eggs. My bite-sized, personal devil just grinned and submitted, “Hey, it’s Wednesday. Live a little.” He’s right. It was in fact Wednesday. I should celebrate or something. So I began heaping the various items on to my plate. Laying sushi rolls over oyster-sauced Chinese broccoli which in turn topped a mound of greasy chow mein. There was no rhyme or reason, just quantity. I kept piling it on until it resembled an orgy of food — the film Caligula if directed by Kaga Takeshi. I returned to the table wild-eyed, drooling and ravenous. None of the food on my plate tasted like how it was supposed to. It wasn’t the restaurant’s fault. Everything was so intermingled, marinating in one another’s juices and sauces and seasonings that I may as well dumped the complete contents of my plate into a Cuisinart and turned the entirety into a smoothie. What was wrong with me? I decided to begin fresh. I left my plate on an unoccupied table and grabbed a clean one from the buffet. This time I cruised all of the steam tables first before putting a single thing onto my plate. When I really looked at the buffet, I realized how very bizarre it truly was. In fact, I had never seen so many exotic choices at a single Chinese buffet in my life. This really was a Deep End Dining buffet. So me and my lil’ devil made a pact: I’d consume a themed buffet lunch allowing just the wild side of the steamy food isles to get on the plate but only in sensible portions. What I came back to the table with was bizarre and beautiful. It was a culinary composition of little sea monsters, amputated parts, stomach salad and Russian roulette on a half-shell. Welcome to my buffet. To start off I took a crack at the sautéed whole shrimp. The way you eat this is by going in head first — meaning bite off the head first and then suck out the briny-sweet, creamy-wetness that is the shrimp’s command and control, its brain and head miscellany. The actual shrimp meat is tossed aside. The next items - the dismembered frog legs and baby octopus tentacles - have a leg or two up on most of the dishes found on this vast buffet. They are special items that seem to be cooked more lovingly than the common dishes, maybe because the cooks enjoy eating these things themselves. The frog legs are coated with a fried chicken-esque batter and deep fried. The meat is tender and sweet with a nice crispy intro, no taste of pond scum in the slightest. The baby octopus tentacles were a bit rubbery though not overly. Its spicy seasoning appeared to be an afterthought as the actual tentacle flesh was unpenetrated and therefore somewhat bland. The boiled whole baby octopus, however, was delightful mainly because it was cooked just right so the wee thing was tender and toothsome. But what really complements and enhances the flavor of this cephalopod is the vinegar/ginger/sugar dipping sauce (which you have to make yourself). Sweet, sour and zingy, the boiled octopus really comes back to life in this sauce. I can’t imagine eating it with anything else. Hitting the other parts of the tongue are the planks of spicy and salty gelatinous pig ears. It would’ve been nice to pair these slick yet crunchy bits with a Chinese beer. Unless they are freshly shucked before my eyes, I call raw oysters on any buffet line “Russian roulette on a half-shell”. I think most sensible people would agree that eating raw shellfish which has been sitting out on a buffet for an undeterminable period of time is not sensible. That’s why it’s on my plate. I am the guy who voluntarily places live squirming creatures into his mouth after all. Thank Fortuna, no messy aftermath involving the toilet with this oyster, just a fresh, salty and delicious nibble. I survived this round of “Russian roulette on a half-shell”. Finally for dessert, a sweet and spicy, tripe salad tossed with green and red chili peppers served cold to refresh the taste buds. I hope you’re not ticklish because the omasum tripe is one of the chambers of the bovine’s stomach that is chock-full of villi — tiny, bristly nubs riddling the surface of this offal and a key texture component to the dish, also aids in the absorption of nutrients (not your nutrients, the cow’s when it was still alive). So it appears my return to the all-you-can-eat buffet can be a civilized affair. At the end of the meal, I didn’t have to loosen notches on the belt. I didn’t need assistance getting up from my seat. There was no waddling to the car. I didn’t moan the words, “Why did I eat so much?” Most importantly, I didn’t hurt myself. The healing begins now. I can’t do anything about my family’s failed restaurant venture. That’s in the past and we have moved on. Well, most of us. I still need to shout at something once in a while, especially when I catch an episode of Ramsay’s Kitchen Nightmares. I scream at full volume, “Where were you, Gordon, you twat?!!! Where was your craggly, abusive ass when I needed you to save my family’s restaurant??” In time, I will be fine. Time heals all wounds, so they promise. Me, Mom and Pops all began our healing with this meal at the World Buffet in charming West Covina. The best part was there was room left in us for a vanilla soft-serve frozen yogurt with sprinkles. Well thanks are in order for representing the "nibbler" who scans the buffet and gets excited because today she can make a salad with bacon bits! And as I'm eating my crunchy salad there is my husband with 5 sticky used plates already piled with a look of "I'm on a mission" glazed over his face. I was laughing out loud in my office reading this. I know EXACTLY who you're talking about (buffet diner class II). I'm in MI; one of the most OBESE states in our union. I don't go to buffets, but I have seen the people who do. I hope the booths are reinforced. It's nice to know there is a semi-classy buffet in the world - something totally unlike The Old Country Buffet - a truly heinous and morbid institution! Ouch. I feel for you, my friend. Running a restaurant is hard, unrewarding work. That's why I'm so big on mom & pops. Babbo, the French Laundry, and Providence don't need our help and support. The hype machine is already working full tilt for them. It's little family run places that need every diner they can get. i feel you both. been on both sides of the buffet eater camps now and i have to say the nibbler is the way to go. steamykitchen, somehow that doesn't surprise me that you suck the daylights out of the head and hand your mom the rest of the shrimp. however, my mind boggles at how many shrimp heads in this country must be tossed into the trash all day long. tragic. anony, glad i could make you laugh at the expense of those buffet bingin' bigguns. chubbs, have you or your family owned a restaurant before? either way, thanks for the sympathy. mom & pop's forever. cheapo david, the buffet is a smidge above 7 bucks for lunch during the weekdays. call the restaurant for dinner prices. info at the end of my post. thanks. I noticed anonymous said they were in Michigan, one of the most obese states in the nation. I'm from Northern Michigan and recently had surgery. When in the surgeon's office I was asked to wrap myself in a sheet gown. I think it went around four times.The surgeon said that's how it is in Michigan now. anonymous...I had very tiny feet sticking from the tent. I hope the gowns are chosen according to size soon. I believe it's the first time in my life that i have heard 'twat' being used by an American Chinese man. The head of shrimps taste good! In fact, sometimes I eat everything, the brains, the body and all the shell. If you chew it enough, it seems to go down all right. Eating the fish eyes of steamed fish kicks ass too. My Mum always offers me the fish eyes whenever we eat a Chinese meal with steamed fish. This isn't punishment, on the contrary, it is a sign of sincere affection and in a way, a sacrifice. My Mum loves the fish head the most, and the eyes too.

Applicants claim the foreign priority benefits under 35 U.S.C. xc2xa7 119 of European Patent Application No. 99113020.4, filed in the European Patent Office on Jul. 7, 1999. The European application is incorporated by reference into this application. The present invention is from the area of notification systems and message brokering. In particular, the present invention relates to the area of processing notifications and in particular of publish and subscribe requests. The present invention has a very general scope. Its basic principles can be applied in any situation in which any notification process or brokering, and in particular publish and subscribe processes take place. The present invention introduces database technology into these matters of interest. It should be understood that for the sake of this invention the data model of the database system is irrelevant. Also, the database system might manage persistent data on disk or might manage data in main memory, i.e. a main memory database. Nevertheless, the terminology of relational database systems is persistently used in here for simplicity and increased clarity. In general, a message broker is an instrument which is applied in a situation where messages are often and sometimes periodically sent from a plurality of message sources m to a plurality of message sinks n in a m/n relationship. Special cases of 1:m and n:1 occur as well. Message brokers xe2x80x98sharexe2x80x99 messages in a way that a sourcexe2x80x94often being any kind of program applicationxe2x80x94needs to transmit only one message and the broker delivers one or many versions of it to one or more sinks which are often applications as well. Further details on message broker systems can be found in R. Schulte, Message Brokers: A focused approach to application integration, Gartner Group, Strategic Analysis Report SSA R-401-102, 1996. More particularly, a message broker is like a hub where messages are streaming in and are streaming out. The messages which are streaming into the broker are referred to hereinafter as being published. Messages which are streaming out of the broker are referred to as being subscribed. A subscription request specifies the subset of all incoming messages a particular application is interested in, and the format in which it has to be presented to the subscriber. For example, various stock exchanges might publish stock data periodically, i.e. the stock data is sent to the message broker. Each stock exchange might use a different format to transfer its data. A subscriber might have registered to all messages about IBM stock data exceeding $103 and might request its delivery in XML format. In state-of-the-art message brokers that provide publish/subscribe functionality significant effort is spent in managing the published messages and the subscriptions. This management is typically performed by using its own mechanisms. The present invention proposes to use object-relational database technology to implement publish/subscribe functionality. State-of-the-art message brokers typically deal with messages that are being published and that subscribers would like to know about. However, subscribers are not just interested in messages that are being published, but also in changes that are applied to data stored in one or more tables in one or more databases. The present invention implements this functionality based on object-relational database technology. Thus, it would be desirable to alleviate this big amount of programming, customizing effort. The above-cited prior art reference analyzes the feasibility of database technology used as a base for message brokering. It concludes that database systems lack many features that are necessary for message brokering, e.g., the middleware designed for performing the brokering, such as interface engines and message switches. Thus, a database technology as a base for message brokering is rejected in the above cited reference as being too difficult and complex to realize, and too slow in performance. When analyzing the behavior of publish/subscribe technology using a database oriented view, the following observation can be made: a subscription request is similar to a query. Based on what has been specified in the subscription request, messages are filtered out and are delivered to its recipient. But there is a fundamental operational difference between a query and a subscription: A subscription does not operate on all messages stored for example in a message warehouse but only on a single message at a time, namely the message that has just been published to the message broker. Furthermore, typically many subscriptions will be registered with a message broker, i.e. identifying subscriptions with queries will result in the situation in which many queries will have to be evaluated on a single message: This situation reverses the situation typically found in query systems where the number of data items to be inspected exceeds the number of queries by many orders of magnitudes. The proposal of the present invention to use object-relational database technology for publish/subscribe technology faces two problem areas that must be solved: Firstly, how to efficiently identify operational data that is relevant to be published and secondly, how to perform subscriptions efficiently based on externalized database technology. The first problem area results from the fact that most message brokers are not implemented based on database technology, and that in business environments having a natural need for management relevant enterprise data particular modifications of e.g., operational data are often seen as events that are relevant for external applications. This is depicted in FIG. 1. For example, if a new tuple is inserted into a table, a person might want to be informed about this fact via a corresponding e-mail, or an application must be invoked because of this, or a message broker in turn has subscribers that want to get this data. Thus, the database may be seen as a source for publications. In particular, when a message broker is used to manage the subscription requests for the changes in operational data and thus the operational data changes need to be published to the message broker, the importance of pre-filtering of publications becomes obvious. If each of the huge number of changes of operational data is pushed to the message broker which then determines whether or not a subscriber for the subject change exists, lots of data may be processed unnecessarily. This might be a waste of resources. Thus, providing subscription functionality within a database system is beneficial, in general. Otherwise, without having subscription features natively provided within the database system the modified data has to be transformed into a message, then has to be sent, i.e. published to a separate message broker, and this message broker has to determine all corresponding subscribers. In this approach the database would be considered to be a publisher only, the message broker""s subscription engine is used to determine whether or not any subscriber is interested in the modified data. If no subscriber is interested in this data communication between the database system and the message broker including associated data transformations etc. then much work and traffic is performed in vain putting unnecessary load onto the overall environment. Furthermore, a usage of a separate subscription engine would ignore the fact, that the database system""s query capability can be immediately used to process the subscriptions directly without needing a separate message broker enginexe2x80x94this will further improve efficiency. The second problem deals with efficiency of implementing subscriptions based on database technology itself. Nearly all relational database systems are supporting trigger mechanisms today. Triggers allow the database system to automatically perform an action based on a registered interest on relevant modifications of data. There seems to be a suggestion for recognizing a xe2x80x98naturalxe2x80x99 fit between triggers and subscriptions. Simply map each subscription request onto a corresponding trigger. For example, assuming that a STOCK table contains rows reporting the NAME of a company, its actual stock PRICE, and the AMOUNT traded. Then, each subscription on modified stock data is mapped to a separate trigger in this table. Please refer to FIG. 2 for a sample mapping of a particular subscription. If a number of S(T) subscribers, with T as an abbreviation for xe2x80x98tablexe2x80x99, have registered for modifications on a given table T, and a number of n(T) modifications happen per second on this table, then S(T)xc3x97n(T) triggers have to be run per second for table T. In practice, this number is even larger because more than one table will be of interest for subscriptions. If there are 10 modifications on the stock table per second and 100 subscriptions, both moderate estimates, 1,000 triggers have to be run on this single table. This is out of the scope of current database technology. Therefore, the object of the present invention is to provide a method and system for efficient usage of database technology for notifications, and in particular for subscriptions. These objects of the invention are achieved by the features stated in enclosed independent claims. Further advantageous arrangements and embodiments of the invention are set forth in the respective subclaims. The present invention teaches in general how to efficiently exploit active database technology and extensible database technology, i.e. triggers and user-defined functions, for processing subscriptions. According to a first aspect of the present invention it is proposed to aggregate all subscriptions on a certain table, or more generally of a plurality of tables, into a single trigger on this table or tables, respectively. This will dramatically improve the trigger-based efficiency. According to a second aspect of the present invention it is proposed to deliver the information a subscriber has registered for, by exploiting the database system provided facility of user-defined functions. This allows the creation of the information to be sent to the subscriber(s) from the address space the database system is running, which is another source of efficiency improvement. The overall processing can thus be summarized as follows: When a first subscription is registered for a table T this kind of xe2x80x9caggregated subscription triggerxe2x80x9d is created on the table T, and a collection of so-called metadata tables suitable to hold all subscriptions for the table T is created which is called ENABLE TABLE, depicted in FIG. 3. It should be noted that this function can also be realized as a separate utility explicitly to be invoked by an administrator, for example. Preferred embodiments for creating suitable metadata tables and for creating aggregated subscription triggers are described later in more detail. Each single subscription is reflected by xe2x80x9csimplyxe2x80x9d INSERTing appropriate tuples into these latter metadata tables, i.e. according to the invention no separate trigger is created and no modification on the single subscription trigger has to be applied. A preferred embodiment for reflecting a subscription as tuples in the associated metadata tables is described in detail. When a tuple is manipulated in table T which corresponds to a publication in a usual prior art message broker the corresponding trigger fires and determines in a single invocation all subscribers interested in modification of tuples. Using a single subscription trigger to achieve the desired efficient usage of the database system""s trigger features has its price in that. The query in the body of the trigger must be a more complicated one as it basically has to search for all potential subscribers in the associated collected metadata tables. Depending on the embodiment of the present invention this might involve at least an n-way join where n is the number of comparison operators supported in subscription filters for the target table. Nevertheless, query systems have been optimized for decades to perform n-way joins very efficiently. With reference to the notification which is initiated by the database trigger it should be mentioned that the inventional concept is very general in this respect. Notification could mean, for example, that a message in the sense of a messaging system is sent, an action is performed on an object managed on an object server, or, an e-mail is sent to the subscriber. It could be even inserted into a table that is maintained for each subscriber, which allows the subscriber to retrieve the appropriate notifications by querying the table. With respect to the second aspect of the present invention as mentioned above the actual construction of the notification to be sent to each qualified subscriber can be done based on a so-called user-defined function (UDF). While the filter of the query in the body of the trigger determines the qualifying subscribers, the SELECT-clause of the query may reference a UDF which initiates the delivery of the notification to each subscriber. This delivery UDF is automatically invoked by the database system for each qualified subscriber. The delivery function will get all data necessary, e.g., the relevant values of the modified tuple which caused the firing of the trigger, the recipients address, etc., to construct the notification. Based on this data passed, the delivery function will construct the notification and send it to the recipient""s address, e.g. via a message queuing system like MQSeries, via e-mail etc. A preferred embodiment of the delivery UDF is described in more detail later. As an advantage, the present invention builds an efficient subscription mechanism on top of existing database functionality. No modifications to the database system are required. Thus, a standard object-relational database system can be utilized, as it is, to implement a publish/subscribe engine. Furthermore, the subscription mechanism described easily transforms a database into a publisher of messages.

Biochemical characterization of the third domain from Bacillus thuringiensis Cry1A toxins. Cry proteins from Bacillus thuringiensis have insecticidal properties. The function of domains I and II has been described but domain III has so far eluded understanding. Domain III from Cry1Ab and Cry1Ac has been cloned, expressed in E. coli and injected to rabbits with the aid of characterizing them immunologically. Interestingly, polyclonal antibodies against Cry1Ab fragment did not recognize either the native Cry1Ab toxin or the Cry1Ac fragment while those against the latter did recognize either the native Cry1Ac toxin or the Cry1Ab protein fragment. A combination of information from sequence comparison and hydrophobicity profile indicates that these protein fragments possibly adopt different spatial dispositions within the respective toxins.

RBI keeps key policy rates on hold as uncertainties loom While the decision on keeping the policy rate unchanged was unanimous, Ravindra H Dholakia voted to change the stance to neutral. In its last bi-monthly monetary policy , the RBI, against the popular opinion had kept the repo rate unchanged at 6.50 per cent. Nokia 7.1 up for pre-orders in India; Price, offers and more For the camera duties, the smartphone comes with an 8-megapixel sensor with f/2 aperture and 85-degree field of view at the front. This is an Android One phone now running Pie, but it will receive OS updates for 2 years and security updates for 3 years. Why Ariana Grande only dates famous men Ariana Grande may have said " thank u, next " to Pete Davidson but that doesn't mean she no longer cares for his wellbeing. As fans know, the star has a song named Pete Davidson on her latest album, Sweetener. "I've kept my mouth shut. "Surviving R. Kelly" Premiere Evacuated Due To Gun Threats Threats of a bomb and possible shooter shut down a much-anticipated NY screening of the upcoming Lifetime docuseries Surviving R. It was also attended by Tarana Burke , who coined the hashtag "Me Too" and works as a prominent activist within the movement. Wolves vs. Chelsea live stream Wolves supporters are hoping that the team that plays up to their competition shows up Wednesday against Chelsea . Chelsea FC are looking to finish in the top four this season after the Blues ended up in fifth spot last term. First baby born via uterus transplanted from dead donor The recipient had her first menstruation 37 days after the uterus transplant , and continued to have regular cycles after that. She was born in December 2017 but details of the case were only released yesterday in The Lancet Journal . Meghan Markle Owes Her Acting Career to Julia Roberts Kensington Palace has issued a rare statement about a recent alleged argument between Meghan Markle and Kate Middleton. The Duchess of Sussex made an announced solo visit to the King's College London on Wednesday, December 5. The royal mom-to-be wore a dark outfit for the occasion, while styling her dark tresses down. Meghan was photographed sitting during the discussions, taking notes. "William and Kate are playing Santa at Christmas" Murphy joked, explaining that the Duke and Duchess of Cambridge are delivering presents and cards they collected at the party on Tuesday from family and friends of the personnel serving in Cyprus. The duchess chose the Lover's Knot, a diamond and pearl encrusted piece that dates back to 1914, previously preferred by her late mother-in-law Princess Diana. "As a university graduate, I know the personal feeling of pride and excitement that comes with attending university". Dean Kirby 1 day Monday December 3rd 2018 The best dumpling chain in the world is about to open in London Food & Drink Guests described the event as "one of the best" as they left afterwards, citing Meghan's reading and a speech from Harry among the highlights. The pair continued to chat about their charitable endeavours with a focus on educational programmes for women in less economically developed countries. Michelle Obama encouraged Meghan to try not to hurry in to doing everything at once and to take her time. Providing them with access to education is the key to economic and social development. Once the newest royal baby arrives, he or she will have plenty of built-in friends, and Kate Middleton recently discussed the family's upcoming arrival during an event last week. "They also talked about shared experiences of pregnancy and raising children, plus shared causes including girls' education". The charity aims to fight poverty in Uganda and it was set up in memory of Henry van Straubenzee, a close friend of Prince Harry who died at the age of 18 in a vehicle crash.

Pages Thursday, March 2, 2017 “Now then,” I told Lady, “we have to get straight down to work, since it now turns out that you absolutely cannot listen to the Tchaikovsky or the Prokofiev that I was trying to fob off on you, yesterday.” “Wonderful,” said Lady, “since I am either under general anesthesia, or very soon to be so, or just out of. Anyway, I’m languishing here at Centro Médico, which, as you know, is ideally suited to languishing. So it’s completely inappropriate that you even think of putting me in your blog, today.” “Deadline,” I told her. “If it’s 31 days, it’s 31 days. And now it turns out that I’ve wasted nearly 1/31th of them, since the Tchaikovsky and the Prokofiev were no-go’s.” “What’s the matter with those guys?” “Well, a very-intelligent reader of this blog deemed Tchaikovsky’s music ‘pathetic….’” “Well, is it?” “Quite possibly,” I told her. “Let’s put it this way: if you are attending a cocktail party held by the International Association of Music Critics, do not drop the name of Tchaikovsky as one of your ‘go-to’ guys….” “Wonderful,” she said. “Another thing for my anesthiated mind to wrap around. Or around which to wrap, just to satisfy Mr. Fernández.” “Yes, about his prepositions he is persnickety. Anyway, today I have to get right on track. Though I have to say, I feel distinctly unsettled today…” “Indeed? And has anybody been doing surgery on you? If not, you’re definitely settled, or even in fact well-populated….” “It’s the day after Ash Wednesday,” I told her, “and Ash Wednesday is always jarring to me. In fact, I won’t feel better until we get Jesus out of the desert, onto the cross, into the tomb, and then resurrected again. I hate not knowing the outcome of things….” “Surely there isn’t much doubt…” “Easy for you to say: You’re a believer.” “Well, I believe in God,” said Lady, “just not so much the other stuff.” “You know, that totally irks me,” I told her. “Because believe me, it’s no fun being an atheist. Everybody thinks I just sail through life, never shedding a scruple. But it’s just the opposite! First of all, I have to work twice as hard to be a good person, and then I have to worry about everything that you believers know is going to happen. So Advent is torment, since what happens if God forgets to blow into Mary’s ear?” “God blew into Mary’s ear?” “Think I read that somewhere, but did a Google search help? Of course not. And that’s the point—if I had any sort of belief, I’d know all about God and the Virgin Mary’s ear. It just increases the angst, somehow, not knowing and having to worry all the same….” “Hmm,” said Lady, “rather like being in the hospital, awaiting surgery?” “Err, yes….” “Well, anyway, don’t you have some work to do? You completely flubbed yesterday, you know, and given that you’re just three days in, it doesn’t look promising.” “That’s the problem,” I told her. “What if I do something really criminal, like recommending Elgar? Or Smetana? They’d probably take away my musician’s license.” “Don’t tell me…” “Well, of course! You wouldn’t want anyone un-credentialed or unauthorized to be performing ‘music,’ would you?” “Hmm,” she said, “not a bad idea. Let’s see, there could be a poet’s license, as opposed…” “…to poetic license,” we said in unison. “Anyway,” I told her, “I’m completely unsure what music to play, or indeed, if it’s OK to play any music at all, during Lent. But obviously it has to be something religious, and that’s a problem, because we could do a whole year of religious music, and still not have scratched the surface. Damn, and at some point, I suppose I’ll have to tackle the passions….” “Tackle the passions,” said Lady. “And exactly what sort of blog am I being dragged into, this dread day that I’m spending in Centro Médico? You might wait a day or two, until the anesthesia entirely wears off, before tackling any passions with me!” “Theologically speaking, you have nothing to worry about,” I told her. “Passion—from the past participle of the Latin verb patī….” “I intend to,” I told her, “though the word ‘passion’ here refers only to the suffering of Christ…” “Only?” she asked.“You call being crucified….” “We’re well astray, here,” I told her. “anyway, it’s very much on my mind to do something about Buxtehude, since generally speaking, very few people do anything about Buxtehude.” “Well, since he died in 1704 why in the world should anyone do anything about Buxtehude? What do you want—a mass said? Flowers on the grave? And is it true, by the way…” “Why do you always hit on the scandalous bits of every composer? Wasn’t it enough that Bach walked 200 unauthorized miles or so to study with Buxtehude? Bach! But now you’re going to dredge up the story…” “Well, I just wanted to know….” “Yes, he seems to have had seven daughters, the eldest of which was Anna Margareta. And yes, Handel, Bach, and a guy named Johann Matheson all got the same pitch. Buxtehude was ready for retirement, and perfectly happy to give up his post to any of the three…” “Hah!” said Lady. “I knew it! So Anna Margareta got thrown into the bargain! And since all three skedaddled, well, she couldn’t have been too much of a beauty! My my, how the human resources profession has blossomed, over the years!” “Surgery has done little to improve your mood,” I told her. “How would you like to go through history as the eldest daughter of Dieterich Buxtehude? Snigger, snigger, all down the centuries!” “I would disdain to snigger,” said Lady. “And certainly not down the centuries. All right—let’s have Buxtehude, if we must. What’s it to be?” “Membra Jesu Nostri,” I told her. “Actually, just the second cantata of the seven. You know, after the seven….” “…limbs of Christ. But I’ve never gotten: why are the knees considered limbs?” “Probably just to get it up to seven,” I told her. “You know, it’s one of those numbers that has all that symbolism attached to it. Anyway, whether the knees are limbs or not, the image is wonderful. ‘You will be brought to nurse, and be dandled on the knees….’ Who doesn’t wish for that?” “It is a particularly strong post-surgical yearning,” said Lady. “Yes, dandling! Well, and is that all for the day? Surely there’s something more up that authorial or musical sleeve?” “Well, there’s always Biber—that is, Heinrich Ignaz Franz Biber….” “Dear me, he certainly went a long way to distinguish himself just Justin…” “Wouldn’t you? Makes checking into a hotel, or a country inn, lots easier.” “Obviously. OK—so what are we hearing from HIF Biber?” “HIF?” “Henry, or whatever…” “A civil tongue,” I told her, “which is what you ought to keep. Well, how about the introit from the Requiem a 15? True, it starts out a bit slow, but after 45 seconds or so, it turns just glorious. And it’s a nice introduction to requiems, you know.” “Am I to be introduced to requiems?” said Lady. “Are they the sort to whom a lady, or especially a Lady, might be introduced? And how much of an acquaintance am I supposed to have with them? It would make a difference, when I set out to buy the Thanksgiving turkey.” “They’re quite circumspect,” I told her, “and really need little in the area of entertaining. And since it is a mass for the repose of the soul of the dead…” “First dandling,” said Lady, “and now repose. Well, well, I suppose I can give it a listen. Unless, of course, you have somebody else that I’m supposed to blather on about? Really, Marc, I have just had surgery!” “Well, there’s always Zelenka,” I started off saying. But the Biber had done its work. I looked at her, and the old nurse in me checked her breathing: yes, the chest was rising and falling rhythmically. It was cold in the room, so I drew the blanket she had brought from home up to her cheeks. And then, since she didn’t have to answer, I asked her the question. Life, Death and Iguanas Life, Death…and Iguanas?Yes, that’s the title of an e-book available on Amazon / Kindle. It’s the story of a woman who took charge of her death, just as she had her life. Of a family that split, and then united. Of a man who decided to live. Oh, and there’s some great stuff about iguanas….Read the first chapter by clicking here!

Blog Posts Protechwood – Laying Patio Pavers in Seven Easy Measures Laying patio pavers is one of the least complicated selections to make an inviting outside residing space. These are a major option since they are elegant, strong and appear in a entire menu of designs, dimensions and layouts so no matter what your taste is, it is easy to uncover patterns that are interesting to you. one. Evaluate – Your initially move in your Diy challenge is to determine the spot or sizing of your paver patio. By figuring out the sq. footage, you will be in a position to estimate the volume of material that you will will need as very well as the cost. Using a can of spray paint, mark your spot. Be absolutely sure to allow for for a footing foundation and edge restraints. 2. Materials – Decide on your paver layouts and estimate how many you will will need primarily based on the measurements. Most concrete and paver sellers will assistance you determine what you will need for your do it by yourself patio. You will also will need to aspect sand and gravel into your options. Preserve in thoughts, you are usually far better off to have a little little bit too a lot item than not more than enough. 3. Preparation – One of the most important actions of the set up is digging and getting ready the spot. Use a shovel or a loader to very clear the space about 8 inches deep. Usually obey any digging guidelines and be conscious of buried cables. For far better assist, lay landscape material down right before you start pouring the gravel. Then, rake the gravel out into the spot. four. Gravel – Using a 2 x four, quality the foundation of the patio to make a sloped runoff for water, usually building absolutely sure that it manipulates water away from your dwelling. If your gravel is dry, use your back garden hose to moist it so that you can pack it far better. 5. Sand – Pour down some mason sand and quality the patio spot once once again. You need to only be introducing a lot less than 50 % of an inch of sand. This will fill in any cracks and give you a clean end to get the job done with. six. Pavers – Lay your pavers down in your preferred pattern. Aim to preserve them as restricted together as attainable. Preserve in thoughts that if you opted for the shape of your patio to have any form of curve, you will have to use a diamond paver blade and a observed to cut and in good shape some of the parts. seven. Finishing Touches – Protected a plastic edge restraint with spikes that are spaced about two ft aside. Pour some extremely fantastic mason sand on the patio and sweep it into any cracks. When laying patio pavers, this is an important move so no objects can get wedged in there this sort of as twigs or tiny pebbles. Fill the edges with black filth and possibly end with edging or lay grass seed in which preferred.

LO Reads 2014: Lewis & Clark College Two-day Symposium Date/Time: Fri, Feb 7, 2014 3:00pm Day #1: Friday, February 7, 3:00 - 5:15 pm; Day #2: Saturday, February 8, 9:30 - 6:00 pm. 0615 SW Palatine Hill Road, Portland, Miller Hall. Free, but please register (link at bottom of page under "Web Links). A free two-day symposium, “You Must Revise Your Life” – Stafford at 100, a Celebration and Reassessment, will be held on the Lewis & Clark campus featuring faculty, students, staff, scholars, and poets. The symposium is an opportunity to see Stafford’s influence on the arts as a whole, look at his work as a photographer, and reflect on his influence on music, art, and the written word.

Q: Slow down CPU to simulate slower computers in browser testing I'm trying to see how our web pages behave on an average customer's computer. We have not yet pinned down this configuration, but it's likely to be slower than what our developers and testers will have. I've seen answers to similar questions that suggest throttling bandwidth and using a VM where the memory has been limited, but do I also need to slow down the CPU? I am under the impression that the CPU will run fairly close to full speed, even in a VM. Are there virtual machine platforms that allow you to limit the CPU cycles? I saw one suggestion to run something like Folding @ Home, but I would welcome other suggestions to throttle the CPU speed. I've seen this question: How to Slow down the browser, and others that talk about limiting bandwidth. Edit: I suppose I need to be concerned about how many cores/processors are available to the VM as well. Do most VM platforms give you the option of limiting this? A: This is a fast solution, but not very accurate when it comes to end-user specs, but it helps a lot to test things on slower systems: Go to Power Options -> Create a power plan -> Change advanced power settings and set CPU Maximum Rate to 5% or how much you need. This usually helps test browser apps on slower configs. A: In multi core systems running vista or better you can set the cpu affinity forcing the browser to run only on a single core For example c:\windows\system32\cmd.exe /C start /affinity 1 notepad.exe Individual cores on most machines these days aren't significantly faster than a couple of generations ago. That said you will find that due to architecture changes the cache is probably larger and the ram will be faster both of which make a significant difference. Have you considered just buying an old pc from ebay or your local free adds. I suspect the cost in wages of having a member of staff do the necessary research, set up your limited ram vm and add core binding shortcuts for the major browsers etc would buy you a fair few old boxes, complete with older os (and if your really lucky all the last owners spyware and browser toolbars for an extra accurate simulation of your end users pcs) A: Adding to CatalinBerta's answer which worked great for me. You also need to keep in mind that it's not just the CPU you want slow down. Browsers typically rely on GPU's for painting and composting the webpage as well as for complex animations. If you want to simulate worst case scenario, try disabling all of your Display Adapters in Device Manager, which will closely resemble clients using computers at public libraries. For Windows: Start > search "Device Manager" > Expand Display Adapters > right click each item > Disable

Synopsis Lucas Davenport has seen many terrible murder scenes. This is one of the worst. In the small Minnesota town of Deephaven, an entire family has been killed—husband, wife, two daughters, dogs. There’s something about the scene that pokes at Lucas’s cop instincts—it looks an awful lot like the kind of scorched-earth retribution he’s seen in drug killings sometimes. But this is a seriously upscale town, and the husband was an executive vice president at a big bank. It just doesn’t seem to fit. Until it does. And where it leads Lucas will take him into the darkest nightmare of his life.

--- abstract: 'In recent years, convolutional neural networks have demonstrated promising performance in a variety of medical image segmentation tasks. However, when a trained segmentation model is deployed into the real clinical world, the model may not perform optimally. A major challenge is the potential poor-quality segmentations generated due to degraded image quality or domain shift issues. There is a timely need to develop an automated quality control method that can detect poor segmentations and feedback to clinicians. Here we propose a novel deep generative model-based framework for quality control of cardiac MRI segmentation. It first learns a manifold of good-quality image-segmentation pairs using a generative model. The quality of a given test segmentation is then assessed by evaluating the difference from its projection onto the good-quality manifold. In particular, the projection is refined through iterative search in the latent space. The proposed method achieves high prediction accuracy on two publicly available cardiac MRI datasets. Moreover, it shows better generalisation ability than traditional regression-based methods. Our approach provides a real-time and model-agnostic quality control for cardiac MRI segmentation, which has the potential to be integrated into clinical image analysis workflows.' author: - | Shuo Wang(), Giacomo Tarroni , Chen Qin ,\ Yuanhan Mo , Chengliang Dai , Chen Chen ,\ Ben Glocker , Yike Guo, Daniel Rueckert, and Wenjia Bai bibliography: - 'ref.bib' title: 'Deep Generative Model-based Quality Control for Cardiac MRI Segmentation' --- Introduction ============ Cardiovascular diseases (CVDs) are the leading cause of death globally, taking more than 18 million lives every year [@WHOScaleStroke.]. Cardiac magnetic resonance imaging (MRI) has been widely used in clinical practice for evaluating cardiac structure and function. To derive quantitative measures from cardiac MRI, accurate segmentation is of great importance. Over the past few years, various architectures of convolutional neural networks (CNNs) have been developed to deliver state-of-the-art performance in the task of automated cardiac MRI segmentation [@bai2018automated; @tao2019deep; @bernard2018deep; @zheng20183]. Although satisfactory performance has been achieved on specific datasets, care must be taken when deploying these models into clinical practice. In fact, it is inevitable for automated segmentation algorithms (not limited to CNN-based) to generate a number of poor-quality segmentations in real-world scenarios, due to differences in scanner models and acquisition protocols as well as potential poor image quality and motion artifacts. Therefore, reliable quality control (QC) of cardiac MRI segmentation on a per-case basis is highly desired and of great importance for successful translation into clinical practice. ### Related work: Numerous efforts have been devoted into quality control of medical images [@tarroni2018learning; @carapella2016towards; @zhang2016automated] and segmentations [@robinson2019automated; @alba2018automatic]. In this work, we focus on the latter, i.e. segmentation quality control. Existing literature can be broadly classified into two categories: **Learning-based quality control:** These methods consider quality control as a regression or classification task where a quality metric is predicted from extracted features. [@kohlberger2012evaluating] proposed 42 hand-crafted features based on intensity and appearance and achieved an accuracy of 85% in detecting segmentation failure. [@robinson2018real] developed a CNN-based method for real-time regression of the Dice similarity metric from image-segmentation pairs. [@hann2019quality] integrated quality control into the segmentation network by regressing the Dice metric. Most of these methods require poor-quality segmentations as negative samples to train the regression or classification model. This makes quality control specific to the segmentation model and the type of poor-quality segmentations used for training. [@liu2019alarm] used a variational auto-encoder (VAE) for learning the shape features of segmentation in an unsupervised manner and proposed to use the evidence lower bound (ELBO) as a predictor. This model-agnostic structure provides valuable insights and an elegant theoretical framework for quality control. **Registration-based quality control:** These methods perform image registration between the test image with a set of pre-selected template images with known segmentations. Then the quality metric can be evaluated by referring to the warped segmentations of these template images. Following this direction, [@valindria2017reverse] proposed the concept of reverse classification accuracy (RCA) to predict segmentation quality and [@robinson2019automated] achieved good performance on a large-scale cardiac MRI dataset. These methods can be computationally expensive due to the cost of multiple image registrations, which could potentially be reduced by using GPU acceleration and learning-based registration tools [@Haskins2020DeepSurvey]. ### Contributions: There are three major contributions of this work. Firstly, we propose a generic deep generative model-based framework which learns the manifold of good-quality segmentations for quality control on a per-case basis. Secondly, we implement the framework with a VAE and propose an iterative search strategy in the latent space. Finally, we compare the performance of our method with regression-based methods on two different datasets, demonstrating both the accuracy and generalisation ability of the method. Methodology =========== Problem Formulation ------------------- Let $F$ denote an arbitrary type of segmentation model to be deployed. Given a test image $I$, the segmentation model provides a predicted segmentation $\hat{S}=F(I)$. The ground-truth quality of $\hat{S}$ is defined as $q(S_{gt}, \hat{S})$ where $S_{gt}$ is the ground-truth segmentation and $q$ is a chosen quality metric (e.g. Dice metric). The aim of quality control is to develop a model $Q$ so that $Q( \hat{S};I)\approx q(S_{gt}, \hat{S})$. Deep Generative Model-based Quality Control ------------------------------------------- Quality control would be trivial if the ground-truth segmentation $S_{gt}$ was available. Intuitively, the proposed framework aims to find a good-quality segmentation $S_{sur}$ as a surrogate for ground truth so that $q(S_{sur}, \hat{S}) \approx q(S_{gt}, \hat{S})$. This is realised through iterative search on the manifold of good-quality segmentations (Fig.\[figure1\]). ![Overview of the deep generative model-based quality control framework. The generative model $G$ is trained to learn a mapping $G(z)$ from the low-dimensional latent space $D_{z}$ to the good-quality manifold $\Sigma$. The input image-segmentation pair $(I, \hat{S})$ is projected to $(S_{sur}, I_{sur})$ on the manifold through iterative search, which is in turn used as surrogate ground truth for quality prediction. $z_0$ is the initial guess in the latent space and it converges to $z_{sur}$. []{data-label="figure1"}](Figures/Fig1.png){width="\textwidth"} ### Good-quality manifold: The core component of this framework is a deep generative model $G$ which learns how to generate good-quality image-segmentation pairs. Formally, let $X=(I, S)\in D_I \times D_S$ represent an image-segmentation pair, where $D_I$ and $D_S$ are the domains of images and possible segmentations. The key assumption of this framework is that good-quality pairs $(I, S_{gt})$ are distributed on a manifold $\Sigma \subset D_I \times D_S$, named as *good-quality manifold*. The generator $G$ learns to construct a low-dimensional latent space $D_z \subseteq \mathbb{R}^m$ and a mapping to the good-quality manifold: $$G(z): D_z \ni z \mapsto X=G(z) \in D_I \times D_S$$ where $z$ denotes the latent variable with dimension $m$. The mapping $G(z)$ is usually intractable but can be approximated using generative models such as generative adversarial networks (GANs) or VAEs. ### Iterative search in the latent space: To incorporate the generator into the quality control framework, we develop an iterative search scheme in the latent space to find a surrogate segmentation for a given image-segmentation pair as input. This surrogate segmentation is used for quality prediction. Finding the closest surrogate segmentation (i.e. projection) on the good-quality manifold is formulated as an optimisation problem, $$z_{sur} = \operatorname*{argmin}_{z \in D_z} \mathcal{L}(G(z), (I,\hat{S}))$$ which minimises the distance metric $\mathcal{L}$ between the reconstructed $G(z)$ and the input image-segmentation pair $(I,\hat{S})$. This problem can be solved using the gradient descent method as explained in Algorithm \[iter\_scheme\]. A trained generator $G: D_z \ni z \mapsto G(z) = (I,S) \in \Sigma$ Image-segmentation pair $(I,\hat{S})$ Quality prediction $Q(\hat{S};I)$ **Initialization** $z=z_0 \in D_z$ $L = \mathcal{L}(G(z),(I,\hat{S}))$ $grad = \nabla_{z}L$ $z = z - \alpha \cdot grad$ $S_{sur}=G(z_{sur})$ $Q(\hat{S};I)=q(S_{sur},\hat{S})$ Generative Model using VAE -------------------------- The proposed framework can be implemented with different generative models as long as a good-quality segmentation generator with smooth latent space is available. In this paper, we employ the VAE (Fig \[figure2\]) which includes an encoder $E_\varphi$ and a decoder $D_\phi$, where $\varphi$ and $\phi$ denote the model parameters [@kingma2013auto]. The image-segmentation pair $(I, S)$ is encoded by $E_{\varphi}$ to follow a Gaussian distribution $\mathcal{N}(\mu_z, \sigma_z^2)$ in the latent space, where $\mu_z$ and $\sigma_z^2$ denote the mean and variance respectively. A probabilistic reconstruction of the image-segmentation pair $(I', S')$ is generated from the decoder $D_\phi$. ![Framework implementation using the variational autoencoder (VAE). In the training stage, the ground-truth image-segmentation pairs are used. In the application stage, the VAE decoder is used as the generator for iterative search of the surrogate segmentation on the good-quality manifold. Initial guess $z_0$ is from the encoder. []{data-label="figure2"}](Figures/Fig2.png){width="\textwidth"} At the training stage, the ground-truth image-segmentation pairs are used to train the VAE. The loss function includes a reconstruction loss and a KL divergence term for regularisation [@higgins2017beta]: $$\mathcal{L}_{VAE}=\mathcal{L}_{recon}+\beta \cdot D_{KL}(\mathcal{N}(\mu_z, \sigma_z^2)||\mathcal{N}(0, \textbf{I}))$$ $$\mathcal{L}_{recon}=BCE(S_{GT}, S_{GT}') + MSE(I, I')$$ where $\beta$ is the hyperparameter that balances between reconstruction loss and regularisation. The reconstruction loss is evaluated using the binary cross-entropy (BCE) for segmentation and the mean square error (MSE) for image, respectively. The effects of the weight $\beta$ and the latent space dimension $m$ will be evaluated in the ablation study. At the application stage, the VAE decoder $D_\phi$ is used as the generator, reconstructing image-segmentation pairs from the latent space. The initial guess $z_0$ in the latent space is obtained from the encoder $E_{\varphi}$. Following Algorithm \[iter\_scheme\], the surrogate segmentation $S_{sur}$ can be found via iterative search (Fig. \[figure2\]b). Finally, the quality metric is evaluated by $q(S_{sur},\hat{S})$, e.g. Dice metric. Experiments =========== Datasets -------- **UK Biobank dataset:** Short-axis cardiac images at the end-diastolic (ED) frame of 1,500 subjects were obtained from UK Biobank and split into three subsets for training (800 cases), validation (200 cases) and test (500 cases). The in-plane resolution is 1.8x1.8 mm with slice thickness of 8 mm and slice gap of 2 mm. A short-axis image stack typically consists of 10 to 12 image slices. Ground-truth good segmentations were generated from a publicly available fully-convolutional network (FCN) that has demonstrated a high performance [@bai2018automated], with manual quality control by an experienced cardiologist. **ACDC dataset:** 100 subjects including a normal group and four pathology groups were obtained from ACDC dataset [@bernard2018deep] and resampled to the same spatial resolution as UK Biobank data. The ground-truth segmentations at the ED frame were provided by the ACDC challenge organisers. Experimental Design ------------------- In this study, we evaluate the performance of our proposed method and compare with two regression-based methods for quality control of cardiac MRI segmentation. Specifically, we focus on the myocardium, which is a challenging cardiac structure to segment and of high clinical relevance. ### VAE implementation and training: {#implementation} The VAE encoder is composed of four convolutional layers (each was followed by $ReLU$ activation), and one fully connected layer. The decoder has a similar structure with reversed order and the last layer is followed by $Sigmoid$ function. The latent space dimension $m$ was set to 8 and the hyperparameter $\beta$ was set to 0.01 from ablation study results. The architecture is shown in Appendix Fig. A1. The model was implemented in PyTorch and trained using the Adam optimiser with learning rate 0.0001 and batch size 16. It was trained for 100 epochs and an early stopping criterion was used based on the validation set performance. To improve the computational efficiency, the VAE was trained on a region of interest (ROI) centered around the myocardium with the window size of 96x96 pixel, which was heuristically determined to include the whole cardiac structure. The cropped image intensity was normalised to the $[0, 1]$ range and stacked with the binary segmentation. ### Baseline methods: Two regression-based methods were used as baselines: a) a support vector regression (SVR) model with 42 hand-crafted features about shape and appearance [@kohlberger2012evaluating] and b) a CNN regression network (ResNet-18 backbone) with the image-segmentation pair as input [@robinson2018real]. Both baseline methods use the Dice metric as the regression target. ### Experiment 1: UK Biobank Besides the ground-truth segmentations, we generated poor-quality segmentations by attacking the segmentation model. White noise with different variance level was added to the original images, resulting in a dataset of poor-quality segmentations with uniform Dice distribution. The quality prediction was performed on the test set of the attacked segmentations. **Experiment 2: ACDC** We deployed a UK Biobank trained segmentation model on ACDC dataset without fine-tuning. This reflects a real-world clinical setting, where segmentation failures would occur due to domain shift issues. **Ablation study:** We adjusted the dimensionality of the latent space $m$ and the hyperparameter $\beta$ and performed a sensitivity analysis on the UK Biobank validation dataset. The result is reported in the Appendix Table A1. Results and Discussion ====================== Quality control performance is assessed in terms of Dice metric prediction accuracy. Pearson correlation coefficient $r$ and mean absolute error (MAE) between predicted Dice and real Dice are calculated. Table 1 compares the quantitative performance of the methods and Fig.\[figure3\] visualises the predictions. On UK Biobank dataset, the hand-crafted feature method performed the worst. The proposed method achieved a similar performance ($r$=0.96, MAE=0.07) as the CNN regression method ($r$=0.97, MAE=0.06). However, on ACDC dataset, the proposed method ($r$=0.97, MAE=0.03) outperformed the CNN regression method ($r$=0.97, MAE=0.17) with a smaller MAE. As shown in Fig. \[figure3\], on ACDC dataset, the prediction of the proposed method aligns well with the identity line, whereas the CNN regression method clearly deviates from the line, even though the $r$ coefficient is still high. ![Comparison of the performance of different quality control methods. The x-axis is the real Dice of each subject and the y-axis is the predicted Dice by each method. The dashed line is the $y=x$, plotted for reference. Top row: UK Biobank data ($n=500$). Bottom row: ACDC data ($n=100$), with five subgroups plotted in different colors. []{data-label="figure3"}](Figures/Fig3.png){width="300pt"} A possible explanation for this is that the proposed generative method works by learning the good-quality manifold and proposing the surrogate ground truth for quality assessment. Thus it is agnostic to the types of poor-quality segmentations. The training of hand-crafted features and CNN-based regression methods require poor-quality segmentations and may be overfitted to the UK Biobank data. When they are deployed onto ACDC dataset, there is a shift not only for image appearance (e.g. difference between 1.5T and 3.0T MRI scanner) but also for types of segmentation failures. In addition, the ACDC dataset consists of more pathological cases, whereas the UK Biobank comes from a general healthy population. Due to the domain shift, the performance of regression-based methods degraded. In contrast, the proposed method maintained a high prediction accuracy against domain shift. This indicates the advantage of a generative model-based framework for generalisation. It also can be potentially used as a system to monitor the performance of deployed segmentation models over time. \[table1\] To gain insights into our proposed method, we visualised several searching paths within a two-dimensional latent space and corresponding image-segmentation pairs reconstructed by our generative model (Fig. \[figure4\]). The poor-quality segmentation could be projected onto the good-quality manifold and refined iteratively to obtain the surrogate segmentation. The surrogate segmentation on the good-quality manifold is more plausible and can potentially be used as $prior$ to correct poor-quality segmentations. It is also expected that the performance could be improved using advanced generative models and better manifold learning [@bojanowski2017optimizing]. ![Visualisation of searching path in a two-dimensional latent space. Left: searching paths for five exemplar samples (green point: initial guess from the VAE encoder; black point: intermediate state during iterative search; red point: convergence point for surrogate segmentation). Right: the input image and segmentation, reconstructed segmentations along the searching path and the ground-truth segmentation.[]{data-label="figure4"}](Figures/Fig4.png){width="280pt"} Conclusion ========== Here we propose a generative-model based framework for cardiac image segmentation quality control. It is model-agnostic, in the sense that it does not depend on specific segmentation models or types of segmentation failures. It can be potentially extended for quality control for different anatomical structures. Appendix ======== ![Network architecture of the VAE.[]{data-label="figureS1"}](Figures/FigS1.png){width="\textwidth"} ---- ------- ------- ----------- ------- 0 1E-3 1E-2 1E-1 2 0.095 0.094 0.105 0.502 4 0.086 0.092 0.114 0.416 8 0.088 0.072 **0.068** 0.229 16 0.147 0.141 0.095 0.091 ---- ------- ------- ----------- ------- : Ablation study of the latent space dimension $m$ and the hyperparameter $beta$. The mean absolute error (MAE) between predicted and true Dice metrics on UKBB validation set are reported. $m$=8 and $\beta=0.01$ were selected as the optimal parameters according to the results. \[tableS1\]

Blogos Mars Lander It strikes me heroic as only heroic can be that the splendid wee Mars lander, Opportunity, bimbles off into the wide yonder, yodelling back across 33.9 million miles (that’s on a close day) images of unearthly clarity. NASA, obviously knowing of what it speaks, describes the ghost as a Dust storm. While ghosts are not generally attributed with shadows, neither are mini-cyclones. Modal logic would allow that if one, then the other: no? Thus, let imagination ricochet from every shiny facet of cheerful wonder on a solitary, shuffling object – which I’m fairly sure chats to itself as merrily as R2-D2 – and allows us to observe that which cannot be seen, a ghost beyond the machine.

/*============================================================================= Copyright (c) 2001-2011 Joel de Guzman Copyright (c) 2001-2011 Hartmut Kaiser http://spirit.sourceforge.net/ Distributed under the Boost Software License, Version 1.0. (See accompanying file LICENSE_1_0.txt or copy at http://www.boost.org/LICENSE_1_0.txt) =============================================================================*/ #ifndef BOOST_SPIRIT_INCLUDE_QI_CORE #define BOOST_SPIRIT_INCLUDE_QI_CORE #if defined(_MSC_VER) #pragma once #endif #include <boost/spirit/home/qi/parser.hpp> #include <boost/spirit/home/qi/parse.hpp> #include <boost/spirit/home/qi/what.hpp> #include <boost/spirit/home/qi/action.hpp> #include <boost/spirit/home/qi/char.hpp> #include <boost/spirit/home/qi/directive.hpp> #include <boost/spirit/home/qi/nonterminal.hpp> #include <boost/spirit/home/qi/numeric.hpp> #include <boost/spirit/home/qi/operator.hpp> #include <boost/spirit/home/qi/string.hpp> #endif

--- author: - 'E. Bozzo' - 'L. Oskinova' - 'A. Lobel' - 'W.-R. Hamann' bibliography: - 'superorbital.bib' date: 'Submitted: -; Accepted -' title: 'On the super-orbital modulation of supergiant high mass X-ray binaries' --- Introduction {#sec:intro} ============ Supergiant high mass X-ray binaries (SgXBs) are a sub-class of high mass X-ray binaries (HMXBs) hosting a compact object and an OB supergiant star [see @walter15 for a recent review]. SgXBs are typically divided in two groups, i.e., the classical systems, which show a virtually persistent high X-ray luminosity, and the supergiant fast X-ray transients (SFXTs), which feature a still highly debated and peculiarly prominent variability in X-rays [@nunez17]. The bulk of the X-ray radiation from the SgXBs can be reasonably well explained as being due to the accretion of the stellar wind from the OB supergiant onto a highly magnetized neutron star (NS), with no evidence supporting the presence of long-lived accretion disks [@bozzo08; @shakura12; @romano15; @hu17]. No clear indication has yet been reported of systematic differences between the properties of the supergiant stellar winds in classical systems and SFXTs (Hainich et al. 2017, in preparation), which also share similar orbital periods [@lutovinov13; @bozzo15] and super-orbital modulations [see Table \[tab:tab1\] and @corbet13]. [@llll@]{} Source Name & class & $P_{\rm NS}$ & $P_{\rm SO}$\ & & (days) & (days)\ IGRJ16479-4514 & SFXT & 3.3199$\pm$0.0005 & 11.880$\pm$0.002\ IGRJ16418-4532 & SgXB & 3.7389$\pm$0.0001 & 14.730$\pm$0.006\ 4U1909+07 & SFXT & 4.4003$\pm$0.0004 & 15.180$\pm$0.003\ IGRJ16493-4348 & SgXB & 6.782$\pm$0.001 & 20.07$\pm$0.01\ 2S0114+650 & SgXB & 11.591$\pm$0.003 & 30.76$\pm$0.03\ The super-orbital variability in disk accreting X-ray binaries is usually ascribed to the precession of the disk or to the precession of the compact object in its center [see, e.g., the cases of HerX-1, SMCX-1, and LMCX4; @petterson75; @ogilvie01; @pot13], but a solid interpretation of the same phenomenon in wind-fed binaries is still lacking. The lightcurves of the latter folded on their super-orbital period display a large variety of morphologies and modulations that are stable over years, although the sources are generally thought to be accreting from a much less regularly structured environment compared to that provided by an accretion disk. In the case of the classical SgXB 2S0114+650, @farrell08 reported on the detection of spectral slope changes as a function of the super-orbital phase but could not detect corresponding variations in the absorption column density [also due to the limited coverage at energies $\lesssim$3 keV provided by the instruments on-board RXTE; @bradt93]. These authors suggested that the most likely cause of the super-orbital variability was a modulation of the mass loss rate from the supergiant star. For all other systems showing a super-orbital modulation, the only X-ray data providing coverage on different super-orbital phases are those collected with /BAT [@gehrels05; @barthelmy05]. The relatively low signal-to-noise ratio of these data and the energy band-pass limited to $\gtrsim$15 keV hampered so far any investigation of spectral variability as a function of the super-orbital phase. @koeni06 proposed that the mass accretion rate modulation could be produced as a consequence of tidal interaction-driven oscillations of the supergiant star, but the authors showed that such mechanism only works for strictly circular orbits. @corbet13 also discussed the possibility that the super-orbital modulations are due to a third body orbiting the inner massive binary. However, the same authors highlighted that a stable three body solution requires a hierarchical system with the third body in a very distant orbit, while all super-orbital modulations discovered so far in SgXBs are not longer than roughly 3 times the orbital periods of these sources. We propose here that the super-orbital periodicities in classical SgXBs and SFXTs are produced as a consequence of the interaction between the compact object with the so-called “corotating interaction regions” threading the winds of OB supergiants. Corotating interaction regions around OB supergiants {#sec:cir} ==================================================== The stellar winds of OB supergiants are well known to be characterized by complex velocity and density structures . The smaller structures, i.e. “clumps”, are typically endowed with an increased density of a factor of $\gtrsim$10 compared to a smooth wind and can be as large as $\sim$0.1 $R_*$, where $R_*$ is the OB supergiant radius. Clumps are usually invoked to interpret the stochastic X-ray variability displayed by SgXBs on time scales of 10-1000 s [see, e.g., @nunez17 and references therein]. The existence of larger structures in the OB supergiant winds was suggested in the early 80s [@mullan84], and confirmed by the detection of discrete absorption components [DACs; see, e.g., @new]. These features are observed to propagate blue-ward on time-scales comparable with the stellar rotation through the profiles of UV resonance lines in OB supergiants [@massa95; @prinja98]. @cranmer96 used hydrodynamic models to show that irregularities on the stellar surface related either to dark/bright spots, magnetic loops, or non-radial pulsations can lead to the formation of corotating interaction regions (CIRs) causing spiral-shaped density and velocity perturbations in the stellar wind up to several tens of stellar radii. The CIRs are invoked to explain modulations of the X-ray emission observed in single OB stars [@Oskinova2001; @Naze2013; @Massa2014]. An advanced model to reproduce the observational properties of DACs in OB supergiants with CIRs was developed by @lobel08, who also investigated the dependence of the extension, velocity, and density profile variations of these structures as a function of the different properties of the stellar surface spots from which they originate. The intensity of the spot, its size, and its rotational velocity (that could in principle be different from that of the star) are the main parameters regulating the density/velocity contrast of the CIR compared to the surrounding unperturbed stellar wind, typically limited to a factor of a few. A larger rotational velocity of the spot also increases the winding of the spiral arms. The available observations of the UV variability of massive star resonance lines can be used to constrain all the spot free parameters of the model. We show in Fig. \[fig:fig1\] a hydrodynamic simulation of @lobel08 obtained from the application of the Zeus-3D code for a radiatively-driven rotating wind in the B0.5 Ib supergiant JPup (HD64760). This star is characterized by a mass of 20 $M_{\odot}$, a radius of 22 $R_{\odot}$, a mass loss rate of 9$\times$10$^{-7}$ $M_{\odot}$ yr$^{-1}$, and a terminal wind velocity of 1500 km s$^{-1}$ [see Table 1 of @lobel08]. ![An example of hydrodynamic calculations of the CIR in the wind of the B0.5 Ib supergiant JPup. There is a bright spot on the stellar surface producing a single CIR. The spot is assumed to be 20% brighter than the stellar surface, and is characterized by an angular diameter of 20$^{\circ}$. A full revolution of the CIR occur in $\sim$10.3 days. The colors code the wind density of the CIR model, relative to the density of the unperturbed, smooth wind. The maximum over-density in the CIR is by a factor 1.22 (red colors). In wind regions shown in yellow this ratio hardly deviates from unity, while in the green regions the wind is rarefied by a factor below 0.97. The black solid drawn lines show 20 overplotted contours of equal radial velocity in the hydrodynamic rotating wind model. The outermost curve marks the isovelocity line at an outflow velocity of 1460 km s$^{-1}$, while the curves at smaller distances from the stellar surface are shown for decreasing steps of 73 km s$^{-1}$. The case with two CIRs mentioned later in this paper is produced by assuming an additional spot that is 8% brighter than the surface of the supergiant star and has an angular diameter of 30$^{\circ}$.[]{data-label="fig:fig1"}](cir.eps) The CIR induced super-orbital modulation in SgXBs {#sec:so} ================================================= In order to show how the presence of CIRs around the supergiant star can introduce a super-orbital modulation of the X-ray luminosity from a SgXB, we assume here a simplified NS accretion scenario, following the treatment in @oskinova12. The cross section of the NS for the capture of the stellar wind material is provided by the so-called accretion radius, $r_{\rm accr}=\frac{2Gm_{\rm X}}{\varv_{\rm rel}^2}$, where $m_{\rm X}$ is the NS mass and $\varv_{\rm rel}$ is the relative velocity between the NS and the massive star wind. For the CIR, both the radial and tangential components of the velocity at the NS location are taken into account in the computation. The mass accretion rate onto the NS is given by $S_{\rm accr}=4\pi \zeta \frac{(Gm_{\rm X})^2}{\varv^3_{\rm rel}}\rho$, and the correspondingly released X-ray luminosity is $L^{\rm d}_{\rm X}=\eta S_{\rm accr} c^2$. In the equations above, we indicated with $c$ the speed of light, with $\rho$ the local wind density (derived from the outputs of the hydrodynamic model), and considered for all cases of interest $\zeta\sim 1$ and $\eta\sim 0.1$ [$\zeta$ is a parameter included to take into account corrections related to the contribution of the radiation pressure and the finite cooling time of the gas, while $\eta$ parametrizes the efficiency of accretion onto a NS; see, e.g., @ostriker]. It is clear from this simplified treatment that both the density and velocity contrasts of the CIR compared to the smooth wind can affect the resulting X-ray luminosity, as they can significantly alter the mass accretion rate and the size of the NS cross section for the capture of the wind material. Let’s consider first a case in which the NS orbital period is given by $P_{\rm NS}$ and a single CIR rotating with a period $P_{\rm CIR}$ is present in the wind of the supergiant companion. A difference between $P_{\rm NS}$ and $P_{\rm CIR}$ can be expected in a not-synchronously rotating binary [see, e.g., @koeni06 and references therein], or in case the stellar spot does not rotate with the same velocity of the supergiant star [@lobel08]. The mass accretion rate onto the NS is altered every time the compact object encounters the CIR along its orbit and the amplitude of the variation is regulated by the CIR velocity/density contrast compared to the rest of the stellar wind. The period of the super-orbital modulation, $P_{\rm SO}$, is thus given by the difference between the NS and the CIR angular velocities: $$P_{\rm SO}=\frac{1}{\left|\frac{1}{P_{\rm NS}}-\frac{1}{P_{\rm CIR}}\right|}= \left|\frac{P_{\rm NS} P_{\rm CIR}}{P_{\rm CIR}-P_{\rm NS}}\right|. \label{eq:po}$$ As an example, we consider in detail the case of the classical SgXB IGRJ16493-4348. The donor star in this system has the same spectral type as JPup and the estimated distance is 6-26 kpc [see @nunez17 and references therein]. Given the typical parameters of a B0.5 Ib star (Sect. \[sec:cir\]) and the measured orbital period of the NS in IGRJ16493-4348 (Table \[tab:tab1\]), the separation between the compact object and the supergiant is $\sim$1.8 $R_*$. According to Eq. \[eq:po\], a single CIR rotating with a period of $\sim$10.3 days is thus expected to give rise to a super-orbital period of $\sim$20 days, as indeed observed in this source. The X-ray lightcurve simulated using the output of the hydrodynamic model for the CIR in JPup (Fig. \[fig:fig2\]) is characterized by an average luminosity which is in good agreement with the observations of IGRJ16493-4348[^1]. The amplitude of the modulation is smaller than that observed from IGRJ16493-4348, but the exact value depends on, e.g., the brightness of the spot on the stellar surface responsible for the CIR generation (in the present case the hydrodynamical simulations were tuned to reproduce the results UV spectroscopic monitoring for J Pup). ![Simulated long term lightcurve of IGRJ16493-4348, assuming a single CIR in this system rotating with a period of $\sim$10.3 days.[]{data-label="fig:fig2"}](dac1cir1.8.ps) In a situation in which multiple CIRs are present and intercept the plane of the NS orbit, it would be naturally expected that their density/velocity contrasts are significantly different, reflecting the distinct properties of the stellar surface spots from which they originated. Assuming that $n$ CIRs cross the NS orbit, the overall period of the super-orbital modulation will be in this case $n$$\times$$P_{\rm SO}$. Several peaks of variable intensities can thus be originated in the modulation profile depending on the different CIR density/velocity contrast at the NS location. We show in the bottom plot of Fig. \[fig:fig3\] an example in which a second CIR is included in our calculations, giving rise to a double-peaked super-orbital modulation (see also the caption of Fig. \[fig:fig1\]). A multiple-peaked super-orbital modulation seems particularly interesting to reproduce structured profiles of the folded X-ray lightcurves displayed by, e.g., the classical SgXB 4U1909+07 and the SFXT IGRJ16479-4514 [see Fig. 8 and 10 of @corbet13]. Figure \[fig:fig3\] shows that the super-orbital variability is critically depending on the difference between $P_{\rm NS}$ and $P_{\rm CIR}$. Although CIRs seem to be an ubiquitous property of all supergiant stars [see, e.g., @massa15 and references therein], the detectability of a super-orbital modulation in the currently proposed model could be hampered in all those unfavorable cases where $P_{\rm NS}\simeq P_{\rm CIR}$ and $P_{\rm SO}$ exceeds the available observational time-span for a SgXB. Although all the free parameters on the number and properties of the CIRs can be fine tuned to obtain a reasonable match with the properties of the super-orbital modulations of all sources in Table \[tab:tab1\], there is not an obvious way to explain the empirical relation connecting the system orbital and super-orbital period as shown by @corbet13. If the relation will be confirmed by future observations, a better understanding of the CIR formation in the SgXBs is required to investigate the possibility of explaining this observational finding in the current model. ![[*Top*]{}: Same as Fig. \[fig:fig2\] but assuming an orbital separation of 2.5 $R_*$, corresponding to an orbital period of $\sim$10.6 days. As this is only slightly larger than the CIR period ($\sim$10.3 days), the super-orbital modulation occurs on a much longer time-scale ($\sim$330 days). [*Bottom*]{}: Same as above but using 2 CIRs. The super-orbital modulation is now characterized by a double asymmetric peak repeating every $\sim$660 days, corresponding to the fact that the NS is crossing two CIRs with different density/velocity contrasts along its orbit.[]{data-label="fig:fig3"}](dac1cir2.5.ps "fig:") ![[*Top*]{}: Same as Fig. \[fig:fig2\] but assuming an orbital separation of 2.5 $R_*$, corresponding to an orbital period of $\sim$10.6 days. As this is only slightly larger than the CIR period ($\sim$10.3 days), the super-orbital modulation occurs on a much longer time-scale ($\sim$330 days). [*Bottom*]{}: Same as above but using 2 CIRs. The super-orbital modulation is now characterized by a double asymmetric peak repeating every $\sim$660 days, corresponding to the fact that the NS is crossing two CIRs with different density/velocity contrasts along its orbit.[]{data-label="fig:fig3"}](dac2cir2.5.ps "fig:") We neglected in the present simplified approach the role of the NS spin period and magnetic field, as well as the effect of eccentric orbits and the interaction between the X-rays from the NS and the stellar wind. A strong NS magnetic field and slow spin period can induce large modulations of the X-ray luminosity, due to the onset of magnetic and/or centrifugal gates [@grebenev07; @bozzo08]. While this is relevant to explain the short time-scale X-ray variability ($\sim$10-1000 s) displayed by classical SgXBs and SFXTs [@bozzo16], we expect this variability to be largely smoothed out when considering the much longer integration times corresponding to the super-orbital modulations (tens of days). As described in @bozzo16, the lack of a proper treatment of the X-ray illumination of the stellar wind by the accreting compact object limits the validity of the outcomes of the calculations to low luminosity SgXBs ($L_{\rm X}$$\lesssim$10$^{35}$ erg s$^{-1}$) and can only provide indications in case of brighter systems. This effect is thus unlikely to be critical in the case of the SFXTs, as their average X-ray luminosity is generally far below the critical level required to produce a systematic disruption of the stellar wind on scales that are as large as those expected for the CIRs [see, e.g., @ducci10 and references therein]. However, this might not apply to bright persistent classical wind-fed SgXBs with average X-ray luminosities $\gg$10$^{36}$-10$^{37}$ erg s$^{-1}$ [e.g., VelaX-1; @watanabe06; @sander17], which we predict to not display super-orbital modulations. Note that all SgXBs discovered so far to display a super-orbital modulation are characterized by relatively low long-term luminosities, the brightest being IGRJ16493-4348 with an estimated average X-ray luminosity of $\sim$1.5$\times$10$^{36}$ erg s$^{-1}$ when the largest allowed distance of 26 kpc is considered. Finally, the usage of circular orbits in our calculation was adopted to limit the number of required hydrodynamic runs and to provide more intuitive examples to promote the proposed scenario. However, we do not expect that our conclusions will change significantly with the introduction of a relatively small eccentricity [$\lesssim$0.2; @corbet13 and references therein], as the range of orbital separations spanned by the NSs would be limited and the density/velocity contrasts within each CIRs are expected to undergo major variations only on several stellar radii (for reasonable assumptions of the model parameters). Discussion and conclusions {#sec:conclusion} ========================== We proposed in this letter that the still poorly understood super-orbital variability displayed by several classical SgXBs and SFXTs is related to the presence of CIRs in the winds of their OB supergiants. The mechanisms leading to the formation of CIRs are not yet fully understood and the model considered in Sect. \[sec:cir\] exploits the most widely accepted idea that CIRs are driven by spots on the supergiant surface with a number of free parameters that can be adjusted to reproduce the observational properties of DACs in many isolated OB supergiants. At present, no observations of DACs are available for the donor stars in classical SgXBs and SFXTs, and it is thus difficult to present an exhaustive exploration of the entire model parameter space (this is beyond the scope of this work, given also the computationally expensive runs of the hydrodynamic simulations). However, the examples provided in Sect. \[sec:so\] show that the number and physical characteristics of the CIRs can be adjusted within reasonable boundaries to reproduce the main observed properties of the super-orbital modulations displayed by all sources in Table \[tab:tab1\]. This paves the way to future theoretical and simulation efforts exploring the proposed model in more details and overcoming the simplifications adopted in the current approach, including the presence of the X-ray irradiation of the stellar wind and eccentric orbits. We remark that an important open question in the context of the present interpretation of the super-orbital modulations is if CIRs can be stable for years. Indeed, most of the DAC observations leading to the concept of CIRs were carried out as part of the MEGA campaign [@mega] performed with the IUE satellite [@iue] and no longer repeated afterwards. Long dedicated monitoring campaigns of the UV spectroscopic variability of the previously observed supergiant stars and the other supergiants hosted in the SgXBs are thus critically required. Acknowledgments {#acknowledgments .unnumbered} =============== We thank the anonymous referee for constructive comments which helped to improve the paper. This publication was motivated by a team sponsored by the ISSI in Bern, Switzerland. EB and LO thank ISSI for the financial support during their stay in Bern. EB is grateful for the hospitality of the Institut für Physik und Astronomie (Universität Potsdam) during part of this work. EB acknowledges financial traveling contribution from the Swiss Society for Astronomy and Astrophysics. LO acknowledges support by the DLR grant 50OR1302 and partial support by the Russian Government Program of Competitive Growth of Kazan Federal University. AL acknowledges partial financial support by the Belgian Federal Science policy Office under contract No. BR/143/A2/BRASS and by the ESA-Gaia Prodex Programme 2015-2017. [^1]: The absolute value of the average X-ray luminosity from IGRJ16493-4348 ranges from $\sim$10$^{35}$ erg s$^{-1}$ to $\sim$10$^{36}$ erg s$^{-1}$, depending on the poorly known distance to the source (6-26 kpc).

Lower copy numbers of the chemokine CCL3L1 gene in patients with chronic hepatitis C. Recently, variation of gene copy numbers was recognized as a novel type of common genetic diversity, but its impact on viral hepatitis is unknown. Here, we determine the influence of copy number variation on the susceptibility and disease severity in hepatitis C virus (HCV) infection, investigating copy number variants (CNVs) of the chemokine CCL3L1 gene, which encodes a potent CCR5 ligand. CNVs were determined in 254 patients with chronic hepatitis C, 144 HCV/HIV co-infected patients, and 210 HCV negative controls, using quality-controlled real-time fluorescent dye-labeled quantitative PCR. Liver biopsies were obtained from HCV infected patients. Copy numbers of the CCL3L1 gene range from 0 to 12 (mean 2.7+/-1.4 copies). Patients with two or less copies are over-represented in the HCV infected cohort compared to HCV negative controls (odds ratio [OR] 1.54; p=0.02). CCL3L1 copies are shifted to lower numbers in HCV infected patients (means 2.6 vs. 2.9 in controls; p=0.011). HCV/HIV co-infected patients carry even lower CCL3L1 copy numbers compared to controls (means 2.2 vs. 2.9; p<0.001), with a higher proportion of patients possessing two or less copies (OR=3.42; p<0.001). No association was detected between CCL3L1 copy numbers and histological grades of inflammation or stages of fibrosis. Lower CCL3L1 gene copy number compared to the population median is associated with chronic hepatitis C. Copy number variation of host genes represents a novel class of genetic diversity associated with viral hepatitis.

An ideal dining place for parents and kids alike, this Italian restaurant offers authentic pizzas and tempting gelatos in a relaxed and friendly atmosphere. Walls are graced with vintage photos of the hotel, adding a touch nostalgic glamour to the inviting space. Overlooking the main pool (adjacent to the main restaurant), up to 24 guests are elegantly accommodated on the outdoor terrace or inside the restaurant for an incomparable view of the open kitchen. Try the Diavola with spicy sausage, the Athenas with mozzarella, parmesan and pesto, or the 4 Estanciones featuring mozzarella, artichoke, mushrooms and olives.

Each time Mad Men lead character Don Draper (a.k.a Dick Whitman) attempts to emerge from his tortured psyche, he succumbs to his unrelenting demons. Not unlike Tony Soprano, he makes half-hearted attempts to be a good guy, but no one believes it for a second. Season 6 finds our “hero” once again flirting with disaster. He is embroiled in an affair (with nasty sexual overtones) with a neighbor friend’s wife (a brilliant Linda Cardellini). Peggy (the reluctant protégé) is continuing her ascension to corporate stardom, but is in love with one of the partners (Ted). Joan (Christina Hendricks) is trying to be a player at the ad agency and the irritating Peter Campbell (Vincent Kartheiser) copes with the disintegration of his marriage. The supporting cast is top-notch. However the emotional impact abates when the focus shifts away from Don. Surprisingly, his daughter Sally (Kiernan Shipka) and her bizarre coming- of-age angst has become a compelling storyline. Jon Hamm’s morose performance is dazzling. It is among the best in the annals of television. Matt Weiner is not afraid to challenge the behavior of the characters. Don is no longer the James Bond of Madison Avenue. He is troubled and depressed. Hipster accomplice Roger (John Slattery) is a grandfather coping with the mundane world of family relations. The story lines integrate contemporary social issues (civil rights, women’s liberation and of course sexual liberation). Direction (even with eight directors) is consistent. Scenes are filmed without gimmickry and allow the actors to deliver their well-scripted lines. And just when you think Mad Men’s emotional punch is gone, a terrific scene reminds everyone why this series is unique. In Season Six, it is the final scene as Don shows his children the brothel that served as his boyhood home. It should be noted that Mad Men airs on basic cable and does not have the same artistic license as premium cable series. Art direction, set design and wardrobe remain a vital cog for this iconic project. The rich, colorful textures and attention to 1960’s cultural details are superb. On Blu-ray, the 5.1 sound is dynamic, capturing the quietest dialogue. Hi-definition is lush and counters the conversation-driven austerity. The instant the show comes on, the viewer is transported back to this era. It appears that Season Six was a set up for the series finale. Bring it on!

Hello Folks! KIAT CEBU is now finally up and is ready to conquer Cebu and beyond from events to parties to food trips- basically anything under the heat of the sun- we are but thrilled to share our world with you. A Hello From Kiat Cebu Hello Folks! This rebirth means a lot, we just turned 1 and because of that, we are giving you a fresh, new look to this blog as well as freshly pressed posts. Of course, old-but-interesting-blog-posts be reblogged, too. This is one of my travel blogs your shouldn't miss. Tune in because KIAT CEBU has a lot in store for you- aside from the hot-inthralling write-ups, we are also hosting some giveaways that you will definitely love and we can't hide our exhilaration for you to win some cool stuff. Are you excited just yet? Cool! We know you are as much as we do. A Hello From Kiat Cebu Simply, Your Kiat Cebu Lastly, we would like to express our gratitude to Gay Aida Dumaguing of www.exoticphilippines.net (one of the top Pinoy bloggers, please visit her amazing blog) for generously sharing your time in helping us set Kiat Cebu up- it feels great to know a person so sweet like you. A Hello From Kiat Cebu Tune in for more... Thank you, dear readers for dropping by today to our humble blog. Please do not hesitate to leave your comments and share your thoughts right here. Let's all have fun and EAT good vibes today and the days to come. Ps. Please make our day by following/ subscribing to our social media accounts. Hello Folks! KIAT CEBU is now finally up and is ready to conquer Cebu and beyond from events to parties to food trips- basically anything under […] About Jeph Hi, I'm Jeph, a Cebu-based lifestyle blogger, a brand ambassador, and a yogi. I am currently the Bloggers' Relation Manager of the massive-growing community of bloggers in the Queen City of the South, Cebu Blogging Community (CBC). I am a proud parent to #KiatCebuJr, a photography enthusiast, and a band vocalist of the Sleek (a local acoustic band in Cebu).

Factors Prognostic for Survival in Japanese Patients Treated with Sunitinib as First-line Therapy for Metastatic Clear Cell Renal Cell Cancer. Factors predictive of survival have been identified in Western patients with metastatic clear cell renal cell carcinoma (mCCRCC) treated with sunitinib. Less is known, however, about factors predictive of survival in Japanese patients. This study evaluated factors prognostic of survival in Japanese patients with mCCRCC treated with first-line sunitinib. This retrospective study evaluated 46 consecutive Japanese mCCRCC patients treated with sunitinib as first line therapy. Clinical and biochemical markers associated with progression-free survival (PFS) were analyzed, with prognostic factors selected by uni- and multivariate Cox regression analyses. Univariate analysis showed that factors significantly associated with poor PFS included Memorial Sloan-Kettering Cancer Center poor risk scores, International Metastatic RCC Database Consortium poor risk and high (>0.5 mg/dl) serum C-reactive protein (CRP) concentrations (p<0.001 each). Multivariate analysis showed that high serum CRP was independently associated with poorer PFS (p=0.040). Six month disease control rate (complete response, partial response and stable disease) in response to sunitinib was significantly higher in patients with normal (≤0.5 mg/dl) than elevated baseline CRP (p<0.001). CRP is a significant independent predictor of PFS for Japanese patients with mCCRCC treated with first-line sunitinib. Pretreatment CRP concentration may be a useful biomarker predicting response to sunitinib treatment.

"I think I was trying to suggest something about the duality of man, sir ... the Jungian thing, sir." Private Joker, Full Metal Jacket Monday, August 11, 2014 Sixth District is all good I live in the Sixth Congressional District where three conservative candidates are vying for the Republican nomination. I have not endorsed one of them because I would be happy to vote for any of them. Each has his strengths and weaknesses, but, on the whole, I can't come to the conclusion that one is clearly preferable to the others. Ashley Schultz thinks otherwise. She is "terrified" of Glenn Grothman who she believes would "set us back fifty years." Now I think that Ashley is a rising young star and a great addition to Purple Wisconsin.* But I see it differently. I am not endorsing Glenn Grothman. His strength is his commitment and engagement with ideas, but, as Ashley points out, his weakness is his tendency to be, at best, overly blunt and, at worst, unmindful of important nuance. If all she is saying is that he has a weakness as a candidate - a tendency to gaffe - that may counsel a vote for one of the others, I have nothing to say. I don't necessarily agree, but it's a fair point. But I do believe that there's a distinction that needs to be made clear. Ashley may have assumed it. I think it needs to be made explicit. It's one thing to criticize a candidate for not adequately negotiating the shoals of our silly public discourse about things like a "war on women." But we still ought to recognize that the discourse is, in fact, silly. We see it happen again and again. Someone will make a statement that is either ambiguous or "objectionable" only for its failure to show proper obeisance to certain sensitivities or to one of the canonical myths of politically correctness. The statement may fail to add a Seinfeldian qualification ("not that there's anything wrong with that") disavowing a bias that has not been expressed. It may come too close to an uncomfortable truth that is susceptioble to misinterpretation (e.g., Paul Ryan's recent statements regarding the interaction of culture and poverty). He or she will then be overwhelmed by charges of "racism" or "sexism." When his or her defenders point out that the charges are untrue, the attackers will just scream louder or say that, even if it was not biased, the statement was in some sense "insensitive" so "just as bad." Because being seen as "racist" or "sexist" is anathema in today's society, people who know better either join the pogrom or head for cover. Now, to be clear, I don't think that's what Ashley is doing. But the examples that she gives are instructive. In our hypersenstive world, they may be political gaffes, but they are not substantive errors. For example, Grothman made a statement about young men being more interested in making money because they may someday be breadwinners. He was arguing that disparities in pay between men and women do not necessarily reflect employer bias. One alternate explanation, he said, might have something to do with life choices. He gave the example of two lawyers who marry. The husband stays at his firm while the wife takes time off to raise the children. At 50, he'll probably be making more money than she is, but this will not be the product of employer bias. The first thing to note is that Grothman is right. This story applies to about many lawyers that I know. For whatever reason, women have been more likely to step out of the workforce - or take less demanding jobs - for family reasons. This has consequences. Indeed, yesterday's New York Times reported on a study finding that "too much" family leave can hurt one's career prospects. The second thing to note is that his point was not normative - he was not saying that this is the way it should be - only that it has been the way it is. It could be that women who are becoming lawyers today will be less likely to do this in the future. It may be that the greater tendency - so far - of women to interrupt their careers (or take more family friendly jobs) is the product of "socially constructed" gender roles. It may be that employers should - whether on their own or by compulsion - adopt more family friendly policies so women are less likely to leave - even if this does impose costs on others. But none of this is what Grothman was addressing. Ashley quotes an old - and admittedly inartful - statement opposing mandatory life sentence for persons committed of two or more counts of sexual assault of a child. While one could read the statement as being "insensitive" to victims, Grothman's point was that all such offenses are not the same and that some sentencing discretion may be in order. For example, do we want to impose a mandatory life sentence on an 18 year old convicted of having sex with his fifteen year old girl friend? He could have said it better, but it seems pretty clear that this is what he meant. Now I understand that many people don't want to think this hard (although it's really pretty easy) about what someone has said. Some don't want to give a political opponent the benefit of the doubt. Others find it easier to suspend critical analysis. For them, it is enough that he said something that - kind of, sort of - has to do with gender roles or some other sensitive topic and that's icky. It's easier to think one has preserved one's own virtue by pre-emptorily throwing the speaker under the bus. Of course, Ashley Schultz is not one of those people. But I think we need to make a distinction between criticizing a candidate's political skills and judgment, on the one hand and his or her substantive positions on the other. * By way of disclosure, Ashley works at St. Anthony's School where I am on the Board of Directors. I have no authority over her, but, even if I did, she should feel to tell me where I'm wrong. God knows I need it. About Me I am President and General Counsel of the Wisconsin Institute for Law & Liberty and an adjunct professor of law at Marquette University Law School. The views expressed here are my own and not those of WILL or Marquette. They are offered in my personal capacity.

Humanitarian health computing using artificial intelligence and social media: A narrative literature review. According to the World Health Organization (WHO), over 130 million people are in constant need of humanitarian assistance due to natural disasters, disease outbreaks, and conflicts, among other factors. These health crises can compromise the resilience of healthcare systems, which are essential for achieving the health objectives of the sustainable development goals (SDGs) of the United Nations (UN). During a humanitarian health crisis, rapid and informed decision making is required. This is often challenging due to information scarcity, limited resources, and strict time constraints. Moreover, the traditional approach to digital health development, which involves a substantial requirement analysis, a feasibility study, and deployment of technology, is ill-suited for many crisis contexts. The emergence of Web 2.0 technologies and social media platforms in the past decade, such as Twitter, has created a new paradigm of massive information and misinformation, in which new technologies need to be developed to aid rapid decision making during humanitarian health crises. Humanitarian health crises increasingly require the analysis of massive amounts of information produced by different sources, such as social media content, and, hence, they are a prime case for the use of artificial intelligence (AI) techniques to help identify relevant information and make it actionable. To identify challenges and opportunities for using AI in humanitarian health crises, we reviewed the literature on the use of AI techniques to process social media. We performed a narrative literature review aimed at identifying examples of the use of AI in humanitarian health crises. Our search strategy was designed to get a broad overview of the different applications of AI in a humanitarian health crisis and their challenges. A total of 1459 articles were screened, and 24 articles were included in the final analysis. Successful case studies of AI applications in a humanitarian health crisis have been reported, such as for outbreak detection. A commonly shared concern in the reviewed literature is the technical challenge of analyzing large amounts of data in real time. Data interoperability, which is essential to data sharing, is also a barrier with regard to the integration of online and traditional data sources. Human and organizational aspects that might be key factors for the adoption of AI and social media remain understudied. There is also a publication bias toward high-income countries, as we identified few examples in low-income countries. Further, we did not identify any examples of certain types of major crisis, such armed conflicts, in which misinformation might be more common. The feasibility of using AI to extract valuable information during a humanitarian health crisis is proven in many cases. There is a lack of research on how to integrate the use of AI into the work-flow and large-scale deployments of humanitarian aid during a health crisis.

Q: HOW: Apache Camel, Regex match files im experimenting in getting camel to do some file operations and pass them through the activeMQ broker, ive taken this project over from a guy who recently quit. what ive got so far: <route id="SVLFTPCOPY"> <from uri="sftp://*****:*******@********/srv/test/?fileName=*2280.xls&amp;noop=true&amp;idempotent=false"/> <to uri="file:/srv/data/test/destination/"/> <to uri="activemq:queue:svl.ftp.copy"/> </route> it works to the point where it runs the route without throwing any errors, but still doesnt copy the file to the local file. Any ideas? . A: Yeah you need to use the include/exclude/filter option if you want to filter out files based on patterns. The fileName option is for a single file. So in your case, remove fileName option and replace it with include=.*2280.xsl. Mind that the include is based on Java regular expressions, so we use dot star to indicate wildcard. More details here: https://camel.apache.org/components/latest/file-component.html. The ftp component inherits 99% of the options of the file component, so that is why I refer to the file wiki page. A: Use the include option that uses Java regular expression: include=.*2280\\.xsl Please, mind the \\ before the dot . Alternatively, use antInclude: antInclude=*2280.xsl

Role of serotonergic input in the regulation of the beta-adrenergic receptor-coupled adenylate cyclase system. The action of desipramine on the norepinephrine-sensitive adenylate cyclase system and the density of beta-adrenergic receptors in rat cortex was studied after selective lesioning of serotonergic neurons with 5,7-dihydroxytryptamine. In animals with lesions desipramine failed to reduce the density of beta-adrenoceptors but decreased the response of adenosine 3',5'-monophosphate to isoproterenol and norepinephrine to the same degree as in animals without lesions. The results demonstrate a functional linkage between serotonergic and noradrenergic systems in the rat cortex, with beta-adrenergic receptors and neurohormonal sensitivity of the adenosine 3',5'-monophosphate-generating system being under separate regulatory control.

Q: Implementing ActionBarSherlock, gradle error I'm a starter at android developing and am currently really stuck with implementing actionbarsherlock. I know this has been discussed before, but I'm getting really confused regarding dependencies and how to set up the project structure. I tried following all the instructions, but it's not working out. I keep getting a different problem with the gradle. I'm using Android Studio 0.2.0. My current error says: >Gradle 'MyAppProject' project refresh failed: >Could not fetch model of type 'IdeaProject' using Gradle distribution "http://services.gradle.org/distributions/gradle-1.6-bin.zip". >Error: Gradle: A problem occurred configuring project ':MyApp'. >Failed to notify project evaluation listener. >A problem occurred configuring project ':Libraries:ActionBarSherlock'. >Failed to notify project evaluation listener. >Main Manifest missing from C:\Users\JJ2\AndroidStudioProjects\MyAppProject\Libraries\ActionBarSherlock\src\main\AndroidManifest.xml My project is build as follows: -MyAppProject |+.idea |+gradle |-Libraries ||-ActionBarSherlock |||+gen |||+libs |||+res |||-src ||||-android.support.v4.app |||||-Watson ||||+com.actionbarsherlock |||-ActionBarSherlock.iml |||-AndroidManifest.xml |||-build.gradle |||-lint.xml |||-pom.xml |||-project.properties |||-README.md |-MyApp ||+build ||+libs ||-src |||-main ||||-java |||||+com.mywebsite.myapp ||||+res ||||-AndroidManifest.xml ||||-ic_launcher-web.png ||-build.gradle ||-MyApp.iml |-build.gradle |-gradlew |-gradlew.bat |-local.properties |-settings.gradle |-MyAppProject.iml -External Libraries |-<Android 4.2.2> ||+android.jar ||+annotations.jar ||+res The content of the build.gradle in the MyAppProject directory: task assemble{} The build.gradle in the MyApp directory: buildscript { repositories { mavenCentral() } dependencies { classpath 'com.android.tools.build:gradle:0.5.0' } } apply plugin: 'android' dependencies { compile project(":Libraries:ActionBarSherlock") } android { compileSdkVersion 17 buildToolsVersion "17.0.0" defaultConfig { minSdkVersion 9 targetSdkVersion 17 } } And the build.gradle in the Libraries\ActionBarSherlock directory: buildscript { repositories { mavenCentral() } dependencies { classpath 'com.android.tools.build:gradle:0.5.0' } } apply plugin: 'android-library' dependencies { compile files('libs/android-support-v4.jar') } android { compileSdkVersion 17 buildToolsVersion "17.0.0" defaultConfig { minSdkVersion 9 targetSdkVersion 17 } } Lastly, my Project Structure looks as follows: Modules -ActionBarSherlock (Dependencies: Android 4.2.2, [v]android-support-v4) -Android -MyApp (Dependencies: Android 4.2.2, [ ]ActionBarSherlock) -Android -Android-Gradle -MyAppProject (Dependencies: Android 4.2.2) -Android-Gradle Libraries None Global Libraries -android-support-v4 (Classes: ...\MyAppProject\MyApp\libs\android-support-v4.jar) I hope somebody can notice anything wrong with the code, although a lot of people seem to have uresolved issues since the new Android Studio release. Thanks in advance! A: Top directory settings.gradle: include ':MyApp', ':Libraries:ActionBarSherlock' include any other libs you may enter to your project Top directory build.gradle: its okay with task assemble {} Actionbar sherlock build.gradle buildscript { repositories { mavenCentral() } dependencies { classpath 'com.android.tools.build:gradle:0.5.+' } } apply plugin: 'android-library' dependencies { compile 'com.android.support:support-v4:13.0.0' } android { compileSdkVersion 17 buildToolsVersion "17.0.0" defaultConfig { minSdkVersion 7 targetSdkVersion 16 } sourceSets { main { manifest.srcFile 'AndroidManifest.xml' java.srcDirs = ['src'] resources.srcDirs = ['src'] aidl.srcDirs = ['src'] renderscript.srcDirs = ['src'] res.srcDirs = ['res'] assets.srcDirs = ['assets'] } instrumentTest.setRoot('tests') } } Also, IN ALL .gradle files that gradle version is set: replace everywhere the gradle version to: classpath 'com.android.tools.build:gradle:0.5.+' Android Studio 2.x uses gradle 0.5.x, and by using + you 'll keep your gradle up to date (they updated it before 2 days, and we have frequent updates!! ) Your gradle settings now will be okay! Note1: Any other erros may occur from iml./idea files ... You can try changing them in Studio's project settings, eg set source files for each module(sherlock, MyApp), their libraries, etc! Note 2: Also if you are using some other libraries, which requires higher version of SDK than your app, you can get an error, w/o explanation!

PROJECT SUMMARY Experimental models and human studies have repeatedly linked persistent organic pollutants (POPs) such as perfluorinated alkylate substances (PFASs) and polychlorinated biphenyls (PCBs) to abnormal fat distribution, body mass index, and glucose and lipid metabolic abnormalities during early life. These are pervasive chemicals to which nearly all children are exposed during early life: PFASs are used in several consumer and industrial applications and PCBs accumulate in food chains. Evidence suggests that these abnormal cardiometabolic trajectories during early childhood may predict insulin resistance, metabolic syndrome, obesity, and even cardiovascular events in adulthood. However, no biomarkers are available to identify in the immediate postnatal period children who are at risk for abnormal cardiometabolic development, thus curbing opportunities for effective, targeted prevention. To address this gap, our long-term goal is to identify novel mechanistic biomarkers in breast milk that reflect environmental influences and predict the risk of abnormal cardiometabolic programming and childhood obesity. We will leverage groundbreaking evidence on the roles of breast milk extracellular vesicles (BMEVs) in metabolic programming. BMEVs are small vesicles that are released by luminal epithelial cells in breast milk. BMEVs have been proposed as conveyors of molecular signals from the mother to the child. In particular, BMEVs transport a cargo of microRNAs (miRNAs) that, once ingested by the child, integrate themselves in recipient cells in the child's body and can remotely affect the expression and translation of child's messenger RNAs. This process has been shown to be key to the child's metabolic programming in early life. To date, no studies have been conducted to identify the potential roles of BMEVs as part of the paths linking PFASs and PCBs exposure to its adverse effects on cardiometabolic trajectories and obesity during childhood. To achieve this goal, we will leverage the unique resources of the longitudinal Faroe Islands birth cohort, a prenatal cohort with biobanked breast milk (N=300, all from nursing mothers), extensive exposure data, and repeated postnatal cardiometabolic measures over 13 years of follow up. We hypothesize that BMEV number, BMEV size, and BMEV-encapsulated miRNAs are modified in response to prenatal (third-trimester of pregnancy) exposure to PFASs and PCBs (Aim 1) and that BMEV number, BMEV size, and BMEV- encapsulated miRNA predict cardiometabolic outcomes over 13 years of follow up (Aim 2). We will use advanced statistical modeling to integrate BMEV biomarkers in the paths linking exposure and abnormal cardiometabolic trajectories (Exploratory Aim 3). This study is a high-risk/high-reward and cost-effective project that will provide new noninvasive tools to identify and reduce the burden of abnormal cardiometabolic programming during childhood.

<?php /** * Copyright © Magento, Inc. All rights reserved. * See COPYING.txt for license details. */ declare(strict_types=1); namespace Magento\Framework\GraphQl\Schema\Type\Output\ElementMapper\Formatter; use Magento\Framework\GraphQl\Config\Data\WrappedTypeProcessor; use Magento\Framework\GraphQl\Config\Element\Field; use Magento\Framework\GraphQl\Config\Element\TypeInterface; use Magento\Framework\GraphQl\Config\ConfigElementInterface; use Magento\Framework\GraphQl\Schema\Type\Input\InputMapper; use Magento\Framework\GraphQl\Schema\Type\Output\ElementMapper\FormatterInterface; use Magento\Framework\GraphQl\Schema\Type\Output\OutputMapper; use Magento\Framework\GraphQl\Schema\Type\OutputTypeInterface; use Magento\Framework\GraphQl\Schema\Type\ScalarTypes; use Magento\Framework\ObjectManagerInterface; use Magento\Framework\GraphQl\Schema\Type\ResolveInfoFactory; use Magento\Framework\GraphQl\Query\Resolver\Factory as ResolverFactory; /** * Convert fields of the given 'type' config element to the objects compatible with GraphQL schema generator. */ class Fields implements FormatterInterface { /** * @var ObjectManagerInterface */ private $objectManager; /** * @var OutputMapper */ private $outputMapper; /** * @var InputMapper */ private $inputMapper; /** * @var ScalarTypes */ private $scalarTypes; /** * @var WrappedTypeProcessor */ private $wrappedTypeProcessor; /** * @var ResolveInfoFactory */ private $resolveInfoFactory; /** * @var ResolverFactory */ private $resolverFactory; /** * @param ObjectManagerInterface $objectManager * @param OutputMapper $outputMapper * @param InputMapper $inputMapper * @param ScalarTypes $scalarTypes * @param WrappedTypeProcessor $wrappedTypeProcessor * @param ResolveInfoFactory $resolveInfoFactory * @param ResolverFactory $resolverFactory */ public function __construct( ObjectManagerInterface $objectManager, OutputMapper $outputMapper, InputMapper $inputMapper, ScalarTypes $scalarTypes, WrappedTypeProcessor $wrappedTypeProcessor, ResolveInfoFactory $resolveInfoFactory, ?ResolverFactory $resolverFactory = null ) { $this->objectManager = $objectManager; $this->outputMapper = $outputMapper; $this->inputMapper = $inputMapper; $this->scalarTypes = $scalarTypes; $this->wrappedTypeProcessor = $wrappedTypeProcessor; $this->resolveInfoFactory = $resolveInfoFactory; $this->resolverFactory = $resolverFactory ?? $this->objectManager->get(ResolverFactory::class); } /** * @inheritdoc */ public function format(ConfigElementInterface $configElement, OutputTypeInterface $outputType): array { $typeConfig = []; if ($configElement instanceof TypeInterface) { $typeConfig = [ 'fields' => function () use ($configElement, $outputType) { $fieldsConfig = []; foreach ($configElement->getFields() as $field) { $fieldsConfig[$field->getName()] = $this->getFieldConfig($configElement, $outputType, $field); } return $fieldsConfig; } ]; } return $typeConfig; } /** * Get field's type object compatible with GraphQL schema generator. * * @param TypeInterface $typeConfigElement * @param OutputTypeInterface $outputType * @param Field $field * @return TypeInterface */ private function getFieldType(TypeInterface $typeConfigElement, OutputTypeInterface $outputType, Field $field) { if ($this->scalarTypes->isScalarType($field->getTypeName())) { $type = $this->wrappedTypeProcessor->processScalarWrappedType($field); } else { if ($typeConfigElement->getName() == $field->getTypeName()) { $type = $outputType; } else { $type = $this->outputMapper->getOutputType($field->getTypeName()); } $type = $this->wrappedTypeProcessor->processWrappedType($field, $type); } return $type; } /** * Generate field config. * * @param TypeInterface $typeConfigElement * @param OutputTypeInterface $outputType * @param Field $field * @return array */ private function getFieldConfig( TypeInterface $typeConfigElement, OutputTypeInterface $outputType, Field $field ): array { $type = $this->getFieldType($typeConfigElement, $outputType, $field); $fieldConfig = [ 'name' => $field->getName(), 'type' => $type, ]; if (!empty($field->getDescription())) { $fieldConfig['description'] = $field->getDescription(); } if (!empty($field->getDeprecated())) { if (isset($field->getDeprecated()['reason'])) { $fieldConfig['deprecationReason'] = $field->getDeprecated()['reason']; } } if ($field->getResolver() != null) { $resolver = $this->resolverFactory->createByClass($field->getResolver()); $fieldConfig['resolve'] = function ($value, $args, $context, $info) use ($resolver, $field) { $wrapperInfo = $this->resolveInfoFactory->create($info); return $resolver->resolve($field, $context, $wrapperInfo, $value, $args); }; } return $this->formatArguments($field, $fieldConfig); } /** * Format arguments configured for passed in field. * * @param Field $field * @param array $config * @return array */ private function formatArguments(Field $field, array $config) : array { foreach ($field->getArguments() as $argument) { $inputType = $this->inputMapper->getRepresentation($argument); $config['args'][$argument->getName()] = $inputType; } return $config; } }

Experimental studies on the pathogensis of temporal lobe epilepsy. In 12 rhesus monkeys the injection of alumina cream into the temporal cortex, amygdala or hippocampus induced seizures after a latent period of six weeks to three months. Clinically the attacks are characterized by an arrest of movement, staring, unresponsiveness to most stimuli, wandering conjugate eye movements, automatisms, twitching of the contraleteral ear and less commonly commonly vocalization, chewing, hiccoughing, vomiting, adversive head movements and twitching of the face. The spiking from the amygdala and hippocampus, which usually fire together, propagates to the temporal cortex and multiple subcortical structures including the hypothalamus, anterior perforated space, anteromedial thalamus, cingulate gyrus, putamen, globus pallidus, subthalamus and mesencephalic reticular formation; from the temporal cortex to the amygdala and hippocampus, and secondarily to the diencephalic centers. There is a fairly consistent sequence of preferential propagation. Although there are some differences in the occurrences of clinical manifestations depending upon the sites of the focus, no specific structural correlation with clinical manifestations could be established. This experimental condition may provide a proper model for the study of clinical psychomotor epilipsy.

Superior Catalytic Performance of Gold Nanoparticles Within Small Cross-Linked Lysozyme Crystals. Bionanomaterials synthesized by bioinspired templating methods have emerged as a novel class of composite materials with varied applications in catalysis, detection, drug delivery, and biomedicine. In this study, two kinds of cross-linked lysozyme crystals (CLLCs) with different sizes were applied for the in situ growth of Au nanoparticles (AuNPs). The resulting composite materials were characterized by light microscopy, scanning electron microscopy, transmission electron microscopy, thermogravimetric analysis, and X-ray photoelectron spectroscopy. The catalytic properties of the prepared materials were examined in the catalytic reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP). It was found that the size of the AuNPs increased with an increase in Au loading for both small and large crystals. In addition, small crystals favored homogeneous adsorption and distribution of the metal precursors. And the size of the AuNPs within small crystals could be maintained below 2.5 nm by managing the HAuCl4/lysozyme molar ratio. Furthermore, the lysozyme functional groups blocked the AuNP activity sites, therefore reducing their catalytic activity. This effect was more pronounced for small AuNPs. Moreover, the mass transfer of reactants (4-NP) from solution to AuNPs within the crystals restricted their catalytic reduction, leading to superior catalytic performance of the AuNPs within small cross-linked lysozyme crystals (Au@S-CLLCs) compared to those within large cross-linked lysozyme crystals (Au@L-CLLCs) at similar Au loadings. Finally, an increase in Au loading clogged the crystal channels with increased quantities of larger AuNPs, thus impeding the catalytic performance of Au@S-CLLCs.

Elizabeth Harrington Elizabeth Harrington is a senior writer for the Washington Free Beacon. Elizabeth graduated from Temple University in 2010. Prior to joining the Free Beacon, she worked as a staff writer for CNSNews.com. Her email address is elizabeth@freebeacon.com. Her Twitter handle is @LizWFB.Email Elizabeth | RSS The Social Security Administration has spent $3 billion on programs designed to incentivize disability recipients to go back to work over the past 16 years. So far, less than 3 percent of beneficiaries have signed up, with “no consistent evidence” the program has helped participants find a job. Prisoners incarcerated in California took in $3.5 million in Social Security payments from taxpayers. The inspector general for the agency reported 123 inmates received the disability and retirement payments despite the Social Security Act prohibiting payments to individuals “confined to a jail, prison, or certain other public institutions for committing a crime.” MARMET, W.Va.—Sen. Joe Manchin said “it could have been anybody” who requested a personal $3 million “Governor’s Helicopter” for him with opioid settlement funding while he was governor of West Virginia.

Biochemical actions of sympathomimetic drugs which overcome cycloheximide-induced amnesia. Earlier investigations of sympathomimetic drugs overcoming the amnesic action of cycloheximide (CXM) in day-old chickens were extended to biochemical studies in vitro. The effects of amphetamine, norepinephrine, alpha and beta noradrenergic stimulants and receptor blockers on Na+/K+ ATP'ase activity in total homogenate of chicken forebrain were investigated. Norepinephrine and the beta stimulant, isoprenaline significantly stimulated the activity of this enzyme, while the beta blocker, propranolol inhibited activity. Amphetamine, the alpha stimulant, methoxamine and the alpha receptor blocker, piperoxane had no effect on Na/K+ ATP'ase activity in total homogenate. In a purified synaptosomal preparation, both amphetamine (5 X 10(-5) M) and norepinephrine (1 X 10(-4) M) produced a slight stimulation of Na+/K+ ATP'ase activity. A similar concentration of amphetamine (1.12 X 10(-4) M) did not inhibit 14C-leucine uptake or incorporation into protein in the synaptosomal fraction. Nor was it able to alleviate CXM inhibition of 14C-leucine incorporation into synaptosomal protein. The results are interpreted in terms of amphetamine (via release of norepinephrine) norepinephrine and isoprenaline stimulating and maintaining the labile, sodium pump-dependent, phase of memory formation for a sufficient length of time until protein synthesis inhibition by CXM wears off.

Introduction {#sec1} ============ Embryonal rhabdomyosarcoma (ERMS) is a devastating pediatric sarcoma characterized by a pathologic block in myogenic differentiation. The initiation and progression of ERMS are primarily driven by RAS-associated signaling pathways.[@bib1] Whether RAS signaling is involved in repressing myogenic differentiation in ERMS is currently unknown. There are also no effective therapies capable of directly targeting activated RAS proteins. In fact, many common cancer oncogenes are undruggable by modern therapeutic approaches.[@bib2], [@bib3] Developing therapies to target these oncogenic drivers remains one of the primary goals of current cancer research. However, creation of new targeted cancer therapies is a time-consuming process, requiring substantial research and development of resources. Directly targeting the genomic DNA of essential cancer genes could overcome many of the challenges associated with developing precision cancer treatments. Advances in genome-editing technology now make it possible to target oncogenes with remarkable precision, paving the way for a new generation of gene-editing cancer therapies. Because genome-editing technology relies only on knowledge of cancer genetics, it can be rapidly customized to the vulnerabilities present in individual tumors. Development of a programmable cancer therapy of this kind could profoundly impact cancer treatment by providing the flexibility to rapidly target a wide range of essential cancer genes in a variety of cancer types. Although a growing number of studies have provided initial evidence that gene-editing technology could be used to target essential cancer genes,[@bib4], [@bib5], [@bib6], [@bib7] several major obstacles remain before a cancer gene-editing therapy could be used in the clinic. The first is the development of high-efficiency gene-editing approaches that can target essential cancer genes with therapeutic efficiency and specificity. Cancer gene-editing therapies will also require the development of an effective gene therapy delivery system to facilitate treatment of cancer patients. Our study used high-efficiency gene-targeting approaches to investigate the dependency of ERMS cells on activated RAS signaling, identifying RAS as a dominant repressor of myogenic differentiation in ERMS. Using this targeting strategy, we developed a novel oncolytic myxoma viral (MYXV) gene-editing vector system to directly target activated RAS genes in ERMS tumors. This study evaluates the therapeutic potential of this recombinant gene-editing oncolytic virus, providing important insights into the emerging field of gene-editing cancer therapy and establishing a framework for further development of this innovative technology. Results {#sec2} ======= Targeting Activated RAS Inhibits Tumor Growth and Induces Myogenic Differentiation of ERMS Cells {#sec2.1} ------------------------------------------------------------------------------------------------ RAS-associated signaling pathways are responsible for ERMS initiation and progression. However, the cellular mechanisms by which RAS signaling promotes ERMS tumor growth are unknown. Therefore, we sought to disrupt RAS signaling in *RAS* mutant ERMS cells using CRISPR/Cas9 gene-editing approaches. Because RAS signaling was essential for the proliferation of ERMS cells, gene knockout required high-efficiency gene-editing approaches that can effectively target the oncogene in all cancer cells. Despite several improvements to CRISPR/Cas9 single guide RNA (sgRNA) design,[@bib8] the insertion and deletion (indel) mutation efficiency of a sgRNA is not sufficient for most cancer therapeutic applications. We previously observed that simultaneous targeting of genes with multiple gRNAs resulted in high-efficiency deletions between sgRNAs that were up to two to three times the average indel efficiency for sgRNAs (i.e., 40%--60%).[@bib7] We therefore adapted a similar high-efficiency gene-editing strategy to examine the phenotypic response of ERMS cells to ablation of *RAS* genes. To target *RAS* in ERMS, *RAS* mutant cancer cells were co-transduced with high-titer lentiviruses expressing *Streptococcus pyogenes* Cas9 (*Sp*Cas9) and dual gRNAs targeting exon 3 of the *NRAS* or *HRAS* genes (*NRAS* A183T mutant 381T and *HRAS* C181A mutant SMS-CTR ERMS cells, respectively). *NRAS* and *HRAS* knockout in RAS mutant ERMS cells resulted in a significant reduction in viability 5 days post-gene targeting ([Figure 1](#fig1){ref-type="fig"}A). We also observed a small but significant reduction in cell viability with *NRAS* targeting in HRAS-driven ERMS cells ([Figure 1](#fig1){ref-type="fig"}A), suggesting a potential role for wild-type RAS signaling in modulating growth of some ERMS cells. Flow cytometry-based annexin V assay for apoptosis revealed that the reduction in ERMS cell growth after RAS targeting was due to a modest but significant increase in cell death ([Figure 1](#fig1){ref-type="fig"}B). The vast majority of *NRAS*- and *HRAS*-targeted cells underwent terminal myogenic differentiation, as shown by a significant increase in myosin heavy chain positive-multinucleated myotubes ([Figures 1](#fig1){ref-type="fig"}C and 1D). Cell-cycle analysis of ERMS cells with *NRAS* A183T and *HRAS* C181A knockout revealed a decrease in the percentage of S phase cells compared with controls because of an increase in the percentage of cells arrested in the G1 phase of the cell cycle (NRAS: S, p = 0.005; G1, p = 0.002; HRAS: S, p \< 0.0001; G1, p = 0.0005; [Figure 1](#fig1){ref-type="fig"}E).Figure 1High-Efficiency Knockout of *RAS* Induces Differentiation of ERMS Cells(A) *RAS* targeting reduces viability in ERMS cells harboring *NRAS* A183T or *HRAS* C181A activating mutations. Annexin V apoptosis (B) and MF20 (C), myosin heavy chain immunostaining analysis, after *NRAS* or *HRAS* knockout. (D) Fluorescent images showing myogenic differentiation of ERMS cells after *RAS* targeting (MF20, green; nuclei, blue; scale bar: 100 μm). (E) Changes in cell cycle in RAS knockout (KO) ERMS cells (n = 3). Cell viability (A) and MF20 (C) data were analyzed 6 days post-*RAS* targeting, and cell death (B) and cell-cycle analysis (E) were taken 4 days post-targeting, prior to myogenic differentiation. Data in (A)--(C) represent the average of four biological replicates with error bars ± SEM. \*\*p \< 0.01; \*\*\*p \< 0.001; \*\*\*\*p \< 0.0001. To further assess the response of ERMS cells to the loss of RAS signaling, we engineered tamoxifen-inducible *NRAS*-targeting ERMS cells, using a system previously developed in our laboratory.[@bib7] We first compared the global gene expression profile of the tamoxifen-induced *NRAS* knockout ERMS cells with non-induced ERMS control cells prior to terminal myogenic differentiation (day 2 after *NRAS* knockout) to gain insight into genes and pathways regulated by NRAS. Disruption of *NRAS* resulted in a decrease in the expression of key cell-cycle and DNA replication genes and an increase in the expression of myogenic differentiation genes ([Figure S1](#mmc1){ref-type="supplementary-material"}). Taken together, our loss-of-function studies and gene expression analysis demonstrate that RAS signaling is required for sustaining ERMS cell proliferation, in part, through its repression of the myogenic program. NRAS Knockout Regresses ERMS Tumor Xenografts *In Vivo* {#sec2.2} ------------------------------------------------------- To examine the response of ERMS tumors to loss of RAS signaling *in vivo*, we established tamoxifen-inducible *NRAS*-targeting tumor xenografts in immunocompromised NOD-SCID Il2rg^−/−^ (NSG) mice ([Figure 2](#fig2){ref-type="fig"}A). The growth of *NRAS*-targeted xenografts was compared with non-induced or control tumors targeted at a safe harbor region of chromosome 4 (58110237--58110808; GRCH38.p2).[@bib7] Treatment of tumor xenografts with tamoxifen resulted in extensive gene editing with complete *NRAS* knockout within a week of treatment ([Figure 2](#fig2){ref-type="fig"}B). The median survival of mice with *NRAS*-targeted tumors increased by approximately 2-fold (i.e., 38.5 days) over non-targeted or safe harbor control-targeted tumors ([Figure 2](#fig2){ref-type="fig"}C). *NRAS* knockout resulted in the regression of ERMS tumors, most of which became undetectable around 10 days after tamoxifen treatment ([Figure 2](#fig2){ref-type="fig"}D). There was a significant difference in tumor volume change, comparing *NRAS*-targeted tumor xenografts with non-treated and tamoxifen-treated control tumors (p \< 0.0001; [Figure 2](#fig2){ref-type="fig"}D).Figure 2Targeting *NRAS* in ERMS Xenografts Inhibits Tumor Growth and Induces Myogenic Differentiation(A) Design of tamoxifen-inducible *NRAS* knockout experiment with *NRAS* gene-targeting strategy showing gRNA target sites (red arrows) and the activating A183T mutation site (red vertical bar). (B) Inducible gene editing in tumor xenografts as shown by the presence of deletion mutations in tamoxifen-treated tumors after PCR amplifying the deletion mutations with primers flanking the gRNA target sites. Efficiency of editing was estimated by combining deletion efficiencies between gRNA target sites. (C) Mouse survival after tamoxifen (Tam) induced knockout of *NRAS* in tumor xenografts (n = 10). (D) Analysis of changes in tumor volume over 21 days with mean ± SD of each treatment group. (E) Histological (H&E) and immunohistochemistry (IHC) analysis of *NRAS* knockout tumors prior to tamoxifen treatment and at 7 and 28 days after treatment. IHC analysis was used to determine the extent of cellular proliferation (Ki67), apoptosis (CC3), and myogenic differentiation (myosin heavy chain, MF20) of tumor samples. (F) Phosphorylated ERK (pERK) immunostaining in tumor xenografts 7 days after tamoxifen treatment. Scale bars represent 100 μm. \*\*\*\*p \< 0.0001. The cellular response of ERMS tumors to *NRAS* targeting was monitored every 7 days by analyzing changes in cell morphology (H&E), cellular proliferation (Ki67), cell death (cleaved caspase 3 \[CC3\]), and myogenic differentiation (MF20). *NRAS* knockout resulted in an initial decrease in cellular proliferation and increase in cell death (day 7), followed by myogenic differentiation throughout most of the tumor mass (day 28; [Figure 2](#fig2){ref-type="fig"}E). This was associated with a decrease in phosphorylated extracellular signal-regulated kinase, aka MAPK (pERK), signaling following *NRAS* targeting in ERMS tumors ([Figure 2](#fig2){ref-type="fig"}F). These findings indicate that RAS is essential for sustaining tumor growth, as well as repressing myogenic differentiation in ERMS. Relapse of NRAS-Targeted Tumors {#sec2.3} ------------------------------- Despite effective *NRAS* knockout in ERMS tumor xenografts ([Figure 2](#fig2){ref-type="fig"}B), relapsed tumor growth eventually occurred in all mice ([Figure 3](#fig3){ref-type="fig"}A). The primary genotype found in NRAS-resistant tumors was a large gDNA deletion (2,270 bp) between the outermost gRNA target sites (gRNA3 and gRNA1; [Figure 2](#fig2){ref-type="fig"}A), resulting in the loss of 67 amino acids (aa) (35% of the protein coding sequence). Consistent with the high fidelity of non-homologous end joining (NHEJ) DNA repair, the majority of deletion mutations were direct fusions between the gRNA cut sites, resulting in frameshift mutations ([Figure 3](#fig3){ref-type="fig"}B). In-frame deletion mutations were also identified ([Figure 3](#fig3){ref-type="fig"}B), but the loss of the *NRAS* core region, including the activating mutation site, likely resulted in a non-functional protein. There was a very small percentage of non-targeted xenograft cells with compromised gene editing, but these cells did not represent the majority of the relapsed tumor mass. Indel mutations and small deletions that resulted in truncating frameshift mutations were also identified ([Figure 3](#fig3){ref-type="fig"}B). The findings suggest that relapsed tumor growth most likely occurred secondary to the resistance of tumor cells to *NRAS* gene targeting rather than the outgrowth of non-targeted cells.Figure 3Relapse of ERMS Tumors following *NRAS* Targeting(A) Change in tumor volume over time in *NRAS*-targeted tumors compared with controls. (B) Example of common *NRAS* mutations found in relapsed tumor xenografts and an isolated *NRAS*-targeting-resistant clone. Development of Recombinant Gene-Editing Myxoma Virus for RAS-Targeted Oncolytic Viral Therapy {#sec2.4} --------------------------------------------------------------------------------------------- The pre-clinical *RAS* knockout studies highlighted the potential for exploiting the myogenic commitment of ERMS cancer cells for differentiation therapy. Because there are currently no viable RAS-targeted therapies, we sought to test the effectiveness of high-efficiency CRISPR/Cas9 technology for therapeutic targeting of the *NRAS* oncogene in ERMS. We recognized that delivery would be a major obstacle for any cancer gene-editing therapy. Our initial attempts to use traditional non-replicating lentiviral and adeno-associated viral gene therapy vectors failed because of low transduction efficiency in ERMS tumors. We therefore chose to investigate the replicating oncolytic MYXV from the *Leporipoxvirus* genus[@bib9], [@bib10] as a potential delivery vector for the *NRAS* gene-editing cancer therapy. MYXV causes myxomatosis in European rabbits but is completely non-pathogenic to humans.[@bib9], [@bib10] However, the virus is capable of replicating selectively in many cancer cells,[@bib11] including ERMS cells,[@bib12] and is currently being developed for a variety of clinical applications. The large genome size (161.8 kb) of MYXV is also capable of packaging all CRISPR/Cas9 gene-editing components into a single viral genome,[@bib10] making MYXV an ideal candidate for a therapeutic CRISPR/Cas9 gene-editing vector. We confirmed the replication efficiency of recombinant MYXV in ERMS cells using a reporter virus that expressed both a constitutive vaccinia virus synthetic early and late promoter (vvSEL)-driven GFP cassette along with a replication-dependent late promoter (p11) expressing RFP[@bib12] ([Figure S2](#mmc1){ref-type="supplementary-material"}A). Incubation of ERMS cells with low-titer MYXV resulted in effective viral infection and replication *in vitro* as shown by the expression of both GFP and RFP in infected cells ([Figure S2](#mmc1){ref-type="supplementary-material"}A). Replication-competent MYXV virus could also be serially passaged in ERMS cells through the transfer of conditioned media or cellular lysate ([Figure S2](#mmc1){ref-type="supplementary-material"}A). Recombinant MYXV exhibited active viral replication (expression of GFP and RFP) in ERMS tumors xenografts when administered by direct intra-tumoral injection ([Figure S2](#mmc1){ref-type="supplementary-material"}B). Despite efficient viral replication, the spread of the recombinant myxoma viral vector was restricted to regional areas within the tumor mass ([Figure S2](#mmc1){ref-type="supplementary-material"}B). This pattern of viral infection is likely reflective of the plaque-forming nature of MYXV infection, as well as the tight cellular junctions present in ERMS tumors. Although the myxoma virus (MYXV) was not able to infect all ERMS cells, we hypothesized that ablation of essential oncogenes could promote viral spread by facilitating the release of viral particles to surrounding cells. Similarly, in therapeutic applications, stimulated immune responses may facilitate the killing of RAS knockout cancer cells in the absence of direct infection. Unfortunately, there are currently no immune-competent, RAS-driven mouse models of ERMS. Therefore, we employed ERMS tumor xenografts to test the ability of engineered recombinant gene-editing MYXV to regress ERMS tumors independent of an active immune system. To target the *NRAS* gene in ERMS cells, we engineered a recombinant gene-editing MYXV containing an additional open reading frame expressing the *Sp*Cas9 CRISPR components from a single viral transcript ([Figure 4](#fig4){ref-type="fig"}A). This approach facilitated the use of high-expressing viral promoters (i.e., vvSEL) to ensure efficient gene editing when transcribed from the cytoplasmic MYXV. Our MYXV gene-editing system consisted of an *Sp*Cas9-2A-Csy4 cassette for simultaneous expression of *Sp*Cas9 and the CRISPR ribonuclease Csy4 ([Figure 4](#fig4){ref-type="fig"}A). The Csy4 ribonuclease is capable of cleaving CRISPR gRNAs at precise recognition sequences to split gRNAs from the 3′ end of mRNA transcripts.[@bib13] To facilitate targeted gene editing, we inserted dual gRNAs targeting the genes of interest into the 3′ end of the *Sp*Cas9-2A-Csy4 open reading frame separated by Csy4 cleavage sequences ([Figure 4](#fig4){ref-type="fig"}A). Human NRAS-driven ERMS tumor xenografts established in immunocompromised NSG mice were then injected intratumorally with four doses of the recombinant gene-editing MYXV (1 × 10^7^ plaque-forming units \[PFU\]/100 μL) targeting the *NRAS* oncogene or a safe harbor locus in chromosome 4 ([Figure 4](#fig4){ref-type="fig"}B). Both gene-editing MYXVs effectively transduced ERMS tumor xenografts with no obvious visual difference in the percentage of infected cells between control and NRAS-targeted tumors ([Figure 4](#fig4){ref-type="fig"}B). This suggested that at least for ERMS tumors, *NRAS* targeting alone did not significantly influence the spread of MYXV viral vectors ([Figure 4](#fig4){ref-type="fig"}B). *In vivo* MYXV-mediated targeting of exons 2 and 4 of the human *NRAS* gene resulted in the removal of 52% of the core region of the NRAS protein (98 aa, xenograft genomic DNA deletion of 6,436 bp; [Figure 4](#fig4){ref-type="fig"}C). Although accurate quantification of gene-editing efficiency is not possible in tumor xenografts, due to incomplete viral infection, *in vitro* infection of ERMS cells with the gene-editing MYXV vectors resulted in over 70% deletion mutations at the target locus ([Figure S2](#mmc1){ref-type="supplementary-material"}C), which is significantly higher than the editing efficiency observed with typical CRISPR lentiviral vectors.[@bib7] MYXV-mediated targeting of the *NRAS* oncogene in ERMS tumors significantly increased mouse survival compared with controls (p = 0.0037; [Figure 4](#fig4){ref-type="fig"}D) and resulted in a significant reduction in tumor growth in the majority of xenografts ([Figures 4](#fig4){ref-type="fig"}E and 4F). However, the effect of MYXV gene-editing therapy did not provide sustained therapeutic benefit because all tumors relapsed during treatment. This may be due to a number of factors, including incomplete viral infection and/or tumor cell resistance to *NRAS* targeting. Histological and immunohistochemical (IHC) analysis of MYXV-infected tumors revealed modest myogenic differentiation in *NRAS*-targeted tumors, with the majority of differentiated cells located in areas of low viral load outside the primary infection sites ([Figure S3](#mmc1){ref-type="supplementary-material"}). This suggests that MYXV infection restricted the ability of ERMS cells to undergo myogenic differentiation.Figure 4Myxoma Oncolytic Gene-Editing Viral Therapy Significantly Reduces ERMS Tumor Growth(A) Schematic of the engineered gene-editing oncolytic MYXV and *NRAS*-targeting strategy with gRNA target sites (red arrows). (B) Phase and GFP fluorescent images showing recombinant MYXV-infected areas in ERMS tumors (scale bar: 1 mm). (C) High-efficiency gDNA deletions detected at the safe harbor (control virus) and *NRAS* target sites in representative MYXV-treated ERMS tumors. Sequencing of the most common *NRAS* deletion mutation is shown. (D) Mouse survival over time compared between *NRAS*-targeted (blue), safe-harbor-targeted (red), and wild-type uninfected ERMS tumors (n = 6, n = 6, and n = 20, respectively). Tumor growth over time (E) and change in tumor volume (3 weeks) (F) for *NRAS*- and safe-harbor-targeted tumors. Error bars represent mean ± SD. \*p \< 0.05. Tumor-Specific RAS Targeting in ERMS {#sec2.5} ------------------------------------ Although we demonstrate that gene-editing technology is capable of enhancing the capacity of MYXV vectors to kill cancer cells, our initial therapeutic strategy was not selective for cancer cells and could result in off-target editing of the *NRAS* gene in non-cancer cells. Future cancer gene-editing therapies would likely benefit from selective targeting of cancer cells, and therefore we examined the ability of CRISPR gene-editing technology to selectively target activating point mutations in *RAS* genes. Developing high-efficiency mutation-specific targeting strategies, however, poses significant challenges for many driver oncogenes because of restrictions on the placement of CRISPR gRNA target sites. Although several previous studies have suggested that tumor point mutations could be targeted with a sgRNA targeting the mutation site,[@bib14], [@bib15] our previous experience with CRISPR/Cas9 gene editing suggests that the efficiency of NHEJ repair at a sgRNA site does not allow for the efficiencies necessary for therapeutic applications. To develop a therapeutic gene-editing strategy capable of specifically targeting the activating mutations in *RAS*, we sought to identify CRISPR gRNA target sites that could specifically recognize the mutations present in ERMS. Unfortunately, the *RAS* mutations found in ERMS cells did not introduce new CRISPR protospacer adjacent motifs (PAMs) that could specify target sites unique to ERMS cells. We therefore looked for gRNA target sites that contained the activating point mutations in the seed region of the gRNAs immediately adjacent to the PAM recognition sequence ([Figure 5](#fig5){ref-type="fig"}A). Mutations in the first 7 bp adjacent to the PAM sequence, termed the seed region, are often not tolerated by the CRISPR system, facilitating the establishment of mutation-specific gRNAs.[@bib16] We have previously shown that mutations in this gRNA seed region blocks Cas9 activity in RMS cancer cells.[@bib7] Although an *Sp*Cas9 PAM recognition sequence was in close proximity to the *HRAS* C181A mutation site, no *Sp*Cas9 target sites were found near the activating *NRAS* A183T mutation site ([Figure 5](#fig5){ref-type="fig"}A). In contrast, the PAM recognition sequence for the CRISPR/Cas9 system isolated from *Staphylococcus aureus* (*Sa*Cas9) was located adjacent to the *NRAS* A183T mutation site in ERMS cells ([Figure 5](#fig5){ref-type="fig"}A). Therefore, we designed gRNA sequences using both the *Sp*Cas9 and *Sa*Cas9 systems to facilitate gene editing of the *HRAS* C181A and *NRAS* A183T mutation sites ([Figure 5](#fig5){ref-type="fig"}A). To enhance gene-editing efficiency, we placed a second gRNA target site in the third intron of the *HRAS* and *NRAS* genes, immediately adjacent to exon 3 containing the activating *RAS* mutations (i.e., gRNA i1; [Figure 5](#fig5){ref-type="fig"}A). This targeting strategy was designed to introduce harmless indel mutations in the third intron of the *RAS* gene in normal cells while creating non-functional indel mutations and high-efficiency deletions at the *RAS* mutation site in ERMS cells ([Figure 5](#fig5){ref-type="fig"}A).Figure 5Tumor Mutation-Specific Targeting of *NRAS* and *HRAS* Oncogenes in ERMS(A) *RAS* tumor mutation-specific targeting strategy with locations of the mutation site (red bar) and targeting gRNAs (red arrows). The placement of the mutation-specific gRNAs is identified. (B) Cell viability after treatment of ERMS cells with *RAS* mutation-specific lentivirus. Data represent mean ± SEM of three biological replicates. (C) Sequencing analysis of the *NRAS* and *HRAS* target site after treatment of *NRAS* A183T and *HRAS* C181A mutant and non-mutant cells with tumor-specific targeting virus. \*\*\*\*p \< 0.0001. To validate the specificity and assess off-target editing of these *RAS* gene-editing strategies, lentiviral CRISPR/Cas9 vectors targeting the activating point mutations in *HRAS* and *NRAS* were transduced into ERMS cells harboring either wild-type or mutant *RAS*. As expected, targeting of these *RAS* mutation sites led to a significant reduction in cell viability, similar to that observed with general targeting of *NRAS* and *HRAS* ([Figure 5](#fig5){ref-type="fig"}B). Next-generation sequencing analysis of the *HRAS* and *NRAS* target sites revealed high gene-editing efficiency from both the *Sp*Cas9 and *Sa*Cas9 systems, with 90.3% and 88.1% of the mutant alleles targeted, respectively (i.e., combination of deletion and indel mutations; [Figure 5](#fig5){ref-type="fig"}C). Both ERMS cell models used in our study exhibited chromosomal abnormalities at the RAS target sites, with *NRAS* A183T cells having at least two copies of the *NRAS* A183T allele[@bib1] and *HRAS* C181A mutant cells exhibiting loss of the wild-type *HRAS* allele.[@bib17] *Sa*Cas9 targeting was highly specific with no indel mutations detected at the *NRAS* A183T target site in non-mutant cells ([Figure 5](#fig5){ref-type="fig"}C). However, a small percentage of deletion mutations between the gRNA target sites were identified in wild-type cells (3.5%; [Figure 5](#fig5){ref-type="fig"}C). In contrast, the chosen *HRAS* C181A mutation-specific gRNA was highly promiscuous, targeting both mutant and wild-type alleles with high efficiency (wild-type allele targeting 76%; [Figure 5](#fig5){ref-type="fig"}C). The observed differences in off-target editing are likely not reflective of the fidelity of each Cas9 variant but instead signify the specificity inherent in individual CRISPR gRNA target sites.[@bib16] These results highlight some limitations in selectively targeting oncogenic point mutations because off-target editing could potentially result in the introduction of new oncogenic mutations in normal cells. Discussion {#sec3} ========== This study establishes a platform for the development of future gene-editing cancer therapies by identifying core RAS vulnerabilities in ERMS cancer cells along with high-efficiency oncogene-targeting strategies. The results provide a unique window into the role of RAS oncogenes in promoting ERMS tumor progression by repressing myogenic differentiation. Our data suggest that ERMS cancer cells are pre-programmed myogenic cells that may respond well to targeted differentiation therapies. Even though the impaired differentiation status of RMS tumors is well established,[@bib18], [@bib19] the molecular mechanisms restricting myogenic differentiation have not been fully explored. We have previously demonstrated that the HDAC3/NCOR epigenetic repressor complex restricts myogenic differentiation in RMS by blocking MYOD1-mediated transcriptional activation.[@bib7] The striking phenotypic similarities between *RAS* knockout and disruption of the HDAC3/NCOR epigenetic repressor complex suggest a role for the HDAC3/NCOR complex as a downstream mediator of RAS signaling, likely through direct interaction with the master myogenic regulatory factor MYOD1.[@bib7], [@bib20] Despite promising data suggesting the importance of these factors for ERMS tumor growth, more research is needed to understand the connection between RAS signaling, MYOD1 regulation, and other additional factors, including the HDAC3/NCOR epigenetic repressor complex, in controlling myogenic differentiation in ERMS. Importantly, many of the driver genes in RMS are currently undruggable, and new inhibitor-based targeted therapies will take significant time and resources to develop. Our study highlights the use of recombinant gene-editing virotherapy as a promising alternative to target non-druggable driver genes in cancer. In the absence of effective anti-RAS therapeutic agents, we examined the potential of using high-efficiency gene-editing approaches to directly target *NRAS* and *HRAS* in ERMS. Although several cancer therapeutic gene-editing studies have observed significant effects from the use of single gRNAs,[@bib6], [@bib14], [@bib15], [@bib21] we found that higher gene-editing efficiency was required for therapeutic applications in ERMS.[@bib7] To establish an effective gene-editing system for ERMS tumors, we employed a multiplex gene-targeting approach to simultaneously introduce multiple disrupting indel mutations along with high-efficiency deletion mutations in ERMS cells. In addition to establishing high-efficiency gene-targeting strategies, effective therapeutic delivery systems are critical for implementing this innovative technology for clinical use. Although previous reports have used non-replicating gene therapy vectors,[@bib6], [@bib15], [@bib21] we found that the transduction efficiency of these vectors was extremely limited in ERMS tumors. This led us to develop an oncolytic MYXV vector capable of replicating within ERMS cells. We demonstrated that this recombinant MYXV system can induce high-efficiency editing of endogenous human genes using a single *Sp*Cas9-Csy4 transcript with cleavable gRNAs. This approach not only facilitated the use of high-expression cytoplasmic viral promoters but can also be used to express large numbers of gRNAs, targeting multiple essential cancer genes. The versatility of this technology facilitates the rapid targeting of a wide range of genetic drivers or cancer types, making it customizable to individual cancer patients. The use of a non-pathogenic, rabbit-derived MYXV also has significant therapeutic potential because the vector is non-integrating and has no acquired immunity in the human population.[@bib11] It is important to note that direct cancer gene-editing therapy has only recently been proposed as a potential therapeutic option for targeting undruggable cancer genes. Although significant obstacles need to be overcome prior to the development of this technology for therapeutic applications, our data suggest that arming oncolytic viruses with gene-editing technology could have significant therapeutic advantages. There are several alternative oncolytic viruses currently used for cancer treatment,[@bib22] which may benefit from integrating CRISPR/Cas9 gene-editing technology into their therapeutic approaches. The primary obstacle to the development of a cancer gene-editing therapy is the inability of most oncolytic viruses to infect all cancer cells. Future oncolytic viral technology will need to overcome this limitation. Therefore, utilizing gene-editing technology to enhance the spread of oncolytic viruses by targeting antiviral genes or to induce potent cancer immune responses may hold more therapeutic potential than directly targeting cancer oncogenes. More research is also needed to understand how the immune system will impact oncolytic gene-editing therapy, using immunocompetent models. Although an active immune system could hamper the spread of oncolytic viruses, ablating essential cancer genes could trigger pathways that downregulate immune evasion or stimulate effective anti-cancer immune responses. The technological approach employed in this research could also be used to directly engineer the expression of immune-stimulatory factors to promote clearing of cancer cells. Although our data support previous claims that gene-editing technology can be used to edit cancer-specific mutations,[@bib6], [@bib15], [@bib21] we find that targeting single-nucleotide variants is prone to low levels of off-target gene editing. These off-target effects could be reduced with thorough gRNA optimization; however, restrictions on the placement of tumor-specific gRNA target sites make finding efficient, high-fidelity gRNAs for many oncogenes a significant challenge. Because the target sites for these mutations likely lie in critical regions of oncogenes, such as *RAS*, the potential to create new oncogenic mutations in healthy tissues is also a major concern.[@bib15] The use of high-fidelity Cas9 variants may help overcome this limitation in gRNA specificity, but off-target gene editing still remains a challenge with all current CRISPR systems.[@bib16] Alternative methods of establishing cancer-targeting specificity could provide a more viable therapeutic strategy that does not rely on directly editing cancer mutations. This may include the use of replication-dependent viral promoters such as the late viral promoter, p11, to restrict expression of the CRISPR components to cancer cells.[@bib23] The enhanced flexibility of this approach would enable a variety of cancer gene-editing strategies, such as targeting non-mutant essential cancer genes, or multi gene-editing applications designed to reduce the probability of resistance. This is particularly relevant given our results with inducible *NRAS* knockout, which identified a sub-population of ERMS cancer cells that were resistant to *NRAS* targeting. RAS-resistant cells are not unique to ERMS and have been isolated after *KRAS* knockout in pancreatic cancer cells.[@bib24] Our study provides valuable insight into the use of gene-editing technology as a potential targeted therapy application in cancer treatment. We have established strong evidence that arming oncolytic viruses with gene-editing capability has significant therapeutic potential for targeting undruggable driver genes in cancer. This study provides an important framework for further development of gene-editing oncolytic virotherapy as a new approach to precision cancer treatment. Materials and Methods {#sec4} ===================== Gene-Editing Vectors {#sec4.1} -------------------- Gene-editing vectors were created to express either *Sp*Cas9 or *Sa*Cas9 from a core elongation factor 1a promoter. Dual gRNAs targeting the genes of interest were expressed from tandem human U6 promoters on independent viral vectors (*Sp*Cas9) or integrated into Cas9 expression vectors (*Sa*Cas9). All gRNA target sites were selected using ChopChopv2 software,[@bib25] and the gRNA sequences used in this study are listed in [Table S1](#mmc1){ref-type="supplementary-material"}. The tamoxifen-inducible CRISPR/Cas9 gene-editing system has been previously described.[@bib7] The key gene-editing vectors used in the research can be found on Addgene (Cambridge, MA, USA). Validation of effective gene editing in target cells was analyzed by PCR amplification of expected deletions created by the targeting vectors. Gene-editing efficiency was estimated in inducible tumor xenografts and cultured cells by analyzing the band intensity of deletion mutations compared with amplification of non-targeted regions of the genome (total gDNA). These efficiency estimates are likely underestimates because we did not analyze the efficiency of indel mutations that occur at each independent gRNA target site. For complete analysis of gene-editing efficiency after tumor-specific RAS targeting, the edited regions of both *NRAS* and *HRAS* were submitted for next-generation amplicon sequencing using 150-bp paired-end reads (greater than 500× coverage; Genewiz, South Plainfield, NJ, USA) to quantify all gene-editing events (deletions and indel mutations). Cell-Based Assays {#sec4.2} ----------------- The cell lines used in this study harbored activating *NRAS* A183T (381T) or *HRAS* C181A (SMS-CTR) point mutations. These cells lines were validated by short tandem repeat profiling performed at the cell line validation core facility at Dana Farber Cancer Institute or from the American Type Culture Collection (ATCC). The characteristic RAS mutations present in each line were also identified using next-generation sequencing. The cells were also confirmed mycoplasma-free prior to experimentation. All cells were cultured under standard high serum growth conditions or low serum differentiation conditions, as described.[@bib7] Cell viability was assessed with relative cell counts, and myogenic differentiation was analyzed with myosin heavy chain immunofluorescence (MF20, DSHB), to determine the percentage of myosin-positive cells. Apoptosis was measured using an annexin V fluorescent flow cytometry assay (Thermo Fisher Scientific). All cell culture experiments were performed in technical triplicate with the results averaged over three to four independent biological replicates as indicated in the figure legend. Recombinant Gene-Editing MYXV {#sec4.3} ----------------------------- To engineer a recombinant gene-editing MYXV, a transgenic cassette expressing the *Sp*Cas9 and Csy4 CRISPR components was integrated by site-directed recombination between genes 135R and 136R of the MYXV genome ([Figure 4](#fig4){ref-type="fig"}A). This design enabled high-efficiency gene editing from a single cytoplasmic mRNA transcript ([Figure 4](#fig4){ref-type="fig"}A). Because MYXV is a non-integrating cytoplasmic virus, all CRISPR/Cas9 components were driven by a single vaccinia vvSEL to facilitate high levels of cytoplasmic expression. In addition to the CRISPR components, the MYXV vectors also expressed a separate vvSEL-GFP cassette to track transduction efficiency *in vivo* ([Figure 4](#fig4){ref-type="fig"}A). The MYXV used in the research was purified and concentrated as previously described.[@bib26] Xenografts {#sec4.4} ---------- Immunodeficient NSG mice were implanted with a single subcutaneous ERMS tumor xenograft on the left flank. After tumor onset (10 mm^3^), the tumor volume was measured every 2--3 days until endpoint (500 mm^3^). Treatment groups were split into *RAS* knockout tumors and control tumors targeted at a safe harbor region of the genome. This safe harbor control was preferred over non-targeting controls to account for any non-specific DNA damage response that may occur in CRISPR-targeted cells. Randomization was not used in grouping of the isogenic mouse strains; however, male and female mice were distributed equally across the treatment groups. Because animals required multiple, sequential experimental treatments, blinding was not performed. For tamoxifen-inducible *NRAS* knockout studies, gene editing was induced with five intraperitoneal injections of tamoxifen over a 10-day period after the tumor had reached a volume of 10 mm^3^. For the time-course xenograft experiments, tamoxifen injections were performed on 100-mm^3^ tumors to facilitate subsequent sampling of the xenografts at multiple time points during tumor regression. For MYXV gene-editing studies, four doses of engineered MYXV virus (1 × 10^7^ PFU/100 μL) were intratumorally administered to 10-mm^3^ xenografts over 8 days, and changes in tumor volume were analyzed until tumors reached endpoint or 50 days post-viral administration, whichever came first. Histological and immunohistochemical analysis of tumors was performed by the University of Washington histology and imaging core. The antibody against phospho-Erk1/2 (p44/42 mitogen-activated protein kinase \[MAPK\]) was obtained from Cell Signaling. All treatment groups were maintained in identical laboratory conditions, with experiments carried out under approved protocols from the University of Washington Institutional Animal Care and Use Committee (IACUC) and the office of animal welfare. Mouse numbers were determined from pilot experiments, using a power analysis with an expected large effect size. Statistics and Data Reporting {#sec4.5} ----------------------------- Experimental data were analyzed with a two-tailed t test or ANOVA statistical test based on the number of treatment groups. Bonferroni corrections were made to the p value, based on the number of statistical comparisons. The mean difference between treatment groups was used for statistical comparisons except for mouse xenograft studies that analyzed changes in median survival between targeted and control mice. All data were analyzed with Prism 6, GraphPad software. The numbers of biological replicates are reported in the figure legends. Data are presented as mean ± SEM with \*p \< 0.05, \*\*p \< 0.01, \*\*\*p \< 0.001, and \*\*\*\*p \< 0.0001. ### Transcriptome Analysis and Data Availability {#sec4.5.1} Expression profiling was performed on NRAS-targeted and control cells 2 days after gene editing to identify genes immediately impacted by *NRAS* knockout, prior to terminal myogenic differentiation. RNA-sequencing analysis was performed by the Fred Hutchinson Cancer Research Center, Genomics Shared Resource Core using protocols previously identified.[@bib7] All transcriptome data produced during this research is available at NIH GEO: [GSE118939](ncbi-geo:GSE118939){#intref0010}. Author Contributions {#sec5} ==================== M.P.P. and E.C. conceived, designed, and oversaw the study; analyzed the data; and wrote the manuscript. M.P.P., H.Y., and S.P. performed most of the experiments and produced all lentiviral, inducible, and MYXV gene-editing vectors. M.M.R. and G.M. were instrumental with the design of MYXV studies and produced the recombinant MYXV. Conflicts of Interest {#sec6} ===================== The authors have no conflicts of interest. Supplemental Information {#appsec2} ======================== Document S1. Figures S1--S3 and Table S1Document S2. Article plus Supplemental Information We thank Terra Vleeshouwer-Neumann and Thao Pham for their assistance with some of the cell-based assays and critical reading of the manuscript. We also thank the University of Washington histology and imaging core for their histopathology expertise. The study is funded by NIH NCI grant 1R01CA196882-01A1 and the Rally foundation. Supplemental Information includes three figures and one table and can be found with this article online at [https://doi.org/10.1016/j.omto.2018.09.001](10.1016/j.omto.2018.09.001){#intref0015}.

Nanogram calorimetry using microscale suspended SiNx platforms fabricated via focused ion beam patterning. Comprehensive characterization of thermal properties in nanoscale heterostructures requires microscale thermally isolated platforms combined with sensitive thermometry in order to measure small heat accumulations. Amorphous SiNx membranes are often used for these measurements due to their low thermal conductivity and compatibility with standard fabrication techniques. The total thermal conductance of such SiNx membranes is typically microwatts per kelvin or higher. Here, we further reduce this thermal coupling to 120 nW/K by using a focused ion beam (FIB) to remove large portions of commercially available amorphous SiNx membranes, leaving a 100 μm × 100 μm square platform suspended by 10 μm wide by 325 μm long support legs. We demonstrate the capability of these platforms by measuring the heat capacity of a 6.2 ng Au sample and show that it matches well with established specific heat of bulk Au.

Increased level of oxidative stress in genomically unstable cell clones. Recently, we reported that ultraviolet radiation induces delayed mutations in mammalian cells. At the same level of cell death the oxidative component of sunlight (ultraviolet A radiation) was as potent in inducing this kind of genomic instability as ultraviolet B radiation. Ultraviolet B radiation predominantly harms cells by direct damage to DNA and thus is much more mutagenic than ultraviolet A radiation. From that study, clones with a significantly increased mutation rate in the hypoxanthine phosphoribosyl transferase gene were obtained. These genomically unstable clones were also found to have a higher variance in the number of chromosomes than the unirradiated control cells, indicating chromosomal instability. The mechanisms for induction and maintenance of radiation induced genomic instability are not known, but some studies suggest that reactive oxygen species might be involved. In the present study, we have measured the level of potentially mutagenic peroxides in the genomically unstable clones. The levels of intracellular peroxides and lipid peroxides were measured using the probes dihydrorhodamine 123 and diphenyl-1-pyrenyl-phosphine, respectively. The unstable clones had elevated levels of oxidants, supporting the hypothesis that intermediate reactive oxygen species might have a role in the maintenance of genomic instability induced by ultraviolet radiation.

Across these songs, Ethiopian jazz, African psychedelic rock and funk, Sudanese dance rhythms, and Tuaregi grooves mingle with the jazz and folk traditions of the Americas. Bandcamp Album of the Day Mar 19, 2019

Panellinios G.S. Panellinios G.S. (Greek: Πανελλήνιος Γ.Σ.), full name, Panellinios Gymnastikos Syllogos (Greek: Πανελλήνιος Γυμναστικός Σύλλογος), is a Greek multi-sport club that is located in Athens and was founded in 1891. It is one of the oldest and more successful multi-sports clubs in Greece and also one of the oldest sports clubs in Europe. The name Panellinios can be translated as Pan-Hellenic in English, and can be interpreted to mean the Greek Nation. Gymnastikos Syllogos can be translated as gymnastics club. Therefore, the club's full name can be translated and/or interpreted as Pan-Hellenic Gymnastics Club. The Greek multi-sports club Panathinaikos A.O. was founded by Giorgos Kalafatis in 1908, when he and 40 other athletes decided to break away from Panellinios Gymnastikos Syllogos, following the club's decision to discontinue its football team. Departments Panellinios B.C. - basketball Panellinios V.C. - volleyball Men's athletics The club had a team of gymnasts compete at the 1896 Summer Olympics in Athens. The team’s leader was Spyridon Athanasopoulos. Members included Nikolaos Andriakopoulos, Petros Persakis, Thomas Xenakis, and 29 others. The team placed second of the three teams in the parallel bars team event, earning a silver medal (retroactively awarded by the International Olympic Committee, as the awards at the first Olympic Games differed from the gold, silver, bronze format used later). Other club members who medaled in athletics at the 1896 Olympics were Alexandre Tuffère, Charilaos Vasilakos, Miltiadis Gouskos, Ioannis Persakis and Sotirios Versis. Men's basketball Panellinios B.C. was founded in 1929 and has been the Greek League champion six times in the years 1929, 1939, 1940, 1953, 1955, and 1957. In the early 1950s era the team was called "The Golden Five", referring to players Panagiotis Manias, Themis Cholevas, Kostas Papadimas, Mimis Stefanidis, and Aristeidis Roubanis. They dominated not only Greek basketball, but European basketball in general. The Panellinios team headlined the 1952 Greek Olympic Team. During the mid-to-late 1950s, the team was led by Antonis Christeas. Titles Men's Basketball - Panellinios B.C.: 6 Greek Championships: (1929, 1939, 1940, 1953, 1955, 1957) Men's Volleyball - Panellinios V.C.: 5 Greek Championships: (1936, 1937, 1939, 1940, 1961) Women's Volleyball: 2 Greek Championships: (2001, 2002) 1 Greek Cup: (2001) Men's Handball: 5 Greek Championships: (2000, 2002, 2004, 2006, 2007) 3 Greek Cups (2000, 2001, 2002) Men's Athletics: 36 Greek Championships: (1901, 1904, 1905, 1906, 1907, 1908, 1909, 1911, 1912, 1914, 1917, 1919, 1933, 1934, 1936, 1978, 1981, 1982, 1983, 1987, 1988, 1991, 1992, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004, 2005) (record) 20 Greek Indoor Championships: (1988, 1991, 1992, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2000, 2001, 2002, 2004, 2005, 2006, 2007, 2008, 2009, 2014) (record) 19 Greek Cross Country Championships: (1907, 1909, 1986, 1987, 1988, 1989, 1990, 1991, 1992, 1993, 1994, 1995, 1998, 1999, 2000, 2001, 2002, 2004, 2006) Women's Athletics: 30 Greek Championships: (1938, 1939, 1940, 1951, 1952, 1984, 1985, 1986, 1987, 1988, 1989, 1990, 1992, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009) (record) 21 Greek Indoor Championships: (1986, 1988, 1989, 1990, 1992, 1993, 1994, 1997, 1998, 1999, 2000, 2001, 2002, 2004, 2005, 2006, 2007, 2008, 2012, 2013, 2014) (record) 13 Greek Cross Country Championships: (1954, 1987, 1993, 1994, 1995, 1998, 1999, 2000, 2001, 2002, 2003, 2004, 2005) (record) Fencing: 18 Greek Épée team Championships, Men: (1953, 1957, 1981, 1984, 1985, 1988, 1990, 1992, 1993, 1995, 1998, 2002, 2005, 2006, 2008, 2009, 2012, 2013) 11 Greek Foil team Championships, Men: (1974, 1976, 1979, 1980, 1981, 1982, 1987, 1988, 1989, 2000, 2002) 12 Greek Sabre team Championships, Men: (1976, 1977, 1986, 1988, 1989, 1992, 2001, 2009, 2011, 2012, 2013, 2014) 4 Greek Épée team Championships, Women: (2009, 2011, 2013, 2015) 5 Greek Foil team Championships, Women: (1980, 1981, 1982, 1983, 1984) 3 Greek Sabre team Championships, Women: (2003, 2004, 2005) Men's Weightlifting: 6 Greek Championships: (1988, 1989, 2005, 2010, 2012, 2014) Women's Weightlifting: 1 Greek Championship: (2003) Men's Boxing: 9 Greek Championships: (1963, 1965, 1987, 1990, 1991, 1994, 2001, 2002, 2004) Table tennis: 6 Greek Championships, Women: (1966, 1967, 1968, 1969, 1975, 1980) 1 Greek Cup, Women: (1967) Shooting: 4 Greek Championships: (1946, 1947, 1948, 1949) Modern Pentathlon: 9 Greek Championships: (1981, 1982, 1983, 1984, 1985, 1988, 1989, 1990, 1991) Judo: 14 Greek Championships, Men: (1980, 1981, 1982, 1983, 1984, 1985, 1986, 1987, 1988, 1989, 1990, 1991, 1992, 1994) (record) 15 Greek Championships, Women: (1984, 1985, 1991, 1992, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2000, 2004, 2005, 2006) (record) References External links Official Website Official Basketball Club Website Panellinios Club's Training Facilities Category:Multi-sport clubs in Athens Category:Athletics clubs in Greece Category:Table tennis in Greece Category:Panellinios Category:1891 establishments in Greece Category:Sports clubs established in 1891

Q: XMLWriter: WriteStartElement with a tag name and string to indicate tag name I have same tag names and different strings to different the tag name. here is the XML. <order> <ID>1001</ID> <config> <properties> <entry key="Total">10</entry> <entry key="Name">name</entry> <entry key="Config">COMMON</entry> <entry key="Delivery">15-FEBRUARY-2013</entry> <entry key="Setting">name</entry> </properties> <id>19</id> </config> <aID>58239346</aID> </order> here is my current code: public String cards(string id) { StringWriter str = new StringWriter(); XmlTextWriter xmlWriter = new XmlTextWriter(str); xmlWriter.Formatting = Formatting.Indented; xmlWriter.WriteStartDocument(); xmlWriter.WriteStartElement("order"); xmlWriter.WriteElementString("ID", "1001"); xmlWriter.WriteStartElement("config"); xmlWriter.WriteStartElement("properties"); /* * Create <entry key> at here * * * * */ xmlWriter.WriteEndElement(); xmlWriter.WriteEndElement(); xmlWriter.WriteElementString("ClientID", id); xmlWriter.WriteEndElement(); xmlWriter.WriteEndDocument(); xmlWriter.Flush(); xmlWriter.Close(); return str.ToString(); } How to write the entry tag for XMLWriter??? I have no idea how to write it. A: The question seems to be about the <entry> tags; that is basically a series of 5 blocks similar to: xw.WriteStartElement("entry"); xw.WriteAttributeString("key", "RecordTotal"); xw.WriteString("10"); xw.WriteEndElement(); However, you might also want to look at XmlSerializer - would probably make this a lot easier: using System; using System.Collections.Generic; using System.Xml.Serialization; static class Program { static void Main() { var order = new Order { ClientId = 1001, Id = 58239346, Config = new OrderConfig { Id = 19, Properties = { new OrderProperty { Key = "RecordTotal", Value = "10"}, new OrderProperty { Key = "InputFileName", Value = "name"}, new OrderProperty { Key = "ConfigName", Value = "COMMON_"}, new OrderProperty { Key = "DeliveryDate", Value = "15-FEBRUARY-2013"}, new OrderProperty { Key = "Qualifier", Value = "name"} } } }; var ser = new XmlSerializer(typeof(Order)); ser.Serialize(Console.Out, order); } } [XmlRoot("order")] public class Order { [XmlElement("clientID", Order = 0)] public int ClientId { get; set; } [XmlElement("config", Order = 1)] public OrderConfig Config { get; set; } [XmlElement("orderID", Order = 2)] public int Id { get; set; } } public class OrderConfig { [XmlElement("id", Order = 2)] public int Id { get; set; } private readonly List<OrderProperty> properties = new List<OrderProperty>(); [XmlArray("properties", Order = 1), XmlArrayItem("entry")] public List<OrderProperty> Properties { get { return properties; } } } public class OrderProperty { [XmlAttribute("key")] public string Key {get;set;} [XmlText] public string Value {get;set;} } A: I'd be tempted to use Linq-to-XML for this: using System; using System.Xml.Linq; namespace ConsoleApplication1 { class Program { static void Main() { XElement root = new XElement("order", new XElement("clientId", 1001), new XElement("config", new XElement("properties", new XElement("entry", new XAttribute("key", "RecordTotal"), 10), new XElement("entry", new XAttribute("key", "InputFileName"), "name"), new XElement("entry", new XAttribute("key", "ConfigName"), "COMMON"), new XElement("entry", new XAttribute("key", "DeliveryDate"), "15-FEBRUARY-2013"), new XElement("entry", new XAttribute("key", "Qualifier"), "name")), new XElement("id", 19)), new XElement("orderID", 58239346) ); Console.WriteLine(root); } } } By way of comparison, if you wanted multiple property elements so the XML looked like this: <order> <clientId>1001</clientId> <config> <properties> <property> <entry key="RecordTotal">10</entry> <entry key="InputFileName">name</entry> <entry key="ConfigName">COMMON</entry> <entry key="DeliveryDate">15-FEBRUARY-2013</entry> <entry key="Qualifier">name</entry> </property> <property> <entry key="RecordTotal">15</entry> <entry key="InputFileName">othername</entry> <entry key="ConfigName">UNCOMMON</entry> <entry key="DeliveryDate">23-FEBRUARY-2013</entry> <entry key="Qualifier">qname</entry> </property> </properties> <id>19</id> </config> <orderID>58239346</orderID> </order> your code could look like this: using System; using System.Collections.Generic; using System.Linq; using System.Xml.Linq; namespace ConsoleApplication1 { class Program { static void Main() { XElement root = new XElement("order", new XElement("clientId", 1001), new XElement("config", new XElement("properties", createEntries(getEntries())), new XElement("id", 19)), new XElement("orderID", 58239346) ); Console.WriteLine(root); } static IEnumerable<Entry> getEntries() { yield return new Entry { RecordTotal = 10, InputFileName = "name", ConfigName = "COMMON", DeliveryDate = "15-FEBRUARY-2013", Qualifier = "name" }; yield return new Entry { RecordTotal = 15, InputFileName = "othername", ConfigName = "UNCOMMON", DeliveryDate = "23-FEBRUARY-2013", Qualifier = "qname" }; } static IEnumerable<XElement> createEntries(IEnumerable<Entry> entries) { return from entry in entries select new XElement( "property", new XElement("entry", new XAttribute("key", "RecordTotal"), entry.RecordTotal), new XElement("entry", new XAttribute("key", "InputFileName"), entry.InputFileName), new XElement("entry", new XAttribute("key", "ConfigName"), entry.ConfigName), new XElement("entry", new XAttribute("key", "DeliveryDate"), entry.DeliveryDate), new XElement("entry", new XAttribute("key", "Qualifier"), entry.Qualifier)); } } sealed class Entry { public int RecordTotal; public string InputFileName; public string ConfigName; public string DeliveryDate; public string Qualifier; } }

The effect of feeding route (i.v. or oral) on the protein metabolism of the neonate. We have examined the effect of the route of feeding (intravenous versus enteral) on the protein metabolism of postsurgical human neonates. Twelve infants, birth weight 2.5 +/- 0.2 kg, gestational age 38 +/- 1 wk, were studied. The IV study was carried out 1-4 days after surgery at a postnatal age of 14 days and a weight of 2.6 +/- 0.2 kg. The repeat (oral) study was carried out 16 days later. Protein intakes were similar during both studies (2.7 g/kg/d). Energy intakes were within the requirement range for age and feeding route and were: IV, 85 +/- 4 kcal/kg/d; oral, 111 +/- 7 kcal/kg/d. Whole body protein metabolism was studied using a continuous infusion of 15N-glycine. Amino nitrogen flux, protein synthesis, and breakdown were 40% higher during the enteral than the IV studies (p less than 0.001). Skeletal muscle degradation was investigated by measuring urinary excretion of creatinine and N-T-methylhistidine. No differences were detected due to feeding route. We suggest that the differences seen in whole body protein turnover rates reflect the rapid growth and development of the gut in the enterally (rather than the IV) fed infant.

High-speed large area atomic force microscopy using a quartz resonator. A high-speed atomic force microscope for scanning large areas, utilizing a quartz bar driven close to resonance to provide the motion in the fast scan axis is presented. Images up to 170 × 170 μm2 have been obtained on a polydimethylsiloxane (PDMS) grating in 1 s. This is provided through an average tip-sample velocity of 28 cm s-1 at a line rate of 830 Hz. Scan areas up to 80 × 80 μm2 have been obtained in 0.42 s with a line rate of 1410 Hz. To demonstrate the capability of the scanner the spherulitic crystallization of a semicrystalline polymer was imaged in situ at high speed.

--- abstract: 'In this paper we classify all blocks with defect group $C_{2^n}\times C_2\times C_2$ up to Morita equivalence. Together with a recent paper of Wu, Zhang and Zhou, this completes the classification of Morita equivalence classes of $2$-blocks with abelian defect groups of rank at most $3$. The classification holds for blocks over a suitable discrete valuation ring as well as for those over an algebraically closed field. The case considered in this paper is significant because it involves comparison of Morita equivalence classes between a group and a normal subgroup of index $2$, so requires novel reduction techniques which we hope will be of wider interest. We note that this also completes the classification of blocks with abelian defect groups of order dividing $16$ up to Morita equivalence. A consequence is that Broue’s abelian defect group conjecture holds for all blocks mentioned above.' author: - 'Charles Eaton[^1] and Michael Livesey[^2]' date: 13th October 2017 title: 'Classifying blocks with abelian defect groups of rank $3$ for the prime $2$ [^3]' --- Introduction ============ Let $p$ be a prime and $(K,\mathcal{O},k)$ a $p$-modular with $k$ algebraically closed. Let $P$ be a finite $p$-group. Donovan’s conjecture states that there are only finitely many Morita equivalence classes amongst blocks of $kG$ for finite groups $G$ with defect groups isomorphic to $P$, and it is natural to strengthen this conjecture to blocks with respect to ${\mathcal{O}}$. Advances in our understanding of blocks of finite groups of Lie type in non-defining characteristic open the possibility of using the classification of finite simple groups to tackle this conjecture and further to classify Morita equivalence classes of blocks. For $p=2$ this process has been started in [@ekks14], where Donovan’s conjecture (with respect to $k$) has been proved for all elementary abelian $2$-groups. For elementary abelian $2$-groups of order at most $16$ the Morita equivalence classes have further been classified, with respect to ${\mathcal{O}}$ (see [@ea17]). Abelian $p$-groups with a cyclic factor of order strictly great than $p$ present a significant problem to the extension of these results. This is because the case of a group generated by a normal subgroup and a defect group is especially difficult to to study with respect to Morita equivalence, and required the application of [@kk96] which applies only to split extensions by a factor of the defect group, and further only to blocks defined over $k$. In [@eatliv17] a partial generalization of [@kk96] was given (generalized further in Proposition \[prop:grunit\] below) which was sufficient to work with the Loewy length of blocks with arbitrary abelian defect groups. In this paper we combine this result with the existence of a certain perfect isometry from [@wa05] to prove Donovan’s conjecture for blocks (defined over ${\mathcal{O}}$) with defect groups $C_{2^n} \times C_2 \times C_2$ for $n>1$ and further show that for each $n$ there are precisely three Morita equivalence classes of such blocks. This completes the classification of Morita equivalence classes of blocks with abelian defect groups of order dividing $16$ (see [@li94], [@ea16] and [@ea17] for the elementary abelian $2$-groups and [@ekks14] for $C_4 \times C_4$, noting that in all other cases ${\rm Aut}(D)$ is a $2$-group and so all blocks with that defect group are nilpotent). In [@wzz17] it is shown that for $m,n \in {\mathbb{N}}$ with $n \geq 2$, if a block has defect group $D \cong C_{2^n} \times C_{2^n} \times C_{2^m}$, then it is Mortia equivalent to it Brauer correspondent in $N_G(P)$ and so to one of ${\mathcal{O}}D$, ${\mathcal{O}}(D \rtimes C_3)$, ${\mathcal{O}}(D \rtimes C_7)$ or ${\mathcal{O}}(D \rtimes (C_7 \rtimes C_3))$. Hence the classification of Morita equivalence classes of $2$-blocks with abelian defect groups of rank at most $3$ is complete. We refer the reader to [@ea17] for a survey of progress on the problem of classifying Morita equivalence classes of blocks with a given defect group. Recall the definition of the inertial quotient of a block $B$ of ${\mathcal{O}}G$ with defect group $D$, where $G$ is a finite group. Let $b_D$ be a block of $C_G(D)$ with Brauer correspondent $(b_D)^G=B$. The stabilizer of $b_D$ in $N_G(D)$ under conjugation is written $N_G(D,b_D)$. Then $N_G(D,b_D)/DC_G(D)$ is a $p'$-group, and is called the inertial quotient of $B$ (unique up to isomorphism). $|E|$ is called the inertial index. $(D,b_D)$ is called a maximal $B$-subpair. \[inertial\_quotient\_lem\] Let $G$ be a finite group and $B$ be a block of ${\mathcal{O}}G$ with defect group $D \cong C_{2^n}\times C_2\times C_2$ for $n>1$. There are two possible fusion systems for $B$, given by $D$ and $C_{2^n} \times A_4$. In particular the possible inertial quotients for $B$ are $1$ and $C_3$. We refer the reader to [@ako] for background on fusion systems. Since $D$ is abelian, the fusion systems on $D$ are given by groups $D \rtimes E$, where $E$ is an odd-order subgroup of ${\rm Aut}(D)$. We have ${\rm Aut}(D) \cong S_3$, so the possibilities are $E=1$ or $C_3$. The main result is as follows (see Theorem \[thm:main\]): Let $G$ be a finite group and $B$ a block of $\mathcal{O}G$ with defect group $D\cong C_{2^n}\times C_2\times C_2$ for $n>1$. Then $B$ is Morita equivalent to the principal block of $\mathcal{O}(C_{2^n}\times C_2\times C_2)$, $\mathcal{O}(C_{2^n}\times A_4)$ or $\mathcal{O}(C_{2^n}\times A_5)$. Combining with the results of [@ea16], [@ekks14] and [@wzz17] we conclude: Let $G$ be a finite group and $B$ a block of $\mathcal{O}G$ with defect group $D$ of $2$-rank at most $3$. Then $B$ is Morita equivalent to the principal block of one of: \(i) ${\mathcal{O}}D$; \(ii) ${\mathcal{O}}(D \rtimes C_3)$; \(iii) ${\mathcal{O}}(C_{2^n}\times A_5)$ for $n \geq 0$; \(iv) ${\mathcal{O}}(D \rtimes C_7)$; \(v) ${\mathcal{O}}SL_2(8)$; \(vi) ${\mathcal{O}}(D \rtimes (C_7 \rtimes C_3))$; \(vii) ${\mathcal{O}}J_1$; \(viii) ${\mathcal{O}}{\rm Aut}(SL_2(8))$. Observe that this means that every block with this defect group is Morita equivalent to a principal block, and so in particular the Morita Frobenius number as defined in [@ke05] is one. Note that if $B$ above is not nilpotent, then the number $l(B)$ of irreducible Brauer characters of $B$ is $3$ and the number of irreducible characters $k(B)=2^{n+2}$ (by Proposition \[per\_isom\], which does not use the classification of finite simple groups). Another consequence of Theorem \[thm:main\] is the following (see Corollary \[cor:derived\]): Let $G$ be a finite group and $B$ a block of $\mathcal{O}G$ with defect group $D\cong C_{2^n}\times C_2\times C_2$ for $n>1$. Let $b$ be the unique block of $N_G(D)$ with $b^G=B$. Then $B$ and $b$ are derived equivalent. Gathering together previous results, this completes the proof of Broué’s conjecture for $2$-blocks of defect at most $4$ and also for those of rank at most $3$ (see Corollaries \[cor:derived16\] and \[cor:derivedrank3\]). The paper is structured as follows. In Section 2 we address the problem of lifting a Morita equivalence from a normal subgroup of index $2$. We obtain a perfect isometry from [@wa05] and show that this may be modified by a perfect self-isometry to produce a Morita equivalence using the central unit described in [@eatliv17]. In Section 3 we apply the classification in [@ekks14] to prove the main theorem, using the results of Section 2 to help reduce to quasisimple groups. Normal subgroups of index 2 =========================== We first introduce some notation. Let $G$ be a finite group and $N \lhd G$. For a block $B$ of ${\mathcal{O}}G$ we write ${\rm Irr}(B)$ for the set of irreducible characters of in $B$ (with respect to $K$) and ${\rm Irr}(B,\psi)$ for the set of irreducible characters in $B$ covering $\psi$ (that is, whose restriction has $\psi$ as a summand). Write ${\rm IBr}(B)$ for the set of irreducible Brauer characters. Write ${\rm prj}(B)$ for the set characters of projective indecomposable $B$-modules. Suppose $B$ has defect group $D$. Let $(D,b_D)$ be a maximal $B$-subpair (see [@alp86] for background on subpairs). Note that all maximal $B$-subpairs are $G$-conjugate. If $u \in D$ and $b_u$ is a block of ${\mathcal{O}}C_G(u)$ with $(b_D)^{C_G(u)}=b_u$, then we call $(u,b_u)$ a subsection in $(D,b_D)$, and write $(u,b_u) \in (D,b_D)$. Let $G$ be a finite group and $B$ a block of $\mathcal{O}G$. We denote by ${\rm CF}(G,B,K)$ the $K$-subspace of class functions on $G$ spanned by ${\rm Irr}(B)$, by ${\rm CF}(G,B,\mathcal{O})$ the $\mathcal{O}$-submodule $$\begin{aligned} \{\phi\in {\rm CF}(G,B,K):\phi(g)\in\mathcal{O}\text{ for all }g\in G\}\end{aligned}$$ of ${\rm CF}(G,B,K)$ and by ${\rm CF}_{p'}(G,B,\mathcal{O})$ the $\mathcal{O}$-submodule $$\begin{aligned} \{\phi\in {\rm CF}(G,B,\mathcal{O}):\phi(g)=0\text{ for all }g\in G\backslash G_{p'}\}\end{aligned}$$ of ${\rm CF}(G,B,\mathcal{O})$. Now in addition let $H$ be a finite group and $C$ a block of $\mathcal{O}H$. A **perfect isometry** between $B$ and $C$ is an isometry $$\begin{aligned} I:\mathbb{Z}{\rm Irr}(B)\to\mathbb{Z}{\rm Irr}(C),\end{aligned}$$ such that $$\begin{aligned} I_K:=K\otimes_{\mathbb{Z}}I:K{\rm Irr}(B)\to K{\rm Irr}(C),\end{aligned}$$ induces an ${\mathcal{O}}$-module isomorphism between ${\rm CF}(G,B,\mathcal{O})$ and ${\rm CF}(H,C,\mathcal{O})$ and also between ${\rm CF}_{p'}(G,B,\mathcal{O})$ and ${\rm CF}_{p'}(H,C,\mathcal{O})$. (Note that by an isometry we mean an isometry with respect to the usual inner products on $\mathbb{Z}{\rm Irr}(B)$ and $\mathbb{Z}{\rm Irr}(C)$, so for all $\chi\in{\rm Irr}(B)$, $I(\chi)=\pm\psi$ for some $\psi\in{\rm Irr}(C)$). An alternative way of phrasing the condition that $I_K$ induces an isomorphism between ${\rm CF}_{p'}(G,B,\mathcal{O})$ and ${\rm CF}_{p'}(H,C,\mathcal{O})$ is that $I$ induces an isomorphism $\mathbb{Z}{\rm prj}(B) \cong \mathbb{Z}{\rm prj}(C)$. We will be using the following well-known result frequently, so we include a proof. \[index\_p\_background\_lem\] Let $G$ be a finite group and $N$ a normal subgroup of $G$ of index a power of $p$. Let $B$ be a block of $\mathcal{O}G$ with defect group $D$ covering a block $b$ of ${\mathcal{O}}N$. Then $B$ is the unique block of ${\mathcal{O}}G$ covering $b$, $D \cap N$ is a defect group for $b$ and the stabilizer of $b$ in $G$ is $DN$. That $B$ is the unique block of ${\mathcal{O}}G$ covering $b$ is [@feit V.3.5]. The rest follows from [@alp86 15.1], noting that there is a one to one correspondence between blocks defined over $k$ and blocks defined over ${\mathcal{O}}$. \[prop:grunit\] Let $G$ be a finite group and $N$ a normal subgroup of $G$ of index $p$. Now let $B$ be a block of $\mathcal{O}G$ with abelian defect group $D$ such that $G=ND$. Then there exists a block $b$ of $\mathcal{O}N$ with the same block idempotent as $B$ and defect group $D\cap N$. Moreover there exists a $G/N$-graded unit $a\in Z(B)$, in particular $B=\bigoplus_{j=0}^{p-1}a^jb$. By [@eatliv17 Theorem 2.1] there exists a $G/N$-graded unit $\overline{a}\in Z(kB)$. Now as every element of $Z(kG)$ can be lifted to an element of $Z(\mathcal{O}G)$ we can lift $\overline{a}$ to $a\in Z(B)$. As the block idempotent of $B$ lies in $\mathcal{O}N$ and $Z(\mathcal{O}G)$ is $G/N$-graded, then we can assume $a$ is $G/N$-graded. Finally, as $Z(B)$ is a local ring and $a$ certainly does not lie in its maximal ideal ($\overline{a}$ is a unit), we have that $a$ is a unit. \[rem:inner\] In the setting of the previous Proposition \[prop:grunit\] we note that conjugation by $G$ induces only inner automorphisms of $b$, and so in particular $Z(b) \subseteq Z(B)$. \[prop:index\_p\] Let $G$, $N$, $B$ and $b$ be as in the Proposition \[prop:grunit\]. Then \(i) Every irreducible character of $b$ is $G$-stable and extends to $p$ distinct irreducible characters of $B$. \(ii) Induction ${\rm Ind}_N^G$ gives a bijection between the projective indecomposable $b$-modules and the projective indecomposable $B$-modules. \(iii) Now let $G'$, $N'$, $B'$ and $b'$ be another quadruple satisfying Proposition \[prop:grunit\]. For each $\chi \in {\rm Irr}(b)$ write ${\rm Irr}(B,\chi)= \{\chi_1,\ldots, \chi_p \}$. Suppose $I:\mathbb{Z}{\rm Irr}(B)\to\mathbb{Z}{\rm Irr}(B')$ is a perfect isometry such that for each $\chi \in {\rm Irr}(b)$ there is $\psi \in {\rm Irr}(b')$ and $\epsilon_\chi \in\{\pm1\}$ such that $I(\chi_i)=\epsilon_\chi \psi_i$ for $i=1, \ldots, p$ where ${\rm Irr}(B',\psi)= \{\psi_1, \ldots , \psi_p \}$. Then the isometry $I_{N,N'}:\mathbb{Z}{\rm Irr}(b)\to\mathbb{Z}{\rm Irr}(b')$ defined by $I_{N,N'}(\chi):=\epsilon_\chi \psi$ is perfect. $ $ (i) By Remark \[rem:inner\] every character $\chi$ of $b$ is $G$-stable. Therefore, as $G/N$ is cyclic, $\chi$ extends to $G$. Taking the product with the $p$ distinct linear characters of $G/N$ inflated to $G$ gives the $p$ extensions of $\chi$ to $G$. Now every constituent of an irreducible character of $B$ restricted to $N$ must lie in $b$ and so every irreducible character of $B$ is the extension of some irreducible character of $b$. \(ii) Certainly every projective indecomposable $B$-module is a summand of some projective indecomposable $b$-module induced to $G$ and Green’s indecomposability ensures ${\rm Ind}_N^G$. To prove we have a bijection we need ${\rm Ind}^G_N(P)$ and ${\rm Ind}^G_N(Q)$ to be non-isomorphic for non-isomorphic projective indecomposable $b$-modules $P$ and $Q$. However, this is true since by \[prop:grunit\], ${\rm Res}^G_N{\rm Ind}^G_N(P)\cong P^{\oplus p}$. \(iii) For $\chi \in {\rm Irr}(b)$ and $\psi \in {\rm Irr}(b')$, write $\tilde{\chi}=\sum_{i=1}^p \chi_i$ and $\tilde{\psi}=\sum_{i=1}^p \psi_i$. Let $$\begin{aligned} \phi=\sum_{\chi\in{\rm Irr}(b)}\alpha_\chi\chi\in{\rm CF}(N,b,\mathcal{O}),\end{aligned}$$ for some $\alpha_\chi\in K$ and consider $$\begin{aligned} \tilde{\phi}:=\sum_{\chi\in {\rm Irr}(b)} \alpha_\chi\tilde{\chi}.\end{aligned}$$ Note that $\tilde{\phi}(g)=p\phi(g)$ for all $g\in N$ and $\tilde{\phi}(g)=0$ for all $g\in G\backslash N$, so $\tilde{\phi}\in p{\rm CF}(G,B,\mathcal{O})$. Now note that $$\begin{aligned} (I_{N,N'})_K(\phi)=\sum_{\psi\in{\rm Irr}(b')}\beta_\psi\psi,\end{aligned}$$ where $$\begin{aligned} I_K(\tilde{\phi})=\sum_{\psi\in{\rm Irr}(b')} \beta_\psi\tilde{\psi}.\end{aligned}$$ As $\tilde{\phi}\in p{\rm CF}(G,B,\mathcal{O})$, we have $I_K(\tilde{\phi})\in p{\rm CF}(G',B',\mathcal{O})$. Again $I_K(\tilde{\phi})(g)=p(I_{N,N'})_K(\phi)(g)$ for all $g\in N'$ and so $(I_{N,N'})_K(\phi)\in{\rm CF}(N',b',\mathcal{O})$. So $(I_{N,N'})_K({\rm CF}(N,b,\mathcal{O}))\subseteq{\rm CF}(N',b',\mathcal{O})$ and by an identical argument $(I_{N,N'})_K^{-1}({\rm CF}(N',b',\mathcal{O}))\subseteq{\rm CF}(N,b,\mathcal{O})$. Now suppose in addition that $\phi\in{\rm CF}_{p'}(N,b,\mathcal{O})$. Then $\tilde{\phi}(g)=p\phi(g)=0$ for all $g\in N\backslash N_{p'}$ and $\tilde{\phi}(g)=0$ for all $g\in G\backslash N$ and so $\tilde{\phi}\in{\rm CF}_{p'}(G,B,\mathcal{O})$. Therefore $I_K(\tilde{\phi})\in{\rm CF}_{p'}(G',B',\mathcal{O})$ and by the previous paragraph $(I_{N,N'})_K(\phi)\in{\rm CF}_{p'}(N',b',\mathcal{O})$ and so $(I_{N,N'})_K$ induces an isomorphism between ${\rm CF}_{p'}(N,b,\mathcal{O})$ and ${\rm CF}_{p'}(N',b',\mathcal{O})$ and hence it satisfies both the properties of a perfect isometry. \[lem:isomcent\] Let $G$ and $G'$ be finite groups, $B$ and $B'$ blocks of ${\mathcal{O}}G$ and ${\mathcal{O}}G'$ respectively and $I:\mathbb{Z}{\rm Irr}(B)\to\mathbb{Z}{\rm Irr}(B')$ a perfect isometry. \(i) The $K$-algebra isomorphism between $Z(KB)$ and $Z(KB')$ given by the bijection of character idempotents induced by $I$ induces an ${\mathcal{O}}$-algebra isomorphism $\phi_I:Z(B)\to Z(B')$. \(ii) Suppose further that $I$ satisfies the conditions of Proposition \[prop:index\_p\]. Then $\phi_{I_{N,N'}}=\phi_I|_{Z(b)}$. $ $ (i) This is proved in [@br90]. \(ii) Let $\chi\in{\rm Irr}(b)$ and $\pm I(\chi)=\psi\in{\rm Irr}(b')$. Then, adopting the notation of Proposition \[prop:index\_p\], we have that $$\begin{aligned} e_\chi=e_{\chi_1}+\dots+e_{\chi_p}\text{ and }e_\psi=e_{\psi_1}+\dots+e_{\psi_p},\end{aligned}$$ where $e_\varphi$ is the block idempotent of $\varphi$ in the appropriate group algebra over $K$. The statement now follows from the definitions of $I_{N,N'}$ and $\phi_I$. Let $n$ be a positive integer. We now work towards constructing all the perfect self-isometries of $\mathcal{O}(C_{2^n}\times A_4)$. These will ultimately be used in Theorem \[index2theorem\]. From now on we assume $p=2$. Let $\omega\in K$ be a primitive $3^{\operatorname{rd}}$ root of unity. We recall the character table of $A_4$, where we also set up some labelling of characters. $$\begin{aligned} \begin{tabular}{|c||c|c|c|c|} \hline & $()$ & $(12)(34)$ & $(123)$ & $(132)$ \\ \hline $\chi_1$ & $1$ & $1$ & $1$ & $1$ \\ $\chi_2$ & $1$ & $1$ & $\omega$ & $\omega^2$ \\ $\chi_3$ & $1$ & $1$ & $\omega^2$ & $\omega$ \\ $\chi_4$ & $3$ & $-1$ & $0$ & $0$ \\ \hline \end{tabular}\end{aligned}$$ \[prop:self\_A4\] The perfect self-isometries of $\mathcal{O}A_4$ are precisely the isometries of the form: $$\begin{aligned} I_{\sigma,\epsilon}:\mathbb{Z}{\rm Irr}(A_4)&\to\mathbb{Z}{\rm Irr}(A_4)\\ \chi_j&\mapsto\epsilon\delta_j\delta_{\sigma(j)}\chi_{\sigma(j)}\end{aligned}$$ for $1\leq j\leq 4$, where $\sigma\in S_4$, $\epsilon\in\{\pm1\}$ and $\delta_1=\delta_2=\delta_3=-\delta_4=1$. Hence the group of perfect self-isometries is isomorphic to $C_2 \times S_4$. We first note that $$\begin{aligned} {\rm prj}(\mathcal{O}A_4))=\{\chi_{P_1},\chi_{P_2},\chi_{P_3}\},\text{ where }\chi_{P_j}=\chi_j+\chi_4\text{ for }j=1,2,3.\end{aligned}$$ Therefore $$\begin{aligned} \mathbb{Z}{\rm prj}(\mathcal{O}A_4))=\left\{\sum_{j=1}^4a_j\chi_j:a_j\in\mathbb{Z},\sum_{j=1}^3a_j=a_4\right\}.\end{aligned}$$ So the isometries $\mathbb{Z}{\rm Irr}(\mathcal{O}A_4)\to\mathbb{Z}{\rm Irr}(\mathcal{O}A_4)$ that leave $\mathbb{Z}{\rm prj}(\mathcal{O}A_4))$ invariant are precisely the permutations of $\{\chi_1,\chi_2,\chi_3,-\chi_4\}$ together with their negatives. These are precisely the $I_{\sigma,\epsilon}$’s. We now describe ${\rm CF}(A_4,\mathcal{O}A_4,\mathcal{O})$. Let $\sum_{j=1}^4a_j\chi_j\in{\rm CF}(A_4,\mathcal{O}A_4,K)$. Now by evaluating at various elements of $A_4$ we get that $\sum_{j=1}^4a_j\chi_j\in{\rm CF}(A_4,\mathcal{O}A_4,\mathcal{O})$ if and only if $$\begin{aligned} a_1+a_2+a_3+3a_4&\in\mathcal{O},\\ a_1+a_2+a_3-a_4&\in\mathcal{O},\\ a_1+\omega a_2+\omega^2a_3&\in\mathcal{O}\\ \text{and }a_1+\omega^2a_2+\omega a_3&\in\mathcal{O}.\end{aligned}$$ These conditions are equivalent to $$\begin{aligned} 4a_1\in\mathcal{O},4a_2\in\mathcal{O},4a_3\in\mathcal{O},4a_4\in\mathcal{O}\\ \text{and }\delta_ja_j-\delta_la_l\in\mathcal{O}\text{ for all }1\leq j,l\leq 4.\end{aligned}$$ One can now check that all the $I_{\sigma,\epsilon}$’s leave ${\rm CF}(A_4,\mathcal{O}A_4,\mathcal{O})$ invariant and the proposition is proved. Let $\zeta\in K$ be a primitive $(2^{n})^{\operatorname{th}}$ root of unity. \[lem:roots\_in\_o\] Let $m$ be a positive integer and suppose $\sum_{i=0}^{2^m-1}\zeta^{l_i}\in2^m\mathcal{O}$, where $l_i\in\mathbb{Z}$ for $0\leq i<2^m$. Then either $\zeta^{l_0}=\dots=\zeta^{l_{2^m-1}}$ or $\sum_{i=0}^{2^m-1}\zeta^{l_i}=0$. We consider $\mathbb{Q}$ as embedded in $K$. First note that $$\begin{aligned} \prod_{\sigma\in\operatorname{Gal}(\mathbb{Q}(\zeta)/\mathbb{Q})}\left(\sigma\left(\sum_{i=0}^{2^m-1}\zeta^{l_i}\right)\right)\in2^{m|\operatorname{Gal}(\mathbb{Q}(\zeta)/\mathbb{Q})|}\mathcal{O}\cap\mathbb{Z}=2^{m|\operatorname{Gal}(\mathbb{Q}(\zeta)/\mathbb{Q})|}\mathbb{Z}.\end{aligned}$$ However, for each $\sigma\in\operatorname{Gal}(\mathbb{Q}(\zeta)/\mathbb{Q})$ we have $$\begin{aligned} \left|\sigma\left(\sum_{i=0}^{2^m-1}\zeta^{l_i}\right)\right|\leq2^m\end{aligned}$$ with equality if and only if $\zeta^{l_0}=\dots=\zeta^{l_{2^m-1}}$, where $|\quad|$ denotes the usual norm in $K$. The claim now follows. Let $x$ be a generator of $C_{2^n}$. For $0\leq i<2^n$ we define $\theta_i\in{\rm Irr}(C_{2^n})$ by $\theta_i(x)=\zeta^i$. \[prop:self\_cyclic\] The perfect self-isometries of $\mathcal{O}C_{2^n}$ are precisely the isometries of the form: $$\begin{aligned} I_{j,l,\epsilon}:\mathbb{Z}{\rm Irr}(C_{2^n})&\to\mathbb{Z}{\rm Irr}(C_{2^n})\\ \theta_i&\mapsto\epsilon\theta_{i+l}^j\end{aligned}$$ for $0\leq i<2^n$, where $0\leq j,l<2^n$ with $j$ odd, $\epsilon\in\{\pm1\}$ and $i+l$ is considered modulo $2^n$. Moreover each $I_{j,l,1}$ is induced by the $\mathcal{O}$-algebra automorphism $x\mapsto\zeta^{-l}x^{\frac{1}{j}}$. Hence the group of perfect self-isometries is isomorphic to $C_2\times[(\mathbb{Z}/2^n)^\times\ltimes(\mathbb{Z}/2^n)]$, where the action of $(\mathbb{Z}/2^n)^\times$ on $\mathbb{Z}/2^n$ is given by multiplication. We know ${\rm prj}(\mathcal{O}C^{2^n})=\left\{\sum_{i=0}^{2^n-1}\theta_i\right\}$ so any perfect isometry $I:\mathbb{Z}{\rm Irr}(\mathcal{O}C_{2^n})\to\mathbb{Z}{\rm Irr}(\mathcal{O}C_{2^n})$ must have all signs the same. Therefore we need only check what permutations of the $\theta_i$’s leave ${\rm CF}(C_{2^n},\mathcal{O}C_{2^n},\mathcal{O})$ invariant. We first note that $$\begin{aligned} \sum_{i=0}^{2^n-1}\zeta^{-i}\theta_i(g)= \begin{cases} 2^n&\text{ if }g=x,\\ 0&\text{ if }g\neq x, \end{cases}\end{aligned}$$ for all $g\in C_{2^n}$. So $\frac{1}{2^n}\sum_{i=0}^{2^n-1}\zeta^{-i}\theta_i\in{\rm CF}(C_{2^n},\mathcal{O}C_{2^n},\mathcal{O})$. Now consider a perfect isometry induced by $\sigma$, a permutation of $\{0,1,\dots,2^n-1\}$. Then we must have $\frac{1}{2^n}\sum_{i=0}^{2^n-1}\zeta^{-i}\theta_{\sigma(i)}\in{\rm CF}(C_{2^n},\mathcal{O}C_{2^n}\mathcal{O})$. So $$\begin{aligned} \sum_{i=0}^{2^n-1}\zeta^{-i}\theta_{\sigma(i)}(g)\in2^n\mathcal{O},\end{aligned}$$ for all $g\in C_{2^n}$. Therefore, by Lemma \[lem:roots\_in\_o\], we have that for each $g\in C_{2^n}$ that this sum is either zero or all the $\zeta^{-i}\theta_{\sigma(i)}(x)$’s are equal. Certainly they can’t all be zero, as we have a non-zero linear combination of characters. Therefore there exists $y\in C_{2^n}$ such that $$\begin{aligned} \theta_{\sigma(0)}(y)=\zeta^{-1}\theta_{\sigma(1)}(y)=\dots=\zeta^{-(2^n-1)}\theta_{\sigma(2^n-1)}(y).\end{aligned}$$ Certainly $y$ must generate $C_{2^n}$ as it takes $2^n$ distinct values on the elements of $C_{2^n}$. Define $0\leq j,l<2^n$ by $x=y^j$ and $\theta_{\sigma(0)}(y)=\zeta^l$ and note that $j$ must be odd. Then $$\begin{aligned} \theta^j_{m+l}(x)=\zeta^{j(m+l)}=[\zeta^m\theta_{\sigma(0)}(y)]^j=[\theta_{\sigma(m)}(y)]^j=\theta_{\sigma(m)}(y^j)=\theta_{\sigma(m)}(x),\end{aligned}$$ for all $0\leq m<2^n$. Therefore, $\theta_{\sigma(m)}=\theta^j_{m+l}$. Finally we note that the isometry $\theta_m\mapsto\theta_{m+l}^j$ is induced by the $\mathcal{O}$-algebra automorphism $x\mapsto\zeta^{-l}x^{\frac{1}{j}}$ and so is indeed a perfect isometry and the proof is complete. For the following theorem we adopt the notation of Propositions \[prop:self\_A4\] and \[prop:self\_cyclic\]. \[thm:C2nA4\] Every perfect self-isometry of $\mathcal{O}(C_{2^n}\times A_4)$ is of the form $$\begin{aligned} (I_{j,l,1},I_{\sigma,\epsilon}):(\mathbb{Z}{\rm Irr}(\mathcal{O}C_{2^n})\otimes_{\mathbb{Z}}\mathbb{Z}{\rm Irr}(\mathcal{O}A_4))\to(\mathbb{Z}{\rm Irr}(\mathcal{O}C_{2^n})\otimes_{\mathbb{Z}}\mathbb{Z}{\rm Irr}(\mathcal{O}A_4)),\end{aligned}$$ where $\sigma\in S_4$, $\epsilon\in\{\pm1\}$ and $0\leq j,l<2^n$ with $j$ odd. The projective indecomposable characters are $$\begin{aligned} {\rm prj}(\mathcal{O}(C_{2^n}\times A_4))=\{\chi_{P_1},\chi_{P_2},\chi_{P_3}\},\text{ where }\chi_{P_j}=\left(\sum_{i=0}^{2^n-1}\theta_i\right)\otimes\left(\chi_j+\chi_4\right).\end{aligned}$$ Let $I$ be a perfect self-isometry of $\mathcal{O}(C_{2^n}\times A_4)$. By counting constituents we see that $$\begin{aligned} \label{align:im} I(\chi_{P_l})=\pm\chi_{P_1},\pm\chi_{P_2},\pm\chi_{P_3},\pm(\chi_{P_1}-\chi_{P_2}),\pm(\chi_{P_1}-\chi_{P_3})\text{ or }\pm(\chi_{P_2}-\chi_{P_3}),\end{aligned}$$ for $1\leq l\leq 3$. Consider the set $$\begin{aligned} X_m:=\left\{j\big{|}\left\langle\theta_l\otimes\chi_j,I\left(\left(\sum_{i=0}^{2^n-1}\theta_i\right)\otimes\chi_m\right)\right\rangle\neq0,\text{ for some }l\right\},\end{aligned}$$ for $1\leq m\leq 4$. By (\[align:im\]) we have shown that $|X_m|=1$ or $2$ for every $1\leq m\leq 4$. If $|X_1|=2$, then by considering (\[align:im\]) for $l=1$ we see that $X_4=X_1$. Similarly by considering $I(\chi_{P_2})$, we get that $X_2=X_4$. This is now a contradiction as then $$\begin{aligned} I\left(\left(\sum_{i=0}^{2^n-1}\theta_i\right)\otimes\left(\chi_1+\chi_2+\chi_4\right)\right)\end{aligned}$$ has at most $2.2^n$ constituents with non-zero multiplicity. Therefore $|X_1|=1$ and so by considering $I(\chi_{P_1})$ we get that $|X_4|=1$ and then by considering $I(\chi_{P_2})$ and $I(\chi_{P_3})$ we get that $|X_2|=|X_3|=1$. Moreover, $X_1,X_2,X_3,X_4$ must all be disjoint. By composing $I$ with the perfect isometry $(I_{1,1,1},I_{\sigma,1})$, for some appropriately chosen $\sigma\in S_4$, we may assume $X_m=\{m\}$ for all $1\leq m\leq4$. Therefore $I(\chi_{P_l})=\pm\chi_{P_l}$ for $1\leq l\leq3$ and by considering $$\begin{aligned} I\left(\left(\sum_{i=0}^{2^n-1}\theta_i\right)\otimes\chi_4\right),\end{aligned}$$ we see that in fact all these signs are the same and we may assume, possibly by composing $I$ with $(I_{1,1,1},I_{1,\epsilon})$, that $$\begin{aligned} I\left(\left(\sum_{i=0}^{2^n-1}\theta_i\right)\otimes\chi_m\right)=\left(\sum_{i=0}^{2^n-1}\theta_i\right)\otimes\chi_m,\end{aligned}$$ for $1\leq m\leq 4$. Next we note that $$\begin{aligned} \frac{1}{12}\theta_j\otimes(\chi_1+\chi_2+\chi_3+9\chi_4)\in{\rm CF}(C_{2^n}\times A_4,\mathcal{O}(C_{2^n}\times A_4),\mathcal{O}),\end{aligned}$$ for $0\leq j<2^n$. As $3$ is invertible in $\mathcal{O}$, this implies $$\begin{aligned} \theta_j\otimes\left(\sum_{m=1}^4\chi_m\right)\in4{\rm CF}(C_{2^n}\times A_4,\mathcal{O}(C_{2^n}\times A_4),\mathcal{O}),\end{aligned}$$ and so $$\begin{aligned} \label{align:im2} I\left(\theta_j\otimes\left(\sum_{m=1}^4\chi_m\right)\right)\in4{\rm CF}(C_{2^n}\times A_4,\mathcal{O}(C_{2^n}\times A_4),\mathcal{O}),\end{aligned}$$ for $0\leq j<2^n$. Now set $\theta_{j_m}\otimes\chi_m:=I(\theta_j\otimes\chi_m)$, for $1\leq m\leq4$. Evaluating (\[align:im2\]) at $(x,1)$, $(x,(123))$ and $(x,(132))$ gives $$\begin{aligned} \zeta^{j_1}+\zeta^{j_2}+\zeta^{j_3}+\zeta^{j_4}&\in4\mathcal{O},\label{zeta1}\\ \zeta^{j_1}+\omega\zeta^{j_2}+\omega^2\zeta^{j_3}&\in4\mathcal{O},\label{zeta2}\\ \zeta^{j_1}+\omega^2\zeta^{j_2}+\omega\zeta^{j_3}&\in4\mathcal{O}\label{zeta3}.\end{aligned}$$ Adding (\[zeta1\]), (\[zeta2\]) and (\[zeta3\]) gives $3\zeta^{j_1}+\zeta^{j_4}\in4\mathcal{O}$. Now Lemma \[lem:roots\_in\_o\] tells us that $\zeta^{j_1}=\zeta^{j_4}$ as certainly $3\zeta^{j_1}+\zeta^{j_4}\neq0$. Therefore, by (\[zeta1\]), $\zeta^{j_2}+\zeta^{j_3}\in2\mathcal{O}$. So again by Lemma \[lem:roots\_in\_o\] $\zeta^{j_2}=\zeta^{j_3}$ as $\zeta^{j_2}=-\zeta^{j_3}$ is prohibited by (\[zeta1\]). Substituting into (\[zeta2\]) gives $\zeta^{j_1}-\zeta^{j_2}\in4\mathcal{O}$. A final use of Lemma \[lem:roots\_in\_o\] tells us that $\zeta^{j_1}=\pm\zeta^{j_2}$ but $2\zeta^{j_1}\notin4\mathcal{O}$ and so we must have $\zeta^{j_1}=\zeta^{j_2}=\zeta^{j_3}=\zeta^{j_4}$. We have shown that we may assume $I$ is of the form $$\begin{aligned} I(\theta_j\otimes\chi_m)\mapsto\theta_{\sigma(j)}\otimes\chi_m,\end{aligned}$$ for $0\leq j<2^n$ and $1\leq m\leq4$, where $\sigma$ is a permutation of $\{0,1,\dots,2^n-1\}$. In particular the $\mathcal{O}$-algebra automorphism of $Z(\mathcal{O}(C_{2^n}\times A_4)$ induced by $I$ leaves $\mathcal{O}C_{2^n}$ invariant. Using Proposition \[prop:self\_cyclic\] we can compose $I$ with $(I_{s,t,1},I_{1,1})$ for appropriately chosen $s$ and $t$ so that the automorphism induced on $\mathcal{O}C_{2^n}$ is the identity. Therefore $\sigma$ is the identity permutation, $I$ is the identity perfect isometry and the theorem is proved. \[normaldefectlemma\] Let $B$ be a block of ${\mathcal{O}}G$ for a finite group $G$ with normal defect group $D \cong C_{2^n} \times C_2 \times C_2$ for some $n>1$. Then $B$ is Morita equivalent to ${\mathcal{O}}D$ or ${\mathcal{O}}(C_{2^n} \times A_4)$. By Lemma \[inertial\_quotient\_lem\] the possible inertial quotients are $1$ and $C_3$. Since in either case the inertial quotient is cyclic the result follows from the main result of [@ku85]. The following appears as [@sa17 Theorem 15], but we include it here for completeness. \[per\_isom\] Let $G$ be a finite group and $B$ a block of ${\mathcal{O}}G$ with defect group $D \cong C_{2^n} \times C_2 \times C_2$ for $n>1$. Then either $B$ is nilpotent or $l(B)=3$. Let $G'=C_{2^n} \times A_4$ and $B'={\mathcal{O}}G'$. If $B$ is not nilpotent then there is a perfect isometry between $B$ and $B'$. Write $E$ for the inertial quotient of $B$. If $E=1$, then $B$ is nilpotent and the result holds. Hence we may assume $|E|=3$. We must first show that $l(B)=3$, and we do this by adapting a method used in [@ks13]. We proceed by induction on $n$. Assume that $l(B')=3$ whenever $B'$ is a block with defect group $C_{2^m} \times C_2 \times C_2$ for $m \geq 1$ and inertial index $3$, and observe that this is known to hold for $m=1$ by [@kkl12]. By [@km13] every irreducible character of $B$ has height zero, and so by [@ro92 1.2(ii)] we have $k(B) \leq |D|$. Let $(D,b_D)$ be a maximal $B$-subpair. Since $D$ is abelian, $N_G(D,b_D)$ controls fusion of $B$-subpairs in $(D,b_D)$. If $u \in D$, then let $b_u$ be the unique block of $C_G(u)$ such that $(u,b_u) \in (D,b_D)$. Write $D=\langle x,y_1,y_2 \rangle$, where $y$ has order $2^n$ and $y_1,y_2$ are involutions. Then $\mathcal{X}:=\{ (1,B),(x^i,b_{x^i}),(x^jy_1,b_{x^jy_1}):1 \leq i \leq 2^n-1, 0 \leq j \leq 2^n-1 \}$ form a complete set of $G$-conjugacy class representatives of subsections in $B$. By a well known reformulation of [@na98 5.12] (see exercise 5.7 of [@na98]) we then have $$2^{n+2} \geq k(B) =\sum_{(u,b_u) \in \mathcal{X}} l(b_u).$$ Now since $D$ is abelian, each block $b$ in the above summation may be chosen to have defect group $D$. First let $1 \neq u=x^i$ for some $i$. Then $b_u$ has inertial index $3$. Now $C_G(u)$ has a non-trivial central $2$-subgroup $Z_u \leq \langle x \rangle$. The unique block $\bar{b}_u$ of $C_G(u)/Z_u$ corresponding to $b_u$ has inertial index $3$ and by induction $3=l(\bar{b}_u) = l(b_u)$. Now let $u=x_jy_1$ for some $j$. Then $b_u$ has inertial index $1$ and so is nilpotent, hence $l(b_u)=1$. Substituting, we have $l(B) + 2^{n+2}-3 = k(B) \leq 2^{n+2}$, so $l(B) \leq 3$. We have a subsection $(u,b_u)$ with defect group $D$ and $l(b_u)=1$. By [@sambale 1.37], the diagonal entries of the contribution matrix of $B$ (with rows labelled by ${\rm Irr}(B)$) are odd squares, and the trace of the contribution matrix is $|D|$. Hence $2^{n+2}$ is a sum of $k(B)$ odd squares, which cannot happen if $k(B)=2^{n+2}-1$ or $k(B)=2^{n+2}-2$. Hence $l(B)=3$. Let $C$ be the unique block of $N_G(D)$ with $C^G=B$. By [@wa05] there is a perfect isometry between $B$ and $C'$. By Lemma \[normaldefectlemma\] $C$ and $B'$ are Morita equivalent, so there is a perfect isometry between $B'$ and $C$, and we are done. In the above, the perfect isometry constructed in [@wa05] is additionally compatible with the $*$ construction in [@bp80] and so could be shown to satisfy the hypotheses of Proposition \[prop:index\_p\](iii). However this can also be shown using the machinery of perfect self-isometry groups developed earlier in this section, and this is what we do in the first part of the proof of the following Theorem. \[index2theorem\] Let $G$, $N$, $B$, $b$ and $D$ be as in Proposition \[prop:grunit\]. Suppose further that $D\cong C_{2^n}\times C_2\times C_2$, for some $n>1$, $D\cap N\cong C_{2^{n-1}}\times C_2\times C_2$ and $b$ is Morita equivalent to the principal block of $\mathcal{O}(C_{2^{n-1}}\times A_4)$ (respectively $\mathcal{O}(C_{2^{n-1}}\times A_5)$). Then $B$ is Morita equivalent to the principal block of $\mathcal{O}(C_{2^n}\times A_4)$ (respectively $\mathcal{O}(C_{2^n}\times A_5)$). First suppose that $b$ is Morita equivalent to $\mathcal{O}(C_{2^{n-1}}\times A_4)$. By Proposition \[prop:index\_p\](ii) $l(B) = 3$ and so by Proposition \[per\_isom\] there exists a perfect isometry $$\begin{aligned} I:\mathbb{Z}{\rm Irr}(B)\to\mathbb{Z}{\rm Irr}(\mathcal{O}(C_{2^n}\times A_4)).\end{aligned}$$ Now $I$ induces an isomorphism of the groups of perfect self-isometries of $B$ and of $\mathcal{O}(C_{2^n}\times A_4)$ via $\alpha \mapsto I \circ \alpha \circ I^{-1}$ for $\alpha$ any perfect self-isometry of $\mathcal{O}(C_{2^n}\times A_4)$, and we denote this isomorphism by $I_{\operatorname{PI}}$. Consider the perfect self-isometry $$\begin{aligned} J:\mathbb{Z}{\rm Irr}(B)&\to\mathbb{Z}{\rm Irr}(B)\\ \chi&\mapsto\operatorname{sgn}_N^G.\chi,\end{aligned}$$ where $\operatorname{sgn}_N^G$ is the linear character of $G$ with kernel $N$, so for each irreducible character $\theta$ of $b$, $J$ swaps the two extensions of $\theta$ to $G$. We know that $J$ is indeed a perfect isometry as it is induced by the $\mathcal{O}$-algebra automorphism of $\mathcal{O}G$ given by $g\mapsto\operatorname{sgn}_N^G(g)g$ for all $g\in G$. Note that $J$ is a perfect self-isometry of order $2$ and that it induces the trivial $k$-algebra automorphism on $Z(kB)$. Furthermore by Proposition \[prop:index\_p\](i) and (ii) every character in ${\rm prj}(B)$ is fixed under multiplication by $\operatorname{sgn}_N^G$ and so $J$ is the identity on $\mathbb{Z}{\rm prj}(B)$. Therefore $I_{\operatorname{PI}}(J)$ must be of order $2$, induce the identity $k$-algebra automorphism on $Z(k(C_{2^n}\times A_4))$ and be the identity on $\mathbb{Z}{\rm prj}(\mathcal{O}(C_{2^n}\times A_4))$. Adopting the notation of Theorem \[thm:C2nA4\], set $I_{\operatorname{PI}}(J)=(I_{j,l,1},I_{\sigma,\epsilon})$, where $\sigma\in S_4$, $\epsilon\in\{\pm1\}$ and $0\leq j,l<2^n$ with $j$ odd. Then the fact that $I_{\operatorname{PI}}(J)$ is the identity on $\mathbb{Z}{\rm prj}(\mathcal{O}(C_{2^n}\times A_4))$ forces $\sigma$ to be the identity permutation and $\epsilon=1$, the fact that $I_{\operatorname{PI}}(J)$ induces the identity $k$-algebra automorphism on $Z(k(C_{2^n}\times A_4))$ forces $j=1$ and the fact that $I_{\operatorname{PI}}(J)$ has order $2$ forces $l=2^{n-1}$. In other words $I_{\operatorname{PI}}(J)$ is induced by the $\mathcal{O}$-algebra automorphism $$\begin{aligned} \mathcal{O}(C_{2^n}\times A_4)&\to\mathcal{O}(C_{2^n}\times A_4)\\ x\otimes y&\mapsto -x\otimes y,\end{aligned}$$ for all $y\in\mathcal{O}A_4$, where $x$ is a fixed generator of $C_{2^n}$. We have shown that $$\begin{aligned} I(\operatorname{sgn}_N^G.\chi)=\operatorname{sgn}_{N'}^{G'}.I(\chi),\end{aligned}$$ for all $\chi\in{\rm Irr}(B)$, where $G':=C_{2^n}\times A_4$, $N':=C_{2^{n-1}}\times A_4$. Therefore $I$ satisfies the hypotheses of Proposition \[prop:index\_p\](iii), where $B':=\mathcal{O}(C_{2^n}\times A_4)$ and $b':=\mathcal{O}(C_{2^{n-1}}\times A_4)$. Let $I_{N,N'}$ be the perfect isometry between $b$ and $b'$ induced by $I$ as in Proposition \[prop:index\_p\] and $I_{\operatorname{Mor}}$ the perfect isometry induced by the Morita equivalence between $b$ and $b'$. Write $I_{N,N'}\circ I_{\operatorname{Mor}}^{-1}=(I_{s,t,1},I_{\tau,\delta})$ in the notation of Theorem \[thm:C2nA4\] applied to $\mathcal{O}(C_{2^{n-1}}\times A_4)$, where $\tau\in S_4$, $\delta\in\{\pm1\}$ and $0\leq s,t<2^{n-1}$ with $s$ odd. By composing $I$ with the perfect self-isometry $(I_{1,1,1},I_{\tau,\delta})^{-1}$ of $B'$ and composing the Morita equivalence $b\sim_{\operatorname{Mor}}b'$ with that induced by the $\mathcal{O}$-algebra automorphism of $b'$ defined by $x\mapsto\zeta^{-t}x^{\frac{1}{s}}$, we may assume that $I_{N,N'}=I_{\operatorname{Mor}}$. Let $\phi_I:Z(B)\to Z(B')$ be the isomorphism of centres from Lemma \[lem:isomcent\] and let $M$ be the $b'$-$b$-bimodule inducing the Morita equivalence $b\sim_{\operatorname{Mor}}b'$. Since $I_{N,N'}=I_{\operatorname{Mor}}$ and by Lemma \[lem:isomcent\](ii) we have that $\phi_I|_{Z(b)}=\phi_{I_{N,N'}}:Z(b)\to Z(b')$ is the isomorphism of centres induced by the Morita equivalence. In other words $$\begin{aligned} \label{centre:mor} \phi_I(\alpha)m=m\alpha,\text{ for all }\alpha\in b,m\in M.\end{aligned}$$ Let $a\in B$ be a graded unit as described in Proposition \[prop:grunit\] and set $a':=\phi_I(a)$. Since $\phi_I$ respects the $G/N$ and $G'/N'$-gradings, $a'$ is also a graded unit. We now give $M$ the structure of a module for $$\begin{aligned} (b'\otimes_{\mathcal{O}}b^{\operatorname{op}})\oplus(a'^{-1}b'\otimes_{\mathcal{O}}(ab)^{\operatorname{op}})\end{aligned}$$ by defining $a'^{-1}.m.a=m$, for all $m\in M$, where \[centre:mor\] ensures that this does indeed define a module. Now by [@mar96 Theorem 3.4] we have proved that $B$ is Morita equivalent to $\mathcal{O}(C_{2^n}\times A_4)$. For the $A_5$ case we note that the principal blocks of $\mathcal{O}A_4$ and $\mathcal{O}A_5$ are perfectly isometric by [@br90 A1.3]. The proof now proceeds exactly as above by replacing the principal block of $\mathcal{O}A_4$ everywhere with that of $\mathcal{O}A_5$ (note that we can replace the principal block of $\mathcal{O}A_4$ with that of $\mathcal{O}A_5$ in Theorem \[thm:C2nA4\]). Proof of the main theorem and corollaries ========================================= \[oddindex\] Let $B$ be a block of ${\mathcal{O}}G$ for a finite group $G$ with defect group $D \cong C_{2^n} \times C_2 \times C_2$ for some $n>1$. Let $N \lhd G$ be of odd prime index $w$ and let $b$ be a $G$-stable block of ${\mathcal{O}}N$ covered by $B$, so that $D$ is also a defect group for $b$. If $b$ is not nilpotent, then either $B$ is nilpotent or $B \sim_{\operatorname{Mor}} b$. By Proposition \[per\_isom\] we have $l(b)=3$ and either $B$ is nilpotent (with $l(B)=1$) or $l(B)=3$. The normal subgroup $G[b]$ of $G$ is defined to be the group of elements of $G$ acting as inner automorphisms on $b \otimes_{{\mathcal{O}}} k$. Let $B'$ be a block of ${\mathcal{O}}G[b]$ covered by $B$. Then $b$ is source algebra equivalent to $B'$, and in particular has isomorphic inertial quotient by [@kkl12 2.2], noting that a source algebra equivalence over $k$ implies one over ${\mathcal{O}}$ by [@pu88 7.8]. Hence we may assume that $G[b]=N$. Then $B$ is the unique block of $G$ covering $B'$ by [@da73 3.5]. Now consider the action of $G$ on the ${\rm IBr}(b)$. If $w>3$, then every $\varphi \in {\rm IBr}(b)$ is fixed and extends to $w$ distinct elements of ${\rm IBr}(G)$. Since $B$ is the unique block of $G$ covering $b$ these all lie in $B$. Hence $l(B)=3w>3$, a contradiction. Hence $w=3$. Then either every element of ${\rm IBr}(b)$ is fixed, in which case $l(B)=3w>3$, a contradiction, or they are permuted in a single orbit, in which case $l(B)=1$ and $B$ is nilpotent. In the following write ${\rm rk}_p(Q)$ for the rank of a $p$-group $Q$, that is, $p^{{\rm rk}_p(Q)}$ is the size of the largest elementary abelian subgroup of $Q$. \[thm:main\] Let $G$ be a finite group and $B$ a block of $\mathcal{O}G$ with defect group $D\cong C_{2^n}\times C_2\times C_2$ for $n>1$. Then $B$ is Morita equivalent to the principal block of $\mathcal{O}(C_{2^n}\times C_2\times C_2)$, $\mathcal{O}(C_{2^n}\times A_4)$ or $\mathcal{O}(C_{2^n}\times A_5)$. Let $B$ be a block of ${\mathcal{O}}G$ for a finite group $G$ with $[G:O_{2'}(Z(G))$ minimised subject to the condition that $B$ has defect group $D \cong C_{2^n}\times C_2\times C_2$ for some $n>1$ and $B$ is not Morita equivalent to the principal block of ${\mathcal{O}}D$, ${\mathcal{O}}(C_{2^n}\times C_2\times C_2)$, $\mathcal{O}(C_{2^n}\times A_4)$ or $\mathcal{O}(C_{2^n}\times A_5)$. Suppose that $N \lhd G$ and $b$ is a block of ${\mathcal{O}}N$ covered by $B$. Write $I=I_G(b)$ for the stabilizer of $b$ in $G$, and $B_I$ for the Fong-Reynolds correspondent. Now $B_I$ is Morita equivalent to $B$ and they have isomorphic defect groups. We have $O_{2'}(Z(G)) \leq O_{2'}(Z(I))$, and if $I \neq G$, then $[I:O_{2'}(Z(I))]<[G:O_{2'}(Z(G))]$. Hence by minimality $I=G$. Now suppose that $b$ is nilpotent. Let $b'$ be a block of ${\mathcal{O}}Z(G)N$ covered by $B$ and covering $b$. By the above argument applied to $Z(G)N$ and $b'$, $b'$ is $G$-stable. Note that $b'$ must also be nilpotent. Using the results of [@kp90], as outlined in [@ekks14 Proposition 2.2], $B$ is Morita equivalent to a block $\tilde{B}$ of a central extension $\tilde{L}$ of a finite group $L$ by a $2'$-group such that there is an $M \lhd L$ with $M \cong D \cap (Z(G)N)$, $G/Z(G)N \cong L/M$, and $\tilde{B}$ has defect group isomorphic to $D$. Note that $[\tilde{L}:O_{2'}(Z(\tilde{L}))] \leq |L| = [G:Z(G)N]|D \cap (Z(G)N)| \leq [G:O_{2'}(Z(G))]$ and that equality only occurs when $N \leq Z(G)O_2(G)$. Hence by minimality $N \leq Z(G)O_2(G)$. We conclude that $B$ is quasiprimitive, that is, every block of every normal subgroup covered by $B$ is $G$-stable, and that if $B$ covers a nilpotent block of a normal subgroup $N$ of $G$, then $N \leq Z(G)O_2(G)$. We claim that $O^2(G)=G$. Suppose otherwise, and let $N \lhd G$ be a subgroup of index $2$. Let $b$ be the unique block of $N$ covered by $B$. Then by Lemma \[index\_p\_background\_lem\] $B$ is the unique block of $G$ covering $b$ since $G/N$ is a $2$-group, $G=ND$ and $b$ has defect group $D \cap N$. Let $b_D$ be a block of $C_G(D)$ with $(b_D)^G=B$. Since $B$ has inertial quotient $C_3$ and $N_G(D,b_D)$ controls fusion in $D$, the inertial quotient of $b$ is $C_3$ (if it were $1$, then $b$ would be nilpotent and so $G=Z(G)O_2(G)$, a contradiction by Lemma \[normaldefectlemma\]). If $D \cap N \cong C_{2^n} \times C_2$, then ${\rm Aut}(D \cap N)$ is a $2$-group and so $b$ is nilpotent, a contradiction. If $D \cap N \cong (C_2)^3$, then by [@ea16] $b$ is Morita equivalent to the principal block of ${\mathcal{O}}(C_2 \times A_4)$ or ${\mathcal{O}}(C_2 \times A_5)$ and so Theorem \[index2theorem\] gives a contradiction. Otherwise, since $[N:O_{2'}(Z(N))]<[G:O_{2'}(Z(G))]$ by minimality we also have a contradiction by Theorem \[index2theorem\]. Hence $O^2(G)=G$. Before proceeding we recall the definition and some properties of the generalized Fitting subgroup $F^*(G)$ of a finite group $G$. Details may be found in [@asc00]. A *component* of $G$ is a subnormal quasisimple subgroup of $G$. The components of $G$ commute, and we define the *layer* $E(G)$ of $G$ to be the normal subgroup of $G$ generated by the components. It is a central product of the components. The *Fitting subgroup* $F(G)$ is the largest nilpotent normal subgroup of $G$, and this is the direct product of $O_r(G)$ for all primes $r$ dividing $|G|$. The *generalized Fitting subgroup* $F^*(G)$ is $E(G)F(G)$. A crucial property of $F^*(G)$ is that $C_G(F^*(G)) \leq F^*(G)$, so in particular $G/F^*(G)$ may be viewed as a subgroup of ${\rm Out}(F^*(G))$. Write $L_1,\ldots,L_t$ for the components of $G$, so $E(G)=L_1\cdots L_t \lhd G$. Note that $G$ permutes the $L_i$. There must be at least one component, since otherwise the block $b'$ of $F^*(G)$ covered by $B$ is nilpotent and so $F^*(G)=Z(G)O_2(G)$. Therefore $D \leq C_G(F^*(G)) \leq F^*(G)=Z(G)O_2(G)$, so that $D \lhd G$, a contradiction by Lemma \[normaldefectlemma\]. We claim that $O_2(G) \leq Z(G)$. Write $N=C_G(O_2(G))$ and $b$ for the unique block of $N$ covered by $B$. Note that $D \leq N \lhd G$. If $O_2(G) \cong C_{2^m}$ for $m \geq 1$ or $O_2(G) \cong C_{2^m} \times C_2$ for $m>1$, then ${\rm Aut}(O_2(G))$ and so $G/N$ is a $2$-group, which forces $N=G$ as $O^2(G)=G$. Suppose that $O_2(G) \cong C_{2^m} \times (C_2)^2$ for some $m \geq 1$. Let $b_D$ be a block of $C_G(D)$ with $(b_D)^{C_G(D)}=b$ (and so $(b_D)^G=B$). Since $N_G(D,b_D)$ controls fusion in $D$ there must be a $G$-stable subgroup of $O_2(G)$ of order $4$. Hence $G/N$ is isomorphic to a subgroup of $S_3$. Since $O^2(G)=G$, we have $[G:N]|3$. Then by Proposition \[oddindex\] and minimality (noting that $Z(G)\leq N$) we again have $G=N$, so $O_2(G) \leq Z(G)$ as claimed. We have shown that $F^*(G)=E(G)Z(G)$. We next show that $t=1$, that is, $E(G)$ is quasisimple. Write $b^*$ for the unique block of $F^*(G)$ covered by $B$. Then $D \cap F^*(G)$ is a defect group for $b^*$. Hence $(D \cap F^*(G))/O_p(Z(G))$ is a defect group for a block of $F^*(G)/O_p(Z(G))$. Therefore $(D \cap F^*(G))/O_p(Z(G))$ is a radical $2$-subgroup of $F^*(G)/O_p(Z(G))$ (recall that a $p$-subgroup $Q$ of a finite group $H$ is radical if $Q=O_p(N_H(Q))$ and that defect groups are radical $p$-subgroups) and so $(D \cap F^*(G))Z(G)/Z(G)$ is a radical $2$-subgroup of $F^*(G)/Z(G)\cong (L_1Z(G)/Z(G)) \times \cdots \times (L_tZ(G)/Z(G))$. By [@ou95 Lemma 2.2] it follows that $(D \cap F^*(G))Z(G)/Z(G) = D_1 \times \cdots \times D_m$, where $D_i = (D \cap F^*(G))Z(G)/Z(G)) \cap (L_iZ(G)/Z(G))$ (and $D_i$ is a radical $2$-subgroup but not necessarily a defect group). Write $b_i$ for the block of $L_i$ covered by $B$ and $\bar{b}_i$ for the unique block of $L_iO_2(G)/O_2(G)$ corresponding to $b_i$. If ${\rm rk}_p(D_i)=1$ for some $i$, then $\bar{b}_i$ has cyclic defect group and so is nilpotent, hence $b_i$ is also nilpotent by [@wa94] (where the result is stated over $k$, but follows over ${\mathcal{O}}$ immediately), a contradiction. Hence since $\sum_{i=1}^t {\rm rk}_p(D_i) \leq {\rm rk}_p(D) = 3$ we have $t=1$. Now by the Schreier conjecture $G/F^*(G)$ is solvable. Suppose that $G \neq F^*(G)$. Since $O^2(G)=G$ there is $N \lhd G$ of odd prime index. Let $b$ be the unique block of $N$ covered by $G$. Note that we may assume $Z(G) \leq N$, as otherwise $B$ and $b$ are Morita equivalent by [@kkl12 2.2] and we may replace $G$ and $B$ by $N$ and $b$. Therefore we have $[N:O_{2'}(Z(N))] < [G:O_{2'}(Z(G))]$ and so Proposition \[oddindex\] leads to a contradiction. Hence we may assume $G=F^*(G)$ and so $G=L_1Z(G)$. Further application of Proposition \[oddindex\] and Theorem \[index2theorem\] allows us to assume that $G=L_1$. Applying [@ekks14 6.1], one of the following occurs, both leading to a contradiction, and we are done: \(i) $B$ is Morita equivalent to a block $C$ of ${\mathcal{O}}H$ for a finite group $H$ with $H=H_0 \times H_1$ such that $H_0$ is abelian with Sylow $2$-subgroup $C_{2^n}$ and the block of $H_1$ covered by $C$ has defect groups $C_2 \times C_2$. In this case it follows from [@li94] that $B$ is Morita equivalent to the principal block of ${\mathcal{O}}D$, ${\mathcal{O}}(C_{2^n} \times A_4)$ or ${\mathcal{O}}(C_{2^n} \times A_5)$, a contradiction. \(ii) There is a finite group $H$ with $G \lhd H$ and $B$ is covered by a nilpotent block of ${\mathcal{O}}H$. In this case by [@pu11 4.3] $B$ is Morita equivalent to the unique block of $N_G(D)$ with Brauer correspondent $B$, a contradiction by Lemma \[normaldefectlemma\]. \[cor:derived\] Let $G$ be a finite group and $B$ a block of $\mathcal{O}G$ with defect group $D\cong C_{2^n}\times C_2\times C_2$ for $n>1$. Let $b$ be the unique block of $N_G(D)$ with $b^G=B$. Then $B$ and $b$ are derived equivalent. By [@ri96 3] the principal blocks of ${\mathcal{O}}A_4$ and ${\mathcal{O}}A_5$ are derived equivalent, and so the same is true of ${\mathcal{O}}(C_{2^n} \times A_4)$ and ${\mathcal{O}}(C_{2^n} \times A_5)$. Hence by Theorem \[thm:main\] there are only two derived equivalence classes of blocks with defect group $C_{2^n}\times C_2\times C_2$, and we are done. \[cor:derived16\] Let $G$ be a finite group and $B$ a block of $\mathcal{O}G$ with defect group $D$ of order dividing $16$. Let $b$ be the unique block of $N_G(D)$ with $b^G=B$. Then $B$ and $b$ are derived equivalent. If $D$ is elementary abelian, then this is by [@li94], [@ea16] and [@ea17]. If $D \cong C_4 \times C_4$, then see [@ekks14] where it is shown that there are only two Morita equivalence classes. If $D \cong C_4 \times C_2 \times C_2$, then this is Corollary \[cor:derived\]. In all other cases ${\rm Aut}(D)$ is a $2$-group and so all blocks with that defect group are nilpotent. \[cor:derivedrank3\] Let $G$ be a finite group and $B$ a block of $\mathcal{O}G$ with defect group $D$ of $2$-rank at most three. Let $b$ be the unique block of $N_G(D)$ with $b^G=B$. Then $B$ and $b$ are derived equivalent. 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[^1]: School of Mathematics, University of Manchester, Manchester, M13 9PL, United Kingdom. Email: charles.eaton@manchester.ac.uk [^2]: School of Mathematics, University of Manchester, Manchester, M13 9PL, United Kingdom. Email: michael.livesey@manchester.ac.uk [^3]: This research was supported by the EPSRC (grant no. EP/M015548/1).

This past week my boyfriend dumped me. Now, under normal circumstances, recovery would have been simple. At first, I'd turn the radio randomly to any given pop song where a lyric about "looking into each other's eyes" would inevitably transition into me sobbing, "WE USED TO LOOK INTO EACH OTHER'S EYES. THIS SONG WAS TOTALLY WRITTEN ABOUT ME AND MY PAIN" followed by dramatic, angsty teen tears. Then, there would be a bitch session with my friends as they confirmed that he was in fact always a douchebag and even though he kind of looked like John Mayer that also kind of added to the doucheyness. Knowing my friends, and our love of festively celebrating the fall season, his picture attached to a pumpkin would probably be presented along with a bat. I can actually attest to the fact that pumpkin smashing really is an effective form of therapy for those who haven't tried it. Candy would be involved, and possibly even a crappy romantic comedy (they are good for approximately NO other purpose). And then, I'd move on with my 17-year-old life. Advertisement However. This was not a normal break up. A girl that I considered to be a close friend sent my boyfriend – who was also one of my best friends – a letter declaring her undying love for him while we were still together (for those of you not up on the Unofficial Girl Code, this is Violation #1). Not to mention she was still with her boyfriend at the time. My boyfriend and friend conferred, apparently decided that their feelings for each other were similar in nature to those felt by Leonardo DiCaprio and Kate Winslet in Titanic / Humphrey Bogart and Ingrid Bergman in Casablanca / Ryan Gosling and Rachel McAdams in the The Notebook and broke up with their significant others to begin their lifelong love affair that film and literature could possibly try to capture in the future, but would pale in comparison to their other-worldy glow of true love. So, left with the eloquent break up of, "This has been fun but I have feelings for one of your good friends and am dumping you for her," delivered to me at school, I was suddenly without two of the people that I had cared about and trusted the most. As a person who doesn't let others into her life easily and carefully considers every person who she gives her heart to in any way, I had chosen these two people with confidence. So on top of feeling betrayed I just felt plain stupid when I realized that they found that getting rid of me was so easy. Now, I know this sounds like a lot of teen drama. Get over yourself, you're probably thinking. This happens all the time and besides, kids are starving, dictators are oppressing people. SHUT UP JULIE. And in reality I am able to see that the fact that they had feelings for each other doesn't make them evil, and getting me out of the way may be the best thing for all of us in the long run (despite how carelessly they handled the whole thing). So I'm going to stop throwing myself a pity party (friends/boyfriends come and go) and instead try to use this situation to help the FBomb community. I didn't have a guide to dealing with this situation – certainly not a feminist guide. Thus I ended up feeling pretty anti-feminist as I remained on the couch in my sweats crying for close to 24 hours and unable to eat for a few days. So. I'm going to explain how my feminist identity helped me through what was (though something trivial in the large scheme of things) the worst emotional experience of my young life. Because maybe (God/Mother Goddess/Extra-Terrestrial Serpent Lord forbid) if you, dear FBomber, are in this situation, with the help of this guide you'll just skip to the empowerment part. How To Get Through the Feeling Betrayed / Feeling Sorry for Yourself / "My Life Sucks And Nobody Has Ever Been In As Much Pain As I Have" Phase: Sisterhood In this garbage dump of a situation, I realized I have an AMAZING group of friends. They brought me every type of candy they could think of. One baked me a massive cupcake (can you possibly think of anything better?). They listened to endless hours of my sobbing and made sure I knew that I was loved when I felt like I had just been shown I clearly wasn't worthy of love. They drove to Speedway (the best gas station chain in America, I must say) to bring me the mixture of Diet Coke and Dr. Pepper that disgusts them but that I'm addicted too. They made me laugh, they let me cry. Which made me realize how important the feminist value of sisterhood is. My female relationships in this situation made all the difference. And while through this ordeal I found that sometimes such (perceived) relationships can fail a girl, as one of mine did (the fact that we exist in this girl on girl crime culture where we are constantly competing with each other, often having to do with boyfriends also didn't help) it's so important to have a close group of girl friends that will get you through to the other end and keep you on track no matter how trivial the problem you're dealing with seems in the scheme of things. My Relationship with my Mom/Other Female Role Model I have always had a strong relationship with my Mom, and this relationship has always been integral to defining myself as a feminist. Strong women breed strong women, and my mom is no exception. She is the one who taught me to have integrity even when the world is beating down on you. She is the one who taught me how to treat everybody else the way I'd want to be treated (AHEM). She is the one who taught me to be strong and ambitious in life but giving and compassionate in relationships and friendships. She also helped get me through this by constantly reminding me that I could not let other people's dumbass moves define me. "You've got so many more important things to deal with in your life than those idiots. Don't let them have such power over you," she said. And that's when I remembered, "Oh right, I'm better than this." Strong women role models – in this case, my Mommy – helped me (and can help you) remember that even when other people act in ways that are pretty low, you can still hold yourself to a higher standard and rise above them. How To Move On To Empowerment Set Yourself Aside and Focus on Other People After a few days, I woke up and stopped getting sad and started getting mad. I was mad that they made me / I let myself wallow (I'm a feminist damn it!). I was also mad that I wasn't the only person they hurt. They put one of my best friends in the middle of this crappy situation not to mention my ex-friend broke the heart of her boyfriend. I wanted to make sure that he was okay (we were in kind of parallel situations after all). Not that I could really do anything, but having people I didn't even really know reach out to me to tell me what jerks my former friend / boyfriend were (which a surprisingly large number of people did) had made me feel supported: it was the least I could do for him. However, to do this, I found myself face to face with two girls (his best friends) who I had had a falling out with in freshman year. Which leads me to Empowerment Point #2… Settle Your Karmic Score I realized that while I was hurting, I had hurt other people. Without going into it, freshman year my two best friends and I had a huge fight. Stupid freshman that I was I walked away thinking that I was the only one who had been hurt. It took nearly 3 years and some heartbreak to figure out I may have hurt them, too. I began to realize the people I had designated "good" and the people I had designated "bad" were turning out to all be in the wrong categories and set out to fix it. I reached out to them on behalf of their friend (broken-hearted boyfriend) and apologized to them for ever having hurt them in the way my friends had just hurt me. Not only have I gained two people back in my life who are truly quality individuals from this experience, but it gives me hope that maybe my ex-friend and ex-boyfriend might realize what they did and apologize to me one day. Not that I'm crossing my fingers. Now. Maybe I didn't react to this experience in the most feminist way. Maybe instead of focusing so much on this one incident I should have channeled that energy into rallying for a more important cause. Instead of curling up in the fetal position, I probably should have volunteered for Planned Parenthood or something. And maybe this advice isn't even the most feminist guide ever. But sometimes life, emotions and just being a freakin' teenager interfere with perfect feminist theory. And when that happens, this is what I have learned: be a kind human being. Treat others the way you want to be treated. When you slip up and do something bad to somebody else, own up to it and make it right. When somebody does something bad to you, try to maintain your integrity and look inwards toward your own strength and outwards towards a future where you are a stronger person for the pain. Because in the end, that's essentially what feminism is. And that is my long-winded way of describing how I, as a feminist trying to employ her feminist morals, survived heartbreak, and how I hope you will, too.

Q: Передать в контроллер значения двух переменных в качестве одного параметра Есть два @Html.DropDownListFor(), один из которых предполагает выбор даты, а второй - времени события. Подскажите, пожалуйста, возможно ли с помощью razor-а передать два значения в качестве одной строки в контроллер из представления? Т.е. получить в результате в контроллере одну переменную формата, например, "MM/dd/yyyy/HH/mm/ss", при том что из отдельных DropDownListFor() берутся дата: "MM/dd/yyyy" и время: "HH/mm/ss". Возможно ли собрать эти строки вместе и передать в метод контроллера как одну строку? A: Вам нужна кастомная привязка модели. Механизм привязки модели в asp.net достаточно умён для простых и для большинства сложных моделей, но в подобных случаях он бессилен. Тут на помощь приходит возможность создания собственных привязчиков модели. Для этого вам потребуется создать класс, реализующий интерфейс IModelBinder. Проще это сделать, унаследовавшись от класса DefaultModelBinder. Примерно так: public class DateTimeModelBinder : DefaultModelBinder { public override object BindModel(ControllerContext controllerContext, ModelBindingContext bindingContext) { var request = controllerContext.HttpContext.Request; var date = DateTime.Parse(request.Form.Get("date")); var time = TimeSpan.Parse(request.Form.Get("time")); date = DateTime.Today.Add(time); return date; } } а затем применить указать этот класс в качестве привязчика модели для вашего параметра. Вряд ли вы хотите делать приваязку модели таким образом везде в вашем проекте, поэтому стоит делать это с помощью атрибута для параметра вашего метода. Примерно так: ActionResult MyAction([ModelBinder(typeof(DateTimeModelBinder))] DateTime arg)