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Dave Grayson David Lee Grayson (June 6, 1939 – July 29, 2017) was an American football defensive back in the American Football League (AFL) and the National Football League (NFL) for the Kansas City Chiefs and Oakland Raiders. He played college football at the University of Oregon. Early years Grayson attended San Diego High School, playing running back and defensive back. As a sophomore, he helped his team achieve an 11-0-1 record, while outscoring opponents 382-65 and being awarded the mythical National championship by the National Sports News Service. After the season he transferred to Lincoln High School. After graduating from high school he went on to play at San Diego City College. Besides football, in track he was a part of the 4 × 200 metres relay team that set a national junior college record. As a junior, he transferred to the University of Oregon, where he played offensive and defensive halfback. In 1982, he was inducted into the Oregon Sports Hall of Fame. In 2010, he was inducted into the Breitbard Hall of Fame. Professional career In 1961, he was signed as an undrafted free agent by the Dallas Cowboys, but because head coach Tom Landry felt he lacked size for the physical play that was needed in NFL at the time, Chief talent scout Gil Brandt called the AFL's Dallas Texans head coach Hank Stram and suggested he give Grayson a look. Grayson made the team and played four years with the Dallas Texans/Kansas City Chiefs. In 1961, he set the franchise and AFL record for the longest interception return with a 99-yarder against the New York Titans. In 1961, he also led the league in kickoff returns. In 1962 and 1963, he finished second in the league in kickoff returns. In 1965, he was traded to the Oakland Raiders in exchange for cornerback Fred Williamson. Grayson held the AFL record for longest interception return for a touchdown, 99 yards, against the New York Titans in 1961. He had an interception off George Blanda in the Texans' 1962 double-overtime championship game victory over the defending AFL champion Houston Oilers. Grayson was an AFL All-Star six times, with the Texans/Chiefs in 1962, 1963 and 1964, and with the Raiders in 1965, 1966 and 1969. In 1967, he was moved from right cornerback to safety. He made a 48-yard return with the opening kickoff against the Oilers in the 1967 AFL Championship Game, helping his team win the game and reach Super Bowl II. In 1968, he led the AFL with 10 interceptions. His 29 interceptions rank seventh all-time in Raiders history. Grayson is the all-time AFL leader in interceptions with 47, for a 20-yard return average and 5 touchdowns, and he averaged 25.4 yards on 110 kickoff returns. He is a member of the AFL All-Time Team. In 2017, the Professional Football Researchers Association named Grayson to the PFRA Hall of Very Good Class of 2017. Personal After football he opened different businesses, which included one of the biggest nightclubs in Southeast San Diego during the seventies. He also was involved with organizations like the Boys Club, YMCA and the Committee for Community Involvement of Black Athletes. Grayson died on July 29, 2017. His son, David Lee Grayson, Jr. played linebacker in the NFL from 1987–1990 with the Cleveland Browns and in 1991 with the San Diego Chargers. References Category:1939 births Category:2017 deaths Category:Sportspeople from San Diego Category:Players of American football from California Category:African-American players of American football Category:American football cornerbacks Category:San Diego City Knights football players Category:Oregon Ducks football players Category:Dallas Texans (AFL) players Category:Kansas City Chiefs players Category:Oakland Raiders players Category:American Football League All-Star players Category:American Football League All-Time Team Category:American Football League champions Category:American Football League players
The four accused were arrested last week after the incident sparked outrage across the country. Highlights The four men had been taken to the scene of the crime at 3 am They were at the spot where the charred body of the woman was found Police said one of the men signaled to the others, possibly to escape In a stunning twist to a crime that horrified the nation, all four men accused in the gang-rape and murder of a young veterinarian in Telangana were shot dead in the early hours of Friday by the police, who claim they had snatched their weapons and fired at them during investigations at the spot where the woman's body was found. The men, Mohammed Arif (26), Jollu Shiva (20), Jollu Naveen (20) and Chintakunta Chennakeshavulu (20), had been taken at 5.45 am for a reconstruction at the spot where the charred body of the woman was found, around 50 km from Hyderabad. They were not handcuffed, says the police. The police claim the accused started attacking them with sticks, stones and sharp objects and snatched their weapons, which were already unlocked. "All four accused got together and started attacking the police party. Officers maintained restraint and asked them to surrender but without listening to us they kept firing. Our officers retaliated," VC Sajjanar, Cyberabad police chief, told reporters. Moments later, four bodies lay scattered on the ground. Two of them held guns - Mohammed Arif and Chennakeshavulu. Two policemen in the 10-member team suffered head injuries (not bullet wounds), said Mr Sajjanar. "The law has done its duty. That's all I can say," the officer said, responding to skepticism. The four, he said, had confessed and were hardcore criminals. Also, "scientific evidence" proved their role, said the police chief. The bodies were moved after six hours. A huge crowd gathered on a bridge overlooking the spot and cheered the police. Many showered rose petals. The Telangana High Court has asked for the post-mortem videos to be submitted and for the bodies of the rape accused to be preserved till Monday, 8 pm. The National Human Rights Commission (NHRC) will send a team to investigate the shooting. The four, arrested a day after the crime, had been in custody of the police since Wednesday. On November 27, the men, all truck-drivers and cleaners, saw the 27-year-old woman park her scooter near a toll-booth on a busy highway. They allegedly deflated her scooter tyre and took her to a truck yard with the promise of fixing her scooter, gang-raped her, strangled her and burnt her body to destroy evidence. The woman's father told news agency ANI: "It has been 10 days to the day my daughter died. I express my gratitude towards the police and the government for this. My daughter's soul must be at peace now." The controversial shooting has divided opinion on an incident has been passionately debated for days and drew people out to the streets in anger. Several celebrities and even politicians praised the police though there were many voices of caution. "All women in this country will have a sense of relief after this encounter. They did the crime and later tried to flee from police custody. The police had no option. My question to people who are questioning the encounter is what would be their reaction if the accused had fled," said BJP MP Meenakshi Lekhi in parliament. Social media was flooded with vastly contrasting reactions. "The most important thing is the justice should be done through judicial process. In this particular incident we don't know the full details. If the cops were harmed or they were trying to take a gun from the police then police may have been justified," said Congress MP Shashi Tharoor. In parliament, several MPs had called for quick trial and hanging of the accused. In some emotional statements, MPs even backed lynching of the men for the crime.
Superb meat carp rig. The hook is ready banded for use. It has a 4x18 Hi-Viz carp meat float with a size 10 hook tied to a hooklength of 0.18 and main of 0.20 and finished with a hair system meat screw. Quality components are used throughout and instructions for use are included on the reverse.
Thoracoscopy in the management of anterior mediastinal masses. Thoracoscopy has been found useful for both the diagnosis and treatment of anterior mediastinal disorders. We have reserved it for use during thymectomy in the management of new-onset myasthenia gravis and for the resection of benign thymic, pericardial, and bronchogenic cysts. The application of thoracoscopic techniques in the anterior mediastinum should be approached conservatively. At this time, we believe it should be limited to diagnostic procedures requiring adequate biopsy and to therapeutic resections in which the extent of the resection is assured and therapeutic efficacy is maintained. We await further advances in both the instrumentation and technique before we are willing to undertake the performance of more radical resections using thoracoscopy. The efficacy of thoracoscopic thymectomy in the setting of myasthenia gravis awaits confirmation by larger clinical trials with adequate follow-up.
Transcript of "Government 2.0 - #socadl" 3. Name this network… Allowed near-instantaneous transmission of news and information around the world Connected people globally, allowing them to maintain distant social relationships as never before People met, fell in love and got married using it It was used to catch murderers and command armies Conmen used it to solicit money and run scams It destroyed many industries, and created new ones 5. Use by governmentFirst used to catch a murderer in the UK, 1837: A MURDER HAS GUST BEEN COMMITTED AT SALT HILL AND THE SUSPECTED MURDERER WAS SEEN TO TAKE A FIRST CLASS TICKET TO LONDON BY THE TRAIN WHICH LEFT SLOUGH AT 742 PM HE IS IN THE GARB OF A KWAKER WITH A GREAT COAT ON WHICH REACHES NEARLY DOWN TO HIS FEET HE IS IN THE LAST COMPARTMENT OF THE SECOND CLASS COMPARTMENT 6. Use by government Brigham Young, governor of Utah, sent the following in 1861 as the first message on the newly established North American transcontinental telegraph system (in relation to the American Civil War): "Utah has not seceded but is firm for the Constitution and the laws of our once happy country.” 9. Government 2.0(in my humble opinion)represents a fundamental shiftin the relationship betweencitizens and governments,to the benefit of both. 10. Government 2.0 includes...Using tools and techniques enabled by digital technologies to bring citizens inside the tent.Empowering citizens to be active participants in government decision-making processes and supporting them to do for themselves.Opening up public data for public reuse to inform and enable new insights, better decisions and more effective policy.Initiatives from individuals and non-government organisations as well as government. 24. Gov 2.0 & social media caveats • Doesnt replace existing approaches... it can supplement and amplify them • Doesnt work for all audiences or issues... but does work for some that are otherwise unreachable/intractible • Gov 2.0 doesnt solve problems... people do 25. Managing risks We’ve considered every potential risk except the risks of avoiding all risks.” 26. 100% correct informationdelivered too late or in thewrong context is worthless(and causes more issues!)
[The HELLP syndrome. 13 cases]. The Hellp syndrome is a complication of raised blood pressure in pregnancy, haemolysis, a rise in liver enzymes and thrombopenia. In this retrospective study we report 12 cases of Hellp syndrome which occurred in the University Hospital Centre of Poitiers between 1982 and 1990 and we discuss causes, the progress, the prognosis and the management. Six patients were helped by prophylactic Caesarean operation. Two patients had eclamptic fits. Fortunately there was no maternal death. There were seven cases of intrauterine growth retardation, two of in utero fetal death and one of early neonatal death. When clinical and biological parameters of the Hellp syndrome come right following delivery, the outlook for the mother is quickly favourable, but the syndrome can continue and sometimes become worse after delivery. Stopping the pregnancy is the basic treatment and conservative treatment has only a very limited success. Finally, the prognosis for the future is usually good and it is unlikely to recur.
Mooresville fire department battles early morning business fire Share this: This is an archived article and the information in the article may be outdated. Please look at the time stamp on the story to see when it was last updated. Mooresville fire department battles early morning business fire Mooresville, Ind. (August 2, 2015) – Fire crews responded to an early morning business fire in Mooresville. The call came in around 5:00 a.m. to the Engineered Assemblies of Mooresville. Crews on the scene had the fire under control by 7:00 a.m. Nobody was at the business when the fire started. There are no reports of injuries.
2012 Serbia Open – Doubles František Čermák and Filip Polášek were the defending champions, but they decided to participate instead at the 2012 BMW Open. Jonathan Erlich and Andy Ram won the title defeating Martin Emmrich and Andreas Siljeström 4–6, 6–2, [10–6] in the final. Seeds Draw Draw References Main Draw Doubles 2012 Serbia Open - Doubles
Q: Removing tags from text with BeautifulSoup I've this code to extract a song name from NightBot's channel page: import urllib.request from bs4 import BeautifulSoup from selenium import webdriver driver = webdriver.Firefox(executable_path=r'C:\Users\gabri\AppData\Local\Programs\Python\Python38-32\geckodriver.exe') driver.get ('https://nightbot.tv/t/tonyxzero/song_requests') html = driver.page_source soup = BeautifulSoup(html, 'html.parser') list_item=soup.select("h4 > strong.ng-binding") print (list_item) name = list_item.text.strip() print (name) But when i run it, shows me something like this: [<strong class="ng-binding">Jamiroquai - Virtual Insanity (Official Video)<!-- ngIf: currentSong.track.artist --><span class="ng-binding ng-scope" ng-if="currentSong.track.artist" style=""> — JamiroquaiVEVO</span><!-- end ngIf: currentSong.track.artist --></strong>] And them this: AttributeError: ResultSet object has no attribute 'text'. You're probably treating a list of elements like a single element. Did you call find_all() when you meant to call find()? Theres another way to just show the text without the tags? A: import urllib.request from bs4 import BeautifulSoup from selenium import webdriver driver = webdriver.Firefox(executable_path=r'C:\Users\gabri\AppData\Local\Programs\Python\Python38-32\geckodriver.exe') driver.get ('https://nightbot.tv/t/tonyxzero/song_requests') html = driver.page_source soup = BeautifulSoup(html, 'lxml') name=soup.find('strong',{'class':'ng-binding'}).text #print (list_item) #name = list_item.text.strip() print (name)
Distribution of prostatic acid phosphatase isoenzymes in normal and cancerous states. We have studied the IEF (isoelectric focusing) profiles and the sedimentation characteristics of intracellular and secretory prostatic acid phosphatase (PAP) in normal and cancerous states. IEF studies show a similar relative distribution of tartrate inhibitable pI 4.9 (approximately 80%) and 5.6 (approximately 20%) forms of this enzyme in normal as well as cancerous prostate. The same IEF profile is obtained regardless of whether an enzymatic or RIA method is utilized for detection of PAP. Of these two isoenzymes, only the form of pI 4.9 predominates in prostatic and seminal fluids and in Stage IV serum. Sedimentation analysis shows that the purified enzyme is exceptionally stable since it retains an S020,w value of 5.7 at low concentrations (ng/ml). While only the 5.7S form is observed in normal and cancerous tissues as well as in prostatic fluid, analysis of Stage IV serum reveals an additional form at 8.7S. Control experiments suggest that the 8.7S form is not induced by non-specific association with normal serum proteins or by the inhibitor tartrate. Our results suggest that: (a) of the two major isoenzymes in tissue, only the pI 4.9 isoenzyme predominates in secretion, (b) this relationship of intracellular to secretory forms is unaltered in the transition from normal to cancerous tissue, and (c) the utility of PAP as a tumor marker is derived at least in part by the intrinsic stability of the 5.7S form. The significance of the 8.7S form is unknown at the present time, but it does not distort the clinical (RIA) measurement of PAP in serum.
require "test_helper" class Admin::StatisticsAnnouncementUnpublishingsControllerTest < ActionController::TestCase include GdsApi::TestHelpers::PublishingApi setup do @user = login_as(:gds_editor) @announcement = create(:statistics_announcement) end should_be_an_admin_controller test "GDS Editor permission required to unpublish" do login_as :departmental_editor get :new, params: { statistics_announcement_id: @announcement.id } assert_response 403 end view_test "GET :new renders a form" do get :new, params: { statistics_announcement_id: @announcement } assert_response :success assert_select "input[name='statistics_announcement[redirect_url]']" end test "POST :create with invalid params rerenders the form" do post :create, params: { statistics_announcement_id: @announcement, statistics_announcement: { redirect_url: "https://youtube.com", } } assert_template :new end test "POST :create with valid params unpublishes the announcement" do redirect_url = "https://www.test.gov.uk/example" stub_publishing_api_destroy_intent(@announcement.base_path) post :create, params: { statistics_announcement_id: @announcement, statistics_announcement: { redirect_url: redirect_url, } } @announcement.reload assert_redirected_to admin_statistics_announcements_path assert_equal redirect_url, @announcement.redirect_url assert @announcement.unpublished? end end
Q: error because of changing the package name hi i created all my apps in a single package name, when i was to upload it, i was success in uploading my first app. when i was to upload my second app i came to know that 2 app with same package name cannot be uploaded. Its not possible for me to create the second app once again with a new package name so because of my urgent i searched for a solution in net and i found that by refactor (i am using eclipse) i can change the package name and i did the same. But the name is not changed in the manifest file and i changed manually. Then i found some errors in all of my java class file showing error in the line "import.(package name).R", so i deleted all those lines. Now there is no error but the new problem is the app is running partially. The parsing activities which have been designed in my app are not running. Main part of my app is that only. Is there any solution to overcome this, as i am a new developer pls help me........ A: Probably you have your activities declared as: <activity android:name=".activities.Name"/> or <activity android:name=".Name"/> If that's the case, you must change them to: <activity android:name="old.package.where.they.are.Name"/> That's because your activities are in the same package where they have been, and the only thing you changed was the name of the application package. So now you need to refer to the activities by their full path. Your new package can be called as you want, and the only thing you have to change in code are the references to the old.package.R class (I think you already did so).
xe2x80x9cNot Applicablexe2x80x9d The present invention relates generally to milling machines, and more particularly to an automated quill drive assembly that is adapted for retrofitted use on a conventional milling machine to drive Z-axis movement of the quill in response to control from a conventional computer numerical control (xe2x80x9cCNCxe2x80x9d) controller or the like. A conventional milling machine, such as a knee mill, includes a table on which a work piece can be supported, and a quill that supports a tool for movement toward and away from the table for milling the work piece. Typically, the table is adjustable within a horizontal plane from side-to-side and from front-to-back relative to the quill. Lateral side-to-side adjustment is considered X-axis adjustment, and front-to-back adjustment is referenced as Y-axis adjustment. As such, the position of a work piece can be changed in two planes, and the quill moves vertically along a Z-axis such that three-axis adjustment of the tool relative to the work piece is possible. Although many milling machines are manual, in the sense that adjustment of the table and movement of the quill is manually achieved, improvements in the art have resulted in fully automatic machines in which X-axis, Y-axis and Z-axis movement of the table and/or quill are computer controlled and carried out by stepper or servo motors. These automatic machines provide many advantages over manual machines, especially with respect to the reproducibility of milling operations performed with such milling machines. However, automatic machines lack the versatility of manual designs, and cost significantly more to purchase and use. Automated drive assemblies are known that can be retrofitted on an existing milling machine to automate the X-axis and Y-axis movement of the table and the Z-axis movement of the quill. Typically, a CNC controller is Wed on the machine at the same time as one or more of these drive assemblies such that the drive assemblies are capable of being operated automatically subsequent to installation. A conventional Z-axis or quill drive assembly broadly includes a housing supported on the quill head of the machine, a stepper or servo motor supported on the housing and operatively connected to a conventional CNC controller, and a transmission that is supported on the housing and connected between the motor and the quill to transmit the motor drive to the quill so that when the motor is operated, the quill is moved between the retracted and extended positions. The housing is secured to the head at three points, one of which is defined by a lower casting lug of the quill head normally used to support a depth stop screw. The second and third points of attachment of the housing are defined by a pair of vertically spaced tramming bolts provided along the right front side of the quill head. In the conventional automated quill drive assembly, the position of the quill is continuously monitored by providing feedback from the motor to the CNC controller indicative of the position or operation of the motor. In addition, limit switches are sometimes employed to provide a positive signal when the quill is moved to either the fully retracted or fully extended limit position. In this way, the CNC controller is able to control operation of the motor to accurately position and reposition the quill along the Z-axis during milling operations. Although conventional automated quill drive assemblies do allow a manual milling machine to be retrofitted for automatic operation, further improvements would be advantageous. For example, because the housing of a conventional assembly is mounted to two of the tramming bolts on the quill head, the housing must be loosened in order to tram the head. Such added complexity makes tramming of the quill head difficult and time consuming. Further, although tree mounting points are provided for the housing of a conventional quill drive assembly, two of the points are in line with one another vertically, and the third point is spaced laterally from the other two by only 1 to 2 inches. As a result, the motor can twist or wind up when milling a heavy cut, reducing the accuracy of the machine, and increasing wear on the quill. Another feature of the conventional quill drive assembly subject to improvement is the source of feedback provided to the CNC controller which allows the position of the quill to be continuously monitored and controlled during automatic operation. Because the conventional assembly monitors quill movement indirectly by sensing motor movement or operation, the CNC controller can only monitor the quill position when the quill is operated by the motor, or when manual quill movement is transmitted back to the motor. As such, manual operation of the quill is either frustrated or must be performed without the benefit of feedback to the CNC controller. When manual operation is performed without such feedback, depth control and repeatability become difficult to achieve. It is an object of the present invention to provide an automated quill drive assembly for use with a milling machine, wherein the presence of the quill drive assembly does not prevent or impede tramming of the quill head and permits quick conversion between automated and manual operation of the machine. It is another object of the invention to provide an automated quill drive assembly in which the position of the quill is sensed directly, rather than indirectly through a motor, allowing the position of the quill to be continuously displayed by a CNC controller regardless of whether quill movement is achieved manually or automatically. Yet another object of the invention is to provide a quill drive assembly that can be rigidly secured to the quill head of a conventional milling machine at three laterally spaced points to fix the motor and other components of the assembly against flexing under the stress of heavy milling operations. In accordance with these and other objects evident from the following description of a preferred embodiment of the invention, an automated quill drive assembly is provided that is specially adapted to be retrofit on a milling machine of the category having a frame presenting a quill head and a quill supported on the head for rotation and for relative shiftable movement along a linear axis between retracted and extended positions. Typically, the quill head of the milling machine includes a centrally disposed lower lug, a quill feed engagement control lever boss located above and spaced to one side of the lug, and a transmission cover boss located above and spaced to a side of the lug opposite the quill feed engagement control lever boss. Further, the milling machine includes a manually actuated lever supported on the head and operatively connected to the quill for moving the quill between the retracted and extended positions. The automated quill drive assembly includes a housing adapted to be mounted to the casting lug, the quill feed engagement control lever boss, and the transmission cover opening, a motor supported on the housing, and a transmission supported on the housing and being adapted for connection between the motor and the quill for transmitting drive to the quill to move it between the retracted and extended positions. A controller, such as a CNC controller, is preferably employed with the quill drive assembly for controlling automatic movement of the quill, as well as for controlling other operations of the milling machine, e.g. X-axis and Y-axis drive assemblies of conventional construction. In accordance with another aspect of the present invention, the automated quill drive assembly includes a housing, a motor, a transmission connected between the motor and the quill for transmitting drive to the quill, and a sensor for continuously sensing the position of the quill as the quill is moved between the retracted and extended positions. The sensor provides an output signal indicative of the position of the quill for both manual and automated movement, and the signal can be supplied to a conventional controller to provide a display of the position of the quill as it is moved. By providing a quill drive assembly in accordance with the present invention, numerous advantages are realized. For example, by providing an automated quill drive assembly that is mounted to the quill head at a first point of attachment disposed in a vertical plane including the longitudinal axis of the quill, and at second and third points of attachment disposed on opposite sides of the vertical plane, the assembly is rigidly secured in place on the quill head, fixing the motor and other assembly components against flexing when a heavy cut is made or when the quill drive assembly is otherwise placed under stress. In addition, because the quill drive assembly of the present invention does not employ the existing tramming bolts as mounting points, it is not necessary to loosen the quill drive assembly or to undertake other cumbersome steps when tramming the head of the milling machine as may be required for certain operations. Another advantage achieved by the present invention resides in the use of a sensor that directly senses quill movement rather than motor movement, enabling the controller to provide an indication of quill position during both automated and manual quill movement. This allows an operator to control the depth of the quill and to repeat milling operations with extreme accuracy, even when performing such operations manually.
The Department of Basic Science concerns, Engg. Mathematics, Engg. Physics,Engg. Chemistry and Humanities, in connection with all other programs which are offered by all other departments of engineering. Laboratories for physics, chemistry, mathematics, communication and soft skills development are taking care by the department. The department provides different trainings in order to increase the linguistic proficiency through fineness and perfection in English grammar, pronunciation and vocabulary as well. Department of Basic Science and Humanities extents the hands to students to access themselves into the world of creativity and innovation. No matter, how talented the students are or what the stream they come from. Irrespective of their subjects and stream specialization, it helps them to be a person of right attitudes towards Engg. Mathematics, Engg. Physics, Engg. Chemistry, Business Economics and to Life Skills. The Department takes special care and arrange specialised classes for the subjects like mathematics, Physics, Chemistry and Englishfor the students after diagnostic test. Dr. Sandip Haldar About the Department The department was established in 1998 during the establishment of college. Five highly experienced and qualified faculties and two skilled lab technicians are working in this department. At the beginning there was only one laboratory in the department. In 2010 another new laboratory was constructed. Both the laboratories are well equipped with latest instruments and facilities. Laboratories consist of following set up like, Frank - hertz set up, Set up for measuring Planck´s constant, Instruments for measuring Hall Coefficients, Solar cell set up , set up for measuring Young’s modulus and modulus of rigidity by dynamic method and static method, set up for measuring thermal conductivity of bad conductor and good conductor, some optical instruments such as Newton’s ring experiment, Numerical aperture of optical fibre etc.
10th Anniversary Mr. Pink & Softgoods Friends, Check this out. To celebrate our 10th Anniversary, we’ve lain down the wildest, most expensive, and awesome paint job we’ve ever put on a bike. Meet the 10th Anniversary Mr. Pink. We’re only doing a limited run of these, and every single one is different and unique. Best of all they are available right now as completes or framesets. Due to the paint cost, these do run a bit more than the standard Pinks, but you get what you pay for. And what you’re paying for is one of the nicest paint jobs around. Completes are $2399 with a sweet Shimano 105 group and tubeless ready wheels Framesets are $1150 Full Details Here A bit about the Mr. Pink: Our flagship road racer was designed to carry you as quickly and efficiently as possible over any road surface. From pot-hole-filled city streets, to smooth country roads, and gravel centuries, this bike does it all with the style and smoothness that can only come from high-end steel. Geometry-wise, it’s a classic racer, but we’ve made tweaks to the equation that remove the limitations associated with your average road bike. It has clearance for 32c tires (28’s w/fenders) for mixed-terrain riding, hidden fender mounts for foul-weather days and an ED coating for rust prevention and longevity. The perennial favorite Columbus Zona tubeset is light weight and provides a stiff, yet remarkably comfortable ride. Dealers who have will have them in stock early September: The Community Bicyclist - Littlerock, AR Kissing Crows Cyclery - Vancouver, BC Lions Cylcery - Kellowna, BC Golden Saddle Cyclery - Los Angeles, CA Huckleberry Bicycles - San Francisco, CA Uptown Bicycles - San Diego, CA Pedal - Littleton, CO Bike Rack - Washington, DC City Bike Tampa - Tampa, FL World of Bikes - Iowa City, IA Syringa Cylcery - Sand Point, ID Wheel Werks - Crystal Lake, IL Cambridge Bicycle - Cambridge, MA Joe's Bike Shop - Baltimore, MD Angry Catfish - Minneapolis, MN Oak City Cycling Project - Raleigh, NC NYC Velo - New York, NY King Kog - Brooklyn, NY Hub Cyclery - Bend, OR Cycleast - Austin, TX Transit Bicycle Company - Dallas, TX Hub - San Marcos, TX Race Ready Repair - Conroe, TX West End Bicycle Company - Houston, TX Shift Cyclery & Coffee Bar - Eau Claire, WI Revolution Cycles - Madison, WI And we're also unleashing some jamming goodies for the occasion. There’s also the matching cap to complete the package. Handmade in the USA by Pace Sportswear. It’s a rad wearable keep sake from this milestone from your favorite bike company. 10th Anniversary Cap And finally there is a 10th Anniversary Shirt featuring a rad illustration by Mike Jandora that encompasses many of our riding passions, past good times and local landmarks . We’ve even made sure our mascot Baroo (the #numberonebrowndoginamerica) was represented. Available in both women’s and men’s cuts. 10th Anniversary Shirt
Use of harmful chemicals is higher in poorer nations, according to data analysed by Unearthed The world’s biggest pesticide companies make billions of dollars a year from chemicals found by independent authorities to pose high hazards to human health or the environment, according to an analysis by campaigners. The research also found a higher proportion of these highly hazardous pesticides (HHPs) in the companies’ sales in poorer nations than in rich ones. In India, 59% of sales were of HHPs in contrast to just 11% in the UK, according to the analysis. The data from Phillips McDougall, the leading agribusiness analysts, are from buyer surveys focused on the most popular products in the 43 nations that buy the most pesticides. It was obtained and analysed by Unearthed, a journalism group funded by Greenpeace UK, and the Swiss NGO Public Eye. The pesticides market is dominated by five companies – Bayer, BASF, Syngenta, FMC and Corteva (formerly Dow and DuPont). These companies sold $4.8bn of products containing HHPs in 2018, making up more than 36% of all their income, according to the analysis. Bayer said the analysis was “misleading” but declined to provide its own figures. Some companies also disputed the list of HHPs used. Phillips McDougall said that it neither approved the public use of its data nor endorsed the findings of the analysis by Unearthed. The Unearthed and Public Eye analysis calculated that almost a quarter of sales by the big five were of products containing pesticides linked to human health effects, including known or presumed carcinogens, while 10% came from pesticides toxic to bees. Another 4% of sales were of chemicals that are acutely toxic to humans, the analysis found. About 200,000 suicides each year are attributed to pesticide poisoning, almost all in developing countries. In rich countries, the average proportion of sales that were HHPs was 27% compared with 45% in low and middle income countries, reaching as high as 65% in South Africa, according to the analysis. A global survey of pesticide management in 2018 by the World Health Organization and the UN Food and Agriculture Organization (FAO) found “various critical shortcomings”, with countries needing to strengthen their rules and enforcement to “minimise their harmful effects on humans and the environment”. Baskut Tuncak, UN special rapporteur on hazardous substances and human rights, said: “It is inappropriate for companies to earn such significant income from HHPs in this day and age. The continued use of these products is unsustainable and is causing a multitude of human rights violations around the world.” A report in 2017 co-authored by Tuncak accused pesticide companies of the “systematic denial of harms”, “aggressive, unethical marketing tactics” and lobbying of governments, which has “obstructed reforms and paralysed global pesticide restrictions”. It also said the idea that pesticides were essential to feed a fast-growing global population was “a myth”. Unearthed used a list of 330 HHPs compiled by Pesticide Action Network International (PAN), based on judgments from authorities such as the US Environmental Protection Agency, European Union bodies, the Stockholm Convention on persistent organic pollutants and the WHO’s International Agency for Research on Cancer (IARC). The FAO and WHO classify some but not all of these pesticides as HHPs on their list and a spokesman for BASF said the PAN list was “inflated”. Keith Tyrell, director of PAN UK, said: “Efforts to strengthen the UN’s approach are consistently blocked by the pesticide industry.” Croplife International, the pesticide industry’s lobby group, has accepted that 15% of the chemicals its members sell are HHPs, but said many of these can be used safely in practice. “Our members support the [voluntary] FAO International Code of Conduct on Pesticide Management,” said a CropLife International spokeswoman. “We support countries to identify, and if necessary, remove HHPs from their markets.” Neither CropLife International nor the five companies responded to a request for an example of the voluntary removal of an HHP. “Pesticides identified on the PAN list are often classified based on the acute toxicity of the active ingredient rather than the formulated product, which is not consistent with practical use,” said the CropLife International spokeswoman. Tyrell said: “Pesticide companies refuse to publish information on the ingredients contained in their products so the UN and others, including PAN, are forced to look solely at the toxicity of the active ingredient.” Bayer also disputes PAN’s list. For example, PAN includes Bayer’s glyphosate on its list based on the 2015 conclusion of the IARC that it is “probably carcinogenic to humans”. But Bayer says glyphosate should not be on the list, based on the conclusions of other bodies, such as the European Chemical Agency in 2017. A spokesman for Bayer said the differing sales from nation to nation reflected the different needs of farmers: “Agriculture is very different from region to region due to different climates, pests, diseases and crops. In Brazil, for example, farmers must manage pests such as Asian Soybean Rust or insect pressure which don’t exist in Europe.” He also disputed the financial analysis by Unearthed and Public Eye: “Bayer finalised the acquisition of Monsanto on 7 June 2018. Before, Bayer had divested parts of its businesses to competitors. Their calculations are therefore misleading.” Asked to provide alternative figures, he said: “Bayer doesn’t break down its sales figures by country, product or active ingredient. These figures are confidential.” Unearthed said its analysis follows standard practice for the financial analysis of merged companies. A spokeswoman for BASF said: “BASF is convinced of the safety of its products when they are used correctly following the label instructions and stewardship guidelines. All products are extensively tested, evaluated and approved by public authorities in the respective countries. Additionally, all active ingredients in these products are approved in at least one OECD country.” Tuncak said: “Systemic issues in many low- and middle-income countries prevent any reasonable assurance of proper handling and use of pesticides.” Juman Kubba, at Greenpeace UK, said: “Keeping the world hooked on an industrial farming model based on crops drenched in toxic pesticides is in these companies’ interests. But these dangerous chemicals have no place in a healthy food system and governments must ban them worldwide.” FMC referred the Guardian to the response from CropLife International and Syngenta and Corteva did not respond to requests for comment. • This article was amended on 28 February 2020 to include a statement from Phillips McDougall that was received after publication. The credit for the graphic was also updated to include the Pesticides Action Network list of HHPs among the sources for the analysis by Unearthed/Public Eye.
As the trial began in Taunton on Tuesday, Maryclare Flynn, a prosecutor, told Judge Lawrence Moniz that Ms. Carter essentially caused Mr. Roy’s suicide, pointing repeatedly to text messages that seemed to urge Mr. Roy to take his life. “Just park your car and sit there and it will take, like, 20 minutes,” Ms. Carter wrote. “It’s not a big deal.” It did not stop with text messages, Ms. Flynn said. With the suicide plan in motion, Mr. Roy at one point got out of the car, apparently feeling fear, the prosecutor said. But in a phone call, Ms. Carter “ordered him back in and then listened for 20 minutes as he cried in pain, took his last breath, and then died,” Ms. Flynn said. Prosecutors say Ms. Carter was driven by a hunger for attention from her peers in Plainville, Mass. She got attention when she talked about her suicidal boyfriend, Ms. Flynn said, and risked that her peers would think she was lying if he did not follow through. “She used Conrad as a pawn in her sick game of life and death,” Ms. Flynn said. But Ms. Carter’s defense lawyer portrayed Mr. Roy as a depressed teenager who had attempted suicide before, planned his death and chose to end his life on his own. Joseph P. Cataldo, the lawyer, said that Mr. Roy had done hundreds of online searches relating to suicide and that Ms. Carter had, at earlier points, suggested that Mr. Roy seek help. “This is a suicide case,” Mr. Cataldo said. “It is not a homicide.” Mr. Cataldo emphasized Mr. Roy’s mental health problems and said he had faced abusive treatment from family members. He described Ms. Carter as a vulnerable teenager, too, saying she had suffered from an eating disorder, had been treated in a psychiatric hospital and was impaired by the side effects of an antidepressant. “She was dragged into this,” Mr. Cataldo said, adding, “There was no infliction of harm by Michelle Carter, who was 30 miles away.”
Here is just a simple tutorial on drawing Tom Nook from the Animal Crossing series. He is a lazy looking tired brown raccoon dog who first appears in 2001. He wears a purple or blue colored towel like wrap around the lower half of his body. The eyes or expression on his face either suggests that he is tired, or a very lazy being. Drawing Tom Nook or this Animal Crossing figure should be easy enough for all to tackle. Have fun and I hope you enjoyed your drawing day. Members Login Here DragoArt members upload artwork and drawing tutorials! They are also allowed to leave comments on tutorials, profiles, etc. Many more features, as well; it's way better than just being a boring guest! Register Now!
Q: radio button switches on 2 clicks There is a radio button for sexes and when first I choose male it works fine, but the second time i click male it jumps to female. Also this happens the other way around. Here is the HTML code: <div class="row" *ngIf="employee.listingRule.includes('is_female')" > <label class="col-12 col-md-3 pb-2 col-form-label">sex:</label> <div class="col-12 col-md-9 pb-2"> <div class="row"> <div class="col-6"> <fa-icon class="mr-2" [icon]="!employee.is_female ? icon.radioSelected : icon.radioBlank" (click)="setSex()"></fa-icon> <span (click)="setSex()"> Man </span> </div> <div class="col-6"> <fa-icon class="mr-2" [icon]="employee.is_female ? icon.radioSelected : icon.radioBlank" (click)="setSex()"></fa-icon> <span (click)="setSex()"> Women </span> </div> </div> </div> </div> And here is a snippet of the code, a function that I use setSex() { this.employee.is_female = !this.employee.is_female; } How can i fix it so that on the second click it doesn't jump to the other sex? A: better option is passing male or female in method and activate based on that (click)="setGender('male')" or (click)="setGender('female')"
Key Stroke Logger - Source Code - 16s http://74.207.233.100/16k/ ====== 16s I wrote a passive key stroke logger (back in 2007) called 16k to demonstrate how these type of key stroke loggers work. No one has ever paid it much attention, until yesterday when several anti-keylogging softwares discovered it and realized that their software did not detect it. Since that time, my hosting provider has received multiple abuse notices and take-down requests that I have had to respond to and a few DNS services have blacklisted my domain names (clear cloud dns). I can't believe this has happened. \-------------------------------- nslookup www.16s.us 74.118.212.1 Server: 74.118.212.1 Address: 74.118.212.1#53 Name: www.16s.us Address: 66.129.99.88 \-------------------------------- My source code and binaries are GPG signed, authenticode signed and MD5'ed and have not changed for more than a year. They've been available for download for many years. And now, all of a sudden, out of the blue they are labeled as malware. I had a small degree of respect for commercial security before this, but now I have none. It seems Security Theater and morons are in charge of companies claiming to make the Web safe. I was hoping HN would help me get the word out. My site <http://16s.us/16k> has no javascript, java, cookies, flash or advertisements. There is nothing malicious _at all_ about it. Edit: Formatting
Q: What is the biggest computation one should use for an induction base First of all sorry for me (informal) language here - i am not a native english speaker. I have tried to look up my question here but couldnt find anything. I also tried to look it up on google but i think its due to my lack of using the right words for it. I would appreciate any editing on my question. I was prooving that a really big number (which was about the size of $10^{4033}$) is not a prime, altough one could just simply use e.g. Wolfram Alpha to verify it by computing the remainder when it is divided by one of its factors. In my proof i used mathematical induction to show that numbers of that form have two certain factors. In my induction base i realised it would end up being something like: $$ 111 \cdot91=10101 $$ Which is true - and therefore i showed that my assumption holds for an $n \in \mathbb{N}$. Normally my induction bases would end up being statements which would be easy to see. But this time one may need a calculator to verify if the statement above is true. Now my question is: If i use mathematical induction for a proof - how "complicated" or "large" should my induction bases are? Should one be able to recognize the true statement without the use of a calculator e.g.? How do i know that the computation which has to be done is fair enough? A: The induction base proof can be as complicated as it needs to be. It is as much a part of your proof as the induction. You need to supply enough detail to convince your audience. If that takes pages (or hundreds of pages) so be it.
What Is Street Name? A security is held in "street name" when a brokerage holds it on behalf of a client. The name that appears on the stock or bond certificate is that of the broker, but the person who paid for the securities retains ownership rights. KEY TAKEAWAYS A security is held in "street name" when a brokerage holds it on behalf of a client. The name that appears on the stock or bond certificate is that of the broker, but the person who paid for the securities retains ownership rights. Having securities held electronically in street name facilitates speedy trading and reduces trading costs. Securities held in street name are covered by up to $500,000 in SIPC insurance at almost all U.S. broker-dealers. While securities held in street name are safe for retail investors, direct registration may be a better choice for larger investors. How Street Name Works When you buy or sell securities with a broker, your name is rarely actually on the stock or bond certificate. Instead, it is held in street name. If an investor purchases 100 shares of General Motors (GM) stock from Morgan Stanley (MS), the broker will hold these stocks in street name. Morgan Stanley does not buy these shares from the market but instead allocates them to the investor from its preexisting inventory to make the trade quick and straightforward. The investor still owns the shares when they are held in street name. As part of the process, Morgan Stanley will assign all ownership rights to the investor by registering him or her as the beneficial owner. The broker will also send updates on how the investment is performing every month or quarter. Registering shares in street name is not compulsory. An investor could request to register the GM shares in his or her own name. However, holding paper certificates is generally not advisable. It does not change the beneficial owner's rights and makes trades more complicated and expensive. Brokerages will charge additional fees for the associated costs and inconvenience. Advantages of Street Name Convenience Imagine the amount of work that would occur if your broker held stocks in your name. Every time you needed to sell them, the broker would have to find the exact stocks you own and deliver them to the buying party. They would then have to send the shares back to the company to have the name on the certificates changed to the new owner's name. This process would take a great deal of time and effort, not to mention the fact that you wouldn't collect payment until the purchasing party physically received the stocks. By holding the securities in street name, the broker can avoid most delays associated with the transfer of ownership and quickly execute trades at a minimal cost. The cost savings of registering securities in street name can provide a material boost to investment returns. Safety If brokers were to hold the physical security certificates, there would be an increased risk of physical damage, loss, and theft. By keeping them in street name, brokerages are able to retain the securities electronically. That reduces the probability of disastrous events occurring. This safety is also extended to payments. By holding the securities in street name, the broker is ensuring that they will be delivered promptly when a transaction occurs. This system removes any uncertainty that would exist if the customer were responsible for providing the security every time a trade took place. Finally, almost all broker-dealers in the United States are members of the Securities Investor Protection Corporation (SIPC). According to the SEC, investors holding securities in street name are covered by up to $500,000 of SIPC insurance. However, it is essential to remember that this insurance does not protect investors from price declines. Disadvantages of Street Name Holding securities in street name also comes with some drawbacks. Since your name is not on the record, you will not be apprised of important details from the company. This information may include reports or any other corporate communications the company sends out. Investors must rely on a brokerage or advisor to pass on information about their holdings. Holding a physical certificate also gives investors the power to use them as collateral for a loan or most other types of credit. Securities held in street name can typically only be used as collateral in a margin account. While securities held in street name are safe for retail investors, direct registration may be a better choice for larger investors. Stocks held in street name may be loaned to short-sellers and resold to others. So, it is possible for more than one person to own shares held in street name. If the brokerage should fail, it may not be possible to recover 100% of all securities. Investors are protected by up to $500,000 in insurance from the SIPC, but that may not be enough for high-net-worth individuals and large organizations.
Christian Ponder stepped to the podium for his first press conference as a starting quarterback in the NFL. "What's up guys?" Ponder said with an easy grin. "Better get used to seeing you every week." The Minnesota Vikings can only hope their laid-back rookie keeps his cool just as effectively when Dom Capers unleashes Clay Matthews and the rest of the Green Bay defense on him on Sunday. With the Vikings off to a miserable 1-5 start, coach Leslie Frazier officially announced on Wednesday that Ponder is taking over for veteran Donovan McNabb for the remainder of the season. "It does not mean that I am giving up on the 2011 season," Frazier said. "The decision was made purely based on what would give us the best chance to win on Sunday. That's why the decision was made. I didn't feel or sense that staying status quo was going to get us a win on Sunday." Ponder joins Carolina's Cam Newton, Cincinnati's Andy Dalton and Jacksonville's Blaine Gabbert as rookie starting quarterbacks in the league. The decision hardly came as a surprise. McNabb has struggled mightily for most of the season in this new offense and has never looked in rhythm while throwing from the pocket. The Vikings passing offence ranks 31st in the league and McNabb ranks 29th in the league in touchdowns, 26th in yards passing and 19th in completion percentage. Frazier declined to give him a vote of confidence after a 39-10 loss in Chicago on Sunday night. It's the second straight season that McNabb has been benched because of his performance, but his close relationship with Frazier seems to have made this one much smoother than how things went down last year in Washington under head coach Mike Shanahan and offensive coordinator Kyle Shanahan. McNabb's agent, Fletcher Smith, openly challenged how the two coaches handled the situation, calling it disrespectful and "unprecedented for a six-time Pro Bowl quarterback such as Donovan." Still, McNabb said he was surprised by Frazier's decision and felt like he had "a lot of football left in me." "He is the head coach and decisions are made," McNabb said. "At this particular point, it's for me to continue to prepare and make sure that we continue to support Christian and make sure that he's ready. But most important for me, is to prepare because I'm just one play from going back in. Just make sure I'm ready when called upon and try to lead us to victory." Ponder completed 9 of 17 passes for 99 yards in the fourth quarter against the Bears on Sunday night, his first NFL game action in the regular season. He also rushed for eight yards and a first down to keep his first drive going, showcasing some of the athleticism that was apparent during his time under center in the pre-season. "When he got a chance to play in the game on Sunday, some of the things he did let me know that the game is not too big for him," Frazier said. "It's not too fast for him. He did some good things in a short period of time." Newton's quick command of the offense and playmaking ability has been one of the most pleasant surprises of the season, Dalton has been a steady contributor and key to the Bengals' fast start while Gabbert has struggled in the early going with the Jaguars. Now Ponder will get the chance to show how he measures up to the rest of a promising rookie class. First-round pick The Vikings selected him 12th overall in April, saying at the time that the Florida State star was the most NFL-ready quarterback in the draft. All signs were pointing to Ponder taking over from the very beginning, but the summer-long lockout prevented him from getting the practice time needed to learn the offense and get on the same page with his new teammates. So Frazier turned to McNabb, a player he got to know very well as an assistant with Philadelphia. The trust the two had in each other was one of the biggest factors in completing a trade with Washington to bring the 13-year veteran to Minnesota, with Frazier saying at the time that he thought McNabb was the best option available to help the Vikings contend in 2011. "I can't say that on July 31 I thought we'd be at 1-5," Frazier said, thinking back to the day the Vikings acquired McNabb. "There's no way I could've predicted that. I thought we'd be further along than we are. I have a ton of respect for Donovan both personally and professionally as well. But the decision was based on what's going to be best for our team and what's going to give us the best chance to win." Frazier said he didn't regret his decision to bring McNabb in and was careful to point out that everyone — not just the quarterback — is to blame for the team's struggles. The offensive line has played poorly, offensive coordinator Bill Musgrave hasn't found a play-calling rhythm yet and the receivers lack a downfield threat to stretch the defence. "This move is not just about the quarterback position," Frazier said. "Our entire team has to play better in order for us to win on Sunday." Teammates took the news in stride, throwing their support behind the rookie and hoping the change will give them the jolt they need. "You get to this point in the season and you're kind of looking for a spark or something to get you going, and obviously coach Frazier and the coaching staff felt like this was something that needed to be done to get us going," left tackle Charlie Johnson said. "So we're behind it, we're on board." Now it's up to Ponder to make the transition from rookie backup to the one everyone in the huddle will be looking to. "I don't think it's hard to do," Ponder said. "I think at the quarterback position, that leadership position comes natural. I don't really think anything of it. I'm just going to go out there and be the same person I've been for the last five years since college. I don't think it's going to be a tough transition."
Q: Is this change in the order of integration correct? Assume we have an integral as follows $$I= \int \int f_X(x) g(x,y) \ dy \ dx$$ Can I do the following $$I= \int f_X(x) \int g(x,y) \ dy \ dx = \int f_X(x) u(x) \ dx$$ where $$\int g(x,y) \ dy= u(x)$$ Thanks in advance. A: It's true so long as the Fubini-Tonelli theorem applies.
Injured in a car crash with her fiancé Horatio, Hannah wakes up alone and finds herself trapped in Dr. Frankenstein’s castle. Horatio’s missing. Help Hannah as she interacts with the castle’s suspicious inhabitants, discovers clues about the doctor’s master plan, and completes puzzles to find an Escape from Frankenstein’s Castle. Dive into this Hidden Object Puzzle Adventure game and save Hannah and Horatio!
Q: MLPClassifier threshold factor to eliminate test samples that are not in match with train data I am using MLPClassifer example from scikit-learn The code for training: from sklearn.neural_network import MLPClassifier X = [[0., 0.], [1., 1.]] y = [0, 1] clf = MLPClassifier(solver='lbfgs', alpha=1e-5, hidden_layer_sizes=(5, 2), random_state=1) clf.fit(X, y) At the predict step, we use test data [2., 2.], [-1., -2.] in clf.predict([[2., 2.], [-1., -2.]]). The output of this function is array([1, 0]) As we observe, the test data [2.,2.] is not in the train dataset we passed. Still, we got the closest match as label 1. What i am trying to find is if the test data i supplied is not in the train dataset, i should print a message to user that data is not valid instead of telling him the wrong label as 1. For instance, in knn classification, i have kneighbours function which tells the distance of my closest neighbours to the test data i supplied in a 0 to 1 scale. So, i could easily eliminate the test data samples which are highly distant from my train data samples by keeping threshold at 0.6 or 0.7. Is there any criteria/threshold like this i could do with MLPClassifier or with any one of Incremental Classifiers mentioned here which can restrict my test samples if not present in train dataset ? Question migrated from SO A: SGDClassifier has desicion_function which tells the distance to the hyperplane, where the values are compared to. This value could imply too big and too low values.
Appropriate technology for neurosurgery. Though more than 50 years have elapsed since neurosurgery has come to the developing countries, vast areas of the population do not have neurosurgical facilities available to them. This is due not only to the economic status of the country but also as a result of the training that the neurosurgical trainee receives. It is proposed in this article that while the young neurosurgeon must, without doubt, be very well trained in the latest technology, at the same time he must be taught to work with confidence with whatever facilities are available without any feeling of inferiority. The locally available appropriate technology should be fully utilized. The neurosurgeon at the periphery must be provided with the minimum essential neurosurgical equipment and also with good compensation. The concerned governments, the public, neurosurgical teachers, and neurosurgical societies and journals have a great role to play in this difficult task.
"Scarborough?" "On the left." "There should be something up here." "This looks all right." "There's a seat there." "Okay?" "Yes." " You'll write or phone, won't you?" " Yeah." "It's only for a week, Tom." "Bye-bye, darling." "Look ater yourself." " And give my love to your grandmother." " I will, I will." "You go now, go on, go on, Tom!" " Bye-bye, darling." " Bye." "If there ever is a next time make it now" "while there's time to make you love me show me how" "I can offer you the autumn of my life." "Please will you share it and I can dress you in a veil that's made of dreams" "will you wear it you've been dancing 'round my mind" "like a bright carousel though the carousel would stop" "I feel I knew you well some days when I look at you" "I'm so sure" "I can see that the misty look of love" "on your face is just for me." "If I'm wrong it's nice pretending it may soon be my next time." "I can offer you the autumn of my life" "will you share it" "I can dress you in a veil that's made of dreams" "but will you wear it." "If I'm wrong it's nice pretending" "it may soon be my next time" "Come in, miss Smith." "Don't weaken, miss Smith." "Please." "The bedroom." "Or perhaps you would prefer the bathroom first?" " The bathroom?" " Yes, yes." "The bathroom is just along here." "Miss Smith?" "Please make yourself look as though..." "You want to be fertilized." "What a charming silence you make, miss Smith." "What you need is a drink." "No pity." "With pity, a man is undermined." "Never again." "Never again." "Oh, god. what am I doing here?" "Come along, miss Smith." "Blow your lonely nose and come out of there." "If things had been the other way around... and Tom had known about you, he'd never had done such a horrible thing." "Horrible?" "Secrets, guilty..." "Yes." "But Tom would imprison you in his little house and kill you slowly... of fatty boredom." "The lock doesn't work." "Come on, miss Smith." "Make an effort." "Breathe calmly." "Relax." "you'd think you were going to be asked to strip before tea." "I am not." "I certainly am not." "If that's what you think, I absolutely am not." "Well, give me your coat then as a token." " Well, I'm doing my best." " Of course you are." "There." "you have that." "Shall we?" "The living room is just here... where one lives." "Excuse me." "Sit here, miss Smith." "Calves of leg, swelling thigh, white breasts," "mouth of desire." "That's right." "that's the way I've seen you for nearly two years... with my door open just a crack, sitting at your desk," "with your knees always neatly together." "I have a headache." "You have a headache?" "Haven't you an aspirin or something?" "You'd like an aspirin?" "Mmmm." "He's mad!" "Aspirin." "Who would've suspected him?" "I mean, nobody hardly noticed him." "I never did." "Aspirin." "In the tea." "Where?" "I don't want them in the tea." "They fell in." "Uh, try it." "I'll take that." "Tea." "Why me?" "Why did you pick on me?" "Because you were there to see." "To look at, but never to touch." "Why don't you drink your tea?" "Were those old aspirins?" "Yes." "Uh, yes." "They may taste funny, Mmm." "Why do you keep staring at me?" "Because now I can stare at you." " I can even touch you." " Only because you're forcing me." "Miss Smith, our agreement..." " says that you are supposed to look happy and willing." " Happy?" "I'm supposed to be getting married in three weeks' time." "Suenly I'm here, forced to do this." "Why don't you take your shoes off and feel comfortable?" "And I hate filthy talk!" "You said that you'd treat me with respect." "There's nothing filthy about shoes." "And I do have full use, miss Smith." "Only in..." "Only, you know, in... in..." "full use." "Any man suffering massive sexual frustration... would be out of his mind if, getting the girl of his dreams, he didn't put her to full use." "Now, be reasonable." "If Tom knew you were saying these things to me..." " Tom is a nothing." " He is not!" "Practice forgetting Tom, miss Smith, and try looking at me as if you were seeinghim." "I love Tom, mr." "Hoffman." "Love is merely a substitute for liking people." "It doesn't make me want you less." "Well, this isn't gonna work anyway." "Where's my handbag?" "I smell your hair in my bathroom." "I smell your... female skin smell in my bathroom." "Can't buy that in a bottle." "Sex, miss Smith, is wasted on the young." "I'm used to being in a bathroom by myself." "Given time, people catch love and sex... the way they catch the measles." "Not me, thank you." "Anyway, I don't know what you're talking about." "I think you do." "I think you do." "If a woman's biological urges can make her wear her skirt up to her crotch," " what can they not do?" " I beg your pardon?" "Idiot girls standing around at bus stops, freezing thighs, blaer trouble spreading wildly." "Are you in good health, miss Smith?" "You don't seem to like women, do you?" "Um, why don't you wash your face?" "Do you mind leaving me alone, please?" "Certainly." "What you are doing to me is atrocious!" "The filthiest thing I've ever heard of." "Yes, I am filthy, yes." "but there's no escaping one's fate, miss Smith." "And I am your fate." "Oh, please, God, let me get away." "Pplease." "Please." "Mr. Hoffman, the water's all overflowing!" "I don't know what I did." "Look." "The water's overflowing." "Well, there's some more towels in the kitchen." "Yes, get some towels from the kitchen." "Miss Smith, where are you?" "Miss Smith?" "Miss Smith!" "Miss Smith." "Have you thought what'll happen to you if you go through that door?" "Yes." "Right." "Well, let's start from the beginning again, shall we?" "Please." "Is... is this the only..." " only bed in use?" " Yes." " What did you expect?" " I don't know." " How did you imagine it?" " I don't know." "Miss Smith, you are here... to be two arms, two legs, a face... and what fits in the mile." "Do you understand?" " I see." " No, you don't." "No, I don't!" "And I'm used to unpacking by myself." "Yes." "These drawers are ready, waiting for you." "Did you phone Mitchell?" "He saw me to the station." "Saw you to the station?" "Well, he knows about my granny up in Scarborough." " You told me you had no parents." " I haven't." "I have my grandmother up in Scarborough." "Well, Tom's never seen her, but he knows she practically reared me... and that she falls down." "Falls down?" "I told him that she'd fallen down the stairs again, and that I had to go up and look after her for a while." " Did he believe you?" " Certainly!" "I don't tell lies." "Only the truly innocent can lie with conviction, miss Smith." "And, um, the girls who share your flat?" " So, in fact, nobody knows you're here?" " No." "Nobody." "What's the matter?" "Nobody." "What are you doing?" "Uh, testing." "Testing what?" "Testing reality." " Me?" " Yes." "I've never, ever touched you before this moment." "All these things have been in my head." "Your legs, your mouth." "I want to eat you." "I want to consume you." "I want to lick your knees." "What do you think of a man who feels like that about you?" "A man does feel that way about me." "Oh, no, he doesn't." "He couldn't." "Please, let me go home." "Please." " I can't." " But you could if you wanted to." "No." "It's much too late for that now." "Much too late." "I don't know what to say to you, mr." "Hoffman." "I mean, you're nothing like you are at work." "Even your voice is different." "Um, yes." "Yes, I have changed." "For the first time in my life, the prisoner within me has escaped." "If only you'd understand my position." "Understand you here, now?" "Oh, no." "All over the world, the simple pleasures of the flesh... are being ruined by women screaming to be understood." "I know what is it now." "You're trying to get your own back on me for that time about a year ago... when you wrote me the note." " Did I write you a note?" " Yes." "Asking me to go out with you." "Said you'd been given tickets to a play or something." "Look, I know I shouldn't have ignored it, but... you did rather more than ignore it, miss Smith." "You told all the other girls about it." " No, I didn't." " Yes, you did." "All those girls giggling in the lift behind my back." "It's not that youth is cruel." "It's not that youth is mindless." "It's just simply... that youth is wasted on the young." "They have no idea how to use it." "I couldn't go out with you because of Tom." "You didn't have Tom then." " Didn't I?" " No." "You were afraid to go out with me because of my maniac face." " No." "No." " Yes." "Yes." "Girls all over the world are afraid of men..." " with my expression." " What expression?" "Plain, sad-faced men." "You look at us, all of you, and you're right." "Every miss Smith, everywhere." "Swarms of mature, sexually starved men," "with their thoughts... full of breasts and bottom s and thighs... in offices, buses and trains." "Men who've missed the boat, but who still need love." "Well, miss Smith, their day is coming." "Their revolution is almost upon you." "Just you wait." "Just you wait." "Hope never dies in a man... with a good, dirty mind." "Mmm." "Miss Smith?" "What?" "Uh, shall you comb your hair?" " What?" " And put on some lipstick." " Now?" " Yes." "And then we'll go out to a restaurant and eat something." "Go out?" "You mean, go somewhere and not stay here?" "Yes, a restaurant." "Food, wine, music, waiters." "Get your handbag." "Oh, but mr." "Hoffman, I can't go anywhere looking like this." "I look terrible." "Hurry, miss Smith!" "Hurry!" "Life is awaiting us." "Eat or be eaten." "Now, let's have a look at what we've got here." "Uh, avocado with seafood dressing?" " A little pasta, perhaps?" " No, thank you." "Uh, prosciutto con melone?" "Maybe you'd prefer some boiled cat." " It's off anyway, isn't it?" " Yeah." "Yes, it's off." "Hmm." "I know." "What a good idea." "Snails." "Snails, yes." "Six each." "And a bottle of valpolicella." " E per dopo, signore?" " Per dopo?" " The osso buco is very good here." " What's that?" "Knuckle of veal on rice." "I can't eat veal." "I... it gives me a funny feeling." "Then perhaps you'd like to have something that doesn't need to be slaughtered?" " Yeah." " Lamb." "Si, signore." "Grazie." "Grazie." "Grazie." "That's a charming schoolgirl frown you have there, miss Smith." "Many a man would drag you into the woods just to experience it." "Am I supposed to say something?" "Have you, by any chance, any snapshots of yourself... as a child playing on the sand at Scarborough?" "No, I don't suppose you have." "No, I don't suppose I have." "It's a pity. there are two people in all of us... the child in the snapshot, and the monster the child grows into." "Ah, the snails." "Good." "Where breaths may co-mingle, two should always eat the same food." "Thank you." "This implement is for holding the snail shell." " Voila." " Have they got garlic?" "Well, I sincerely hope they have, yes." "Tom's mother says that only french railway workers eat garlic." "You're very witty, miss Smith." "Really?" "Witty and informative." "You tell me volumes about Tom's mother in one simple sentence." " Aren't you gonna eat them?" " I don't like them." "How do you know you don't like them if you haven't tried them?" "Go on, try one, miss Smith." "Free yourself." "Be venturesome." "It's a new eating experience." "I remember the day my father introduced me to snails." ""Hello, snails," I said." ""How are you?"" ""Tres bien, merci," they said." ""We who are about to be eaten salute you. "" "I said, "they're worms, father. "" "He said, "no, they're not." "they're snails. "" "And did I but open my mind to experience, and also to snails." "Did you know that stone age men ate snails at fertility feasts?" "This butter disgusts me." "And that it's rather rude to talk with your mouth full?" " Anything wrong, madam?" "No, no." "It's fine, thank you." "I should like to propose a toast." "To your snails, miss Smith, to your knees, miss Smith, and to you, miss Smith." "Cheers." "Cheers!" "Snails, snails." "Osso buco and his rhythm section." "Well, miss Smith, what do you like before going to bed?" "Cocoa?" "acupuncture?" "Hmm?" "What's the matter?" "Are you not feeling well?" "The waiter kept filling up my cup with black coffee." "Ah, well, you should go to bed." "I'm not tired." " Oh, yes, you are tired." " No." "Oh, yes, I am." "I am tired." "Yes, you are tired." "Now, then, unfortunately," "I don't have a dressing room." "So I'll get my toothbrush, and you can have first call on the bathroom." "How would that suit you?" "That be all right?" "I... shall use the servants' quarters." "You're tired, miss Smith." "I'll take five or six aspirin, and that'll make me feel numb all over." "I hope you're worth it." "That's all I can say." "Put on lots of perfume, miss Smith." "Everywhere." "I like it." "Have you everything you want, miss Smith?" "Have I what?" "I say, have you everything you want?" "I feel sick." "Heartburn." "It's all that black coffee." "Well, you should've told the waiter to stop filling your cup." "Should've told the waiter to stop filling my cup." "Once I loved a pretty girl" "I loved her as my life and I'd gladly give my heart and hand to make her my wife" "Make her my wife" "My God." "He's getting drunk." "I put my hands around her neck and relieved her of her life" "I relieved her of her life" "Yyou didn't have to take me out and give me things to make me feel sick." "I'll be in bed should you be searching for me, miss Smith." "Are you setting up house in the bathroom, miss Smith?" "Miss Smith?" "What is happening in your life, miss Smith?" "I have a headache." "You have another headache?" "I have heartburn." "You have heartburn and another headache?" "Why not malaria and prickly heat?" "Well, have you any bread soda in the house?" "No, but I do have a spare piece of rope." "Night thoughts, saturday, october the third." "Every girl is a flower garden... with a compost heap at the bottom." "And many a noble man... has had to drown his dwarf wife in a zinc bath... or strangle an idiot girl on a muy common... in order to draw attention to himself." "Reality betrays us all." "Reality betrays us all, miss Smith." "Miss Smith?" " Take a letter." " What?" "Ttake a letter, miss Smith." " Now?" " Yes, now." "To miss Janet Smith, care of this aress." "Dear miss Smith." "Go to bed." "Yours faithfully, Benjamin Hoffman." "Come, miss Smith." "Embrace your fate." "Do you know the most natural thing in the world?" "No." "To awaken one morning... and find a strange, beautiful, naked girl... asleep by your side." "My dream." "Every man's dream." "I beg to remind you, mr." "Hoffman, that you said you'd treat me with respect." "Yes, yes, of course." "Hand me the alarm clock, please." "What's that for?" "I've set it for 6:00." "I'm one of those people that wake up full of energy and passion for life... in the early morning." " 6:00 in the morning?" " Yes." "Never partake of the best things in life, miss Smith, when one is tired." "Experience teaches that." "Is there anything you need?" "A long-playing record?" "Hat pin?" "No, no." "What's that?" "Sleeping pills." "It will calm the nerves after this day of excitement." "And when I awake," "I shall find your fair, serene face... asleep beside me... on that pillow." "How will I ever look Tom in the face again?" "With guilt, apprehension, remembering the unspeakable... me." "I feel terrible." "Miss Smith?" "It's not only homosexuals who don't like women." "Hardly anybody likes them." "Now, please, miss Smith, lie down, go to sleep, to awaken and find... your fair form... beside me." "He's sleeping." "Freshening himself up." "I can't ever remember being awake at 4:00 in the morning." "I should've told Tom." "I should." "I should." "He'd have known what to do." "At night is bad enough, but at 6:00 in the morning with the little birds singing, no, I won't, ever!" "Barbara... that's better." "Oh, naked, strange, pale girl... found in my bed... one summer morning." "What?" "What?" "What?" "what, indeed, miss J. Smith." "What?" "Tell me, miss Smith, is it your habit to go to bed... wearing a costume, coat, hat and high-heeled shoes?" "I was cold." "This is something you do with Tom." " What is?" " Going to bed in a rubber mackintosh." " I do not!" " You mean you don't go to bed with Tom?" "No!" "y... what's that got to do with it?" "Are you trying to tell me that you have no pills, no experience?" "That you are, in fact, a complete novice?" "Lots of girls like me are like that." "This is utterly, utterly, utterly ridiculous." "Stay there." "Don't move." "Don't move." "Stay there." "Women cheat by instinct." "Put the kettle on." "Put the kettle on!" "Miss Smith?" "Unplug the kettle by disconnecting the plug, please." "The cups and saucers are over there." "The tea is in that... small colored tin with the chinese gentleman painted on the front." "And, uh, you'll find the cow... tethered in the refrigerator." "all these things blended together in their correct proportions... should result in a concoction known as tea." "Incidentally, miss Smith, now that we've given up escaping, we won't need... to eat our breakfast dressed for the street." "And we won't need your bag by the front door." "No." "Hmm. incidentally, have you brought... stout walking shoes with you?" "No." "Hmm." "Problem." "Anything else?" "Yes." "Yes." "How fresh it is." "How clean the air." "Only 80 tons of soot per acre falling today." "Come along, miss Smith." "Come along." "Look." "London." "And could you but hear yourself speak over the traffic's roar, you might be in the heart of the country." "Come along, miss Smith." "Come along." " It's a windmill!" " Yes, a wind machine... on a wild heath in London." "That's Richmond park over there, or we could walk to the Thames down this way." "I don't want to go to Richmond park." "Mr. Hoffman!" "Am I walking too fast for you?" "Ccome on, miss Smith." "Use your body." "It's good for you." "Come on." "Mr. Hoffman, I've skinned my heel!" "Food, food, boys!" "Hanging would be too good for you." "I should've told Tom and let him kill you!" "Mr. Hoffman!" "Come along, miss Smith." "Come along." "Mr. Hoffman!" "Mr. Hoffman!" "Look how red it is." "Look." "Hmm." "Feet are bad enough, miss Smith." "Skinned heels are going much too far." "Uh, take your stocking off." "Stockings!" "Here, clean it up." "I can't touch it." "You're not looking at it." "Give me the plaster, please." "Many a good man has been destroyed by pity, miss Smith." "You're just like my granny." "She puts ointment on plaster." "It is not my ambition to become your granny." "I don't think that plaster is big enough." "It is quite big enough." "Now then, I suggest you try... an antiseptic cream and skinned heel sandwich." "They're very good." "Why don't you drink some coffee?" "It'll waken you up." "Coffee?" "It was all that black coffee... that kept me awake last night." " What?" " You'll have to lie down, miss Smith." " I what?" " Come and have a little sleep." "Oh, no, I don't want to go to bed." "No, you don't want to go to bed." "You just want to have a little sleep." "All that fresh air has knocked you out." "Well, I don't want to go to bed." "I'll keep the army out, miss Smith." "You have a little sleep." "Wake up, miss Smith." "Wake up." ""Chicken 'cacciatore. '" "Medallions of 'buff. '"" "Ham." "Yeah." ""I'll have roasted ham..." ""with baked potatoes in their jackets." ""And then afterwards" ""uh, afterwards," "I think I'd better have some stewed prunes. "" ""Varbara Anne Hoffman. "" "Barbara Hoffman." ""To appear in high court three weeks hence, monday morning, 10:00."" ""How did she become, in so short a time," ""such a..." ""vain, demanding, treacherous woman?" ""She was old enough." ""It should have shown from the beginning." ""What blinded us?" "Or am I several people?" ""To think that many a man hanged for such a wife." "Where was my judgement?"" " How much did you read?" " Read?" "Nothing." "Nothing." "You never told me you were married." "Who escapes, miss Smith?" "You, of course, read the last entry first." ""A lifetime to be consumed in a week." ""Can I consume her utterly in a week?" ""Miss Smith has a soft, young body..." ""and a soft, young mind." ""If a man could eat a girl's soft, young body like an ice cream," ""he would not have to struggle to live... with her soft, young mind. "" "Where did you get those slippers?" "What's the matter?" "Take them off, please." "Well, I have a sore heel." "Now you have murderer's feet." "You can't win this game, miss Smith." " Game?" " You don't know the rules." "Let's have some breakfast and ease the horror a bit." "I suggest... toast, just golden, dressed with cold-pressed virgin olive oil, wheat germ and maple syrup, chinese lapsang souchong tea with lemon and honey." "Can you scramble eggs?" "Yes." "Your accomplishments never cease to amaze me, miss Smith." "Oh, mother." "Was it for long?" "Your marriage, I mean." "No, fortunately." "Was it recently?" "Yes, very recently." "Most men have their disasters early." "I, being careful, came to mine somewhat later." "She... she's not likely to come back now or anything, is she?" "Highly unlikely." "Madam." "Good afternoon." "Thank you very much, sir." "Thanks very much." "Let's go home, miss Smith." "How very pretty you look, miss Smith, in the fading light." "I could do with a little help in the kitchen." "My mother always told me to keep out of the kitchen, that I might get boiled in mistake for a potato." " These forks smell." " Why don't you wash them?" "That woman you have, she doesn't clean them properly." "Once I knew a pretty girl oh, I loved her as my life..." "Why have you stopped?" "An amateur performance, miss Smith." "An amateur performance." "I've heard that before." "I heard it somewhere, but I can't remember what the words are." "The words?" "Once I knew a pretty girl." "I loved her as my wife." "But I put my hands about her neck... and relieved her of her life." "Why don't you want me to like you?" "Why don't you stop staring me in the face with your doomed youth?" "I didn't invent life or death, miss Smith." "And why don't you ever call me Janet?" "And have you become a human being?" "I haven't got time for all that mess." "Do you mind if I start?" "I'm hungry." "Mmmm." "Hungry, yes." "Women are always hungry for something." "Fallopian tubes with teeth." "Have some wine, miss Smith." "Are you satisfied with your day of domesticity, mr." "Hoffman?" "Yes, yes." "I saw your strong, handsome legs... standing at my sink, and I was satisfied." "Yes, yes." "My head's in a fog." "Then drive carefully, miss Smith." "Have you anything in the house for... for this?" "For what?" "For not going, you know..." "Well, it happens to me when I'm in strange places." "I looked in the bathroom cabinet, and there was only one senna pod there." "Miss Smith, you are here... so that you may give me... a tremendous sensual and erotic experience." "Well, how do you think I feel having to say this?" "And how do you think I feel having to give you colonic irrigation?" "Open your mouth, please." "Liquid paraffin?" "oh, no, I don't think I could." "It's too oily." "It is not oily, miss Smith." "open your mouth, please." "Open your mouth!" "Girls with vain faces and pert airs and graces... would have you suppose that under their clothes... there was more than a tube and some lumps." "Very well." "And there's more where that came from." "Liquid paraffin." "Everybody's wedding night." "Reassure yourself." "Tell yourself you're calm and sleepy." "Repeat 20 times:" ""lips that touch kippers shall never touch mine. "" "you must never become a person, miss Smith." "That would be... unendurable." "Oh, god!" "What... a cramp in the arch of the foot!" "It travels up the leg, grips the leg muscle like iron." "The only thing to do is to stamp it hard on the ground." "The japanese have a name for it." "I can't think of what it is." " The pain is..." " Oh, God!" "What are you doing, miss Smith?" "Now do I know what I'm doing or where I am..." "Or what's going on or anything?" "Get back into bed, miss Smith." "Get back into bed." "I just want to say this to you, mr." "Hoffman." "I just want to say this." "I don't know where you came from, by my father was a master carpenter in Dublin." "I was an only child, and I was brought up very, very well." "It is the mile of the night, miss Smith." "You forced me to come and live with you for a week." "All those threats." "We'd go to prison, Tom would do hard labor." "Frightening me." "And then, after all that, what?" "After all that, nothing!" "Days and days keeping me in suspense and misery!" "Every cripple must creep his own way, miss Smith." "I've done my very best." "When a woman starts complaining, it means... that she is feeling thoroughly at home." "Well, I didn't come here to feel thoroughly at home." "My God." "If I told anybody in their right minds... that you brought me here to take sleeping pills every night and snore..." " ... just one moment!" " I beg your pardon?" " I do not snore." " Oh, yes, mr." "Hoffman, you do snore." " Immediately I go to sleep?" " Immediately." " Softly?" " Loudly." " Loudly?" " Very loudly." " Has nobody ever told you before, mr." "Hoffman?" " Stop!" "I recognize this conversation." "Good night, miss Smith." "Good night!" "It just shows how you can be mistaken about people." "Everybody in the office thinks, "oh, yes." "quiet and firm." "A gentleman. "" " God, I wish I was dead!" " It is the mile of the night, miss Smith!" "I don't care!" "I've been telling you for days!" "Oh, God!" "It's all this uncertainty." "I don't even know what you really know about Tom." " You don't?" " Right." "No." "We'll settle that once and for all." "Take a memo, miss Smith." "The firm we work for transports... 30,000 pounds of cigarettes at a time on each truck." "Your Tom sold information to thieves... where a truck would be, at what time and at what route... and received, or receives, from the thieves a commission." "and when he went to the cafe to meet the men, I saw it." "They gave him money." "A truck stops, the driver goes into a lavatory." "When he comes out the truck's gone, and Tom gets a few hundred pounds... towards your house, your wedding." "He said he'd never do it again." "I'll see he never does, never!" "What does it matter what he did?" "All that matters is that you're here now." "But you promised..." " Yes, I promised..." " That... that you'd say nothing..." " That I'd say nothing." " ... if I came here." "And I did." "I came here, and I've been here three whole days." "Please, miss Smith," "Take the rest of the night off and go to sleep." "What good is it to you, me just hating you?" "Just hating you?" "Sleep, sleep, sleep, miss Smith." "I hate you." "I hate you." "Hate you." "Mr. Hoffman?" "Mr. Hoffman, I can't move my head." "Miss Smith, you are highly susceptible to physical ailments, but this is, by far, the most attractive you have yet presented me with." "Come into my surgery, please, and sit down." "There." "Now." "What's that?" "Rheumatism lineament or leather dye?" "I don't want leather dye." "Bare your neck, please." "Now, where does it hurt?" " In there." "Aall there." " All there?" "Mmmm." "Right." "Ow!" "That burns." "It may burn, miss Smith, but it's doing you good." "Is that better?" "A little." "Your neck that beckoned to me... through office walls... and arranged your fate." "Your neck... so young, so pretty, so defenseless." "What did you say?" "In the office, the back of your neck... was forever calling to me for help." "Rubbish." ""Help me." "Help me," your neck said." ""Lead me to my fate. "" "You kissed me." "Shall I take a memo, mr." "Hoffman, that you kissed me?" "You're mistaken, miss Smith." "My fingers merely brushed your neck." "Bbut you blush, miss Smith." "Could it be that you've been touched by my maleness?" "No, mr." "Hoffman." "Could it be that you've been touched... by the soul behind this bloodhound face?" "No, mr." "Hoffman." "Then what?" "By your liquid paraffin." "Reality betrays us all." "Reality betrays us all, miss Smith." "No, No." "Go on, have a guess." "All right, nothing." "Nothing." "You win." "Three guesses." "And here we are." "Here we are what?" "Here we are, miss Smith." "Who lives here?" "I will." "I will live here in my new flat." "Come and have a look inside." "Of course, there's still a lot to be done, but it's coming along slowly but surely." "Don't you think?" "This unit's going over there." "Of course, this'll have to be enlarged." "Otherwise," "Santa Clause will never get up it or down it." "This is nice, isn't it?" "Teak oil." "What's wrong with the old place?" "Oh, well, you know." "Treacheries, miseries, failure, despair." "It's haunted." "What colors are you going to have?" "I'm gonna have white for purity, yellow for experience, and black to make me cheerful." "It's nice making an old house into a new house." "Good afternoon, captain." " Who's that?" " That's Fred down there." "Hello, Fred, down there." "Hello, miss." " Did the new boiler arrive?" " Yes, sir." "We've stuck it in the corner, shortened the pipes." "Ah." "It should really go over there." " Just a minute." "I'll come down and show you." " All right." "This must be the kitchen." "I would have a table here... with a different sort of tablecloth." "And... the stove's going there." "Oh, well, that's all right." "I'd have..." "I'd have a clock over there, cupboards running underneath, lots of jars." "And I'd have check curtains." "Well, mrs." "Mitchell, have you decided to take it?" "Or perhaps one of the upper-floor flats?" "Modest ground rents, long leases." "Very good investment." " You've bought the whole house?" " Oh, yes, yes." " Will the upstairs flats be very expensive?" " Excessive, yes." "Enough to allow one a sort of private life, freedom." "It's a very nice house, mr." "Hoffman." "Yes." "Would you like to see the rest of the house?" " Yes." " Good." "Right." "Is that the only song you know?" "Come here." "I'll teach you something from my extensive repertoire." "This is known as "chopsticks. " Right?" "And you start by playing these two notes... together, and then you go to these two notes." "They're a little bit further apart." "then these two notes." "Then these two notes, which are quite a long way apart, see?" "Don't worry about the bits in the mile." "I'll do that." " Okay." " Think you can do that?" "I don't know." "I'll try." "Really, we start there, and there, and there." "Right." "And I'll play down here." "You play up there." "Okay." "That'll be a duet for instant cacophony." " Are you ready?" " I'm ready." "One, two, three." "Good." " You've got it." " Yes." "Now, one more time." "You're going too fast." "You're going too fast." "Wait for me." "I am waiting for you." "Tom plays the guitar." "I should've phoned Tom... to tell him how I was and everything, and how granny was." "But I couldn't." "I mean, he'd have..." "He'd have known it was from London, wouldn't he?" "Well, you can phone him anyway." "Tell him the call's coming from Scarborough." "I'll be the long-distance operator." " You would?" " Yes, yes, yes." " Do you know the number?" "Dial it." " Oh, yes." "Go on." "Go on." "It's ringing." "It is ringing." "Hello?" "Uh, this is the long-distance operator." "We have a call for a mr." "Tom Mitchell, please." "It's his mother." "Hold the line, please." "Hello, mrs." "Mitchell?" "Yes, it's me, Janet." "Oh... oh, granny?" "Oh, she's fine." "We'll, she'll be better in a day or two." "Yeah, and could I speak to Tom?" "Oh." "At the tennis club." "I see." "Um... um..." "No." "Just... just tell him, um, that I rang, and that everything's fine and that I'll be home soon." "Oh, no, he can't." "No.. no, he mustn't." "I won't be here." "And..." "No." "Mrs. Mitchell, my granny, she's better now, yeah." "And I'll be home to London tomorrow." "Yeah, on the first train." "Well, if not the first train, an early train anyway." "But Tom is not to come up." "Is that clear?" "Um, I have to go now." "Good-bye." " Tomorrow?" " It was all I could think of... to stop him from going up and knocking on my granny's door." "Wh-what could I do?" "I had to say something." "But tomorrow, miss Smith." "I've only had four days." "What difference does it make to you?" "Well, it makes all the difference in the world." "The last days were to be the most important." "Well, I will be here..." "Until tomorrow." "I'm sorry." "Sorry it wasn't like what you thought or anything." "No." "Nothing like I thought." "Nothing like I have to do now." "I must go out... for about 20 minutes." "There's something I have to do." "About 20 minutes." ""Barbara Anne Hoffman. "" ""Dear Ben." ""You and your ideas of cozy family life make me sick." ""I'm going to be famous..." ""and have lots of beautiful men..." ""make love to me." "And be free... "" "Miss Smith?" "Miss Smith?" "Miss Smith, are you there?" "Can you hear me?" "Coming." "I'm just in the bathroom." "I was afraid being on my own, so I put the chain on." "Are you in bed?" "Yes." "Not tonight, miss Smith." "Not tonight." "I'm not going to have anything to hold over me when I'm married, if that's what you think." "Oh, naked, pale, fair girl... found in my bed... one summer morning." "I hate you." "I hate you!" "I want to say something to you, mr." "Hoffman." "You insulted me." "Insulted me!" "That was never my intention, miss... what's wrong with you is that you're afraid even to kiss someone." "Just because you married that awful woman and her gin bottles." "You couldn't even look me straight in the face." "You think everyone's like that, don't you?" "Looking at the back of my neck in the office." "You've made a fool of me, mr." "Hoffman!" "But I have... treated you always with the utmost respect." "Exactly!" "Did you find me all that repulsive?" "You know, when I came here, I came prepared for the very worst." "You're just a rotten hoaxer, mr." "Hoffman." "You never even kissed me!" "I hate you." "You never even kissed me." "You'll remember me, miss Smith." "You'll remember me... in weeks of grinding domestic boredom... when you're married to..." "Tom's mother." "You see, I wanted to show you things." "I wanted to baby you." "you need an older man." "will Tom brush your hair?" "Will Tom... ru-rub the back of your neck?" "You could live like a little mouse in my pocket." "We'd dance and sing... and drive in the sun with the hood down." "I wanted a chance to show you that..." "A man's face..." "doesn't matter all that much." "I've loved you, miss Smith, like a doting idiot... for 18 months... and two weeks." "I wanted to woo you." "You what?" "I..." "I wanted to woo you." "Get out!" "Go on, get out!" "It's getting late." "What... what are you doing?" "Look, you can't go yet." "Um..." "This... this is our last morning." "You must have breakfast in bed." "I insist." "You insist?" "Please, please." "Yes." "Please." "There, there." "I'll peel your egg for you." "There." "That's that." "Put the radio on now." "I'm used to having my breakfast by myself." "Yes, yes, yes." "Yes, of course." "Actually, I'll, um..." "Well, I'll..." "I'll just get a newspaper, and, um, you can readthat by yourself." "Uh, yes." "There's The Times." "Don't read the obituaries." "They're always depressing." "Radio." "I'll just take this out of your way." "Well,bon appetit." "Times." "Yes?" "Do you live here, sir?" "Yes." "I'm Tom." "Tom Mitchell." "Oh, yes, yes." "Mitchell from the office." "I suppose you must have some message." "Oh, no, no, no, mr." "Hoffman." "I'm..." "I'm looking for someone." " It's so bloody silly." "Someone must be having me on." " Who?" "What?" "Who... who are you looking for?" "My fiancee, Janet Smith." "She works in the typing pool." "Come in." "Oh, thank you, sir." "Um..." "Uh, we're a little late." "She's only just having breakfast." "I do hope it's not bad news or anything." "She was so... so happy this morning." "Um, but anyway, as it's obviously so urgent, you'd, uh..." "you'd better see her." "Um, she's, um... she's... in there." "I'm a lucky man doing the best I can" "but it's plain to see that you don't love me" "Oh, mother." "Why aren't you in Scarborough with your grandmother?" "I'm sick." "I couldn't go." "I put you on the train." "Well, um, I had to come back." "I thought this was written by a raving loony." "I was gonna throw it away." "What are you doing here?" "This was at the office this morning." "It was on my desk." ""Once you had a pretty girl." ""You and she were to be wed." ""Now she's at 24 Malet Court..." ""in another man's bed." ""Signed, wellwisher." ""p. s.: take a friend's advice." ""Catch a boat tonight." "Canada is the land of opportunity. "" "God, Tom, I never, never..." "look, he said that if I came here..." "No, no, no." "I'll tell you from the beginning." " You and him?" " No!" "Not me and him!" "I thought you were in Scarborough with your grandmother." "What is she doing here?" "Well, Mitchell, look." "Nowadays, people demand greater freedom, more from life." "We are each called upon for tolerance, understanding." "Well, what is she doing here?" "Well, we shall have to tell him, darling." "No, mr." "Hoffman." "I'll tell him." "Look, Tom, I'll be ready in a moment." "You just wait for me downstairs." "You've no time for niceties, Mitchell." "You're about to be found out." "Janet and I... well, we're very, very old friends." "Tom, he's a lunatic!" "Don't listen to him." "Please!" "I know you've been selling information to people... who steal the firm's goods in transit." " I know." " Why did you tell him?" " I've already paid the deposit on our house!" "Why?" " But I didn't!" "Resign, disappear." "Canada, Australia." "The South African police needs you." "Disappear, Mitchell." "Disappear." "I might even... pay your fare." "You're not gonna listen." "You're not." " Go on, please, Tom." "Wait for me downstairs." " Janet, I can't go..." " Tom, please!" " Look, please, Janet!" " Let me stay here!" "Wait for me, please." " Janet!" " Wellwisher!" "You!" "Now you know he only cares about himself." "If there was a crime to stop hanging with people like you in the world..." " Where are you going?" " Where do you think I'm going?" "To get on with my own life." "He won't want you now." "Why don't you shut up!" "He thinks you've been living with me." " He'll never understand." " He will." "He will." "I..." "I'll take him away somewhere." "I'll make him understand." "And I love you." "I adore you." "I worship every inch of your idiot body." "Your hair, your teeth, your being a girl." "Stay with me, Janet." "Why?" "Why did you bring Tom here?" "Well, you see, it was all or nothing." "It turned into that." "You... or nothing." " You and me?" " Yes." "You and me." "Look at you." "Who wants you?" "You're mad... and... and you're ugly." "Janet!" "Miss Smith!" "Please, miss Smith." "Listen to me." "I..." "I wanted to take advantage of you, but I found I couldn't." "I love you too much for that." "I wanted you to love me." "Just a little." "Oh, mr." "Hoffman." "Good-bye." "If I'm wrong it's nice pretending" "it may soon be my next time" "I can offer you the autumn of my life" "will you share it..." "You and that horrible old man, getting mixed up with people like that." "Oh, dear God." "What are we going to do?" "It's so bloody unfair." "Lots of people do it." "They get away with it." "Why me?" "Yes, and lots of people go to prison too, Tom." "Where are we to go?" "He was getting on so well." "He was only saying the other day how much the people at work liked him." "We can't go away." "We can't go to a cold climate." "I can't leave my home." "We'll find a way out, mum." "You could go to the police." "Police?" "No, thank you." "Look, what's the worst that can happen, Tom?" "A year in prison?" "A year?" "You wouldn't talk like that if you had to go through it." "I did say I'd take half the blame." "And all you'd get would be your picture in the papers." "Janet, couldn't you talk to that man again?" "I mean, you spent a week with him." " Four days." " Can't you... can't you find out?" "Make sure he'll say nothing." "If only." "Oh, if only." "Yes, I could speak to him again." "Tom?" "Tom, would you like me to go back and speak to him again?" "Yes, yes, Anything you can do." "You mean, you wouldn't mind if I went back to him... to talk to him?" "You've been living with him!" "What difference does it make?" "Oh." "I see." "I see." "Well, I'm going home now... to think about it." "Don't come with me, Tom." "Stay with your mother." "She needs you." "Go away." "There's something I want to ask you." "What do you want to ask me?" "Can I give up going to work?" "Yes." "And..." "Can I have piano lessons?" " Yes." " From a real teacher?" "Yes." "And can I choose the things for the new kitchen?" " Yes." " And..." " And can I..." " Yes, anything." "And..." "Can you kiss me now, please?" "Now?" "Well, it's all right." "I just wanted to make sure it would be all right when you did kiss me." "Oh." "Can I go to bed now, please?" "Because I'm tired." "I can offer you the autumn of my life" "will you share it" "Miss Smith?" "Take a memo." "What, mr." "Hoffman?" "Welcome home." "Yours sincerely..." "If I'm wrong it's nice pretending" "it may soon be my next time"
Green Stinger Ephedra by Schwartz Labs is one of the strongest ephedra diet pills for weight-loss available on the market. Green Stinger contains a high effective fat burning formula ingredients that are synergistically blended to achieve the utmost fat loss. Benefits of Green Stinger Ephedra Fast weight-loss Improve your feeling of well-being Increases your energy levels Reduce your amount of body fat Great to take before working out or training Amazing ECA Stack Increase your vigor Green Stinger is a powerful ECA Stack containing the ultimate blend of Ephedra, Caffeine & Aspirin. You will be amazed with the strength of Green Stinger and it's ability to increase your energy levels and burn those unwanted calories! What is in Green Stinger by Schwartz Labs Ephedra Extract(Ephedra sinica) - Is a member of the family of herbs known as the Ephedracae. It has been used in China for more than 4000 years to treat symptoms of asthma and upper respiratory infections. Varieties of the herb are also grown in Europe, India, Australia and Afghanistan. American ephedra, native to the dry southwest, was used as tea by the early settlers, and was known as "Mormon tea" and "Squaw tea." It has also been used in the treatment of headaches, fevers, colds and hay fever. Today, compounds derived from this herb are commonly found in many over-the-counter cold and allergy medications. Ephedra contains two alkaloids, ephedrine and pseudoephedrine. Ephedrine, the main constituent, is a bronchodilator and stimulates the sympathetic nervous system. It has valuable antispasmodic properties, acting on the air passages by relieving swellings of the mucous membrane. Ephedra is often combined with caffeine, guarana and other ingredients to improve its effectiveness. These chemicals are found to suppress the appetite and increase metabolism. Citrus Aurantium - also known as bitter orange, Seville orange and synephrine. It is a well known bronchial dilator, and is used medically to treat chest congestion and indigestion, stimulate gastrointestinal functions, and improve circulatory and liver functions. It's regularly used in combination with diet pills and weight loss formulas. It's also used as a substitute for ephedrine and caffeine, since it increases the metabolic rate without affecting heart rate or blood pressure. Thus, causing thermogenesis, which burns calories. It offers all the advantages of a stimulant, without the drawbacks. It functions to burn fat, increase physical performance, and build lean muscle mass. Acacia Rigidula - A rare, natural compound that consists of several different alkaloids that provide a source of norepinephrine. The alkaloids from the Acacia rigidula are biologically and physiologically similar to those found in ephedra, and possess properties that are shared with ephedra alkaloids. One such property is the ability to pass readily into the brain. The most powerful of these alkaloids is phenylethylamine. It is responsible for effects on mood, appetite and sense of well-being. It is one of the strongest and most effective thyroid stimulating compound in the world. It has the ability to increase the metabolic rate by stimulating your thyroid gland and inducing a powerful thermogenic effect through the conversion of fats into heat. This compound is truly a scientific breakthrough in the world of fat loss and fat burning. Phenylethylamine HCL - Commonly referred to as the "love drug" because of it's effect on beta endorphins, an opioid peptide responsible for pleasureable feelings. It's also the chemical found in chocolate giving it it's well known aphrodisiac effects. Theobroma CoCoa - A small tree that produces cocoa pods that are fermented and after a long process, packed and sold as chocolate products. The flavanols found in these cocoa pods have been proven in studies to have positive effects on vascular health. In addition, recent research has found improvements in blood circulation and the ability of arteries to dilate, a decrease in the body's inflammatory immune response and oxidation of LDL cholesterol. Cocoa is believed to surpass even garlic as a protective antioxidant food. And, it just tastes so darn good! Green Tea Extract - Green tea itself has been the drink of choice for centuries in many Asian countries. It contains chemical compounds called polyphenols, specifically the epigallocatechin (ECGC), which act as powerful antioxidants. These antioxidants neutralize destructive free radicals (that can lead to cancer) and support cardiovascular health by preventing the oxidation of cholesterol. This helps to maintain the integrity of arterial cell walls. Using tea extracts allows for the standardization of the polyphenol content; the assurance that a consistent concentration of these compounds is in each dose. Yohimbe Yohimbine HCL - is found in the inner bark of a tree that grows in southern Africa. It has long been known for It's aphrodisiac effects, but is now more commonly used for the treatment of obesity and erectile disfunction in animals. It has appetite suppressant qualities, which would decrease overall energy intake in those lean and obese who take it. Yohimbine works by blocking the alpha-2 adrenoreceptors. This is important because it increases blood flow in adipose tissue, which prevents fat from being retained in that area. The stubborn fatty areas for men and women are where you will find an abundance of alpha-2 receptors, making it particularly effective in these areas. Yohimatrix TM: Yohimatrix is the name given to the blend of yohimbe compounds Schwartz Laboratories uses to potentiate the effect of green stingers. Yohimbe has be a around for a long time and it is clear that "good" yohimbe - works. In the product Green Stingers, three very specific forms of yohimbe have been combined in specific ratios. Schwartz Laboratories found that this "shotgun" effect of the three different chemical preparations created an uptake and utilization synergy never attained from yohimbe extracts until this discovery. Naringen - A citrus flavanoid commonly found in grapefruit. There is some evidence that the effects and levels of caffeine can be extended when consumed with naringen, making it great as an addition to any fat burner, since 99% of all fat burners contain caffeine or a derivative of. Who wouldn't want to improve and extend the effects of such a powerful ingredient if they could? Lastly, cholesterol-lowering effects have also been seen. Pure White Willow Bark Extract (salicin) -which the body converts to salicylic acid when ingested. This active ingredient has a synergistic effect when combined with Ephedra to promote the thermogenic process. Thermogenesis is the raipid conversion of the food we digest into heat before the calories can be stored as fat. Aspirin (today's version of salicylic acid) is very similar, actually made from a different salicin-containing herb, but works in the same way. Salicin has the same pain relieving medicinal effects as aspirin, but doesn't have the common side effects of today's aspirin (GI bleeding and discomfort). White Willow Bark has been shown to be an effective addition to widely used herbal weight-loss supplements. Evodiamine - A bioactive alkaloid extract from a plant called Evodiae Fructus. It is found in many weight loss products. It is known to produce a stimulating and thermogenic effect, which warms the body's inner core to a point where fat and water weight are burned. It has been found to be very effective for weight loss and adding that extra energy boost for workouts. Caffeine - Found in varying quantities in beans, leaves, and the fruit of over 60 plants. Caffeine is most commonly consumed by humans in coffee and tea, as well as various foods and drinks containing products derived from the kola nut, yerba mate, and guarana berries. It is a central nervous system stimulant, having the effect of temporarily warding off drowsiness, and restoring alertness. It is highly effective as a thermogenic for weight loss and improving performance when working out. Note: Proper Hydration is important to the effectiveness and safety of all thermogenics. Warning: Not for use by individuals under the age of 18 years. Do not use if you are pregnant or nursing. Individuals who consume caffeine with this product may experience serious adverse health effects. Individuals who are sensitive to the effects of caffeine should consult a licensed health care professional before consuming this product. Sale to persons 17 years of age or younger is prohibited. In case of accidental overdose, seek professional assistance or contact a poison control center immediately. Avoid alcohol while taking this product. Do not exceed recommended serving. Exceeding recommended serving may cause serious adverse health effects, including heart attack and stroke. Discontinue use and call a physician or licensed qualified health care professional immediately if you experience rapid heartbeat, dizziness, severe headache, shortness of breath, or other similar symptoms. Improper use of this product may be hazardous to a person's health. Exceeding recommended serving will not improve results. If you have a negative reaction to this or any products contact the FDA's MedWatch at 1.800.332.1088 KEEP OUT OF REACH OF CHILDREN. These statements have not been evaluated by the Food and Drug Administration. This product is not intended to treat, cure, diagnose, or prevent any disease. 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The list above is just ridiculous. Every player on there (minus David Buehler) has a shot at being a 1st day pick. Digging deeper, you have 5 potential 1st rounders in Mark, Cush, Rey, Clay, and Fili plus three legitimate sleeper picks in Kevin Ellison, Kaluka Maiava, and Cary Harris. Both PT and Kyle Moore can be solid contributors if placed in the right situations; Kyle was actually a surprise performer at the Senior Bowl. As for Josh Pinkard, he's made his intentions clear that he'll return for his 6th year if he is granted eligilibity by the NCAA. If Josh comes back, he'll likely start in the FS role alongside Taylor Mays who is looking to play closer to the line. In Nickle packages, we'd see Josh slide over and Will Harris step in. Considering Josh was once one of our more talented players on defense, he can definitely boost his draft stock with a solid injury-free season. January 20, 2009 Best first impression: LB Brian Cushing, an All-American fromSouthern Cal, showed up to the weigh-in cutting an imposing 6-3, 243-pound frame. However, he failed to impress in the same manner at practice. Strongest man: DTFili Moala, a 6-4 and 303-pounder fromSouthern Cal, stood out from the rest with his strength, at one point scooping up an offensive lineman and tossing him aside in a pass-rush drill. Best catch: After struggling for much of the afternoon, WRPatrick TurnerofSouthern Cal laid out to haul in a badly overthrown pass. Based on reports I've read, Clay Matthews and Brian Cushing's stock are rising; Rey has struggled in individual drills. Fili seems to be a player that has something to prove during this week. The knock on him is consistency and discipline. He's a 1st day lock, but ranging anywhere between late 1st-mid 3rd. One non-SC player that is getting a lot of praise is Alphonso Smith, the CB out of Wake Forest. In almost every game I watched him in this past season, he flat out dominated. Very good looking player that doesn't get enough credit. March 08, 2008 USC defensive tackle Fili Moala was arrested early Sunday morning for resisting and obstructing an officer after a melee at a Newport Beach bar was broken up by police. Moala posted $500 bail Sunday morning. The fight broke out at 3950 Campus Road in Newport Beach in the parking lot of Hoagie Barmichaels bar. Officers from the Newport Beach and Irvine police as well as the Orange County sheriffs department arrived and ordered everyone in the vicinity on the ground. Moala (Western High) initially cooperated, according to Newport Beach Sgt. Evan Sailor, but then got up and ran into the bar. An officer followed and arrested Moala, who is listed at 6-foot-5 and 295 pounds. The fight was between John Vuki, 19 of Buena Park, who was arrested for assault with a deadly weapon, and a 17-year old from Long Beach, who was arrested for battery. Sailor said one of the men swung a bat at the other. "(Moala) was not part of the fight at all, but police were dealing with mass bedlam and when a guy gets up and runs away it doesn't help things," Sailor said. It's unclear whether Moala would be charged. As of Friday afternoon, no charges had been filed with the Orange County District's Attorney office. It's that time of year again. Why would Fili get up and run back into the bar? This isn't the first time Fili has been involved in a bizarre arrest. September 11, 2007 On Monday, after comparing a mugshot to Moala's roster photo and confirming fingerprint identification, police said the Trojans player was not the man who had been taken into custody early Sunday and released about six hours later with no charges pending after a "standard detoxification." Moala said after practice that he didn't recognize the man in the mugshot, which was obtained by USC coaches. He also said he had neither lost nor gave out his identification. "I don't know why someone would do that," Moala said. "I just know I don't want anything to be on my record."
issuer:Test CA subject:Test Delegated Responder subjectKey:alternate extension:extKeyUsage:OCSPSigning
Q: Difference between tables created in SQL DataWarehouse and Database I know it sounds very silly question but I want to know in what way the tables and their properties would differ if it is created in data warehouse and database. A: So data warehouse is an another way to store data but it remains a database. DATABASE: Any collection of data organized for storage, accessibility, and retrieval. DATA WAREHOUSE: A type of database that integrates copies of transaction data from disparate source systems and provisions them for analytical use. The main differences are on high level schema, but at low level they're both databases. For a more deep explanation: https://www.differencebtw.com/difference-between-database-and-data-warehouse/
Q: Python 2.7 [Errno 113] No route to host I have 2 computers on the same LAN. The first PC has an ip address 192.168.178.30, the other PC has an ip address 192.168.178.26. Ping, traceroute, telnet, ssh, everything works between the two PCs. Both PCs run the same OS - CentOS 7 and both PCs have the same python version 2.7.5 (checked with the python -V command). I copied simple python code from a computer networking book. client.py from socket import * serverName = '192.168.178.30' serverPort = 12000 clientSocket = socket(AF_INET, SOCK_STREAM) clientSocket.connect((serverName,serverPort)) sentence = raw_input('Input lowercase sentence: ') clientSocket.send(sentence) modifiedSentence = clientSocket.recv(1024) print 'From Server:', modifiedSentence clientSocket.close() server.py from socket import * serverPort = 12000 serverSocket = socket(AF_INET,SOCK_STREAM) serverSocket.bind(('192.168.178.30',serverPort)) serverSocket.listen(5) print 'The server is ready to receive' while 1: connectionSocket, addr = serverSocket.accept() sentence = connectionSocket.recv(1024) capitalizedSentence = sentence.upper() connectionSocket.send(capitalizedSentence) connectionSocket.close() The code works when it is ran on the same PC (where the server is listening on localhost). When I run the client code on one PC and the server code on the other PC I get this error on the client side. Traceback (most recent call last): File "client.py", line 5, in <module> clientSocket.connect((serverName,serverPort)) File "/usr/lib64/python2.7/socket.py", line 224, in meth return getattr(self._sock,name)(*args) socket.error: [Errno 113] No route to host Can someone help? A: Check the firewall (on the server). A: I stopped the firewall like Messa suggested and now it works. service firewalld stop I still don't understand what the problem was. I even tried using different distributions. Do all distributions have strict firewalls or something. For example Ubuntu to Ubuntu, Ubuntu to CentOS, CentOS to Ubuntu I still had the same problem (error).
A web server owned by game publisher Electronic Arts has been compromised and used in a phishing attack against users of Apple services, a security firm has claimed. The server, apparently used to host a calendar under the ea.com domain, is said to be used to try and acquire the Apple ID credentials of potential victims by posing as an account verification site. The site in question attempts to trick the viewer into signing in to verify their Apple ID and password, according toNetcraft. The Internet security firm alleges the phishing site then asks for more personal information to confirm the victim's identity, including their full name, credit card details, date of birth, phone number, mother's maiden name, and other related sensitive information. Completing this second form takes the victim to a genuine Apple ID site, in an attempt to cover their tracks. Screenshot of Apple ID phishing page on EA domain It is believed the server was infiltrated via a vulnerability in WebCalendar 1.2.0, software which was first issued in 2008 but has since received a number of security-related updates. This could have allowed the attacker to install scripts to the server, as well as access to other data stored on the server itself. In a statement to theBBC, EA said "Privacy and security are of the utmost importance to us, and we are currently investigating this report."
Use of quantitative immunofluorescence microscopy to study intracellular trafficking: studies of the GLUT4 glucose transporter. Insulin regulates the glucose uptake in muscle and adipose cells by acutely modulating the amount of the GLUT4 glucose transporter in the plasma membrane. The steady-state cell surface distribution of a membrane protein is an equilibrium between exocytosis and endocytosis. The authors study the effect of insulin on GLUT4 using quantitative immunofluorescence microscopy adapted to single-cell analysis. They use an HA-GLUT4-GFP reporter molecule as a surrogate of GLUT4 trafficking. Insulin induces an increase of GLUT4 in the plasma membrane by both increasing GLUT4 exocytosis and decreasing its endocytosis. Quantitative immunofluorescence techniques such as those described in this review can be used to study the trafficking of virtually any membrane protein.
Murray Targets More Slams After Wimbledon Win http://archive.newsleader.com/VideoNetwork/2534581096001/Murray-Targets-More-Slams-After-Wimbledon-Winhttp://cdn.newslook.com/b0/b075771d0f0521a74ff6b7be2e7117b0/mp4_low/b075771d0f0521a74ff6b7be2e7117b0-mp4_low.mp4http://archive.newsleader.com/VideoNetwork/2534581096001/Murray-Targets-More-Slams-After-Wimbledon-Winhttp://cdn.newslook.com/b0/b075771d0f0521a74ff6b7be2e7117b0/images/frame_0008.jpgMurray Targets More Slams After Wimbledon WinAndy Murray said Monday he is determined to push on from his stunning Wimbledon win and add further Grand Slam titles to his achievements.Andy MurraysportsnewslookUnited KingdomLondon00:42
Q: How to use regex in PHP to extract a sitemap reference from a robots.txt file? I want to parse a robots.txt file and extract the sitemap reference. Assuming that the file is something like this; stuff foobar Sitemap: http://www.cgdomestics.co.uk/sitemap.xml hello world more stuff I'm trying to use regex to extract exactly this; http://www.cgdomestics.co.uk/sitemap.xml So far I have this PHP code; <?php $robots_url = "http://www.cgdomestics.co.uk/robots.txt"; $robots_file = file_get_contents($robots_url); $pattern = "/Sitemap: ./"; $i = preg_match($pattern, $robots_file, $match); echo $match[0]; ?> The output of the above is; Sitemap: http://www.cgdomestics.co.uk/sitemap.xml but I want it to output only; http://www.cgdomestics.co.uk/sitemap.xml Can I use regex to return exactly what I want or do I need to do another step to remove the "Sitemap: " part? Or is there a better way to do this? As you can probably tell I'm an infrequent user of PHP and regex. Thanks. Nigel A: Set a sub pattern and grab it from the matches array <?php $robots_url = "http://www.cgdomestics.co.uk/robots.txt"; $robots_file = file_get_contents($robots_url); $pattern = "/Sitemap: ([^\r\n])/"; $i = preg_match($pattern, $robots_file, $match); echo $match[1]; ?>
Pat Favero said he works to cure patients in his medical practice, and he now hopes to do the same with the county’s ailments, such as job creation, education, providing a good quality of life and keeping taxes low. Favero, 32, is running for the Iriswood District seat on the Henry County Board of Supervisors in the Nov. 5 election. Favero, a doctor of osteopathic medicine, opened a family medical practice about three years ago. A doctor of osteopathic medicine can do everything a medical doctor does plus manipulations such as a chiropractor does, he said. As a small business owner, Favero said he would concentrate on small business development as a primary goal if elected. “I think we should focus more on small business development and try to encourage multitudes of small businesses” to locate to the area, he said. To that end, he supports using tax incentives “not just to build shell buildings, but also to renovate some of the older existing buildings.” The Clock Tower, in the former Tultex plant on Franklin Street in Martinsville, is a prime example of how that could occur. Its owner, The Lester Group, has “done a good job of renovating it and trying to create new businesses. Another example is uptown, where old buildings were renovated” to house the New College Institute offices and classrooms, he said. Larger “old factory buildings can be subdivided into smaller” spaces that would be attractive to smaller businesses, Favero said. If elected, he said he would bring fresh ideas and help find alternate ways of growing business and the tax base. Both are imperative to the community, for its quality of life and drawing young, educated people back home, he said. “I think our county faces lots of issues on an economic level. Being a physician, I can cure people, but I can’t provide them with an income or insurance. Time and time again, I see people who can’t afford insurance. They can’t afford their medicine,” and Favero said he feels it is up to him to help. Growing the economy is one way to do that, he added. While he is willing to maintain confidentiality for prospective companies interested in locating in the area, Favero said, “we still require some type of transparency.” He said he is convinced there are ways to accomplish both. For example, if a small engine group was considering the area, Favero said, county and economic development officials could say publicly it was a small engine group because that would cover a broad area. He said an estimate of the number of jobs also could be provided. Confidentiality would be maintained, while providing transparency and accountability, Favero said. Then, if the company located here, “everybody would know, and if not, there would be some accountability as to why they didn’t come,” he said. “The average person would not have the ability to do the research” to identify the company, Favero said. “I think we can still be vague, but give some transparency to the public who is paying EDC’s wages and still respect privacy” and confidentiality agreements with prospects, he added. The grading of Commonwealth Crossing Business Centre also needs to be pursued, he said. Currently, federal officials have refused to issue a permit for the project because of a lack of a committed industry. “We still need to look for ways to make sure it succeeds. There’s been a substantial investment up to this point, and we need to work with state and federal officials to reach (a) solution,” Favero said. Education is critical to having a well-trained workforce, which is essential to growing the economy, he said. “It is critical to support the continued development of NCI and Patrick Henry Community College” and their work with industries to provide a strong education for students and training for those who are under- or unemployed, Favero said. Having a well-trained workforce “will be a big asset” and will make the area more attractive to potential businesses, he said. Favero said he supports pay raises, especially for teachers and law enforcement officers. “I think our teachers are underpaid. They are paid significantly less, on average, than the state average,” he said. The same is true for law enforcement, he added. “If we could have more economic development,” local tax revenues would increase, and “we could have more money to give raises,” Favero said. “I think everybody deserves raises,” he said, but noted that he would have to research the pay of county employees to determine whether it is also below the state average. The emergency services career (paid) staff program also must be expanded, Favero said.
project_path: /web/_project.yaml book_path: /web/updates/_book.yaml description: 让我们来讨论如何使用一个Web API以在桌面创建一个浮动视频窗口。 {# wf_updated_on: 2017-09-12 #} {# wf_published_on: 2017-09-12 #} {# wf_tags: news,media #} {# wf_featured_image: /web/updates/images/generic/picture-in-picture.png #} {# wf_featured_snippet: 让我们来讨论如何使用一个Web API以在桌面创建一个浮动视频窗口。 #} {# wf_blink_components: Blink>Media #} # 画中画 (PiP) {: .page-title } {% include "web/_shared/contributors/beaufortfrancois.html" %} 自2017年4月起，[Android O的Chrome支持画中画](https://developer.android.com/about/versions/oreo/android-8.0.html#opip)。这功能可让用户在同个时间，在悬浮窗中的`<video>`元素播放视频，一边做其他的事情。要如何使用画中画呢？首先开启Chrome, 然后开启一个拥有视频的网页吗，然后将那个视频在全屏中播放。然后按主页按钮以回到Android的主页，你将会发现正在播放着的视频将会自动地进入画中画模式。是不是很酷呢? <figure> <img src="/web/updates/images/2017/09/picture-in-picture-hero.jpg" alt="Android Picture in Picture photo"> <figcaption><b>图 1.</b> Android的画中画模式</figcaption> </figure> 但是... 要怎样在桌面中使用画中画? 网页要怎样控制画中画呢? 好消息是[画中画Web API的规范](https://wicg.github.io/picture-in-picture/) 已经在草稿阶段中了。这规范能让网页使用这API来控制画中画在网页中的行为，这包括： - 通知网页当视频进入或退出画中画。 - 允许用户使用手势来进入或退出画中画模式。 - 允许网页退出画中画。 - 允许网页检查是否可以使用画中画模式。以下是画中画Web API的示例代码： ``` <video id="video" src="https://example.com/file.mp4"></video> <button id="pipButton"></button> <script> // 如果不支持画中画，将按钮隐藏 pipButton.hidden = !document.pictureInPictureEnabled; pipButton.addEventListener('click', function() { // 如果没有元素在画中画模式，我们将为那视频 (video)元素 // 请求进入画中画模式。若是已经是在画中画模式中， // 我们将请求退出画中画模式。 if (!document.pictureInPictureElement) { video.requestPictureInPicture() .catch(error => { // 视频无法进入画中画模式 }); } else { document.exitPictureInPicture() .catch(error => { // 视频无法退出画中画模式 }); } }); </script> ``` Note: 目前没有任何的游览器可以运行以上的代码。 ## 反馈您觉得这个画中画怎样呢? 欢迎你在[Picture In Picture WICG的软件源](https://github.com/WICG/picture-in-picture)提供建议及提出问题。我们渴望能听到你的想法！ ## 阻止Android中的画中画的默认行为今天，你可以使用resize event来阻止在Chrome运行的网页中的视频进入Android默认的画中画模式。您可以通过resize event来检测窗口大小是否有变化（见以下的代码）。直到画中画Web API被正式的实施，使用resize event来阻止Android中的画中画的默认行为的方法只是暂时的，这不是长期的解决方法。 ``` // See whether resize is small enough to be PiP. It's a hack, but it'll // work for now. window.addEventListener('resize', function() { if (!document.fullscreenElement) { return; } var minimumScreenSize = 0.33; var screenArea = screen.width * screen.height; var windowArea = window.outerHeight * window.outerWidth; // If the size of the window relative to the screen is less than a third, // let's assume we're in PiP and exit fullscreen to prevent Auto PiP. if ((windowArea / screenArea) < minimumScreenSize) { document.exitFullscreen(); } }); ``` Translated by {% include "web/_shared/contributors/henrylim.html" %}
Q: font face and color syntax errror I am trying to add font face and color and running into following error #Create the body of the message msg_body=("<HTML><head></head>" "<body>BCC Warning:" "<br>Hi All, <br>" "<br><br>" "<font face = "Arial" color="#990000" > Wiki @<a href=%s>%s</a> (listed @ go\wbit)</font> <br><br>" "<b>Release notes:</b> %s <br><br>" "<b>Build Combo:</b><br>%s<br><br>" "<b>Loading instructions:</b><br>%s<br><br>" "<b>CR fixes:</b><br>%s<br><br>" "Thanks,<br>" "Build team" "</body></html>" ) % (wikiURL,wikiURL,Releasenotes,table,Load_ins,crInfo) Syntax error "<font face = "Arial" > Wiki @<a href=%s>%s</a> (listed @ go\wbit)</font> <br><br>" ^ SyntaxError: invalid syntax A: write in below format "<font face = 'Arial' > Wiki @<a href=%s>%s</a> (listed @ go\wbit)</font> <br><br>" However it not recommended to use font tag anymore. Use style='font:arial normal' instead. Updated syntax: msg_body=("<HTML><head></head>" "<body>BCC Warning:" "<br>Hi All, <br>" "<br><br>" "<div style='font:Arial normal; color:#990000'> Wiki @<a href=%s>%s</a> (listed @ go\wbit)</div> <br><br>" "<b>Release notes:</b> %s <br><br>" "<b>Build Combo:</b><br>%s<br><br>" "<b>Loading instructions:</b><br>%s<br><br>" "<b>CR fixes:</b><br>%s<br><br>" "Thanks,<br>" "Build team" "</body></html>" ) % (wikiURL,wikiURL,Releasenotes,table,Load_ins,crInfo)
# ---------- # src/test/regress/parallel_schedule # # By convention, we put no more than twenty tests in any one parallel group; # this limits the number of connections needed to run the tests. # ---------- # run tablespace by itself, and first, because it forces a checkpoint; # we'd prefer not to have checkpoints later in the tests because that # interferes with crash-recovery testing. test: tablespace # ---------- # The first group of parallel tests # ---------- test: boolean char name varchar text int2 int4 int8 oid float4 float8 bit numeric txid uuid enum money rangetypes pg_lsn regproc # ---------- # The second group of parallel tests # strings depends on char, varchar and text # numerology depends on int2, int4, int8, float4, float8 # ---------- test: strings numerology point lseg line box path polygon circle date time timetz timestamp timestamptz interval inet macaddr macaddr8 tstypes # ---------- # Another group of parallel tests # geometry depends on point, lseg, box, path, polygon and circle # horology depends on interval, timetz, timestamp, timestamptz # ---------- test: geometry horology regex oidjoins type_sanity opr_sanity misc_sanity comments expressions # ---------- # These four each depend on the previous one # ---------- test: create_function_1 test: create_type test: create_table test: create_function_2 # ---------- # Load huge amounts of data # We should split the data files into single files and then # execute two copy tests parallel, to check that copy itself # is concurrent safe. # ---------- test: copy copyselect copydml insert insert_conflict # ---------- # More groups of parallel tests # ---------- test: create_misc create_operator create_procedure # These depend on create_misc and create_operator test: create_index create_index_spgist create_view index_including index_including_gist # ---------- # Another group of parallel tests # ---------- test: create_aggregate create_function_3 create_cast constraints triggers select inherit typed_table vacuum drop_if_exists updatable_views roleattributes create_am hash_func errors # ---------- # sanity_check does a vacuum, affecting the sort order of SELECT * # results. So it should not run parallel to other tests. # ---------- test: sanity_check # ---------- # Another group of parallel tests # Note: the ignore: line does not run random, just mark it as ignorable # ---------- ignore: random test: select_into select_distinct select_distinct_on select_implicit select_having subselect union case join aggregates transactions random portals arrays btree_index hash_index update delete namespace prepared_xacts # ---------- # Another group of parallel tests # ---------- test: brin gin gist spgist privileges init_privs security_label collate matview lock replica_identity rowsecurity object_address tablesample groupingsets drop_operator password identity generated join_hash # ---------- # Another group of parallel tests # ---------- test: create_table_like alter_generic alter_operator misc async dbsize misc_functions sysviews tsrf tid tidscan # rules cannot run concurrently with any test that creates # a view or rule in the public schema test: rules psql psql_crosstab amutils stats_ext # run by itself so it can run parallel workers test: select_parallel test: write_parallel # no relation related tests can be put in this group test: publication subscription # ---------- # Another group of parallel tests # ---------- test: select_views portals_p2 foreign_key cluster dependency guc bitmapops combocid tsearch tsdicts foreign_data window xmlmap functional_deps advisory_lock indirect_toast equivclass # ---------- # Another group of parallel tests (JSON related) # ---------- test: json jsonb json_encoding jsonpath jsonpath_encoding jsonb_jsonpath # ---------- # Another group of parallel tests # NB: temp.sql does a reconnect which transiently uses 2 connections, # so keep this parallel group to at most 19 tests # ---------- test: plancache limit plpgsql copy2 temp domain rangefuncs prepare conversion truncate alter_table sequence polymorphism rowtypes returning largeobject with xml # ---------- # Another group of parallel tests # ---------- test: partition_join partition_prune reloptions hash_part indexing partition_aggregate partition_info # event triggers cannot run concurrently with any test that runs DDL test: event_trigger # this test also uses event triggers, so likewise run it by itself test: fast_default # run stats by itself because its delay may be insufficient under heavy load test: stats
Q: Builder pattern for polymorphic object hierarchy: possible with Java? I have a hierarchy of interfaces, with Child implementing Parent. I would like to work with immutable objects, so I would like to design Builder classes that construct these objects conveniently. However, I have many Child interfaces, and I don't want to repeat the code for building Parents in each type of child builder. So, assume the following definitions: public interface Parent { public Long getParentProperty(); } public interface Child1 extends Parent { public Integer getChild1Property(); } public interface Child2 extends Parent { public String getChild2PropertyA(); public Object getChild2PropertyB(); } How can I efficiently implement builders Child1Builder and Child2Builder? They should support operation like: Child1 child1 = Child1Builder.newChild1().withChild1Property(5).withParentProperty(10L); and Child2 child2 = Child2Builder.newChild2().withChild2PropertyA("Hello").withParentProperty(10L).withChild2PropertyB(new Object()); I don't want to implement a special case of withParentProperty for each child builder. Edited to add second property to Child2 to clarify that this cannot be done with simple generics. I am not looking for a way to combine Child1 and Child2 - I am looking for a way to implement a Builder system that does not duplicate the work of building the parent class for every child class. Thanks for any help! A: The solution I imagine is like the Curiously Recurring Template Pattern, or CRTP. You can define a base class to handle the parent-related initialization, but you still may find the two boilerplate getParent() and getThis() methods to be too much repetition in each derived child-related builder class. Take a look: abstract class ParentBase implements Parent { @Override public final Long getParentProperty() { return parentProperty_; } protected void setParentProperty(Long value) { parentProperty_ = value; } private Long parentProperty_; } abstract class ParentBuilder<T extends ParentBuilder<T>> { T withParentProperty(Long value) { getParent().setParentProperty(value); return getThis(); } protected abstract ParentBase getParent(); protected abstract T getThis(); } final class ConcreteChild1 extends ParentBase implements Child1 { @Override public Integer getChild1Property() { return childProperty_; } public void setChild1Property(Integer value) { childProperty_ = value; } private Integer childProperty_; } final class Child1Builder extends ParentBuilder<Child1Builder> { public Child1Builder() { pending_ = new ConcreteChild1(); } public Child1Builder withChild1Property(Integer value) { pending_.setChild1Property(value); return this; } @Override protected ParentBase getParent() { return pending_; } @Override protected Child1Builder getThis() { return this; } private final ConcreteChild1 pending_; } As you can see, the ParentBuilder type expects to be cooperating with a derived type to allow it to return a properly-typed instance. Its own this reference won't due, because the type of this within ParentBuilder is, of course, ParentBuilder, and not, say, Child1Builder as intended to maintain the "fluent" call chaining. I owe the "getThis() trick" to Angelika Langer's tutorial entry. A: I don't think getParent() and getThis() are necessary, if you're willing to accept the restriction that the withXXXProperty() methods be called from "youngest" to "oldest": class Parent { private final long parentProperty; public long getParentProperty() { return parentProperty; } public static abstract class Builder<T extends Parent> { private long parentProperty; public Builder<T> withParentProperty( long parentProperty ) { this.parentProperty = parentProperty; return this; } public abstract T build(); } public static Builder<?> builder() { return new Builder<Parent>() { @Override public Parent build() { return new Parent(this); } }; } protected Parent( Builder<?> builder ) { this.parentProperty = builder.parentProperty; } } class Child1 extends Parent { private final int child1Property; public int getChild1Property() { return child1Property; } public static abstract class Builder<T extends Child1> extends Parent.Builder<T> { private int child1Property; public Builder<T> withChild1Property( int child1Property ) { this.child1Property = child1Property; return this; } public abstract T build(); } public static Builder<?> builder() { return new Builder<Child1>() { @Override public Child1 build() { return new Child1(this); } }; } protected Child1( Builder<?> builder ) { super(builder); this.child1Property = builder.child1Property; } } class Child2 extends Parent { private final String child2PropertyA; private final Object child2PropertyB; public String getChild2PropertyA() { return child2PropertyA; } public Object getChild2PropertyB() { return child2PropertyB; } public static abstract class Builder<T extends Child2> extends Parent.Builder<T> { private String child2PropertyA; private Object child2PropertyB; public Builder<T> withChild2PropertyA( String child2PropertyA ) { this.child2PropertyA = child2PropertyA; return this; } public Builder<T> withChild2PropertyB( Object child2PropertyB ) { this.child2PropertyB = child2PropertyB; return this; } } public static Builder<?> builder() { return new Builder<Child2>() { @Override public Child2 build() { return new Child2(this); } }; } protected Child2( Builder<?> builder ) { super(builder); this.child2PropertyA = builder.child2PropertyA; this.child2PropertyB = builder.child2PropertyB; } } class BuilderTest { public static void main( String[] args ) { Child1 child1 = Child1.builder() .withChild1Property(-3) .withParentProperty(5L) .build(); Child2 grandchild = Child2.builder() .withChild2PropertyA("hello") .withChild2PropertyB(new Object()) .withParentProperty(10L) .build(); } } There's still some boilerplate here: the anonymous concrete Builder in each builder() method, and the super() call in each constructor. (Note: that assumes that every level is designed for further inheritability. If at any point you have a final descendant, you can make the builder class concrete and the constructor private.) But I think this version is easier to follow, for the next programmer who comes along and has to maintain your code (no self-referential generics, for starters; a Builder<X> builds Xs). And IMHO requiring the child properties to be set on the builder before the parent properties is as much an advantage, in terms of consistency, as it is a disadvantage in terms of flexibility.
PixelFed es un proyecto todavía en fase de pruebas pero que trata de ser el reemplazo de software libre y descentralizado a Instagram. La comunidad de software libre va proponiendo alternativas a las redes sociales privativas y centralizadas. Así podemos encontrar redes sociales como diaspora, GNUsocial o Mastodon. Todas ellas tienen el común denominador que están construidas con software libre y que son descentralizadas. ¿Qué significa eso? Lo primero es obvio, el código es accesible y abierto para verlo, modificarlo, etc. No existen funcionalidades malévolas, ya que es auditado. Lo segundo significa que no existe un único servidor donde todo el mundo tenga que registrarse. Hay diferentes opciones y puedes abrir una cuenta en un nodo y otra persona en otro y ambos se siguen comunicando. Piensa en el símil del correo electrónico, una persona tiene cuenta en un servicio de correo, y otra persona en otro. ambas usan el correo y ambas se pueden comunicar entre sí. A estas se suma un nuevo proyecto llamado PixelFed, que podríamos calificar de un “Instagram” libre, por lo parecido de la interfaz y propósito y que cumple con esas condiciones de software libre y descentralizado. El proyecto todavía está en fase de desarrollo, por lo que hay algunas opciones de la interfaz que todavía no están funcionando al 100%. Por ejemplo no se puede configurar un avatar personalizado, el sistema de notificaciones es mejorable, etc. Está basado en Activity Pub y Fediverso. Pero aún así ya tiene las funcionalidades básicas perfectamente funcionando. En definitiva es un lugar en el que poder mostrar fotografías o imágenes, etiquetarlas, descubrir, comentar o decir que te ha gustado el material subido por otras personas. Tiene la posibilidad de aplicar filtros a las imágenes que subimos para darles un toque retro, en blanco y negro, luminoso, etc. Podemos descubrir el material que otras personas han subido, seguir a aquellas que nos parecen interesante y que queremos que se muestre en nuestra línea de tiempo, podemos bloquear y ver qué se publica de manera pública. Es una interfaz muy sencilla y similar a Instagram, por lo que en poco tiempo sabremos movernos por ella sin problemas. El proyecto está creado por un desarrollador llamado Daniel, y tienes el código publicado en GitHub. De momento el desarrollo está en fase alfa, por lo que hay ciertas restricciones. Tiene cuenta en Patreon por si quieres donarle dinero. El registro de nuevas cuentas no es público, se abre de vez en cuando para que quien lo desee se registre, en su cuenta de Mastodon lo anuncian. Todavía, como he comentado, hay algunas funcionalidades que se están desarrollando. Aunque puedes instalar tu propia instancia, todavía no federan entre sí, además de que puede presentar inestabilidades. Yo me he abierto una cuenta y ya he subido alguna foto. No esperéis selfies en frente del espejo, o tomando el sol en la playa, más bien podréis encontrar fotos de gatos, graffitis y cosas geek! Si tienes cuenta por allí saluda! 🙂 Te recomiendo este artículo de Astheroth en su web con más información. ——————————————————————————-
Human cytomegalovirus inhibits maturation and impairs function of monocyte-derived dendritic cells. Dendritic cells (DCs) play a pivotal role in the generation of virus-specific cytotoxic T-cell responses, but some viruses can render DCs inefficient in stimulating T cells. We studied whether infection of DCs with human cytomegalovirus (HCMV) results in a suppression of DC function which may assist HCMV in establishing persistence. The effect of HCMV infection on the phenotype and function of monocyte-derived DCs and on their ability to mature following infection with an endothelial cell-adapted clinical HCMV isolate were studied. HCMV infection induced no maturation of DCs; instead, it efficiently down-regulated the expression of surface major histocompatibility complex (MHC) class I, CD40, and CD80 molecules. Slight down-regulation of MHC class II and CD86 molecules was also observed. Lipopolysaccharide (LPS)-induced maturation of infected DCs was strongly inhibited, as indicated by lower levels of surface expression of MHC class I, class II, costimulatory, and CD83 molecules. The down-regulation or inhibition of these surface markers occurred only in HCMV antigen-positive DCs. DCs produced no interleukin 12 (IL-12) and only low levels of tumor necrosis factor alpha (TNF-alpha) upon HCMV infection. Furthermore, cytokine production upon stimulation with LPS or CD40L was significantly impaired. Inhibition of cytokine production did not depend on viral gene expression as UV-irradiated HCMV resulted in the same effect. Proliferation and cytotoxicity of T cells specific to a recall antigen presented by DCs were also reduced when DCs were HCMV infected. This study shows that HCMV inhibits DC function, revealing a powerful viral strategy to delay or prevent the generation of virus-specific cytotoxic T cells.
--- author: - 'J. J. Eldridge and C. A. Tout\' title: 'Exploring the Divisions and Overlap between AGB and Super-AGB Stars and Supernovae.' --- Introduction ============ The primary factors that affect a stars evolution are initial mass, initial metallicity, mass-loss, duplicity and extra mixing above and beyond that from convection described by mixing-length theory. The interplay between these factors determines the evolutionary path taken and whether a star gives rise to a supernova (SN) or produces a white dwarf. These factors are linked. A more massive star experiences more mass loss, as does a star with initially higher metallicity. We have been studying these factors to determine their effect on the population of SNe progenitors [@et1; @eldridge1]. By using observations of SN types and WR ratios we have been able compare a number of mass-loss prescriptions and decide on a best fitting prescription. One interesting aspect of our work is the nature of the lowest-mass stars that explode as SNe. @IBEN2 suggested that these would be super-AGB stars which are similar in structure to AGB stars but have oxygen/neon (ONe) cores rather than carbon/oxygen (CO) cores. In this paper we give details of the mass ranges over which we find the different courses of evolution, AGB, super-AGB and SN. We also discuss observational evidence from SNe on super-AGB evolution and the lowest mass for a SN to occur. We find that the nature of the lowest mass SN progenitors may provide a tight constraint on convection in stellar interiors. The Mass Ranges of AGB Evolution ================================ AGB stars result from two courses of evolution. For lower masses the helium burning shell catches up with the hydrogen burning shell. While for more massive AGB stars (above $3\,M_{\odot}$), the convective envelope penetrates down to the CO core at second dredge up. Both cases put the hydrogen and helium burning shells in close proximity, an unstable arrangement that leads to thermal pulses rather than steady shell burning. Furthermore, because the hydrogen burning shell is now at a higher temperature near the helium burning shell, hydrogen burning occurs at a much greater rate and the luminosity of the star rises by a factor of at least 10. Most AGB stars have CO cores and do not ignite carbon there. These go on to form CO White Dwarfs as the envelope is removed by a stellar wind during the thermally pulsing phase. If the envelope is not removed these stars would eventually approach the Chandrasekhar mass ($M_{\rm Ch}$) and carbon would ignite in the centre leading to a thermonuclear SNe. The resultant SNe would have observational characteristics of type Ia SNe with a type II masks. They are often referred to as a type $1 \frac{1}{2}$ [@type1.5]. However stars above about $7\,M_{\odot}$ experience carbon burning [@IBEN1]. The lowest-mass stars in this range ignite carbon in a shell around the more degenerate central regions. This shell slowly burns inwards, raising the degeneracy as it goes. In more massive stars carbon ignites in the core and then burns outwards in brief shell flashes rather than in a steady burning shell. This is due to the mild degeneracy of the CO core when the burning reaction takes place. Carbon burning leaves an ONe core and the star becomes a super-AGB star. The carbon burning continues outwards until it reaches the base of the helium burning shell at which point it extinguishes. However the hydrogen and helium shells can still continue to burn outwards until $M_{\rm Ch}$ is reached. At this point the core collapses but now there is no carbon to ignite and prevent collapse. Densities can be reached of around $9.6 <\log_{10} (\rho / {\rm g \, cm^{-3}}) < 9.8$ at which electron capture on to $^{24}$Mg can occur. This accelerates the core collapse and formation of a neutron star in a type II SN. The only difference to other SNe is that the core collapse is via electron capture rather than iron photodisintigration. Our work uses the Cambridge stellar evolution code written by @E71 and most recently updated by @P95 and @etopac. We include convective overshooting as described by @SPE97. Because of new nuclear reactions rates and opacity tables the mass ranges for different behaviour are shifted relative to previous studies. We list the ranges when we include convective overshooting ($M_{\rm OS}$) and when we remove it ($M_{\rm noOS}$). The behaviour is as follows. - $M_{\rm noOS} \le 7\,M_{\odot}$, $M_{\rm OS} \le 5\,M_{\odot}$ – stars undergo second dredge-up and thermal pulses with a central CO core. They lose their envelopes and leave CO white dwarfs before before their cores reach $M_{\rm Ch}$. - $M_{\rm noOS} \approx 8\,M_{\odot}$, $6\,M_{\odot} \le M_{\rm OS} \le 7\,M_{\odot}$, during or after second dredge-up carbon ignites in a shell because the core is degenerate and has a temperature inversion caused by neutrino losses. The star then undergoes thermal pulses with an ONe core. Because the core mass after dredge-up is far from $M_{\rm Ch}$ we assume these stars lose their envelopes and form ONe white dwarfs. These are super-AGB stars. - $M_{\rm noOS} \approx 9\,M_{\odot}$, $M_{\rm OS} \approx 7.5\,M_{\odot}$ – carbon ignites before second dredge-up, in a shell if the centre is degenerate). Thus at dredge-up there is a growing ONe core. If this can reach $M_{\rm Ch}$ before the envelope is lost then the star undergoes a SN. The outcome depends on the nature of the thermal pulses and the core mass after dredge-up. Only those with cores close to $1.38\,M_{\odot}$ undergo SNe. - $M_{\rm noOS} \approx 10\,M_{\odot}$, $M_{\rm OS} \approx 8\,M_{\odot}$ – the CO core is greater than $M_{\rm Ch}$ before dredge-up. However shell carbon burning, enhanced by a thin neon burning shell in the most massive stars of this type, drives a convection zone that reduces the size of the CO core to $M_{\rm Ch}$ so dredge-up can occur. This CO material is mixed with the envelope and increases the CO abundance at the surface during second dredge-up. After dredge-up the star has an ONe core of $M_{\rm Ch}$ which progresses to a SN by electron capture on to ${\rm Mg}^{24}$. These are extreme super-AGB stars. - $M_{\rm noOS} \ge 11\,M_{\odot}$, $M_{\rm OS} \ge 9\,M_{\odot}$ – the helium core or CO core masses are too great for dredge-up to occur. The limiting mass for the helium core is $3\,M_{\odot}$ and for the CO core $1.5\,M_{\odot}$. Nuclear burning in these stars progresses until it cannot support the core and a SN explosion ensues. If super-AGB stars do undergo SN then the luminosity of the lowest-mass SN progenitors depends upon the occurrence of second dredge-up in the late stages of evolution [@Smartt2002]. In the mass range of interest second dredge-up can increase the final luminosity from $\log_{10} (L/L_{\odot}) < 4.6$ to $\log_{10} (L/L_{\odot}) > 5.2$. Therefore these stars, if they occur in nature, should provide a large population of luminous red giant progenitors. The more massive models increase in luminosity 100 down to $10\,$yr before the SN. This is because, before second dredge-up, the stars have more massive cores. This leads to denser cores after second dredge-up with less time required to achieve the densities for electron capture. We take this to occur at a central density of $\log_{10} (\rho / {\rm g \, cm^{-3}}) = 9.8$ [@ecapture1; @ecapture2]. We define this as the point when the SN explodes. Most super-AGB stars probably do not undergo SNe. They lose their envelopes and form ONe white dwarfs before core collapse can occur. Their much higher luminosities enhance mass loss and, in our models, it can take $100{,}000\,$yr or longer for the burning shells to advance and for the core to reach the conditions for core collapse if the core is smaller than $1.38\,M_{\odot}$. To lose their envelopes during this time a mass-loss rate of only $<10^{-4}\,M_{\odot}\,{\rm yr^{-1}}$ is required and this is not unreasonable for a luminous red giant. Also if the helium-burning shell is unstable and thermal pulses do occur the burning shell’s advance is slower and there is even more time for mass loss. However there are a class of stars, extreme super-AGB stars, that have CO cores greater than $M_{\rm Ch}$ when second dredge-up occurs. Figure \[sagb1\] shows an example of such a star at solar metallicity and without convective overshooting. An intershell convective region forms and reduces the CO core mass before the convective envelope penetrates into this region when it mixes helium-burning products to the surface of the star. Whether these stars exist or some process prevents second dredge-up is unknown. Only evidence from observations of SN progenitors will show whether these stars occur in nature. Eventually the star becomes too massive for second dredge-up to occur before core collapse either by electron capture or photodisintigration after the formation of an iron core. However this change over in behaviour and absence of second dredge-up provides a sharp change in the luminosity of SN progenitors. SN Observations =============== There are two SNe that provide evidence for the upper mass for super-AGB evolution and that super-AGB may undergo SNe. An important question to ask is what type of SN would a super-AGB stars give rise to? Extreme super-AGB stars undergo second dredge-up only just before the SN and so have little time to lose their envelopes. They probably give rise to type IIP SN. Between these and the stars that have time to loose their envelopes in a wind there is a range of super-AGB stars that would lose a large fraction but not all of their envelope and will give rise to a IIL SN. In our calculations we do not see any thermal pulses. However we do use low resolution models in this case. This only affects the stars that have CO core masses less than $M_{\rm Ch}$. The super-AGB stars that we assume explode as SNe have cores that collapse very soon after second dredge-up. No further burning needs to take place for the SN to occur. First we consider SN1980K, a type IIL SN, that could have had a super-AGB progenitor. IIL SN progenitors have lost most of their hydrogen envelopes so they cannot sustain a plateau phase in their light curve. Most progenitors are thought to evolve from massive single stars that have lost a large fraction of their original envelopes, either in winds or by a binary interaction. SN1980K’s progenitor was not observed in pre-SN data but a limit could be placed on its initial mass of less than $20\,M_{\odot}$ [@S03]. With the models of @et1 we can rule out a massive single star as progenitor so it is most likely that the progenitor was in a binary system. However it has been suggested by @crazy1 that super-AGB stars might give rise to IIL SNe. This agrees with the mass limit from pre-SN observations and there is another observation that provides further evidence. @crazy2 deduced the mass-loss history from radio observations. There was an increase in mass loss $10{,}000\,$yr before the SN. This is the same period of time a $7.5\,M_{\odot}$ model with overshooting experiences between second dredge-up and SN. The mass loss during this time would reduce the envelope to the small amount required for a IIL SN. So, though there are more likely alternatives from binary evolution, if we hope to find super-AGB progenitors, we must look at both IIP and IIL SNe. The other SN to consider is SN2003gd. It is the only red giant progenitor observed with a pre-SN luminosity of $\log_{10} (L/L_{\odot}) = 4.3 \pm 0.3$. If we match this against our models, solid curve in Figure \[sagb2\] we can see that they only just agree with the upper error bar. We know that the progenitor did not go through second dredge-up because the pre-SN observations were taken less than one year before the SN and our models in this range undergo second dredge-up 10 to $100\,$yr before the SN. The dashed curve in Figure \[sagb2\] is what we would expect the luminosity of SN progenitors to be if second dredge-up were not to occur once the CO core is greater than $M_{\rm Ch}$ so that no extreme super-AGB stars would exist. These agree slightly better with SN2003gd so we might need to prevent second dredge-up in these stars. A simple way to prevent dredge up would be to restrict convection at the base of the envelope so that dredge up does not occur and the core collapses before this. Other possible variables that are likely to have an effect are the $^{12}$C$+\alpha \rightarrow$ $^{16}$O reaction rate and neutrino cooling rates. Convection itself is very uncertain and models are simple. In future we can refine our theory and use observations of SN progenitors similar to that of SN2003gd to provide a limit on the nature of convection in stellar interiors. Future Work =========== Our future plans include exploring the effect of convection on lowest-mass SN progenitors and looking for low-luminosity progenitors in models of binary stars. JJE would like to thank PPARC for his studentship and Fitzwilliam College for his scholarship. CAT thanks Churchill College for his fellowship. Eggleton P. 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Coauthors ========= This work is a collaborative effort among [Presidential Leadership Scholars](https://www.presidentialleadershipscholars.org/), [Aspen Institute Health Innovators](https://www.aspeninstitute.org/programs/health-innovators-fellowship/), [Eisenhower Fellows](https://www.efworld.org/), and their teams. All coauthors: SreyRam Kuy, MD, MHS, FACS; Rohit Gupta, BA; Ricardo Correa, MD, EsD, FACP, FACE, FAPCR, CMQ; Raymond Tsai, MD, MS; Sameer Vohra, MD, JD, MA, FAAP; Tracey L. Henry, MD, MPH, MS, FACP; Lenore Jarvis, MD, MEd, FAAP; Mansi Kotwal, MD, MPH, FAAP; Reshma Gupta, MD, MSHPM; Joseph V. Sakran, MD, MPH, MPA, FACS; Benson S. Hsu, MD, MBA, FAAP, FCCM; Pritesh Gandhi, MD, MPH; Sachin "Sunny" Jha, MD, MS; Amy G. Fiedler, MD; Quyen D. Chu, MD, MBA; Lauren S. Hughes, MD, MPH, MSc, FAAFP; Michael K. Hole, MD; Loren K. Robinson, MD, MSHP; Jay Bhatt, DO, MPH, MPA; Deborah Gordon, MBA. Introduction ============ In times of crisis, health systems leaders need a clear, systematic approach that will enable them to quickly evaluate critical needs, identify areas of weakness, and develop a strategic plan of attack. Given the rapidly evolving Covid-19 pandemic and the speed of its spread, health care organizations across the nation are frantically deciding which steps are needed to prepare for Covid-19 while continuing usual health care delivery operations. We provide a compilation of best practices for Covid-19 preparedness that will allow health systems leaders to rapidly identify key areas to address. Recommendations are based on established guidelines and frontline experiences from a national collaboration of 18 providers with collective expertise in quality improvement, patient safety, health care administration, and clinical care on the front lines of the pandemic. All collaborators are [Presidential Leadership Scholars](https://www.presidentialleadershipscholars.org/), [Aspen Institute Health Innovators](https://www.aspeninstitute.org/programs/health-innovators-fellowship/), or [Eisenhower Fellows](https://www.efworld.org/), and their teams. The cornerstone of a health system's Covid-19 preparedness plan needs to address the following critical elements: (1) mitigating local transmission; (2) conserving, supporting, and protecting staff; (3) eliminating nonurgent strains on the system; and (4) coordinating communication. Mitigating Local Transmission ============================= Hospitals and clinics are hubs for the spread of Covid-19.[@r1] Three core strategies should be taken to minimize unnecessary exposure and transmission of Covid-19: (1) limit those entering the health care facility; (2) reduce staff to essential personnel; and (3) screen all people entering the facility. Limit Those Entering the Health Care Facility --------------------------------------------- Limiting the number of individuals who enter the hospital and clinic is essential to help protect patients and health care workers from Covid-19 exposure and to mitigate local transmission. In addition, patients are at risk for exposure to Covid-19 in transit to --- and during --- their visit. Patients should remain at home unless they require urgent or emergent medical care. Instead, telemedicine should be utilized as the default approach. Telemedicine allows continued care while reducing unneeded exposure to patients and health care workers.[@r2]^,^[@r3] Although reimbursement and policy barriers have prevented widespread adoption of telemedicine, legislation as of March 6, 2020, reduced such barriers by allowing Medicare fee-for-service billing for telemedicine services.[@r4] In addition, restrictions surrounding patients and physicians being in different states have been relaxed. The United States Veteran Affairs Department issued a policy statement on March 18, 2020, stating any platform of video communication, including FaceTime, Google Hangouts, Skype, and others, are allowed for telemedicine. Furthermore, the U.S. Centers for Medicare & Medicaid Services (CMS) has waived penalties for [HIPAA violations](https://www.hhs.gov/hipaa/for-professionals/special-topics/hipaa-covid19/index.html) when serving patients in good faith through these modes of communication.[@r5] Visitors and vendors should be limited or excluded altogether, as they could be potential vectors of spreading infection. While some hospitals employ passive strategies to deter visitors, implementing strict visitation policies at health care facilities is essential.[@r6] Though many facilities have chosen to exclude all visitors, some are allowing visitors only in extenuating circumstances. In those instances, any visitor should remain in the room of the person they are visiting. Patients who need to be accompanied (such as minors, those with cognitive or developmental delays, behavioral concerns, obstetric patients needing support, or patients undergoing a procedure) should be allowed no more than one person with them. Patients at the end of life or those in hospice care may need more lenient guidelines. Elderly or immunocompromised visitors should be strongly discouraged from visiting facilities in order to protect themselves. Confirmed Covid-19 patients, and Patients Under Investigation (PUIs) should not be allowed to have visitors in their room. Reduce Staff to Essential Personnel ----------------------------------- To limit hospital and clinic staff foot traffic, non-frontline health care workers, defined as those not involved in direct patient care, should be deemed nonessential personnel and asked to work from home, if possible. > In times of crisis, health systems leaders need a clear, systematic approach that will enable them to quickly evaluate critical needs, identify areas of weakness, and develop a strategic plan of attack. This goal can be accomplished by canceling and rescheduling any nonurgent procedures (discussed more below), converting in-person meetings to virtual meetings, and implementing mechanisms for telework and telehealth. Paring down in-person staff to only essential personnel (including physicians, advanced practice providers, nurses, technicians, engineering and environmental management workers, and food service workers) will not only mitigate local transmission, but also provide for staff conservation and protection. Students have been removed from clinical clerkships at many hospitals, not only to limit foot traffic, but also for their own protection. Among essential health care workers, foot traffic with PUIs and confirmed Covid-19 cases should be minimized to every degree possible. Any procedures for PUIs or confirmed Covid-19 cases should be performed by the attending physician to limit exposure to trainees who may require more than one attempt in procedures such as intubations or bronchoscopies. Such strategies will also minimize the use of essential supplies, a vital component of crisis-management strategies for Covid-19. Measures to reduce nonessential foot traffic among non-PUIs should also be enforced to minimize cross-infection. These measures include rounding on patients using fragmented teams (e.g., if on a team with two residents, rounding on one resident's patients, then separately rounding on the other resident's patients), communicating with other patient care team members (e.g., consult services, social work, etc.) via phone instead of face-to-face, and minimizing coincidental congregation in patient rooms (e.g., waiting until the nurse is finished taking vital signs and exiting the room before the primary health care team enters the room to examine the patient). Screen All People Entering the Facility --------------------------------------- Anyone entering the health care facility (patients, staff, visitors, and vendors) should be screened outside the point of entry for Covid-19 risk. Screening may be through active means (assessing fever, asking about known or presumed exposure, symptoms, and recent travel), but if that is not possible, at the very minimum, passive screening (signage at every entrance with screening questions, directing self-identified at-risk individuals to a triage area) should be enacted ([Figure 1](#f1){ref-type="fig"}). ![Covid-19 Active Screening Template](CAT.20.0108-f1){#f1} If a patient screens positive and is stable, they should be given a mask and sent to a triage area for further evaluation by staff in full personal protective equipment (PPE). If symptoms are mild and they are stable, they could be sent home with anticipatory guidance for self-care, when to seek emergency care, and instructions for self-isolation. If the patient screens positive and exhibits respiratory compromise, including hypoxia or respiratory distress, they should be admitted for further diagnostic workup and management. If patients screen negative, they should be allowed entry as normal. For health care workers, if they screen positive, but appear medically stable, they should be sent home for self-quarantine, per the Centers for Disease Control and Prevention (CDC). If possible, two separate screening stations should be established --- one for patients and visitors and a separate one for health care workers --- to minimize congregation in screening areas and decrease risks of cross-infection. Facilities may also consider implementing drive-through screenings in parking garages or other spaces outside the facility, thereby preventing patients and visitors with an infection risk from entering the hospital.[@r7] Additionally, facilities should encourage patients and visitors to call into the hospital or clinic ahead of time if they feel poorly or have presumptive Covid-19 symptoms to ensure they go to triage stations and further reduce exposing others at screening stations. *Pitfalls regarding screening:* Despite proactive outreach, patients are still likely to present to outpatient clinics for nonurgent care. In resource-poor communities, many patients lack stable housing, phones, or Internet access and can be difficult to reach. In addition, patients, after visualizing the bottleneck upon entry to the hospital or clinic, may mischaracterize their subjective symptoms during mandatory screening to gain entry faster, only later to reveal they have concerning symptoms of Covid-19. Given that pulmonary pathology can be an early sign of Covid-19, auscultating the lungs in addition to temperature check may help identify PUIs.[@r8]^,^[@r9] Conserving, Protecting, and Supporting Staff ============================================ Health care systems must rapidly evolve staffing protocols to keep their health workforce strong enough to treat rising volumes of patients. In China, as of March 12, 2020, an estimated 3,000 health care workers had been infected and 22 died.[@r10] In Vacaville, California, one case of Covid-19 --- the first documented instance of community spread in the United States --- resulted in 200 hospital workers being quarantined and unable to work for weeks.[@r11] As community transmission of Covid-19 explodes in the United States, health care systems must be flexible with staffing, paying key attention to conserving, supporting, and protecting frontline staff.[@r12] Strategic workforce planning should be developed and preemptively implemented well before the number of Covid-19 infections surges locally. Health care facilities should also rotate staff in high-risk settings to minimize exposure, consider maintaining minimal staffing levels in house, and keep other colleagues at home for back-up and to deliver telehealth services and run virtual clinics. It is imperative that health care facilities postpone elective procedures. This approach will protect staff from unnecessary exposure to Covid-19; preserve PPE equipment, especially surgical masks, eye protection, and gowns; release anesthesiologists to provide ICU care; and conserve back-up staff for when in-house staff become incapacitated. Delaying elective surgeries will cause financial strain for hospitals and health systems. Rural hospitals are particularly precarious and risk closure due to revenue loss. Congress has responded with \$100 billion in hospital funds through the CARES Act.[@r13]^,^[@r14] > The cornerstone of a health system's Covid-19 preparedness plan needs to address the following critical elements: (1) mitigating local transmission; (2) conserving, supporting, and protecting staff; (3) eliminating nonurgent strains on the system; and (4) coordinating communication. Supporting frontline clinical and administrative staff is paramount. Expanding the essential clinical workforce will be instrumental in doing so. The governors of New York, California, and Colorado, among others, have asked retired doctors and nurses to reenter clinical care to create a reserve pool of health care professionals to replace frontline staff who become ill or need respite.[@r15] Revising approaches to clinical training and utilization of resources can contribute to supporting essential staff. Traditionally, attending physicians round on patients with a large team of trainees and advanced care providers; during Covid-19, only a skeleton crew should visit patients confirmed or suspected to have the disease. Instead of PUI consults being seen by the student, intern, chief resident, and ultimately the attending, much of the hierarchical redundancy must be cut to promote safety and efficiency and preserve PPE. As states enact more stringent social distancing measures and order nonessential businesses to close, health care workers struggle to find adequate childcare while schools and daycare centers temporarily cease operations or convert to distance learning. Although some employers provide paid leave to their health care staff, this is not universal, and there are other ways to support frontline staff. Nonessential staff and trainees, including medical students and some residents who are barred from working at the hospital during the outbreak, may be able to fill in this gap by assisting physicians, nurses, and other essential staff with childcare and other needs. University of Minnesota medical students have assisted more than 160 providers in caring for their children.[@r16] Protecting Frontline Employees Using Personal Protective Equipment ------------------------------------------------------------------ The use of PPE for health care personnel on the front lines is vital for the safety of caregivers. Currently, the CDC recommends the use of PPE in all known or suspected cases of Covid-19, including: (1) face mask or respirator, (2) eye protection, (3) non-sterile gloves, and (4) isolation gowns.[@r17] For aerosol-generating procedures (such as sputum collection), N95 respirators or Powered Air Purifying Respirators (PAPRs) are recommended. These CDC recommendations are widely accepted, currently mirroring the inpatient PPE care recommendations from the [World Health Organization](https://apps.who.int/iris/bitstream/handle/10665/331498/WHO-2019-nCoV-IPCPPE_use-2020.2-eng.pdf), the Surviving Sepsis Campaign on the Management of Critically Ill Adults with Covid-19 from the [Society of Critical Care Medicine](https://www.sccm.org/getattachment/Disaster/SSC-COVID19-Critical-Care-Guidelines.pdf?lang=en-US), and the [European Society of Intensive Care Medicine](https://www.esicm.org/resources/coronavirus-public-health-emergency/#GUIDELINES). All health care personnel caring for suspected or confirmed Covid-19 patients should be instructed in the proper donning and doffing of PPE, as well as how to properly dispose or disinfect used PPE. Refresher training should be offered. N95 respirators must be fit-tested to the individual, and PAPR education needs to be provided for those utilizing respirators. *Pitfalls regarding supplies:* Despite recommendations to use strict PPE protocols when seeing PUIs and confirmed Covid-19 cases, there are critical shortages of essential equipment and services, including PPE, lab tests, and imaging. Hospitals must balance rationing resources to meet public health needs with the ethical dilemmas that come with doing so.[@r18] Forward-thinking and creative solutions for both conserving and obtaining additional resources through alternate supply chains can help mitigate shortages, as can ensuring hospital staff have up-to-date information on PPE guidelines and recommended practices ([Table 1](#t1){ref-type="table"}). ###### Practices to Conserve Resources During the Covid-19 Pandemic ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Resource Conservation Practice ---------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Covid-19 tests • Only use tests for those who need it, or when determining public health ramifications (e.g., testing a sick health care worker who was recently in contact with other immunocompromised patients)\ • Consider whether the test will change management and decision-making processes prior to using a test kit\ • Work toward transitioning from CDC testing to in-house testing capabilities PPE • Reschedule elective procedures and surgeries\ • Keep PPE in secure locations to deter unnecessary use and theft\ • Reuse PPE (e.g., goggles that can be cleaned and reused, wear N95 masks until visibly soiled or torn or disinfected, keep single-use gowns in the room of patient)\ • Limit number of staff who enter each patient's room\ • Find ways to make or manufacture PPE (e.g., 3-D printing, sewing patterns) Equipment • Reschedule elective procedures and surgeries to conserve resources for critically ill patients\ • Borrow from areas (e.g., operating rooms), outpatient centers, other hospitals that have equipment that is not in use Hospital beds • Reschedule elective procedures and surgeries that would require a hospital bed\ • Use phone services to triage sick patients and keep low-acuity patients at home to self-quarantine\ • Utilize telemedicine services ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Notes: \PPE = Personal Protective Equipment; CDC = Centers for Disease Control and Prevention. Source: The authors. Eliminating Nonurgent Strains on the System =========================================== The Covid-19 pandemic does not change the need for the operating room, the gastrointestinal suite, or the dental clinic for many patients. However, we must minimize stress on systems during this crisis. To do this, facilities need to postpone elective procedures. This approach has a significant financial impact on hospitals because elective procedures are a major source of revenue. However, reducing cross-infection risks and conserving resources must be the first priority. Furthermore, cancellation of elective procedures has been recommended by CMS and multiple state licensing boards and health departments.[@r19] Reducing procedure volume in this way will minimize PPE consumption, decrease unnecessary Covid-19 exposure, save valuable critical care and floor rooms, conserve medications and blood products (which are already thinning with the millions of Americans self-isolating), open procedure rooms for more emergent cases, and provide the opportunity to move health care workers and equipment (e.g., ventilators, infusion pumps, monitors) where they are urgently needed. However, there is not broad agreement on a standard definition of elective. As a result, there is wide variation in how hospital systems and group practices have adopted, or in some cases, not adopted these recommendations during the Covid-19 crisis.[@r20] The American College of Surgeons (ACS) published guidelines[@r21] establishing a triage system that allows providers to objectively assess the urgency of surgical cases ([Table 2](#t2){ref-type="table"}). These have now been also adopted by CMS. Different surgical specialty societies have put forth field-specific guidelines. ###### Triaging Elective Surgeries --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Tier* Definition Locations Examples Action -------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------- ----------------------------------- ----------------------------------- ------------------------------------ Tier 1 Tier 1a: Low-acuity surgery/healthy patient\ HOPD\ Carpal tunnel release\ Perform at ASC or Postpone surgery Outpatient surgery\ ASC\ Penile prosthesis\ Not life-threatening illness Hospital with low Covid-19 census EGD (esophagogastroduodenoscopy)\ Colonoscopy Tier 1b: Low-acuity surgery/unhealthy patient Tier 2 Tier 2a: Intermediate-acuity surgery/healthy patient, not life-threatening but potential for future morbidity and mortality HOPD\ Low-risk cancer\ Perform at ASC or postpone surgery ASC\ Nonurgent spine\ Hospital with low Covid-19 census Ureteral colic Tier 2b: Intermediate-acuity surgery/unhealthy patient Tier 3 Tier 3a: High-acuity surgery/healthy patient Hospital Most cancers\ Do not postpone Highly symptomatic patients\ Emergent disease processes Tier 3b: High-acuity surgery/unhealthy patient --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Notes: HOPD = Hospital Outpatient Department; ASC = Ambulatory Surgery Center. Source: The authors, based on American College of Surgeons. COVID 19: Elective Case Triage Guidelines for Surgical Care. Updated March 27, 2020. Accessed March 24, 2020. <https://www.facs.org/-/media/files/covid19/guidance_for_triage_of_nonemergent_surgical_procedures.ashx>. However, patients may feel their medical needs are deemed less important when told their procedures will be postponed. Thus, while upholding ACS guidelines, comfort and assurance should be provided, along with allowing opportunity for shared decision-making. This is essential, as health care professionals can provide calm and reason during this pandemic. Coordinating Communication ========================== With daily changes in the Covid-19 crisis, communication between senior leadership and frontline health care staff on a regular basis is essential. Effectively carrying out this communication requires (1) establishing a centralized Covid-19 response team; (2) disseminating daily staff-wide information; and (3) hosting virtual town halls or broader virtual staff forums at least twice per week, which should be recorded and available asynchronously for those who cannot be spared from clinical duties during the forums. > Health systems should not wait until they are at a crisis point in the midst of a surge in Covid-19 infections. The centralized Covid-19 response team should include supervisors of each of the clinical and administrative departments and should meet every morning to review the latest developments, develop a cohesive plan for the day, and coordinate among departments. Nightly update emails should be sent to all staff to communicate amendments in clinical and operational protocols; staff should be required to review these communications regularly. In addition, a single shared intranet site for the latest information minimizes the risk of staff using outdated protocols or documents. Finally, virtual town hall meetings will allow every staff member an opportunity to be part of the discussion. These can be effectively led by a clinical lead, such as the chief medical officer or chief of staff. There should also be a system to allow staff to report issues to leadership, with the option for the report to be anonymous. Coordinating communication with patients before they come to the facility, during their stay, and as they leave the hospital is also important. Clinical training on communication with patients on quarantine instructions should be implemented, as well as active evaluation for vulnerabilities (e.g., a patient's housing situation). As patients leave the hospital or clinic, this general information should be given both in oral and written form. Essential Considerations ======================== During the Covid-19 crisis, health system leaders need a concise, systematic approach to quickly evaluate critical needs, identify areas of weakness, and develop a strategic plan of attack. This compilation of best practices for health system preparedness for Covid-19 is based on firsthand experiences on the front lines of the Covid-19 pandemic. There are many other important considerations not discussed here, such as treatment for Covid-19--infected staff and patients, special populations including low-income, pediatric, and transplant patients, and how to obtain additional PPE. However, these are the cornerstones of any effective Covid-19 preparedness plan for a health system: (1) mitigation of local transmission; (2) staff conservation, support, and protection; (3) eliminating nonurgent strains on the system; and (4) coordinating communication. Health systems should not wait until they are at a crisis point in the midst of a surge in Covid-19 infections. Instead, action needs to be taken proactively. Through early implementation of a strategic preventive plan, health systems may avoid being crippled by these challenges, and be able to continue to be operational and provide critically important care. Disclosures: SreyRam Kuy, Rohit Gupta, Ricardo Correa, Raymond Tsai, and Sameer Vohra have nothing to disclose.
/******************************************************************************* * Copyright (C) Git Corporation. All rights reserved. * * Author: 代码工具自动生成 * Create Date: 2014/03/10 17:31:35 * Blog: http://www.cnblogs.com/qingyuan/ * Description: Git.Framework * * Revision History: * Date Author Description * 2014/03/10 17:31:35 *********************************************************************************/ using System; using System.Collections.Generic; using System.Linq; using System.Text; using System.Data; using Git.Framework.ORM; namespace Git.Storage.Entity.Check { [TableAttribute(DbName = "JooWMS", Name = "CloneTemp", PrimaryKeyName = "CloneID", IsInternal = false)] public partial class CloneTempEntity : BaseEntity { public CloneTempEntity() { } [DataMapping(ColumnName = "CloneID", DbType = DbType.Int32, Length = 4, CanNull = false, DefaultValue = null, PrimaryKey = true, AutoIncrement = true, IsMap = true)] public Int32 CloneID { get; set; } public CloneTempEntity IncludeCloneID(bool flag) { if (flag && !this.ColumnList.Contains("CloneID")) { this.ColumnList.Add("CloneID"); } return this; } [DataMapping(ColumnName = "OrderNum", DbType = DbType.String, Length = 50, CanNull = false, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string OrderNum { get; set; } public CloneTempEntity IncludeOrderNum(bool flag) { if (flag && !this.ColumnList.Contains("OrderNum")) { this.ColumnList.Add("OrderNum"); } return this; } [DataMapping(ColumnName = "ID", DbType = DbType.Int32, Length = 4, CanNull = false, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public Int32 ID { get; set; } public CloneTempEntity IncludeID(bool flag) { if (flag && !this.ColumnList.Contains("ID")) { this.ColumnList.Add("ID"); } return this; } [DataMapping(ColumnName = "Sn", DbType = DbType.String, Length = 50, CanNull = false, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string Sn { get; set; } public CloneTempEntity IncludeSn(bool flag) { if (flag && !this.ColumnList.Contains("Sn")) { this.ColumnList.Add("Sn"); } return this; } [DataMapping(ColumnName = "StorageNum", DbType = DbType.String, Length = 50, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string StorageNum { get; set; } public CloneTempEntity IncludeStorageNum(bool flag) { if (flag && !this.ColumnList.Contains("StorageNum")) { this.ColumnList.Add("StorageNum"); } return this; } [DataMapping(ColumnName = "StorageName", DbType = DbType.String, Length = 100, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string StorageName { get; set; } public CloneTempEntity IncludeStorageName(bool flag) { if (flag && !this.ColumnList.Contains("StorageName")) { this.ColumnList.Add("StorageName"); } return this; } [DataMapping(ColumnName = "LocalNum", DbType = DbType.String, Length = 50, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string LocalNum { get; set; } public CloneTempEntity IncludeLocalNum(bool flag) { if (flag && !this.ColumnList.Contains("LocalNum")) { this.ColumnList.Add("LocalNum"); } return this; } [DataMapping(ColumnName = "LocalName", DbType = DbType.String, Length = 100, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string LocalName { get; set; } public CloneTempEntity IncludeLocalName(bool flag) { if (flag && !this.ColumnList.Contains("LocalName")) { this.ColumnList.Add("LocalName"); } return this; } [DataMapping(ColumnName = "LocalType", DbType = DbType.Int32, Length = 4, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public Int32 LocalType { get; set; } public CloneTempEntity IncludeLocalType(bool flag) { if (flag && !this.ColumnList.Contains("LocalType")) { this.ColumnList.Add("LocalType"); } return this; } [DataMapping(ColumnName = "ProductNum", DbType = DbType.String, Length = 50, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string ProductNum { get; set; } public CloneTempEntity IncludeProductNum(bool flag) { if (flag && !this.ColumnList.Contains("ProductNum")) { this.ColumnList.Add("ProductNum"); } return this; } [DataMapping(ColumnName = "BarCode", DbType = DbType.String, Length = 50, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string BarCode { get; set; } public CloneTempEntity IncludeBarCode(bool flag) { if (flag && !this.ColumnList.Contains("BarCode")) { this.ColumnList.Add("BarCode"); } return this; } [DataMapping(ColumnName = "ProductName", DbType = DbType.String, Length = 400, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string ProductName { get; set; } public CloneTempEntity IncludeProductName(bool flag) { if (flag && !this.ColumnList.Contains("ProductName")) { this.ColumnList.Add("ProductName"); } return this; } [DataMapping(ColumnName = "BatchNum", DbType = DbType.String, Length = 100, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string BatchNum { get; set; } public CloneTempEntity IncludeBatchNum(bool flag) { if (flag && !this.ColumnList.Contains("BatchNum")) { this.ColumnList.Add("BatchNum"); } return this; } [DataMapping(ColumnName = "Num", DbType = DbType.Double, Length = 8, CanNull = false, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public double Num { get; set; } public CloneTempEntity IncludeNum(bool flag) { if (flag && !this.ColumnList.Contains("Num")) { this.ColumnList.Add("Num"); } return this; } [DataMapping(ColumnName = "CreateTime", DbType = DbType.DateTime, Length = 8, CanNull = false, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public DateTime CreateTime { get; set; } public CloneTempEntity IncludeCreateTime(bool flag) { if (flag && !this.ColumnList.Contains("CreateTime")) { this.ColumnList.Add("CreateTime"); } return this; } [DataMapping(ColumnName = "CreateUser", DbType = DbType.String, Length = 50, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string CreateUser { get; set; } public CloneTempEntity IncludeCreateUser(bool flag) { if (flag && !this.ColumnList.Contains("CreateUser")) { this.ColumnList.Add("CreateUser"); } return this; } [DataMapping(ColumnName = "CreateName", DbType = DbType.String, Length = 100, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string CreateName { get; set; } public CloneTempEntity IncludeCreateName(bool flag) { if (flag && !this.ColumnList.Contains("CreateName")) { this.ColumnList.Add("CreateName"); } return this; } [DataMapping(ColumnName = "Remark", DbType = DbType.String, Length = 400, CanNull = true, DefaultValue = null, PrimaryKey = false, AutoIncrement = false, IsMap = true)] public string Remark { get; set; } public CloneTempEntity IncludeRemark(bool flag) { if (flag && !this.ColumnList.Contains("Remark")) { this.ColumnList.Add("Remark"); } return this; } } }
Image copyright Harvard Law School Library When thousands of British men were interned in Germany at the start of World War One, they rolled up their sleeves and made the best of it. In their prison camp on the River Spree in Berlin, they built a Little Britain - using the barbed wire as a trellis on which a thousand flowers bloomed. More than 5,000 British civilians found themselves caught in Germany when war broke out. They were rounded up and held captive for the duration of hostilities in sheds and stables on a racetrack at Ruhleben, on the western outskirts of Berlin. Unlike prisoner of war camps, Ruhleben was not a labour camp. These were interned civilians and the over-riding obligation imposed was not to escape. There were 200 German guards but they stayed on the perimeter, allowing the prisoners "home rule". Accordingly, the inmates selected "captains" for each block, with a "captains' committee" running the camp, and sub-committees organising everything from the camp's own postage stamps to a police service. The result was a version of the homeland in the heart of enemy territory. Streets and squares in the camp were named Trafalgar Square, Bond Street and Marble Arch. But the captains also created a mini-British Colony, with all the class distinctions and racial prejudices of the era. Image copyright Harvard Law School Library Black seamen caught on British ships at the start of the war were not allowed to have a black leader of their group - it had to be a white "captain". At least one Jewish inmate said there was anti-Semitism. There were rich and poor within the camp. The toffs employed the proles to work. A Jewish view In 1917, inmate Israel Cohen wrote down his impressions of the camp in which he was interned: "On the seventh day of our internment (on Thursday morning, November 12th, 1914, to be exact) we were summoned by the alarm-bell, which was vigorously struck by one of the guards, to line up in front of our barracks, and we awaited impatiently the new order that was to be promulgated." Jews were identified and then marched off to another, far worse, camp. As they marched out, German guards and what Israel describes as "un-English Englishmen" jeered at them. Eventually, they were allowed back into the main camp after the American ambassador to Germany intervened. Ruhleben prison camp record On the plus side, the inmates created the sporting and recreational associations you might find in any respectable Home Counties town. The inmates built a five-hole golf course and established an Association Football Club, a Cricket Association, a Rugby Football Club, a Lawn Tennis Association, a Hockey Club and a Boxing Club. There were classes with 200 teachers drawn from among the internees and a library with 2,000 books. There was an orchestra of inmates which gave its first concert on 6 December 1914. It performed Gilbert and Sullivan and some demanding classics. On 2 May 1915, for example, a "Grand Concert" consisted of the Grieg Piano Concerto in A Minor, soloist William Lindsay. Image copyright Harvard Law School Library There was also a Ruhleben Song, sung heartily by the inmates: "So line up boys and sing this chorus, shout this chorus all you can. We want the people there, to hear in Leicester Square, That we're the boys that never get downhearted. Back, back, back again in England, then we'll fill the flowing cup, And tell them clear and loud, of that Ruhleben crowd, That always kept their pecker up." There was also a Horticultural Association affiliated to the Royal Horticultural Society in London, though the inmates did not do the sort of gardening you might expect in a place where food was scarce. In the bleak world of the war-time camp, the standard diet was no more than black bread and turnip soup - but, at least to begin with, the British gardeners opted for flowers to hide the barbed wire rather than vegetables to fill their stomachs. Image copyright RHS Lindley Library The internees were a varied crowd, but not a cross-section of British society - they were men, aged from 17 to 55, who either lived and worked in Germany, or happened to have been there when war broke out. Many were seamen on ships caught in Hamburg but there were also musicians who played in the Wagner Festival at Bayreuth. There were professional soccer players and British and Irish jockeys, all having to make a life together. Find out more Image copyright RHS Lindley Library Listen to Stephen Evans' full report on Ruhleben on the World Tonight, on Tuesday 29 July on BBC Radio 4 at 22:00 BST Or catch up on iPlayer Initially, many were held near where they were captured so sailors in Hamburg were kept in floating hulks on the Elbe. But by November 1914, the old racetrack at Ruhleben on the banks of the Spree had been identified as a central internment camp. Prisoners were held in the stables. Each block contained an average of 27 stalls designed for horses but now inhabited by men. Each was about 10 feet square, in which six men lived. But this was much better than the lofts above which housed 200 men per block. Privacy did not exist. The accommodation was primitive but the internees improved it by building chairs and tables. By spring 1915, at the end of the camp's first winter, the rains had turned much of it into a mud pool, so interned engineers built drains and elevated pathways over the mud between buildings. In June 1915, new latrines were built and showers constructed so that warm showers were available once a week and cold showers all the time. Escape and suicide "Several men gave up the struggle of trying to reconcile themselves to their lot: they attempted either to escape or to commit suicide, or they became victims of mental derangement. The number of attempts at escape was comparatively small, and the successes were fewer still. "In July, 1915, Messrs. Edward Falk and Geoffrey Pyke escaped one night from the Camp. Two months later Mr. Alfred Delbosq, who had a week's furlough, escaped. And in April, 1916, Messrs. Gaunt and Colston also escaped. "The first attempt at suicide was made early one morning in March, 1915, by a prisoner with a razor, who was not stopped until he had inflicted a gash in his throat; and one or two attempts were made in the following summer. Cases of mental derangement were unfortunately more frequent." Israel Cohen - inmate But it was the gardening that really stands out. Fiona Davison, head of Libraries and Exhibitions at the Royal Horticultural Society, says it started in a small way, with inmates growing flowers in biscuit tins. "It gradually grew, and being proper English gentlemen, they decided that they should have a horticultural society, and they contacted us, the Royal Horticultural Society, to ask if they could become an affiliated society - which meant that we would send them instructions on how to run a flower show. Image copyright RHS Lindley Library Image caption Extract from a letter sent by internee T Howat to the Royal Horticultural Society "The RHS got very excited about it and put out an appeal to nurseries across the country to provide seeds and bulbs and we sent them out in Red Cross parcels throughout the war on quite a large scale. "We sent out boxes and boxes and at its peak the Ruhleben horticultural society was producing 33,000 lettuces, 18,000 bunches of radishes. They grew 83 varieties of sweet pea, dahlias, chrysanthemums. It was not just hobby gardening, it was large-scale horticulture with hot houses and nurseries… They used it to supplement their diet." But that was by the end. Initially, the focus was on flowers. Nobody quite knows why but there is a theory - the captive gentlemen of leisure could afford to buy food, either from guards or from home as food parcels or other prisoners so they wanted flowers, particularly English climbing plants which would disguise the barbed wire. Image copyright Doreen Black Doreen Black's grandfather, David McKay Tulloch was at the camp for four years and four months. He was a Scottish merchant seaman who was trapped in Hamburg when war broke out, and he kept a diary which Doreen still has. "There certainly was a Gentlemen's Club in the camp where other prisoners served the gentlemen tea," she says. "It may explain the contentious decision not to grow vegetables. It wasn't until 1917 that they grew vegetables, and they ended up selling their produce to Berlin, and the proceeds helped their destitute wives at home." McKay Tulloch returned to Scotland at the end of the war and lived the rest of his life near Aberdeen, where he drew on his Ruhleben experience to teach Doreen gardening. When she picked strawberries he asked her to whistle, so that he could be sure she wasn't eating them. In many ways, despite the scarcities and privations, the men of the camp were not badly off. The Little Britain they created was far from the trenches of Flanders or the gunsights of a U-boat on the high seas. And they were better fed than the people of Berlin who, because of the tight British naval blockade of Germany, often starved. While the inmates at Ruhleben rejoiced in the size of their marrows, the citizenry of the city around them were so hungry that if a horse dropped dead in the street, crowds scurried forward to butcher it. There were certainly worse places to spend the Great War than in Little Britain by the Spree, particularly if you played football, golf, rugby, cricket or billiards. Or liked music or wanted to read and learn. Or if you fancied a bit of gardening. Image copyright Doreen Black Subscribe to the BBC News Magazine's email newsletter to get articles sent to your inbox. The Royal Horticultural Society is planning an exhibition about Ruhleben this autumn and is very keen to hear from people whose relatives were there, particularly if they have diaries and photographs. Please email Fiona Davison at libraryenquirieslondon@rhs.org.uk Listen to Stephen Evans' full report on the World Tonight, on Tuesday 29 July on BBC Radio 4 at 22:00 BST or catch up on iPlayer.
Late surge propels Huskers to 5-2 win over MSU Lincoln, Neb. – The Nebraska baseball team (31-17-1, 13-6-1 Big Ten) tied the series against Michigan State (27-20, 9-11 Big Ten) with a 5-2 win over the Spartans at Hawks Field on Saturday afternoon. Senior right-hander Derek Burkamper made his 12th start of the season, and earned the win with 7.0 innings of work. He struck out three Spartans, while allowing two runs, neither of which were earned. Chad Luensmann came in for 1.0 inning, and Luis Alvarado picked up his team-leading ninth save with 1.0 inning of work. Nebraska trailed 2-0 heading to the bottom of the sixth after Michigan State scored one run in both the third and fifth innings. The Huskers loaded the bases in the bottom of the second, but Jesse Wilkening hit into a triple play. Ben Miller went 2-for-3 on the day to join Nebraska’s top-20 career hits list. He is in 19th on NU’s all-time list with 224 career hits. NU scored three runs on four hits to take its first lead of the game in the sixth inning. Angelo Altavilla singled, and advanced to second on a wild pitch. Mojo Hagge drove in Altavilla with his single to center field. Scott Schreiber also singled, advancing Hagge to second base. After a Spartan pitching change, Miller doubled down the right field line, which brought in two runs. NU’s no-out scoring flurry ended after three consecutive batters were retired. In the eighth inning, the Huskers added two runs to take a 5-2 lead. The bases were loaded with no outs after a Hagge double, Schreiber walk and Miller walk. Brison Cronenbold was also walked, scoring one run for the Huskers. Alvarado flew out to centerfield, scoring Schreiber. Michigan State threatened to cut into the lead in the top of the ninth, loading the bases with one out. Back-to-back outs ended the Spartans’ hopes and gave NU the win in its penultimate home game of the regular season. Sunday’s series finale will start at 12:05 p.m., with Senior Day recognition taking place before the game.
Bridget Bites : Smile Lines and Getting Older Q: Hi Bridget! As always, I absolutely love reading your posts, they are so encouraging. You seem very wise for your years and on the topic of smile lines, I am turning 31 in 15 days and while in my 20s I felt happy and carefree, I now look at my smile lines (I smile a lot too) and feel very insecure about getting older. I literally spent my entire youth on exercise, healthy foods and happy and kind relationships and I really cherish that, but I worry that now that I have these smile lines, I will have trouble finding the one as there are younger girls out there. I keep telling myself that I did my absolute best to stay healthy and happy, but I still feel insecurity when I notice the lines in the mirror. ps. Any insight you may have would be so so helpful! I really struggle with self doubt on some days.. Much love to you! You rock! A: Thank you so much for your kind kind words! Means the world to me. I wouldn’t say wise, just have had a lot of hard earned experience in certain topics. But I appreciate it 😀 First thought when reading your email - do you really want to be with someone who is only attracted to you because you look young?! That seems like such a red flag to me. You are better than that, you deserve (and will find) someone who loves the fact that you have lived. My experience with finding ‘the one’ is that it is an illusion designed to sell you things. I love my husband with all my heart, and he certainly is the one for me. But my life didn’t exist to find ‘the one’. We were actually friends for years before we decided to date. The point I am trying to make here is that “a woman needs a man, like a fish needs a bicycle” (Gloria Steinem). Whilst it can be incredible to find your bicycle, it shouldn’t be the center of your life. It should be like a melting of two kindred souls. Not throwing yourself blindly into a roaring furnace and hoping you make it out alive. It sounds to me like you are aware of your lovely relationships – I’m happy you have and recognize this! These people are the cornerstone to a good life. They bring you light and a long life. Value these people. Just because a romantic relationship ends, doesn’t mean an amazing friendship can’t exist in its place. And whilst healthy food and fitness is good, I hope it has a correct place in your life. It should be but an aspect of a life well lived. And it shouldn’t be a crutch that we cling to in the hopes of not looking older. Because it’s going to happen. In life there are two guarantees – that we die, and that everything changes. Our faces are going to change. Our bodies, our likes and dislikes. Everything. And then we die. It is our attachments to the things that change (remember – this is everything) that causes stress and suffering. So we have to work to cut these attachments, and choose to lead our lives existing in every moment. I can guarantee that once you let go of how you look, your life will open up. Someone will come along who makes sense for you as a fully grown woman. Not someone who is seeking a young looking person to make them look better. You know what happens when someone chooses a young looking partner specifically for their looks? When they start to age (because everything changes) discord will be sown between the two of them. Not always – but the odds are higher for a couple based on materialistic ends. I have always chosen my partners based on the connection between us. Sometimes these decisions lead to disaster. But it only has to work once. When you are in your 20’s you are learning about yourself. You are learning what behavior you will and will not stand for, and what is a deal breaker in a relationship. Be thankful that you are past this stage – that you are wise enough to know a massive red flag when you see it, and walk away. This is wisdom to me. Knowing what you will and will not stand for. In the modeling world, whenever a girl starts to look too old, she stops getting work. We are in a society where youth is valued above all else, even though youth rarely has much wisdom. I was sexualized from a very young age without even realizing it - before I had learned what real love was. And what the feeling of truly existing in my body felt life. I had not yet learned what it meant to be sensual when I was selling sensuality. It is a very strange and damaging system. I would not swap the experience that has come with my age for the world – and neither should you. Smile lines are awesome. Choose to live your life. Because otherwise it will pass you by. And whilst I don’t believe that death is something to be feared, not truly living is definitely something to be feared. When you inhabit your body to the best of your ability, and take your gaze from the mirror, you put yourself in the path of other people who will love you for exactly who you are. Who wants to be loved by someone only for your outward projection? My love for and connection with my husband stems from a deeper connection. And that nourishes me way more than attempting to fight the inevitable.
1. Field of the Invention The present invention relates to an image forming apparatus such as a copier, a printer, a facsimile, and a multi-function printer including a plurality of the functions, and more specifically to a configuration thereof including a plurality of fixing apparatuses fixing a toner image on a sheet. 2. Description of the Related Art Hitherto, an image forming apparatus adopting an electro-photographic system or the like is configured to fix a toner image onto a sheet on which the toner image has been formed by heating and pressing the sheet in passing through a nip between a fixing roller and a pressure roller composing a fixing apparatus. Because the surface roughness of the fixing roller affects the quality of the image formed on the sheet in such an image forming apparatus, an arrangement is made to roughen the surface of the fixing roller by a roughening roller to keep desirable surface roughness as disclosed in Japanese Patent Application Laid-open No. 2008-40363. Japanese Patent Application Laid-open No. 2008-40363 proposes to roughen the surface of the fixing roller to the desirable roughness by bringing the roughening roller rotated at a surface moving speed different from a surface moving speed of the fixing roller into contact with the fixing roller to imprint fine flaws on the surface of the fixing roller. Japanese Patent Application Laid-open No. 2008-40363 restrains streaky gloss unevenness from being generated on an output image by widthwise both edge parts (referred to as ‘coba parts’ hereinafter) of a sheet passing through the nip, even if streaky flaws are imprinted on the surface of the fixing roller by the coba parts, by roughening the surface of the fixing roller to the desirable surface roughness. However, in the fixing apparatus configured to bring the roughening roller into contact with the surface of the fixing roller to restrain such gloss unevenness caused by the coba parts, the fine flaws imprinted on the surface of the fixing roller by the roughening roller possibly generate fine gloss unevenness on the output image. It is possible to make such fine gloss unevenness inconspicuous by refining the flaws imprinted on the surface of the fixing roller. However, it is hard to suppress the gloss unevenness from being generated due to the coba parts if the flaws imprinted on the surface of the fixing roller are further made finer. Accordingly, it is desirable for an image forming apparatus required to output a high quality image to be able to suppress a drop in quality of the output image by suppressing the generation of the fine gloss unevenness in addition to the gloss unevenness caused by the coba parts.
It is well known that so called single-handle faucets are utilized in sinks, lavatories, showers and tubs in many homes. In such a faucet, the handle of the faucet is lifted to cause the flow of water to commence, with the handle thereafter being pushed down to cause the flow volume to diminish, or to shut off entirely. In addition, moving the handle to one side, such as to the left, brings about the flow of hot water, whereas moving the handle to the right typically causes the flow of cold water to commence. With a bit of experimentation with regard to movements of the faucet handle, the user can relatively easily bring about the desired volume of water, and at the desired temperature, flowing from the faucet. One manufacturer of faucets, including single-handle faucets, is Moen Incorporated of North Olmsted, Ohio. Inside the valve body of a Moen single-handle faucet is a cartridge, such as a cartridge manufactured under U.S. Pat. Nos. 3,840,048, 3,916,950 or 4,330,011. Typically, such a cartridge is slightly under ¾″ in diameter and approximately 4″ in length, being made of brass or plastic. A plurality of apertures are located in the exterior of such a cartridge, and a plurality of O-rings are arrayed around the circumference of the cartridge. This arrangement is utilized in order to prevent leakage occurring between the cartridge and the interior of the valve body in which the cartridge is operatively mounted. Slidably yet relatively tightly mounted inside the cartridge is a stem having apertures at preestablished locations therein, which can on occasion be caused to line up with apertures in the cartridge. The volume of water flowing from the faucet in which the cartridge is utilized, as well as the temperature of the water, is determined by the relationship of the apertures of the stem with respect to the apertures in the cartridge in which the stem is mounted. At the top of the stem is an internally threaded connector, which enables a desired connection to be made to the faucet handle. Because of the above-described arrangement, when the faucet handle is lifted, the stem is caused to move up with respect to the cartridge, to cause the flow of water to commence. Movement of the faucet handle to the left or to the right causes rotation of the stem, which in turn causes hot water or cold water to flow from the faucet, in accordance with the user's positioning of the faucet handle. All of this is well known. From time to time, a faucet may begin to leak, which may occasion the cartridge and its stem being removed from the valve body. That this may be readily accomplished, Moen provides a “T” shaped cartridge removal tool that can be used to engage the stem of the faulty cartridge after the faucet handle has been removed. A handle is located at one end of this “T” shaped tool, with the other end of the tool being configured to engage the end of the cartridge. An elongate screw loosely disposed along the centerline of the tool body represents an intrinsic part of the T-shaped tool, with the threaded inner end of the elongate screw being able to threadedly engage the internally threaded connector located at the upper end of the previously mentioned stem. The proper engagement of the cartridge removal tool with the stem of the cartridge enables the plumber or other user of the tool to grasp the handle of the tool firmly, and then proceed by a rotating, pulling motion to cause the faulty cartridge to be withdrawn from the valve body. In most instances this procedure takes place without incident, following which the new cartridge can be installed into the valve body. From time to time however, the cartridges fails or fractures during the withdrawal procedure, meaning that, for example, only the stem portion of the faulty cartridge is removed from the valve body. Quite unfortunately, this permits some or all of the outer portion of the cartridge to remain in an interior portion of the valve body. In many instances it is quite difficult to remove the fractured portion of the cartridge remaining in the valve body, with this causing the plumber to improvise an arrangement for removing the remaining, dismembered portion of the cartridge. The plumber may use a screwdriver, needlenose pliers, a tap, or other such tool in an attempt to grasp and remove the fractured cartridge portion. This is not only an inexact, time consuming procedure, but also there is a distinct risk of the interior of the valve body being damaged. It is a fact that if the interior of the body becomes scratched or scarred, there is a distinct risk of undesirable leakage occurring after the replacement cartridge is in place in the valve body. It is therefore obvious that if the function of the conventional T-shaped cartridge removal tool could be extended to permit a dismembered cartridge to be engaged and then readily removed, the task of the plumber could be greatly simplified. It was in an effort to enable such an expanded role for the conventional T-shaped tool that the present invention was evolved. I am aware of the existence of certain tools having some similarity to the conventional T-shaped cartridge removal tool with which my novel elongate threaded device is intended to be used. For example, the Johnson U.S. Pat. No. 1,382,835 entitled “Bushing Tool” involves a device involving a T-shaped handle, to which is attached a tapered, externally threaded component. The Abbott U.S. Pat. No. 4,799,832 entitled “Ratchet Tap Wrench” teaches a device having a T-shaped handle having jaws 71 for engaging three or four tap shank sizes. The Hedspeth U.S. Pat. No. 6,643,904 entitled “Shank Removal Tool for a Carburetor” is somewhat relevant, but the Hedspeth device has no capability for removal of a faulty cartridge from a valve body, and its utilization could not be increased to accommodate an elongate threaded member for utilization should a cartridge fracture during the cartridge removal procedure. It is clear that an improved device is needed for utilization with the conventional cartridge removal wrench or tool, for improving and expanding upon the utilization of such tool.
"Subtitles by demonseye" "Hey, this area's restricted." "Oh, hi." "Yeah, I know." "They called me down here." "Some of this wiring got screwed up." "Nobody called it down to me." "I'm gonna have to see a work order." "Yeah." "Just a second." "There you are." "Nothing personal." "Well, I guess that wraps it up." "Good work, everybody." "Marty, I couldn't be happier with the way this worked out." " Congratulations." " Good for you." " Oh, hold that." " Whoa." "Gee, thanks." "Thanks for pushing that, Bob." "The light's on." "But you never know." "It really might be broken." "Shut up." "So, remember, honey..." "No!" "Please!" "Jesus." "Bob, what button did you push?" "Peter!" "Come on!" "Mr. Bagwell, make sure these other elevators remain locked down and empty." " Yes, sir." " Now, there's no other way, no doors, no other way in or out except through access panels." " Is that correct?" " Yes, sir." "All right, gentlemen, what we have here are 13 passengers in an express elevator." "Below floor 30." "Bomb's already taken out cables." "Bomber wants 3 million dollars, or he blows the emergency brakes." " What's our clock?" " He gave one hour." "That leaves us 23 minutes exactly." "Anything else that'll keep this elevator from falling?" "The basement." "The city would like to avoid that event, officer Traven." " We can't just unload the passengers?" " This is an express elevator, gentlemen." "The only way in or out is through access panels." "The bomber's also wired the hatch to trigger the bomb, which seats him in the crazy but not stupid section." "Sir, Harry volunteers to examine the device." "Yeah, right." "Fine." "The two of you check it out." "The nearest access panel's on the 32nd floor in the lobby." "I want reports only." "We're in a holding pattern." "Worthy and Briggs, I want you to secure the base area." "No one in or out." "Everyone else, I want you to affirm building evac." "Move!" "Looks like we're walkin'." " Hurry, folks, but watch your step." " Twenty-nine!" "All the way down to the lobby!" "Let's go, folks!" "Thirty!" "Thirty-one!" "Thirty-two." " Hello?" " What's going on?" " Come on, man." "Get us out of here!" " Hello?" " What's that?" " Hello!" "Please, help us!" "Help!" "Please!" "Get us out of here!" "Please!" "Please, get us out of here!" "Who's up there?" "Who's up there?" "What's going on?" "Ladies and gentlemen, this is the L.A.P.D." " Thank God!" " What are you doing up there?" "There's been an elevator malfunction, so just relax." "Hey, come on!" "What are you guys waiting for?" "We'll have you out of there as soon as possible." "Am I lying?" "How come they sent cops here?" "Shouldn't they send repair guys?" " Yeah." " Doesn't make any sense." "What do you think?" " You're the expert." "I just work here." " Looks pretty solid." " Anyone we know?" " I don't recognize the work, but he's a pro." "Oh, he's cuttin' it close." "I don't like it." "Yeah, well, what's to like?" "Mac said we hold, so we hold." "All right, pop quiz." "The airport." "Gunman with one hostage." "He's usin' her for cover." "He's almost to a plane." "You're a hundred feet away." "Jack." "Shoot the hostage." " What?" " Take her out of the equation." "Go for the good wound, and he can't get to the plane with her." " Clear shot." " You're deeply nuts." "You know that?" ""Shoot the hostage." Geez." "Harry, this is wrong." "He's gonna blow it anyway." "Why?" "I don't know." "Gut feeling." "Well, right now, Mac outranks your gut, so we sit." "This is taking way too long." "How much you think that elevator weighs?" "Jack, come on." "Maybe we can do something about those hostages." "We're not gonna shoot 'em, right?" "Hey, where are you going?" "What's going on?" "Don't go!" "Don't leave us here!" "No, we just take them out of the equation." " You sure it'll hold?" " It'll hold." "Six minutes." "I can't get any more time." "He's not talkin'!" "I need the goddamn money now!" "Tell me again, Harry." "Why did I take this job?" "Aw, come on." "Thirty more years of this, you get a tiny pension and a cheap gold watch." "Cool." "Hoa!" " God, it's hot in here." " There's no air." " Can't they just pry the doors open?" " I can't breathe." "Don't fuck with daddy." "Oh, my God!" "Oh, my God!" "Oh, my God!" " Oh, my God!" "What's happening?" " Grab her hand!" "Usually they fall down now." "Get her up!" "He's early." "The son of a bitch is early." "Mac, we need more help up here." "Now!" " Oh, please open the door!" " I don't wanna die!" "Please!" " Save me!" "I wanna get out!" " Open the door!" " Please, help me!" " Joan, get back!" "We'll get you out!" "Give me your hands!" " It's okay." "Give me your hands." " Pull me through!" " Oh, God!" " Watch your head." "Watch your head." " Help me!" " Okay, I've got you." "I've got you." " Take it easy!" " You're fine." " Oh, thank you!" " You're fine." " Take her." "Okay, let's go!" "Next!" " Okay, lady, come on." " Thank you." "Oh." " I've got you, ma'am." "Just move back, please." "What the hell is all this?" "Help us!" "Hurry!" "Hurry!" "Hurry!" "Let's go!" "Go!" "Go!" " Let's go!" "Let's go!" " Come on!" "Come on!" " Oh, my God!" "Oh, my God!" " Come on." " Help me out!" "Please help me out!" " Watch your head, watch your head." " Come on, lady!" "Come on!" " No." "Come on, lady!" "Come on!" "Grab my hand!" "Come on!" "Go!" "There's one more." "Can you get her out?" "Come on." "Come on, let's go!" " No." " It's going to fall." "No, I can't!" "Just take one step, reach out and take my hand." " Come on!" " Hurry!" "Come on!" "Oh, God!" "Don't let go of me!" "You're okay." " Great God!" " Oh, my shoe!" "Let's go, let's go!" "Was it good for you?" "Oh, it was great for me." "How was it for you, honey?" " Elevator dropped." " Oh, good." "That's good to know." " Is your watch slow?" " Uh-uh." "No, no." "He jumped the gun." " We had three minutes left." " Why does he do that?" "He's losing his three million." "I don't know." "Maybe he couldn't hold his wad long enough." "It's a common problem among middle-aged men." "So I'm told." "He's here." "He could've blown that thing from Pacoima." "No." "He knew we were up to something." "He's close by." "He's not gonna corner himself in a building." "We evacuated anyway." "Come on." "He'd wanna be here, but he must stay mobile, right?" "The elevators." "Passenger cars were stopped." "They checked them out." "What about the freight elevators?" "Will the mystery guest please sign in?" "What?" "Jack." "Damn it!" "Get to the floor!" "Shit!" "Shit!" "Shit!" "Up!" "Get your ass up!" "I don't suppose anybody'll give me three million just for you." "Hold it!" "Pop quiz, hot shot." "Terrorist holding a police hostage." "Got enough dynamite strapped to his chest to blow a building in half." "Now, what do you do?" "There's gonna be 50 cops waiting for you in the basement." "Oh, standard flanking deployment, right?" "Well, maybe we'll get off on the third floor, huh?" "At least that's what they'll think." "I want location of those goddamn shots!" "Briggs, where's Jack and Harry?" "Lieutenant, we've got movement on the freight elevator." "It's on three." "Let's move!" "End o' line." "This day has been real disappointing, I don't mind saying." "Why, because you didn't get to kill everyone?" "There will come a time, boy, when you'll wish you'd never met me." "Mister, I'm already there." "But, you see, I'm in charge here." "I drop this stick, huh?" "and they pick your friend up with a sponge." " Are you ready to die, friend?" " Fuck you." "Oh!" "In 200 years, we've come from" ""I regret but I have one life to give for my country" to "Fuck you"?" " Go ahead, drop the stick." "Do it." " Shut up, Harry." "Aw, we've got all the balls in the world right here, man!" "Give it up!" "You got nowhere to go!" "Shoot the hostage." "Say goodbye, Harry." "You fuck!" "Freeze!" "Freeze!" "Give it up!" "You're out of options!" "Through dedication and bravery, these next two officers... effected the rescue of 13 citizens of this city." "Thanks to them, the only life taken by the terrorist's bomb was his own." "You shot me." "I can't believe it." "They're giving you a medal for shooting me, you little prick." "Harry... you told me to." "... the Medal of Valor is the highest honor for a member of Los Angeles Police Department." "Officer Harry Temple." "Congratulations." "Officer Jack Traven." "Way to go, Jack." "Way to go." " There we go." "There we go." " Harry, my man." "Oh, beautiful." "A toast to me." "All right." " Make me feel good about myself." " There you go." "Hey, Sandy!" "Here we go!" "Okay, so how we do..." "Oh, whoa, whoa, whoa!" "I need a bib!" "Here we go." "All right." " You can't take me anywhere." " That's mine." "And here... is to Harry." "For his quick thinking... for his grace under pressure... and for his brave and selfless act." " Hear, hear!" " Hear, hear!" "And... to Jack..." "for shooting Harry." "Something we've all wanted to do for a very long time." "Hey, hey, hey!" "Okay, no, no." "Here it is." "Here it is." "Here's to you guys, for doing your job... and for not getting dead." " Mazel tov." " Mazel tov." "I can't do that." "We are the two luckiest guys in the world, you know that?" "We got the bad guy and we didn't lose any civilians." "Yeah, we're good." " No, you were lucky." " No, we were lucky." "You'd better understand it." "We were dealing with a total psycho." "This guy could've blown us up at any time." "Whew." "And I got a bullet in me." "Six inches off the mark, and they're giving the medal to my wife." "Harry, come on, man." "I mean, we won, we got 'im." "Do you listen?" "Do you ever..." "Because I am not gonna be around to back you up, so you'd better start thinking." "Guts will get you so far, and then they'll get you killed." "Luck runs out, sooner or later." " Right, chief?" " That's right." " Ho!" " I'm all right." "I'm all right." "I'm gonna go home, have some sex." "Harry, you're gonna go home and puke." "Yeah, well, that'll be fun too." "Come on, you gimp." "Hey, Jack, I saw you on TV." "Congratulations." " Thanks, Bob." " Yeah, you looked fat." "Be easy on him, Bob." "The boy was up late last night partying'." " A wild party, huh?" " Yeah, well, I don't remember that well." "Couldn't have been too great." "I woke up alone." "Yeah?" "Well, you know, the last time I partied like that," "I woke up married, huh, Vinnie?" "Hey, Jack, you forgot your muffins." " Have a good one, Bob." " Thanks, Jack." "Take care, huh?" "Thanks." "See you tomorrow." "Call 911!" "What do you think, Jack?" "You think if you pick up all the bus driver's teeth, they'll give you another medal?" "Jesus!" "You think I wouldn't have been prepared?" "Two years I spent setting up that elevator job." "Two years I invested myself in it." "You couldn't understand the kind of commitment that I have." "You ruin a man's life's work, and you think you can walk away." "You got blinders on to the world." "But I got your attention now, didn't I, Jack?" " Why didn't you just come after me?" " No, this is about me." "This is about my money." "This is about money due me." "Which I will collect." "3.7 million dollars." "It's my nest egg, Jack." "At my age, you gotta think ahead." " When I find you..." " Pop quiz, hot shot." "There's a bomb on a bus." "Once the bus goes 50 miles an hour, the bomb is armed." "If it drops below 50..." "it blows up." "What do you do?" "What do you do?" "I'd wanna know what bus it was." "You think I'm gonna tell you that?" " Yes." " Very good." "There are rules, Jack, and I want you to get this right." "No one goes off the bus." "You try to take any passengers off the bus, I will detonate it." "I want my money by 11:00 a.m." " We can't pull that kind of money in time." " Focus, Jack!" "Your concern is the bus." "And don't try to call." "The radio's down." "Now, the number of the bus is 2525." "It's running downtown from Venice." "It is at the corner of Ocean Park and Main." "Sam!" "Sam!" " Annie." " Sam!" "Tell him to stop!" "Shit!" "Excuse me!" "Comin' through." "Sam!" "God..." "Shit." "Whoa!" "Stop!" " This ain't no bus stop." " Oh, Sam!" " Get rid of your butt, Annie." " Okay, it's gone, it's gone." "You are..." "a good, kind man." "One day people will write songs about you." " Hi." " Hi." "First time in L.A." " Oh, no, I live here." " No, I mean mine." "Oh, that's just funny." "You heard me wrong." " No, I'm sightseeing'." " Oh, really?" "Yeah, I hate to use the word "tourist", but... it's not like I can hide it." "Not really." "Aw, geez, you know, it took me three hours just to get here from the airport." "I got so lost." "L.A. is one large place." "Course, you live here, you probably don't notice." " I'm such a yokel." " Oh, geez." "There, I said it." "You know what?" "I..." "I got gum on my seat." "Gum!" "Excuse me." " Morning." " Hi." "Hey!" "Watch it!" "I just couldn't handle the freeways anymore." "I got so tense." "This way I can just relax all the way to work." "Yeah, well, I love my car." "I miss my car." "Oh, God, look at that." " Hey, Sam!" " Shit!" " Sam!" " What?" "Why don't you just drive over these people or something?" " Don't spit on my bus, Annie." " Such a mess." "Stop!" "Open up!" "Get off the door, man!" "This ain't no bus stop!" " That guy really wants to get on the bus." " Open up!" "Stop!" "Don't, Sam!" "Don't let him on!" " L.A.P.D.!" " I can't hear you." " Stop this bus!" " What?" "L.A.P.D.!" "Stop the bus!" "L.A.P.D.!" "Stop!" "Stop!" "Stop!" "L.A.P.D.!" "Get out of the car!" "Jesus, not again." "This is my car." "I own this car." "It's not stolen." " It is now." "Move over." " Fuck!" "Oh, man." "You scratch this puppy, and me and you are gonna have words, you understand?" "Okay, look, man, we don't have to go so fast, all right?" "Just slow down a little bit, all right, man?" "Just slow do..." "Oh, shit!" "Oh, come on, man!" "Just don't tear up my car, all right?" "Okay, okay, okay." "Just slow down just a bit, okay?" "We don't have to go so fast, do we?" "I mean, we don't..." "we don't have to go so..." "That was a nice move, man." "Whoo-hoo!" "Shit, shit, shit, shit!" "Oh, shit!" "The least you could do is slow down!" "Come on!" "Holy shit!" "Oh, shit!" "Oh, shit!" "Move, move, move!" "Move!" "Is that that guy?" "Man sure has a hard-on for this bus." "Hey!" "I'm a cop!" " What?" " I'm a cop!" "L.A.P.D.!" "There's a bomb on your bus!" " There's a bomb on your bus!" " What?" " There's a..." " What?" "Fuck!" " There's a bomb on your bus!" " Watch the road!" "Grab that, will ya?" "I want you to write on it." "I want you to write on the back "Bomb on bus"." "Write it, write it, write it!" "Watch the road!" "Oh, shit!" "Oh, shit!" "No!" "Don't slow down!" "No, no!" "No, no, no, no, no!" "Speed up!" "Op..." "Open your door!" "Open the doors!" "Fifty!" "Stay above 50!" " Okay." " All right?" "470-8000." "Ask for detective Harry Temple." "Harry." "Harry, it's Jack." "Yeah." "You'd better not be calling in sick, cause I dragged my ass outta..." " Harry, he's alive." " What?" "The bomber." "He's back." "He hit one in Venice already." "Fire chief said there's nothin' left." "Temple, we just got a ransom demand from your dead terrorist." " Says he's rigged a city bus." "Where's Jack?" " Where do you think?" " I gotta get on that bus." " You gotta get..." "Yeah, yeah, you get on the bus." "Drive straight!" "Stay in this lane!" "Watch the road." "W-wait a minute." "What are you doin'?" " Are you insured?" " Yeah." "Why?" "No!" "No!" "Ah!" "Broke my... my door." "Sir..." "I need to take your phone." " Take the phone." " Take the wheel." "What are you..." "What?" "Oh!" "Oh, shit!" "Oh, shit!" "Drive straight!" "Oh, shit." "Oh, shit!" "Whoa, shit!" "Whoa, shiit!" "This guy's out of his mind." "Okay, listen." "You gotta stay above 50." "Excuse me." "Are you out of your mind?" " Whatever it takes." " Hello!" "Everybody, I'm Jack Traven, L.A.P.D." "We have a slight situation on the bus here." "Ma'am, if you'll please sit down..." "No, I won't sit down." "You're scaring the shit out of these people." "Ma'am, please!" "If everybody will stay in your seats and remain calm, we should be able to diffuse the problem." " So sit tight and..." " Get away from me!" "I don't know you, man." "I'm not here for you." "Let's not do this." " Stop the bus!" " He can't!" " Sit down!" " Listen..." " Stop the bus!" "Stop it!" " Look, look!" "Listen!" "Look, I'm putting my gun away, okay?" "Okay?" "Now, listen." "I don't care about your crime." "Whatever you did, I'm sure... that you're sorry." "So, it's cool now." "It's over." "I'm not a cop right now." "See?" "We're just two cool guys just hangin' out..." "No, don't!" "Sam!" "I've got the wheel!" "I've got it!" "I've got it!" "I've got it!" "Sam!" "Oh, God, Sam!" "Sam, come on, you gotta move your legs." "Somebody move his legs!" "Sam, get your foot." "Sam, get your foot off the pedal!" " We gotta stop this thing!" " No!" "Don't!" "Stay above 50!" "But Sam's been shot!" "We gotta get him off!" "You slow down, and this bus'll explode!" "There is a bomb on this bus." "If we slow down..." "it'll blow." "If anyone tries to get off, it'll explode." "Bullshit!" "Yeah, there's a bomb." "Some funny joke, man!" "Are we gonna have a problem now?" "He's bleeding so much, I don't know what to do." "There's so much blood!" "Put pressure front and back, keep his legs up and put this under his head." " Hold on, man." " Sam, lift your head." "Hold on." "Miss, can you handle this bus?" "Oh, sure." "It's just like driving a really big Pinto." " I need to know, can you handle this bus?" " I'm fine, I'm fine, I'm fine." "Just tell me what the plan is." "Is there a plan?" "Just for you to drive." "We're okay for now." "Just keep us above 50." "Good plan." " So, you're a cop, right?" " That's right." "Well, I should probably tell you that I'm taking the bus because I had my driver's license revoked." " What for?" " Speeding." "Harry, we're on our way to the chopper." "If anything changes, let us know." "Anything we haven't seen should be in here." "... wrong with the driver, but at least one car, a Jaguar, has been driven off the road by the speeding bus." "It appears it is somewhere between Los Angeles the bus apparently came onto the freeway at the Lincoln on-ramp." "It began picking up speed, swerving, and hasn't slowed down since." "Minutes ago, a Los Angeles police officer boarded the bus by jumping onto it from a moving car." "Oh, would that be you, Jack?" "... to have been able to stop the bus which is..." " Where do we start?" " All right." "Check the speedometer." "Has it been fucked with or loosened or any wires..." " See any wires or anything?" " Excuse me, ma'am." " No, it's clean." " Huh?" "All right, then it's gonna be under the bus." "Probably it was rigged to one of the axles." "I can't get under the bus right now, Harry." "It's kind of in motion." "Excuse me." "Excuse me!" "Hold on." "There's... access panel..." "in the floor." "Underneath you, man." "All right, Harry, we're in." "Passenger relay." "Sir!" "Take this." "I want you to tell him what I see." "Okay!" "We got a wad!" "Pretty big!" "There's a pretty big wad." " Brass fittings!" " Brass fittings." " I think I can reach the circuit wire." " He can reach the circuit wire." "No!" "No, no!" "No." "Don't-don't!" "Don't do that!" " That's a decoy." "Classic." " That's a classic decoy." " What else?" " What else?" " Hold on." " Hold on." "Fuck me!" "Oh, darn." "Harry, there's enough C-4 on this thing to put a hole in the world." "Okay." "All right." "Just stay... just stay calm." " What else?" " Three triggers." "One on the axle I can't really see," " a cellular remote..." " Officer." "... and a timer running off a wristwatch." " A watch?" "What kind of watch?" " Gold." "Gold band, fairly cheesy." " Officer." "Officer!" " What's on your mind, Harry?" "Shit, what do I do?" "Officer!" " What do I do?" "What do I...?" " Aw, shit!" "Which way?" "Which way?" "!" " Get on the shoulder." " Okay." "Watch it, watch it!" "Um, stay on or get off?" " Stay on or get off?" " Off!" "Off!" "Hold on!" "Oh, God." " Keep going." " It's red!" " Go!" "Go!" " Wh-What?" "Ow!" "My foot!" "This is much better." "... city streets." "The bus is on Western, heading in a southbound direction." "Now, when the bus did exit here, it had a couple of close calls with a few cars on the..." "Yeah, yeah!" "All right!" "Oh." "We don't know what authorities are planning to do, but we can..." "I don't get it." "The watch is a shitty timer." "Why use it?" "What's he sayin'?" " Lots of people have watches, Harry." " This guy has no M.O." "A bomber falls in love with one kind of bomb and they're very monogamous." "This guy uses C-4, dynamite, different trigger every time, and now he throws in this watch." "He's an encyclopedia of bombs." "He knows every kind." "Yeah, and everything we do to dismantle it." "Wait a minute." "I wanna look at the files for the last ten years." "We did the mug shots already." "That's not gonna help." " No." "I wanna look at cops." " Come on." "Let's go." "Yeah." "Mac, where have you been?" "I had to bail on the freeway." "We're in the city." "I can see you." "Just keep going straight." "I'm gonna try to clear the roads for you." "Just stay on line." "Shit!" "Oh, Jesus!" "God!" "No!" "Go left!" " Sorry." " Oh, my God!" "Oh, geez!" "People, stay outta my way!" "Stay outta my way!" "Ma'am, up to the right." "Okay, okay, okay." "I see it, I see it, I see it!" "Shhhh..." "Mac." "Mac, you gotta" " get me outta here!" " Oh, God-iiiiii!" "A few more blocks, you're gonna come up to a soft turn." "Right." "Then hold straight." "I've got some units waiting for you there." "They're gonna lead you to the 105 Freeway." "It's not in use." "It'll be empty." "You'll be totally clear." "Got it." "In a few blocks, we take a soft turn to the right." "I'll find you, okay?" "Okay." "Wait a minute." "Wait." "Escort to where?" " Where do we get an escort to?" " Look out!" "What?" "What?" "Oh, God!" "Son of a bitch!" "My God!" "I just hit the baby!" " Cans!" " I just hit the baby!" " Cans." " Oh, my God!" "Oh, my God!" " There's no baby." "It was full of cans." " Are you sure?" " Yes." " Are you sure?" " Yes." " Oh, my God!" "Okay, let's go." "Jesus!" "No!" "No!" "No!" "Get back!" "Why aren't they in school?" "Why aren't you in school?" " Mac, we're boned." " I'll get you out, Jack." "All right, listen." "We got an entrance coming up, Jack." "It's gonna be a real ugly turn, though." " How ugly?" " What's ugly?" "Okay, we got a hard right comin' up at the construction site." "This should be it." " That is a dead end." " There's a turn." " I can't make that turn." " You can make it." "No." "Keep left." "Keep left." "You make it wide." "Oh, God, we're gonna tip over." "We're gonna tip over." "You're right." "We're gonna tip over." "Everyone on this side of the bus now!" "All right." "On this side of the bus, as far as you can, please!" "Hold on!" " Over here, over here!" " As far as you can, now!" "That's it." "Mac, you'd better clear this site out." " Everybody hold on!" " This side of bus!" "Hold on!" "Hold on!" "Oh, God!" "Here we go!" "Here we go!" "Here we go!" "Whoo!" "Oh, my God!" "Oh, God!" "Is everybody all right?" "Yes!" "Take me to that interchange at the 105!" "Oh, my God!" "We might have died." "I can't think." "It's okay." "If you need to, you go right ahead and vomit." "Hold it right there!" " Mac, I got 'em patched!" " Right." "Get rid of that scaffolding and replace it with webbing." " Okay." " Norwood, I want aerial units up ahead." "No obstructions in the freeway." "We have a window here." "I wanna make sure it stays open." "Right." "You, sir." "This gentleman's gonna drive you..." "Thank goodness for this freeway." "Shoot." "Could you do me..." "this tiny favor and hold the wheel for me for a second?" "Hold the wheel?" "Thank you." "Ma'am, you did very well." "Actually, you were incredible." "I've never seen driving like that." " Annie." " What?" "It's... it's my name." "Annie." " Annie." " As opposed to "ma'am"?" "Okay." "So..." "Why is all this happening?" "I mean..." "What did we do, bomb the guy's country or something?" "No, it's just a guy who wants money." "I don't buy that." "It's not a very good way to make money." "So, um, what is this guy's deal?" "A while back he held some people for ransom." "It went sour, and now he's a little pissed at me." "What does that have to do with us?" "Nothing." "It's a game." "If he gets the money, he wins." "If the bus blows up, he wins." " What if you win?" " Then tomorrow we'll play another one." "But I'm not available to drive tomorrow." "Busy." "We got no match for that description." "No one's lost a thumb for at least the last ten years." " He could be from anywhere." " I can't access all that." "Forget the files." "I want you to start going through the pension fund." "This guy's drawin' disability." "He may not be L.A.P.D., but he's livin' here now." "I want pictures!" "I've seen this asshole." " Hey!" " Hey, Mac!" "Let's get these passengers off the bus!" " We can't do it, sir." " There's no time for any stunts, Traven." "We gotta get these people out of harm's way." "I got orders!" "We move these people, he'll see." "Remember." "Crazy, not stupid." "All right, look." "Harry's tryin' to find out who this guy is." " We think maybe he's a cop." " Lieutenant!" "It's him." "He wants to talk to Jack." " He's on the line for you." " Okay, give him the number." "Give 'im the number!" " How's he doing?" " The bleeding is less, but..." " Are they going to help us?" " Sure they are." "They're the police." "Hey, your taxes are payin' their salary." "If we die, they gotta take a pay cut." "I mean, you kn... you know..." " Yeah." " I think we have trust." "But it looks on TV like you're tryin' to get those passengers off the bus." "Look, you gotta let me have one." " Now, we went over the rules." " As an act of faith." "We have an injured man here." "The driver's been shot." "Jack, now tell me that you haven't been shooting the passengers." "I thought it was customary for a police officer to, you know, shoot the bad guys, huh?" " This man has no time." " No one gets off!" "It'll grease the wheels with the money men if you show a little charity." "There's still gonna be plenty of us to kill." "Okay, son, you can try and unload the driver." "You tell that wildcat behind the wheel not to slow down, though, or he won't even get a chance to bleed to death." "And, Jack?" "Don't slip." " He's letting us unload the driver." " Norwood, get us closer!" " We're gonna get the bus driver off the bus!" " We're gonna get the driver off." " Just him?" " For now." "Gigantor!" " Ortiz." " Ortiz." "I'm gonna need your help." " Okay." " Okay, I need you to pass him to me." "You have to keep him straight, or I think the wound will tear." " What about the rest of us?" " Hey, hey, hey!" "Lady!" " Come on, Sam." "I got you." " I can't stay!" "I can't..." " How you feelin'?" " Like I've been shot." " Take care, Sam." " Okay, Annie." " Drive straight!" " Keep it straight!" "Okay, Annie, get as close as you can, okay?" "All right." "Closer!" "A little closer, Annie!" " Annie, a little closer!" " Okay." "Okay, how's this?" "Sorry!" "Sorry." "Okay, Annie, no problem." "Let's try it one more time." "A little more!" "Okay!" "Okay!" "Right there!" "Steady!" "Hold it steady!" "You got 'im?" "You got 'im?" " Hold him!" " I got him!" "We're clear!" " All right!" "Oh." " I'm all right." "Thanks." "Oh, my God." "Yes!" "Oh!" "It's gonna be okay." "Come on!" "Come on, lady, give me your hand!" " I have to, Annie." " No, Helen!" "No!" "Helen, no!" " Come on!" "Right there!" "Over there!" " Helen, no!" "No!" "... here at the 105 Freeway where the police have successfully led the runaway bus..." "No!" "Helen!" "Goddamn it, Mac!" "We gotta get those fuckin' choppers out of here!" "... was driving the bus." "Well, I c-I couldn't tell how old..." "An explosion." "Some kind of an explosion." "The bus hasn't exploded, but..." "Oh, my God." "A woman caught in the blast fell." "She was pulled under the wheels." "This is terrible." "Interactive TV, Jack." "Wave of the future!" "Ha-ha-ha, huh?" "I can't be here." "I can't, you know." "This is the wrong bus." "I mean, for me to..." " I can't die here." " Hey, shut up, man." " I got a wife." " Oh, you do?" "Hey!" "So if you have a wife... and I don't, does that mean I'm expendable?" "Hey, what are you talkin' about, man?" "The guy's just talkin' crazy." "Gets on my nerves." " Gets on everybody's nerves." " Oh, yeah?" "Well, I think I have the right to be a little..." "What are you staring at anyway, man?" " After all that we've been..." " You nose in..." "Why don't you just let everybody die in peace, if that's what's gonna happen, huh?" "So you're a really tough guy, huh?" " I got a right to be upset." " You're really tough, huh, Gigantor?" " Why don't we just step outside?" " Hey!" "Hey!" " How are you doing?" "You all right?" " Mm-mm." "What can I do?" " When that bomb went off..." " I know." "I thought that was it." "I thought that was the bomb and I was dead." "And then, when I saw her body fall under the bus, it was like..." " You were glad you were still alive." " Mm-hm." " I'm so sorry." " Don't be." "You should be glad." "We all are." " Doesn't mean you don't care." " I know, but she was so scared." "She was scared." "She was a nice lady who didn't deserve to get killed." "But, Annie, if she'd gotten off, it would've killed us all." "He's the asshole, Annie, the guy who put us here." "Remember that, okay?" "Big asshole." "Okay." "You sure?" "Well, how far?" "Sir, uh, we have a serious problem." " What?" " This freeway isn't finished." "What are you talkin' about?" "The aerial unit caught it about three miles ahead." "There's a section missing." "Section missing?" "But it's on the map." "It's finished on the goddamn map!" "I guess they fell behind." "Fuck." "You're fired!" "Everybody's fuckin' fired!" "Get me closer!" "Hey, get closer." "Watch 'im in the mirror." "Jack!" " How big is the section?" " Fifty feet." "At least." "There's a gap in the road up ahead." "It's big." "You're kidding." "How big?" " Fifty feet." "Jack..." " What?" "We gotta get these people off the bus somehow." "You know I can't." "What did..." "What did he say?" "Jack?" "Jack!" "What'd he say?" "What's the matter?" " There's a gap in the freeway." " What?" " What do you mean?" " How big is a gap?" "Fifty feet." "A couple of miles ahead." " This is crazy." " Right along up there?" " What is this?" " Geez." "Jack!" "Jack!" "What if I shift into neutral and just keep the engine revving?" " No, he'd have thought of that." " What then?" "What?" "What?" " What?" "Jack!" " Floor it." " What?" " Floor it!" "It's an interchange." "There might be an incline." "Floor it!" "Fine." "Everybody, hold onto your seats or whatever you can." "When we hit the gap, heads down." "That's it?" "That's it?" "That's all we can do." "Let's put these underneath your seat, all right?" "Put your bags underneath the seat." "Hey, I didn't mean to shoot the guy." "Hold on." "Is this really gonna work?" "Jack!" " Yeah." " Jack." " Come on, come on, come on, come on." " Oh, God." " Come on, come on." " God." " Come on!" " God!" "Oh, shit." "Everybody, hold on!" "I wanna see our baby." "Oh, God." "Jack." "Shit!" "Okay." "Okay." "Yes!" " We are way out of control!" " We made it!" " You okay?" " Yeah." " You okay?" " I'm okay." "I'm okay." "All right!" "All right!" "Let's go!" " Is everybody okay?" " Yes!" "Whoa!" " We did it!" " We made it." "You are the man." "You are the man!" " Thank you." "Thank you very much." " Goddamn!" "Yes!" " Oh, shit." " I think you missed your calling." "Yeah?" "What was it?" "Watch the road." "Should've been a pilot." "Ow." " Sweet Jesus." " Get off!" " What?" " Get off this." "Now, now!" "Get off this!" "In there." " Where?" "Right here?" " Yeah." " Right here?" " Yeah." "Hey." "Hey, hey, stop!" "Stop!" "He's just entered the airport." " All right!" " The airport?" " There's thousands of people there." " That's my boy, Jack." "He should be able to circle the runways and buy us some time." "Choppers can't fly in there." "It's restricted airspace." "He's headed for the end of the field." "That must be Bravo Tango, an emergency runway." "Yeah, let's hope it's built." "Let's move!" "We're at the airport." "Yeah." "So?" "I already seen the airport." "Yeah?" "Very, very exciting, Jack." "Some close calls, huh?" " But you've done all right for yourself." " What do you want?" "I want money, Jack." "I wish, uh, that I had some loftier purpose, but, um, I'm afraid in the end it's just the money, Jack." "I would like, uh, large, uh, nonsequential bills in two clear plastic bags, unmarked..." " Can you remember all that?" " What are you telling me for?" "Because I want you to help me to get it before it gets too late." "I hate negotiators, Jack." "They talk to you like they're your best friend, and they don't even know ya." "Why are they messing with me, huh?" "Do they think I'm doin' this for fun?" " Aren't you?" " Oh, that's unfair, Jack." "You don't know how I feel about this." "You don't even know me." "I know you want a shitload of money you didn't earn." "Oh, I earned it." "I spent my life earning it." "I got a medal, too, Jack." "A medal and a pink slip and a "sorry about your hand"." " You have to let me off." " Oh, no!" "That's not good." "You want me to help you?" "I need to talk to these people face-to-face." "They think you're bullshit." "They don't think that." "Look, you want the money, I don't want anyone else to die." "Let me get on the ground." "Just me." "That's not against the rules." " All right." "I want you back real fast." " Fine." "Jack, nothing tricky now." "You know that I'm on top o' you." "Do not attempt to grow a brain." "It could encourage other terrorists to try and pull up another..." "So, I guess there's a plan now?" "Could be." " Yeah?" " He's letting me off." " What?" " Just keep circling." "You'll be fine." "Everybody, sit tight." "I'm getting off for a minute." " Do you think that's a good idea?" " It'll be okay." " What, are you just gonna leave us here?" " I would." "Don't worry." "I won't go far." "Hey." "Don't forget about us." "The choppers are gone, Jack." "Let's dump the passengers now." "No way." "He's ready for that." "How is that possible?" "I don't know how, Mac." "I just know he is." "He's been a step ahead every time." "If we unload, he'll take them out, I guarantee." " So where does that put us?" " I've to try and dismantle that bomb." "That's an incredible ride..." "the 10 Freeway, leaving Los Angeles to the 105 Freeway, this Santa Monica bus has ended up here at Los Angeles International Airport circling the runway." "I'm tellin' ya, honey, he's somewhere jerkin' off." "He didn't have to get on the bus in the first place, Ortiz." "Hey, get your ass behind the yellow line." "What is that?" "I have no idea." "We won't be able to hold this thing steady for very long." "I just need a few minutes." "If I can't do it by then, I can't do it at all." " Harry, you with me?" " Yeah." "You be careful, Jack." "What is he doing?" "Oh, my God, he is insane." "Okay, Jack, this is it." "Don't get dead." " This is not a very good plan." " Have faith, sister." "Oh, Christ." "Just keep it steady." "Oh, thank you for the tip, Ortiz." " This guy is nuts!" " Gosh darn." "Okay, we're gonna have to try to bypass the remote current with the battery." "Can you find the trip wire for the remote?" "I don't know." "I got a few choices here." " Black and red?" " And green." "Okay." "All right." "I-I'm gonna guess he's not gonna go with standard copper for the remote." "That'd be too weak." "I'd use a fiber alloy." "Uh, Jack, I'm gonna need you to look at the wire." " Harry, it's covered." " Yeah, I know." "You gotta cut off the sheath." "But don't cut the wire." "Right." "Fuck me!" "Shit!" "Bull's-eye!" "Great." "Okay, I want you to clip on the battery" " and run it to the lead wire." " Copy." "I can't bypass." "It'll fire." "Oh, shit!" "It's a collapsible circuit." ""Howard Payne, Atlanta P.D. Bomb squad." "Retired in Sun Valley in 1989 when a small charge left him with fingers numbering nine."" "That's our scumbag!" "We got him, Jack." "We found 'im." "We can get to his place inside of 15 minutes." "Great." "Jack, I want you to get out of there and sit tight." "We're gonna go after the source." " Watch your back." " Wait, wait, wait for me!" "Mac, get me out of here." "Somebody go to the back and check and see if he came out the back!" "Go!" " Can you see 'im?" " He's not behind us!" " What?" "!" " He's not back here!" "Oh, my God, oh, my God, oh, my..." "Go-go look!" "Go look and lay down and look under the bus and see if you can see him down there." " Can you see 'im?" " No!" "You don't see him, like, back by the tires if you look down..." " I can't see 'im!" " Are you sure?" "I can't see 'im!" " Oh, my God, I hit 'im!" " What the hell was that?" " Oh, my God!" "Do you see 'im?" " Did we hit 'im?" "Look out the side of the window and see the other side!" " My tools!" " Will somebody get 'im his tools?" "Please, help him!" "Hurry!" "Oh, God." "We're dragging him." "Do you see 'im?" "Where is he?" "Is he there?" " Do you see 'im?" " Jack!" "Jack!" " I see him!" " What?" " I see him!" " You do?" "Is he okay?" " He's all right!" "He's all right!" " Yeah!" "Whoo!" "Hold my legs!" "Hold my legs!" "Somebody, hold my legs!" "Hold his legs!" "Hold his legs!" "Come on!" "Come on!" "I gotcha!" " Is he hurt?" "Is he okay?" " Pull!" "Pull!" "Come on!" "Come on!" "We got 'im now!" "Come on, pull!" "Jesus, I can't believe it." "You are a complete jerk!" "You know that?" "Oh, thank God!" " Did you have any luck with the bomb?" " Yeah." "It didn't go off." " Ortiz, thanks." " How many lives you got, man?" "You're not too bright, man, but you got some big, round, hairy cojones." "That's... very gross, Ortiz." "Can't even pay him a compliment." "How you doin'?" "You scared the shit out of me, Jack!" "Ow." "Other than that, I'm fine." "What is that smell?" " It's gas." " We're leaking gas?" "We are now." "What, you thought you needed another challenge or something?" " Mac." " Mac here." "Go ahead." "Can you get a fuel truck to pace us here?" "We're losing gas." " I'll see what I can find." "How much time?" " I don't know." "Ten minutes." " It doesn't look good." " Gotcha." "Norwood, get a fuel car out here on the double." "Right." "Is that gonna work?" "I don't know." "Come on, Harry." "Save my life." "Harry..." "Tell me good news, man." "Oh, I'm sorry, Jack." "He didn't make it." "You... fuck!" "It was the watch that led him to me, wasn't it?" "Huh?" "It seemed a little hammy to me to build the bomb outta my precious retirement gift, but, you know, I figured a sign that said Howard Payne would be pushing it." "I'm gonna rip your fuckin' spine out, I swear to God." "You're gonna do exactly as you're told." "Jack, we both know that he was the brains of your particular operation." "You can't beat me." "You're gonna pay me every dollar." "Otherwise, you, the wildcat and every innocent person on that bus are gonna end up just like your friend." "Are you paying attention?" "Jack, are you listening to me?" " Jack?" "Jack!" " Yeah." "Good." "Now, you tell them that the drop point is Pershing Square." "There's a garbage can on the northeast corner." "You drop the bags and leave." "I don't show until all your people are gone." "It's gettin' on to 11:00 a.m., Jack, and I think it's gonna be a very pretty day." " Jack!" " Damn it!" "Jack." "Come on, Jack." "Come on." "Don't give up on me, Jack." "Come on, please." "Jack, stop it!" "Jack, come on!" "Stop it, okay?" "Don't give up on me right now, all right?" "Hey, we're really scared, and we need you right now, all right?" "I can't do this by myself." "Please?" "Jack, please." "Okay?" "Please." "All right?" " We're gonna die." " No, we're not." "We got this far, okay?" "I'll be damned." "You go to the..." "University of Arizona?" " Yeah." "So?" " Good football team." "Yeah, I guess so." "I don't really know." "Arizona Wildcats." " Right." " He can see you." " What?" " He can see you." " He can see me..." " Just keep looking straight ahead." "He called you a wildcat before." "I didn't even pick up on it." "Bastard's got a camera right in your face." "He can see the whole bus." "He's been playing me from minute one." "Yeah, well, he-he can see me, but can he hear me?" "Doesn't look like it." "He's just watching you." "This is a special news bulletin." "We are following the progress of what is turning out to be a harrowing and amazing story as a city bus, rigged to explode if it slows down, races around literally in circles at the Los Angeles airport." "The two dead are a female passenger and the driver of another bus, both blown up by the bomber." "And the other people in jeopardy are, of course, the passengers of the bus held hostage at the whim of a madman." ""The whim of a madman." I like that." "There's a camera on the bus just over my left shoulder." "I want you to stare straight ahead." "Don't make any big movements." "Okay?" "It's Jack." "Yeah, I know about Harry." "Is that news van still around?" " Get those cameras to stop taping." " Right." "L.A.P.D. I need this unit." "Now, you can broadcast UHF, right?" "Yeah, sure." "There's a signal going to that bus." "I want you to find it." "We're gonna have to take you off the air temporarily." "Yeah, sure." " Please, sir, stop taping." " Come on, come on, come on." "Hurry up." "Good!" "Tape off of that." "Remember." "No big movements." "Just look whipped." "That ain't gonna be too hard." " Tape it." "Good." "Come on, tape it!" " It's taping!" " Jack." " Yeah." "Look." " Mac." "Fuel." " Yeah." "Jack, five minutes." "Not enough time." "Run the tape." "We have to unload." " I only have a minute of tape." " Do it now!" "I want you to make a tape and loop it so that it runs over and over, okay?" " All right, run it." "Run it!" " All right." "Tape's... rolling." "We still have no live picture, but reports are that the bus continues to circle inside L.A.X." "and that everyone is safe for the moment." "... hard to imagine what's going through their thoughts at this time." "Certainly, a sense of community..." "Rig the steering wheel and the gas pedal." "All right, let's get 'em off." "Just step and walk." "Okay, you, you and you." "Policehavejustissued a general statement, which really doesn't tell us much more than all the previous statements." "Grab my wrist." "That's it." "Good." "Come on." "Look straight ahead." "Watch your head, ma'am." "Come on." " Come on." " It's okay." " That's good." "That's good." " Come on, you can do it." "Grab my wrist and come across." " Put your hand out." "Take his hand." " Don't look down." "Good." "That's it." "Come on." "That's it." "You got it." "Come on." "Come on." "All right, let's go." "Let's go!" " Come on, buddy!" "I gotcha." " Give me your hand." " Give me your hand." " Come on." " The hand." " Come on." "Come on." "Hold on down." " Hold on." " Just grab my hand." " I gotcha." " Come on." "Don't look down." " Shit." " Hold on!" "Hold on!" "Jack!" "Grab my hand!" "My hand!" "Grab my hand!" "All right." "All right!" "Jack!" "Jack, I can't hold this anymore." "Annie." "Hold on!" "Jesus, Jack!" "No, no." "No." "Hold it!" "Jack." " Oh, God." " Wedge down the gas pedal." "Okay." "Okay, I got it." " You got it?" " Yeah, I got it." "I got it." "Okay." "Okay, Annie, get on." "God, I can't do this." "Jack, I can't do this." " Let's go, let's go!" " Shit." "Shit." " Jack." " Shit!" " Hold on!" " Okay." "Okay." "Okay." "Shit!" "Are you all right?" "No." "It's okay." "It's okay." "It's over." "It's over, Annie." "You did it." "You did it." "Oh, fuck." "Oh, I hate the airport." "Yeah." "You're not gonna get mushy on me, are you?" "Maybe." "I might." "Hope not, cause, you know, relationships that start under intense circumstances, they never last." "Oh, yeah?" "Yeah." "I've done extensive studying on this." "Here comes the cavalry." "How you doin'?" "We're okay." "We're okay." "Well, I just might be a nice guy and let you have the rest of the day off." "Oh, boy." "Mac... this is Annie." "Annie... meet lieutenant McMahon." " How're you doing?" " Okay." " This should take care of it." " Ow!" " Watch it." " I'm sorry." "We're gonna take you guys back and have you checked out." "Lieutenant!" "It's him." "He wants to know when he's gonna get his money." "Son of a bitch." "I can tell him what to do with his goddamn money." "He doesn't know it blew up." "Thirty minutes." "I'll be right back." " All right, here's our target." "Fox?" " Yes, sir." "I want you in 4-1, you in 1-2, you're in 3." "Let's move it." "Norwood, are you sure the paint bomb is in with the money?" "It's done, sir." "Too bad, Jack." "You could've made a good cop." "Okay." "We still have no live picture, but reports are that the bus continues to circle inside L.A.X..." "Potentially a disastrous situation, and it's definitely been defused to some extent." "However, there are still a number of..." "No!" "No!" " Miss." " Hmm?" "You can't be this close." " You need to move back." " Oh, no." "Jack Traven said..." "Jack Traven, yes, he asked that you be brought out of harm's way." "Just move right over here." " He's running a little late." " He's not late." " What?" " He's never late." "Well, that money hasn't moved." "We got 200 eyes on that can and a bird dog in the bag." "I'd say he's covered." " Turn it on." " What for?" "It hasn't moved." "Just do it!" " Shit, it's moving." "He's got the money." " Jack!" "Shit!" "Freeze!" "Pop quiz, asshole." "You have a hair trigger aimed at your head." "What do you do?" "What do you do?" "Turn around." "Turn around!" " Oh, no." " I'm sorry." "Be prepared." "It's the Boy Scout marching song." "What are you gonna do, Jack?" "I don't think you can shoot 'er." "Let her go." "No, I don't think I'm gonna do that." "Fill it." "Now." "Well, I think Harry would be very disappointed, feeling that we're right back where we started, huh?" "Let her go." "You don't need her." "You have the money." "Take it and walk." "Come on." "Just take it and walk." "You don't need 'er." "Do it!" "Just take your goddamn money and walk!" "Hey, hey, stay right there!" "Stay right there." "I'll do it." "I'll let go." "I'll let go." "Oh, yeah." "You still don't get it, do you, Jack?" "Huh?" "The beauty of it." "A bomb is made to explode." "That's its meaning, its purpose." "Your life is empty because you spend it trying to stop the bomb from becoming." "And for who?" "For what?" "Do you know what a bomb is, Jack, that doesn't explode?" "It is a cheap gold watch, buddy." "You're crazy." "You're fuckin' crazy." "Oh." "No, poor people are crazy, Jack." "I'm eccentric." "Get the money." "Let's go." "Come on!" "Let's go!" "Move it!" "Move it!" "You stay!" "Move it!" "Move it!" "In the door!" "In that door, now!" "Bye, Jack." "Punk." "All right!" "Get in there." "Go on." "Get in." "You get back in there!" "You get this train moving'!" "Go on!" " Are these seats taken?" " No." "No." "All aboard." "Doors will be closing." "Come on!" "Back over here!" "Hands around the pole." "All aboard." "Doors will be closing." "Damn." "Come on, come on, come on!" "Pleasereport, westbound 501." "What is your position?" "Westbound 501, please check in." "You see?" "You're beginning to see how it works, huh?" "You have police orders to return to the station, westbound 501." "Do you copy?" "You have to hold this." "It's like a grenade." "You have to help me now." "Come on, hold it." "Don't let it go." " Huh?" "Counting on you." " Do you copy?" "Hey!" "I'll take it from here." "No!" "No!" "No!" "No!" "No." " Ho!" "Uh-oh!" "Wait, wait." " No." "No." "Maybe you'd better let me have this after all." "I'm afraid you're a bit hysterical, and you might let this go a mite early." "Hey." "Hey." "Buckaroo!" "It's not cause you're a woman, all right?" "Hey, it's all right." "Looks like we're all alone." "Look, you won." "Okay?" "You beat Jack." "You beat everybody." "Just... just throw me off the train." "I don't care." "Okay?" "This stick, huh?" ", works on a remote." " When you explode..." " Yeah." "... that's where they'll come, but that's not where I'll be." "I have a different plan." "Mess like that, they don't even count body parts." "Gives me more time." "It's not gonna hurt, Annie." "Hey, Jack!" "Is that you?" "He is so persistent." "He always gets his man." "Wouldn't be able to interest you in a bribe, would I?" "I've got, uh, plenty to go around!" "My money!" "You bastard!" "How does that feel?" "You like that, huh?" "You like it, you bastard?" "My money!" "Shit." "You!" "I'm comin' for you, Jack!" "Hey, I'll drop this stick, boy." "You want that?" "Huh?" "I'll get you." "I'm gonna get you." "Ohhh, yes!" "Yahoo!" "Yes!" "What do you do, Jack, huh?" "What do you do?" "You're so smart." "Right, Jack?" "You piece of shit." "I'm the guy with the plan cause I'm smarter than you." "I'm smarter than you." "You..." "You..." "Yeah?" "Well, I'm taller." "Jack?" "Jack!" "Oh, God, I thought you were dead." "Jack." " Turn around." " Where's Payne?" "He lost his head." "Oh, God." " Let's take this off, shall we?" " Yes, let's take this off." " Take it off." " Hello?" "Hello?" "Come in." "Copy." "Jack, this is Mac." "Do you hear me?" "Jack, if you're there, you got to stop the train." "The track isn't finished." "I repeat..." "Mac, I copy..." "Mac." " Do you copy?" " Mac." " Mac, can you hear me?" " Try the emergency brake." "Jack, do you copy?" "Jack, can... you..." "Nothing works!" "Annie, you won't believe this." " What?" " Jack, ...is... ack... an't..." " We have to jump." " You can't stop it?" "Well, um..." "Okay, well, undo me and I'd love to go with you." "Come on." "Please." " I don't have the key." " What?" "I don't have the key." "Shit." "You gotta get off the..." "You gotta get off the train." "Jack, please!" "This track dead-ends, Jack." "You gotta get off this train." "This is crazy." "There's a curve ahead." "I'm gonna speed it up, make it jump the track." "This is really stupid." "Jack." "Jack, please." "You can still jump." "Jack, please." "Please!" "Jack." "Holy shit!" "I can't believe he hit my van." "No, it's all right." "Unreal." "You didn't leave me." "I can't believe it." "You didn't leave me." "Didn't have anywhere to be just then." "Check it out." "I've to warn you," "I've heard relationships based on intense experiences never work." "Okay." "We'll have to base it on sex then." "Whatever you say, ma'am." "That's so romantic."
Court of Appeal judges in London have stuck two fingers up to Nestle's attempts to trademark the shape of its famous four-fingered KitKat bar. The ruling is the latest twist in a decade-long UK chocolate wars saga between Nestle and Cadbury. The Dairy Milk maker failed in its own attempt to trademark the shade of purple it uses after Nestle complained. But on Wednesday, it was the Cadbury bosses celebrating the latest attempt to foil KitKat's plans. Nestle claimed that the shape of the bar was so unique, it should be protected by law. But time after time, judges have thrown out the attempt. Its case was not helped by the existence of a similar Norwegian bar, called Kvikk Lunsj, which means "quick lunch" and has been around since 1937. Image caption Norway's "Kvikk Lunsj" looks similar to the KitKat and is available in some parts of the UK A spokesperson for Nestle said the company is weighing up its options. "Nestle is disappointed by the Court of Appeal judgment and is considering next steps. "KitKat is much loved around the world and its four-finger shape is well known by consumers. "Nestlé's four-finger shape has been granted trademark registration in many countries of the world, for instance Germany, France, Australia, South Africa and Canada, further protecting it from imitations." Copycat versions Cadbury's owner, Mondelez, which fought the attempt, said: "We are pleased with the Court of Appeal's decision today and welcome their conclusion. "As we have previously stated, we do not believe the shape of the KitKat bar should be protected as a trademark in the UK." The ruling could lead to copycat versions of the bars hitting shelves, a practice some discounter supermarkets have popularised. Aldi and Lidl have both been accused of selling own-brand versions that are remarkably similar to famous brands. KitKats were first snapped up by the public in 1935 by Rowntree, when it was called the Chocolate Crisp. Image copyright Getty Images Image caption Cadbury failed to trademark its famous purple colour In September 2015, Nestle failed to persuade European judges of its arguments. The European Court of Justice said that the company had to demonstrate the public relied on the shape alone to identify the snack. They concluded this was difficult to prove if goods also showed a brand name, such as KitKat. Nestle has experience of trying to register difficult trade marks. It took more than 40 years for it to register the slogan "Have a Break" as a trade mark, finally succeeding in 2006. Chocolate wars Nestle first tried to trademark the shape of the four-fingered chocolate bar in 2010, but its attempts were opposed by Cadbury. The two have also battled over other trademarks. In 2013, Nestle blocked Cadbury's attempts to register the shade of purple used in the packaging of Dairy Milk. Nestle has not sought to trademark the two-fingered bar. Shapes can be trademarked for certain distinctive products - such as the familiar Coca-Cola bottle - but others can struggle. Get news from the BBC in your inbox, each weekday morning
Exposure, to me, is a very important word. When you are exposed to things in life, you are more aware and well-rounded to the world around you. What does exposure mean to you? Maybe it means being exposed to the cold weather, or rather, here in Austin, the heat. Maybe to you it means being exposed to someone in a vulnerable way. In the world of landscape architecture, exposure is everything. It is being in the know of new technologies, new advances in design, new ways we can help the environment through our designs, etc. selfie, obviously Landscape Architecture is not a very well known major among high school students selecting a career path. Without exposure to the fields of design, our industry misses out on talent critical to our future and students may lose the chance to tap into their passions. This is the problem that AIA Design Voice aims to solve. Through the 3×2 program, high school students intern with a minimum of 3 design offices throughout one week in July. The disciplines range from Architecture, Landscape Architecture, Urban design and planning, Interior Design, Graphic Design, Mechanical, Civil, and Structural Engineering. The students get to choose which offices they wish to visit and are exposed to office culture and what each profession does. Three students joined dwg. on Monday, July 17 and sat through a short presentation of what type of work dwg. does around Austin. Mindy, Francisco, and I shared our experiences of finding the profession and why we all personally chose landscape architecture. The students asked questions and shared why they wanted to participate in AIA Design Voice and what types of design professions they were interested in. Getting a tour of the 804 Congress parklet The students received a tour of the office and were able to see how our colleagues work throughout the day, and were exposed to the critical elements of a design studio including our materials library and print room. After the tour we traveled around downtown to visit a few dwg. projects. We told them about the large scope of work an L.A. might work on in an office – anywhere from a parklet to a major office plaza renovation. From the site visit, they were able to see the many different subjects that one may work with as an L.A. – from plants to hardscape materials to art and ecology. The students, in a two-hour period, were exposed to landscape architecture and are better equipped with a full range of knowledge regarding the design industry as they move forward to choose their career paths. We look forward to participating again next year!
--- author: - Rujie Yin bibliography: - 'ref.bib' title: 'Content-Aware Neural Style Transfer' --- Motivation {#motivation .unnumbered} ========== In the emerging inter-disciplinary field of art and image processing, algorithms have been developed to assist the analysis of art work. In most applications, especially brush stroke analysis, high resolution digital images of paintings are required to capture subtle patterns and details in the high frequency range of the spectrum. Algorithms have been developed to learn styles of painters from their digitized paintings to help identify authenticity of controversial paintings. However, high quality testing datasets containing both original and forgery are limited to confidential image files provided by museums, which is not publicly available, and a small sets of original/copy paintings painted by the same artist, where copies were deferred to two weeks after the originals were finished. Up to date, no synthesized painting by computers from a real painting has been used as a negative test case, mainly due to the limitation of prevailing style transfer algorithms. There are two main types of style transfer algorithms, either transferring the tone (color, contrast, saturation, etc.) of an image, preserving its patterns and details, or distorting the texture uniformly of an image to create “style". In this paper, we are interested in a higher level of style transfer, particularly, transferring a source natural image (e.g. a photo) to a high resolution painting given a reference painting of similar object. The transferred natural image would have a similar presentation of the original object to that of the reference painting. In general, an object is painted in a different style of brush strokes than that of the background, hence the desired style transferring algorithm should be able to recognize the object in the source natural image and transfer brush stroke styles in the reference painting in a [content-aware]{} way such that the styles of the foreground and the background, and moreover different parts of the foreground in the transferred image, are consistent to that in the reference painting. Recently, an algorithm based on deep convolutional neural network has been developed to transfer artistic style from an art painting to a photo[@Gatys2015c]. Successful as it is in transferring styles from impressionist paintings of artists such as Vincent van Gogh to photos of various scenes, the algorithm is prone to distorting the structure of the content in the source image and introducing artifacts/new content in the background of the transferred image. We investigate conditions and methods to improve this neural style transfer algorithm to be content-aware along with the goal of synthesizing a high resolution painting in more realism style. Background {#background .unnumbered} ========== Deep convolutional neural network (CNN) has been extensively applied to various image processing following its initial success in image classification of ImageNet[@Deng09imagenet:a]. A CNN typically consists of a sequence of sets of convolutional layers followed by non-linear rectifier and local pooling. Like classical image processing, each convolutional layer performs linear spatial filtering on the input image or the output feature maps from the previous layer; the local pooling down-samples spatial information similar to dyadic down-sampling in classic wavelet decomposition of images. On the other hand, the non-linearity introduced by the rectifier enables CNN to approximate complicated non-linear transforms, mapping images to a feature space where different classes of images become linearly separable. The depth of CNN is proportional to the capacity of the function space that can be approximated, hence a deeper CNN is more “expressive" than a shallower one, encoding more feature information of image classes. Neural Style Transfer {#neural-style-transfer .unnumbered} --------------------- Due to the richness of features that a deep CNN can possess, pre-trained CNN models on massive datasets like ImageNet with high accuracy in image classification have been used as feature mappings from image domain to abstract feature spaces for other image processing. In particular, the neural style transfer algorithm in [@Gatys2015c] is based on VGG-Network(VGG-Net)[@simonyan2014very], a near-human performance deep CNN model in image recognition. Given an input image ${\mathbf{x}}$, let ${\mathbf{f}}_{l,k}({\mathbf{x}})$ be the output $N_l$ dimensional feature map[^1] of VGG-Net at the $l^{th}$ layer and the $k^{th}$ filter, where $N_l$ is the size of the corresponding spatial grid, then the neural style transfer is formulated as the following optimization problem, $$\begin{aligned} \label{eq: style-opt} {\mathbf{x}}^* = {\text{argmin}}_{{\mathbf{x}}'} &\sum_{l \in {\mathcal{L}_c}}\sum_{ k}\big\Vert\, {\mathbf{f}}_{l,k}({\mathbf{x}}_c)-{\mathbf{f}}_{l,k}({\mathbf{x}}')\,\big\Vert^2_2 \notag\\ &+ \lambda \sum_{l\in{\mathcal{L}_s}}w_l\sum_{i, j}\big\vert\, {\mathbf{f}}_{l,i}^\top\, {\mathbf{f}}_{l,j}({\mathbf{x}}_s) -{\mathbf{f}}_{l,i}^\top\,{\mathbf{f}}_{l,j}({\mathbf{x}}')\,\big\vert^2\end{aligned}$$ where ${\mathbf{x}}_c$ is the source (content) image, ${\mathbf{x}}_s$ is the reference painting (style image) and ${\mathbf{x}}^$ is the style transferred source image. The first term in penalizes the difference between the feature vectors of source image and transferred image at a set of layers ${\mathcal{L}_c}$ in VGG-Net, such that the content of these two images are close. To measure the closeness of styles, the second term involves the covariance of feature maps ${\mathbf{f}}_{l,\cdot}$ corresponding to different filters at a fixed layer $l$ in the set ${\mathcal{L}_s}$ weighted by $w_l$. This formulation is also used in another closely related neural algorithm for texture synthesis[@Gatys2015b], where only a texture (style) image is used to generate a synthetic image presenting similar texture. In the style transfer algorithm, the sets of constraint layers are chosen as ${\mathcal{L}_c}:$ `conv4_2` and ${\mathcal{L}_s}^{\text{style}}:$ . In the texture synthesis algorithm, ${\mathcal{L}_s}^{\text{txtr}}:$ . We defer the comparison of these two settings of constraint layers to the discussion of methods in the next section. Methods {#methods .unnumbered} ======= We propose a content-aware neural style transfer algorithm based on the framework of . We first present the base algorithm for the simple case where the source content image and the reference style image are of the same resolution. The algorithm is then generalized to the case where the content image is in lower resolution than the style image. The output of our algorithm is a synthesized painting that could have been painted by the same painter of the reference painting from the content image. We always assume that the content image (photo) and the style image (painting) contain similar objects to minimize the ambiguity of how the generated painting should look like. Style Layers ${\mathcal{L}_s}$ {#style-layers-mathcall_s .unnumbered} ------------------------------ For each layer $l$ in the network, let $s_l = N_{l-1}/N_l$ be the scaling factor of that layer. For a convolutional layer, the scaling factor is 1; for a pooling layer, the scaling factor is its kernel size. Therefore, the scale of features characterized at level $l$ is $\sigma_l = s_1\cdots s_l$. Specifically, a convolutional layer has the same feature scale as the last pooling layer ahead of it, and the final pooling layer has the maximum feature scale in a network. It is observed in both [@Gatys2015b] and [@Gatys2015c] that a texture image can be synthesized by fitting the covariance of feature maps ${\mathbf{f}}_{l,\cdot}$ at layer $l\in{\mathcal{L}_s}$, namely minimizing the second term in with random initialization. Moreover, the generated texture image is spatially uniform and it represents similar texture of the reference style image at the scales of style layers ${\mathcal{L}_s}$. In style transfer [@Gatys2015c] and texture synthesis [@Gatys2015b], different style layers ${\mathcal{L}_s}$ are used, but the scales of these layers are the same, namely $1, \sigma_{{\text{\path{pool 1}}}}, \sigma_{{\text{\path{pool 2}}}},\sigma_{{\text{\path{pool 3}}}}$ and $\sigma_{{\text{\path{pool 4}}}}$. Using layers at different scales collaboratively enforces a hierarchical structural constraint on the texture in the synthesized image. Given a reference style image whose texture is at scale $\sigma_s$, that is its energy concentrated within a circle of radius $\sigma_s^{-1}$ centered at the origin of the frequency spectrum, ${\mathcal{L}_s}$ should contain layers at scale larger than $\sigma_s$ to retain full texture pattern. Although restricting ${\mathcal{L}_s}$ to layers at smaller scales than $\sigma_s$ results in less satisfactory result, the statistics of the reference style pattern at finer scales are still preserved in the generated image. In fact, a style pattern at scale $\sigma_s$ consists of sub-patterns at finer scales, such as color dots, single or group of brush strokes, etc. Therefore, preserving statistics of ${\mathcal{L}_s}= \{\text{\path{conv1_1}}\}$ results in a synthesized style image consists of color dots, where the portion of areas in different colors is roughly the same as that in the reference image, see results in [@Gatys2015c] and [@Gatys2015b]. More generally, the sub-patterns at scale $\sigma_l, l\in{\mathcal{L}_s}$ are preserved in the synthesized image, which is a [re-arrangement]{} of the composition of reference style image at unconstrained scales. Together with the fact that VGG-Net is not rotation invariant, this insight of re-arrangement leads to an important condition on the input content image and the style image for content-aware style transfer: the object in content image and that in style image should be in the same orientation and in the same relative scale to image size, which is also numerically validated in section Experiments. Content Layers ${\mathcal{L}_c}$ and Intialization {#content-layers-mathcall_c-and-intialization .unnumbered} -------------------------------------------------- In contrast to collaborative multi-scale style layer constraints, a single deep layer is typically used in content constraint. As discussed in [@Gatys2015c], the output feature maps from a shallow layer in VGG-Net is highly redundant and sufficient to reconstruct the input image. The similarity between the reconstruction and the input image decreases as the layer whose output feature maps are constrained becomes deeper. Choosing a shallow content layer (e.g. ) thus does not provide much freedom in transferring the content image into a new style, whereas choosing a very deep content layer (e.g. ) does not penalize big distortion of object in the synthesized image. In [@Gatys2015c], is used as content layer constraint together with random initialization of the optimization . This choice of content layer works well for indefinite style transfer where the style and the content are almost independent. As the weight $\lambda$ before the style penalty term in changes, the result synthesized image varies from presenting highly similar object in the content image with minimal fusion of the reference style to showing only the reference style without the knowledge of content. However, simply adjusting $\lambda$ does not provide a synthesized image that retains adequate information in both content and style, which is required in content-aware style transfer. To resolve this problem in content-aware style transfer, we initialize the optimization algorithm with an image close to the content image instead of a random image. It is well known that optimization on deep neural network like using stochastic gradient descent achieves local minimum hence starting from an image close to the content image puts a strong prior on the final optimization result. On the other hand, this change of initialization degrades the style constraint as the potential barrier between the initial point and the set of points (images) $\mathcal{I}_s$ in the reference style is higher than that between $\mathcal{I}_s$ and a random point. In numerical experiments, we observe that solving with fixed $\lambda$, and the same ${\mathcal{L}_s},{\mathcal{L}_c}$ as that used in [@Gatys2015c], the synthesized image is much more similar to the content image if initialized with the content image than with random initialization. Therefore, we enhance the style constraint and weaken the content penalty in by setting ${\mathcal{L}_s}:{\text{\path{conv 1_1}}},{\text{\path{pool 1}}},{\text{\path{conv 2_1}}},{\text{\path{pool 2}}},{\text{\path{conv 3_1}}},{\text{\path{pool 3}}},{\text{\path{conv 4_1}}},{\text{\path{pool 4}}},{\text{\path{conv 5_1}}} $ and ${\mathcal{L}_c}:\text{\path{conv5_2}}$, where ${\mathcal{L}_s}$ contains layers at all scales and ${\mathcal{L}_c}$ contains one layer at coarsest scale. As $\lambda \rightarrow \infty$, degenerated to the texture synthesis formulation. As long as we don’t initialize randomly and keep a mild penalization on content in the objective function, the result image fully combines style and content from the inputs. Experiments {#experiments .unnumbered} =========== In this section, we demonstrate style transfer algorithms with different configurations of style layers ${\mathcal{L}_s}$, content layers ${\mathcal{L}_c}$, optimization weight parameter $\lambda$, initialization and input alignment. We first show results on same-resolution style transfer, where the style pattern of the input style image is in almost the same resolution as that of the content image. Based on the best configuration for content-aware style transfer in this easier case, we then discuss its extension to the super-resolution case, where the style pattern of the input style image is in much higher resolution than that of the content image. Data and Preprocessing {#data-and-preprocessing .unnumbered} ---------------------- ![Left: content image, a photo of humming bird with white background (1896 $\times$ 1864 pixel), right: reference painting, a humming bird painted on a square wood board (2024 $\times$ 1947 pixel)[]{data-label="fig: input"}](hummingbird.jpg "fig:"){width=".49\textwidth"}![Left: content image, a photo of humming bird with white background (1896 $\times$ 1864 pixel), right: reference painting, a humming bird painted on a square wood board (2024 $\times$ 1947 pixel)[]{data-label="fig: input"}](Nr2_orig.jpg "fig:"){width=".45\textwidth"} In the following numerical experiments, a pair of content image and style image shown in Fig.\[fig: input\] have been used. The style image is a high resolution scan of a real painting of a humming bird by Charlotte Caspers,[^2] and it’s available to download at <http://services.math.duke.edu/~rachel/charlotte_new2/Nr2_original.tiff>. The content image was manually found through Google search, where the foreground humming bird is in similar type and pose to that in the painting. The content photo is originally1896 $\times$ 1864 pixel and the painting is rescaled to 2024 $\times$ 1947 from 4049 $\times$ 3894, such that it has the same resolution as the content image. We use the implementation of the style transfer algorithm in [@Gatys2015c] on Github [@neuralstyle], which allows flexible configuration of the original algorithm including the one we propose. [l]{}[0.45]{} Due to the size of the input content image and style image and the limitation of our computation resource, it is impossible to directly take the content image and style image as input and synthesize a style transferred image. To understand the potential problems of applying the original style transfer algorithm to the full content image and style image, we run the algorithm on input images of decreased size (512 $\times$ 503). The result is shown in Fig.\[fig: full-transfer\], where the background is not well synthesized and the color of the body of the humming bird is not close to that in the painting. These problems are not related to the resolution of the input images, but they are closely related to the initialization as we will show below, as we will show in experiments of same-resolution style transfer. In order to generate synthesized image of the same resolution of the input image, the content image is segmented into major parts such as head, body, tail and wings, see Fig. \[fig: parts\]. Each part overlaps with its adjacent parts such that a full-size style transferred image can be reconstructed by merging the synthesized image on parts. The foreground object in the painting is segmented into parts and accordingly the content image. The segmented parts in both images are in the same relative spatial configuration except that for part (f), the secondary wing in the content image, is matched with a sub-region of of part (c), the major wing in the style image for better consistency. We thus focusing on content-aware style transfer on each part instead of the full image in our experiments. ![cropped corresponding parts from content image and style image in Fig.\[fig: input\]: (a) head, (b) nape, (c) full wing, (d) body, (e) tail, (f) second wing. []{data-label="fig: parts"}](hummingbird-parts.jpg "fig:"){width=".49\textwidth"}![cropped corresponding parts from content image and style image in Fig.\[fig: input\]: (a) head, (b) nape, (c) full wing, (d) body, (e) tail, (f) second wing. []{data-label="fig: parts"}](Nr2_orig-parts.jpg "fig:"){width=".49\textwidth"} Same-resolution Style Transfer {#same-resolution-style-transfer .unnumbered} ------------------------------ The goal of same-resolution style transfer is to transfer the style pattern from the style image in its original resolution to the content image. Moreover, when the style is content-dependent, e.g. the brush stroke and wood grain pattern in background is different from the brush stroke used to depict foreground object, the algorithm should transfer the background pattern to the background of the content image and the foreground style to the foreground. \ We first show the necessity of input alignment and non-random initialization. Consider transferring style on part (a), the head of the bird. a-1 and a-2 in Fig.\[fig: input-p1\] are cropped part (a) from the full content image and style image respectively. The difference of detailed features between a-1 and a-2 are shown in the middle columns of Fig.\[fig: input-p1\]. The painting doesn’t capture very fine details in the photo, such as the pink lump on the tip of the beak and the vein of feathers on the head. Besides the local dissimilarity in texture, the two input images are not globally aligned in the same direction. For input with alignment, we use a-1’ in Fig.\[fig: input-p1\] as the content image together with a-2 in our experiment. We consider the following four configurations solving : (i) basic style transfer, i.e. the original algorithm in [@Gatys2015c], (ii) texture enhanced style transfer, where the style layers ${\mathcal{L}_s}^{\text{txtr}}$ in [@Gatys2015b] is used instead of ${\mathcal{L}_s}^{\text{style}}$, (iii) texture enhanced with input alignment, which is the same as (ii) but use a-1’ instead of a-1 as content image, (iv) content-aware style transfer without input alignment, (v) content-aware style transfer, our proposed configuration. Fig.\[fig: Nr2\_p1\] shows the results and a table of these four configurations. \ \ \ \ \ [ \| >p[6em]{}\| >p[5em]{}\| >p[4em]{} \| >p[1.5em]{} \| >p[5.5em]{}\|>p[5em]{}\|]{} configuration & style layers & content layers & $\lambda$& initialization & input alignment\ I & ${\mathcal{L}_s}^{\text{style}}$ & & 20 & random & no\ II & ${\mathcal{L}_s}^{\text{txtr}}$ & & 20 & random & no\ III & ${\mathcal{L}_s}^{\text{txtr}}$ & & 20 & random & yes\ IV & ${\mathcal{L}_s}^{\text{txtr}}$ $+\, {\text{\path{conv 5_1}}}$ & & 200 & content image & no\ V & ${\mathcal{L}_s}^{\text{txtr}}$ $+\, {\text{\path{conv 5_1}}}$ & & 200 & content image & yes\ As shown in Fig.\[fig: Nr2\_p1\], the results with random initialization, the first to third rows, suffer from un-even lightening in the background despite of the difference in style constraint and input alignment. This is because that the covariance of feature maps, which encodes style information, is estimated globally across the full image in not distinguishing the foreground and the background. As the style penalty term is not content-aware, the style of the foreground and the background in the synthesized image can be mixed. In particular, the background of the painting is uniform of small variance, and that of the synthesized image has larger variance due to the constraint on variance of color channels in style layers ${\mathcal{L}_s}$ mainly contributed by the foreground object in the painting. Therefore, the spatial information contained in the initial point is a strong regularization, and the results initialized with the content images have uniform lightening in the backgrpund as in the style image. Furthermore, the results with input alignment (i.e. using a-1’ and a-2 as input), the third and fifth rows, have better brush stroke simulation than those without alignment (i.e. using a-1 and a-2 as input). In particular, the direction of brush strokes of the beak aligns in the same direction of the beak when the inputs are aligned, but not when mis-aligned, see the third column of Fig.\[fig: Nr2\_p1\]. This is due to the fact that VGG-Net is not rotation-invariant and the same object with different orientations are encoded in different filter channels in the layers of the network, especially in the shallow layers, where feature information is not highly aggregated. When the content is consistent with the content image, it cannot be consist with the style image, so are their feature maps in shallow layers, unless both input images are in the same orientation. On the other hand, the shallow layers cannot be dropped from ${\mathcal{L}_s}$ for reconstruction of texture in fine scale. In addition, including pooling layers in ${\mathcal{L}_s}$ helps to enhance textures from the style image and diminish fine details from the content image in the synthesized image. See the first and second rows in Fig.\[fig: Nr2\_p1\] for comparison of basic configuration and the texture enhanced configuration. \ \ [ \| >p[6em]{}\| >p[5em]{}\| >p[4em]{} \| >p[1.5em]{} \| >p[5.5em]{}\|>p[5em]{}\|]{} configuration & style layers & content layers & $\lambda$ & initialization & input alignement\ VI & ${\mathcal{L}_s}^{\text{txtr}}$ & & 20 & &\ VII & ${\mathcal{L}_s}^{\text{txtr}} + {\text{\path{conv 5_1}}}$ & & 20 & &\ VIII & ${\mathcal{L}_s}^{\text{txtr}} + {\text{\path{conv 5_1}}}$ & & 200 & &\ V & ${\mathcal{L}_s}^{\text{txtr}} + {\text{\path{conv 5_1}}}$ & & 200& &\ Once the style-transfer algorithm is initialized with the content image, this strong prior on content limits the searching region of the algorithm in the image space. To ensure that a good style-transfered image is achievable, it’s necessary to weaken the content constraint term in and set ${\mathcal{L}_c}$ to a deeper layer at a coarser scale than . The second row of Fig.\[fig: Nr2\_p3-2\] compares results of different configurations with aligned input and content-based initialization. Configuration VI to VIII provide almost the same results (the first three columns) where the feather veins are more prominent than that generated by configuration V, our proposed content-aware style-transfer configuration (the last column). We apply the content-aware style transfer to pairs of content and style images for part (a) to (f). Fig.\[fig: stitch-result\] shows an overlay of the synthesized result on part (a), (c), (d) and (e) up on the content photo. Fig.\[fig: merge-result\] shows style transfer result on the whole object, which is obtained by overlaying the synthesized results of each part over the content photo and merging the overlapping regions between parts[^3]. There are some minor artifacts in the result shown in Fig.\[fig: merge-result\]. The background color is not consistent within parts and there are white brush strokes in the background of part (a), (c), (d) and (f). Compare Fig.\[fig: merge-result\] with the photo and the painting in Fig.\[fig: input\], the humming bird in the photo is slimmer than the painted bird who wears more white feathers, and the extra white feathers in the painting are redistributed to the background in the synthesized image. Although the white feathers is not in the photo, it is introduced by the style constraint to match the covariance of feature maps, resulting in a bias toward the object in the style image. The framework does not achieve a strict separation of content and style information in a neural network. Futhermore, because of the spatial-independent property of the style constraint, there is no restriction where the white brush strokes could appear in the background. Next, we extend this algorithm for same-resolution content-aware style transfer to the super-resolution case. Super-resolution Style Transfer {#super-resolution-style-transfer .unnumbered} ------------------------------- In the super-resolution case, we use the same photo and painting as previously discussed but downscale the photo to one-fourth of its original size. We apply the following iterative algorithm to generate a synthesized image of the same resolution of the style image: 1. [ Input:]{} content image $I_c^0$ at scale $\alpha_0$, style image $I_s^{K}$ at scale $\alpha_K$ 2. downsize $I_s^K$ to $I_s^k$ at scale $\alpha_k, \, k < K,\, s.t. \,\alpha_{k-1}<\alpha_k<\alpha_{k+1}$ 3. [ for $k = 0,\cdots,K$]{} 4. [2.1]{} generate synthesized image $I_g^k$ transferring the style of $I_s^k$ to $I_c^k$ 5. [2.2]{} upscale $I_g^k$ to $\alpha_{k+1}$ and set as $I_c^{k+1}$ 6. [ Output:]{} synthesized image $I_g^K$ Fig.\[fig: super-res\] shows the generation of $I_g^k$ along in the super-resolution algorithm. The final output is more similar to the painting than the synthesized image in the same-resolution case. In fact, the extra white feathers in the painting emerges gradually in $I_g^k$ as the scale increases.The iterative algorithm can regularize where to add the extra feature because the global structure of the object is captured and preserved through scales. In the first iteration, the VGG-Net encodes global structure of the downsized input images $I_c^0,\,I_s^0$ at deep layers after several spatial pooling layers, and this structural information is kept in $I_g^0$ and passed on to the next iteration. In the $k^{th}$ iteration, the result of the last iteration is upscaled by a factor of $\alpha_k/\alpha_{k-1}$ and used as the new content image to generate $I_g^{k}$ in higher resolution. On the other hand, some fine content features such as gray spots on the neck of the bird diminishes along the iteration. The level of degradation in the $k^{th}$ iteration is proportional to $\alpha_k/\alpha_{k-1}$, or equivalently how underdetermined is the optimization. Conclusion {#conclusion .unnumbered} ========== In this paper, we show that the formulation of the optimization in [@Gatys2015c] doesn’t account for spatial dependency of style patterns in the reference style image, and the basic style transfer algorithm is not content-aware, which is resolved by setting a strong initial prior on content while weaken the content constraint in the optimization algorithm. In addition, we show that it’s necessary to align the input images to the same orientation, otherwise the induced content constraint and style constraint are not consistent as the VGG-Net is not rotation invariant. Furthermore, we extend this content-aware configuration into an iterative algorithm that transfers high resolution style to a low-resolution content image. Our proposed configuration for content-aware style transfer significantly improves the basic algorithm, and the extra features from the reference style image present in the synthesized image introduced by the style constraint means that the content and the style information is not completely separated by neural network. [^1]: this is the same as the term [filter response*]{} used in[@Gatys2015c] [^2]: this painting is selected from a collection of paintings painted by Charlotte Caspers in 2012, served as a public research dataset for digital art authenticity analysis. The dataset is available at <http://services.math.duke.edu/~rachel/resources/charlotte2012.html> [^3]: The merging process is down in GIMP using the blending tool, which creates a mask on each part image with a smooth decay on the overlapping boundaries with other part images
Q: Probability (Bayes Rule) One quarter of twins are identical. Identical twins are always of the same sex. With fraternal (= non-identical) twins, the sexes are independent 50-50, like tossing a fair coin twice. What fraction of same-sex twins are identical? I know that this is a conditional probability question and I understand how conditional probability works. But, how can I get the answer when I do not know the percentage of same-sex and different-sex twins for identical twins? A: $Pr(A\mid B)=\dfrac{Pr(A\cap B)}{Pr(B)}=\dfrac{Pr(B\mid A)Pr(A)}{Pr(B)}$ Let $A$ represent that the twins are identical. Let $B$ represent that twins are samesex. The problem tells us $Pr(A)=\frac{1}{4}$, that $Pr(B\mid A)=1$ and we can show that $Pr(B\mid A^c)=\frac{1}{2}$ due to the independence and uniformity assumption. We have then: $$Pr(B)=Pr(A\cap B)+Pr(A^c\cap B) = Pr(A)Pr(B\mid A)+Pr(A^c)Pr(B\mid A^c)$$ $$=\frac{1}{4}\cdot 1+\frac{3}{4}\cdot\frac{1}{2}=\frac{5}{8}$$ We are asked to find $Pr(A\mid B)$ $$Pr(A\mid B)=\frac{Pr(B\mid A)Pr(A)}{Pr(B)}=\frac{1\cdot \frac{1}{4}}{\frac{5}{8}}=\frac{2}{5}$$
A simple cobalt catalyst system for the efficient and regioselective cyclotrimerisation of alkynes. The intermolecular cyclotrimerisation of terminal and internal alkynes can be catalysed by simple cobalt complexes such as a CoBr2(diimine) under mild reaction conditions when treated with zinc and zinc iodide with high regioselectivity in excellent yields.
Hi Michael, Olemis, On Wed, Feb 10, 2010 at 10:30 -0500, Olemis Lang wrote: > On Wed, Feb 10, 2010 at 10:15 AM, Michael Foord > <fuzzyman at voidspace.org.uk> wrote: > > On 10/02/2010 14:02, holger krekel wrote: > >> > >> Hi all, > >> > >> This year i plan to work a lot on testing and Python - and one of my plans > >> is to build up some collective computing resources for testing. Not tied > >> to > >> any particular testing tool or practise but rather to Continous > >> Integration > >> methods. > >> > >> Here is the practical start of this effort:: > >> > >> http://testrun.org> >> > >> > > > > The hudson output looks nice. Good work. > > >> And has intermittent green thingies (I like it !!!) >> :P thanks :) If you two like to integrate dutest and unittest-ext own tests you are very welcome :) You just need some junitxml output generating mechanism and a way to checkout things with svn, hg or git to get started. I believe (but haven't tried) that using "parametrized" builds one could instrument it to test against different Python interpreter versions - currently i do this rather manually. What i like about hudson is that it's rather straight forward to setup and configure TTW and can also be tweaked directly on the server from the command line. holger
#MeToo movement inspires candidate for Minnesota state House MINNEAPOLIS (KMSP) - With a wave of sexual misconduct allegations shaking the halls of power from Washington to Hollywood, more women are speaking out and speaking up about their experiences--even, in at least one instance here in Minnesota, running for office on a platform of empowerment. A small business owner with a history in the healthcare industry, Sara Freeman never thought she'd end up in politics. It wasn't until the resounding chorus of voices began to come forward alleging several instances of sexual harassment at the state Capitol that she reflected on her own experience as a survivor of sexual violence and decided her voice was one that needed to be heard. “Someone has to start these conversations," she said. "What has struck me speaking with voters at public forums and just online is the number of people who are saying to me—me too.” Freeman is running for Gubernatorial candidate Paul Thissen's old seat in House District 61B, speaking openly and often about her traumatic experience being raped at gunpoint nearly 20 years ago--a decision that has put her squarely in the middle of a cultural reckoning and made her the target of significant pushback. "“I have been intentional about using the word rape and using the term gun violence--I am a survivor of both," she said. “The threats and the harassment that I have received as a result of being so public and talking about gun violence—just using those terms has stirred up a tremendous backlash and response." But with the example of so many strong women to follow, Freeman says she has no regrets--and hopes to inspire others to tell their stories as well. “I was empowered by Lindsay Port and Erin Maye Quade and so many other women this fall and this year who have stood up and said this isn’t ok anymore," she said. "I hope that seeing survivors like me emboldens and empowers other survivors to step forward and tell our stories.”
No Comments Posted Yet Tax Services & Enforcement NOTE: The City of Alexandria Tax Services and Enforcement Division has mailed more than 1,000 wage liens to more than 700 employers. If you receive a wage lien and have additional questions, call 703.743.3937. Note: A taxpayer may simultaneously apply for Real Estate Tax Relief and Personal Property Tax Relief using the combined application form. If more than one vehicle is owned, the City will apply the benefit to the vehicle with the highest assessment, subject to certain guidelines. Residence must be occupied as the principal residence of a qualified surviving spouse. Dwelling must be zoned as single family residential. Dwelling assessed value is not in excess of the City’s average assessed value for the current year. (Average assessed value of dwellings zoned as single family residence is $500,000 for year 2015). The surviving spouse must not be remarried. The exemption applies regardless of whether the spouse was killed in action prior to the effective date of the amendment, but applies only to real property taxes to be paid on or after January 1, 2015. Exemption from taxation applies to surviving spouse’s principal place of residence, even if he or she moves to a new principal place of residence. Exemption would not require the surviving spouse to have been residing in the commonwealth at the time his or her spouse was killed in action. Required Documentation: Copy of death certificate of member in United States armed forces killed in action. Copy of marriage certificate. Note: There is no deadline to file this application, however applicants are encouraged to file by April 15. Tax Enforcement: Delinquent Taxes All taxes are considered delinquent on the day following the due date. The due dates for all City taxes can be found on the Finance Calendar. If the usual due date falls on a weekend, tax payment will be due on the first business day following the due date and the delinquency date will be one day later. Collections Tools Tax Services & Enforcement uses a number of tools to ensure the collection of all delinquent taxes, penalties, interest, and fees owed to the City of Alexandria. Payment Plans On occasion, taxpayers may not be able to pay when taxes are due. The payment plan, which spreads the total tax liability over time, is designed only to stop legal action for collection of delinquent taxes. It is a formal, signed agreement between the City and the taxpayer. The typical payment plan requires that the taxpayer make an initial payment of 20 percent of the taxes due; the remaining balance will then be paid in installments over a time period designated by the City. Interest will continue to accrue during the payment period. In-House Collections Tax Services & Enforcement mails a variety of letters informing taxpayers that they are delinquent on their taxes and may face collection action. If the taxpayer does not respond, staff initiates legal action to collect the delinquent taxes. Once collection begins, staff mails letters explaining the collection process. DMV Stops Through the Virginia Department of Motor Vehicles Vehicle Registration Withholding (DMV Stop) Program, the City will ask the DMV Commissioner to withhold registration or registration renewals for any taxpayer who owes delinquent taxes, penalties, interest, and fees to the City of Alexandria. Once a DMV Stop has been placed on an account, the taxpayer must pay the entire amount due with certified funds (cash, money order, or cashier's check) or credit card to get the Stop removed. The stop will be removed within one business day of payment. An administrative fee is assessed on all delinquent accounts for the administration associated with collecting the debt. (Virginia Code Section 46.2-752) NOTE: This information applies to DMV Stops for unpaid taxes only. Please see here for DMV Stops placed due to unpaid parking citations. Set-Off Debt Through the Set-Off Debt Program, the City asks the Virginia Department of Taxation to withhold all or part of a taxpayer's Virginia State Income Tax refund to cover any balance due to the City. An administrative fee is assessed on all delinquent accounts for the administration associated with collecting the debt. (Virginia Code Sections 58.1-520.1 and 58.1-523) Collection Agencies and Credit Bureaus In some cases, Tax Services & Enforcement determines that an outside agency has information or methods that are more likely to result in the collection of delinquent individual or business taxes. These cases are referred to outside collection agencies under contract. Accounts referred to collection agencies may also be reported to credit bureaus and appear on the taxpayers' credit reports. Publication of Delinquent Taxpayers List Delinquent taxpayer lists are published annually in the local newspaper and/or on the City's website for all taxpayers with delinquent balances greater than $20 as of June 30. (Code of Virginia Section 58.1-3921) Wage Liens Tax Services & Enforcement makes arrangements with the delinquent taxpayer's employer to garnish the wages of the delinquent taxpayer in the amount that is owed. It may be necessary to garnish more than one paycheck in order to satisfy the tax liability. Bank Liens Tax Services & Enforcement makes arrangements with the delinquent taxpayer's bank to recover from the taxpayers' account(s) the amount that is owed. Rent Liens Tax Services & Enforcement places a lien against all rental income due the taxpayer to recover the amount that is owed. (Code of Virginia Section 58.1-3944) Third Party Liens Tax Services & Enforcement applies in writing to any person indebted to or having in his hands estate of a taxpayer for payment of taxes more than 30 days delinquent. Payment by this third party will entitle him or her to a credit against such debt or estate. The taxes, penalties, and interest constitute a lien on the debt or estate due the taxpayer from the time the application is received. For each application served, the person applied to is entitled to a fee of $20. Staff will also send a copy of the application to the taxpayer with a notice informing him or her of the lien. (Code of Virginia Section 58.1-3952) Till Taps Finance staff prepares a Distress/Seizure Warrant for the Sheriff's Office to enter a business and seize cash from the cash register for payment of delinquent taxes. (Code of Virginia Sections 58.1-3919 and 58.1-3941) Bonds for Fiduciary Taxes Any business more than two months past due in the payment of admissions, meal sales, or transient lodging taxes may be required to post a bond for these taxes. Since fiduciary taxes collected from customers are held in trust by the business owner, they should not be commingled with the business's operating funds. Seizure of Personal Property or Assets In extreme cases, Tax Services & Enforcement may work with the Sheriff's Department or Police Department to seize property and/or assets that can be used to satisfy or can be sold to satisfy delinquent taxes. These properties are sold through auctions that are open to the public. Seizure of Real Estate When real estate taxes remain delinquent as of the December 31 following the second anniversary of the original due date, Tax Services & Enforcement may work with the Court to seize the property and sell it to satisfy the delinquency. These properties are sold through public auctions. (Code of Virginia Section 58.1-3965) Non-Registered Vehicles on Private Property If you are concerned about vehicles which may not be properly registered with the City parking on a private lot you own or manage, or on private property you own or manage, please fill out the following form to allow Tag and Parking Enforcement Personnel to patrol the property. Return the completed form to the Alexandria Police Department Parking Enforcement Unit. Field Visits Finance Department staff conducts “door to door” field inspections of businesses operating in the City for a period of three to four months each year. Staff verifies tax compliance by requesting confirmation that businesses are currently licensed and up to date on taxes owed. City staff will take the following steps to provide businesses with additional information and time to comply: Staff issues Warning Notices to businesses that do not have a valid City business license. The Warning Notice advises the business owner that he or she must obtain a City business license and file for business personal property tax. (Sample Warning Notice) The business is given a packet of information that includes a copy of the Alexandria Small Business Resource Guide. This guide provides information to the business owner regarding procedures and requirements for establishing a business in the City of Alexandria. Also included in the packet are the current year business license application and business personal property tax return and the interdepartmental approval form. This form requires the business owner to contact the Zoning Division, Code Enforcement, and other applicable City agencies. If the taxpayer fails to respond to the Warning Notice within the specified time, staff will make a courtesy call to remind the business owner that he failed to comply with the City business license and business personal property tax requirements. If the taxpayer fails to respond, staff will check state sales tax records for the following: gross receipts reported by the business for the current and last three years; the date the business began to operate in the City; and a brief description of the type of business conducted by the company. If staff cannot find the company’s information, they will review their field notes to determine the business tax classification then statutorily assess (see below) the business for the estimated length of time the company has operated in the City. Statutory Assessment If a taxpayer fails to file a tax return by the due date, the relevant office's staff will assess the tax based on the best information available. Tax Services & Enforcement will enforce this statutory assessment. Business License or Business Personal Property Tax: If the company has previously reported gross receipts or tangible personal property information to Business Tax, staff will use the previously reported information to prepare a statutory assessment. If staff is unable to obtain the necessary information, staff will prepare a statutory assessment by reviewing the gross receipts or tangible personal property filings of a similar company. If this information is not available, staff will statutorily assess the business based on the best possible estimate. Personal Property Tax: If a taxpayer fails to file for personal property tax, staff will assess the vehicle based on Virginia Department of Motor Vehicles records and a recognized pricing guide. Any business that receives a statutory assessment of business license or business personal property taxes and wishes to appeal the amount of the assessment must fill out and return either a delinquent business license application or a business personal property tax return. Any business or individual that receives a statutory assessment of a vehicle and disagrees with the value placed on the vehicle must follow the normal personal property appeal procedure. Any business or individual that has been assessed for a vehicle that is not located in the City or has been disposed of (sold, traded, donated, etc.) should contact Personal Property Tax for assistance. Penalties, Interest and Fees The City of Alexandria imposes penalties for failure to file or pay taxes on time, assesses interest on delinquent taxes, and charges fees to cover the cost of collection. Late Filing Penalty Personal Property Tax: All vehicles must be registered for personal property tax within 30 days of purchase or within 30 days of moving into the City. After an additional 90 day grace period, the City assesses a late filing penalty of $10 or five percent of the tax due from the taxpayer, not to exceed the amount of the tax payable by the taxpayer. (City Code Section 3-2-229). Business Personal Property Tax: Business personal property tax returns must be filed by May 1 of each year. The City assesses a late filing penalty of ten dollars or five percent of the tax due, whichever is greater, for failure to file a business personal property tax return by the due date. In no case may a late filing penalty exceed $500 if a return is filed within the first 30 days after the due date. If the tax filing is more than 30 days late, the late filing penalty is five percent of the total tax due amount. (City Code Section 3-2-229) All Other Taxes: The City assesses a penalty of $10 or ten percent of the tax due, whichever is greater, for failure to file a return.The penalty may not exceed the amount of the tax. Information on the filing dates for other taxes can be found in the Alexandria Tax Guide. Late Payment Penalty The City assesses a late payment penalty of $10 or ten percent of the tax due, whichever is greater, on all tax accounts paid after the due date. No penalty may exceed the amount of the tax billed. Interest Interest on all delinquent taxes accrues at an annual rate of ten percent the first year and five percent each year thereafter until all taxes and penalties are paid. Administrative Fees The City will assess an administrative fee on all delinquent personal property tax accounts on a per vehicle, per year basis. This fee is $20 for accounts with balances between $20 to $49.99 and $45 for accounts with balances of $50 or more. There is no administrative fee on accounts with balances below $20. The administrative fee is applied towards processing costs incurred in the collection of delinquent taxes through the DMV Stop and Set-Off Debt Programs. (Code of Virginia Sections 46.2-752 and 58.1-520.1; City Code Section 3-2-230) Waiver of Penalty and Interest Any business or individual that does not receive a tax bill three weeks prior to the due date should call the Treasury Division at 703.746.3902 to determine the total amount due. Failure to receive a tax bill does not relieve the taxpayer of the obligation to pay taxes by the due date and is not grounds for the waiver of late payment penalty and interest. Penalty and interest may only be waived in cases of late payment when one of the following conditions is met: The taxpayer can substantiate, with his or her own affidavit and a supporting statement from the postal service, that the tax filing or tax payment, although postmarked subsequent to the due date, was in fact mailed on or before that date; or It is substantiated through appropriate documentation that the taxpayer died in the six-month period immediately preceding the due date or that the taxpayer was, for medical reasons, incapable of making the tax filing or tax payment on the due date; or The tax bill is mailed to a prior owner of the taxpayer's property after a deed of transfer has been recorded but before the City's assessment records have been updated.
Q: Promise.all not working as expected ignoring unresolved promise I have this code onRemove = (fileId) => { this.setState({ removing: true }); Promise.all([this.props.onRemove(fileId)]) .then(() => { console.log('I execute after'); this.setState({ removing: false }); }) .catch(() => { this.setState({ removing: false }); }); } onRemove is triggered by onClick from my jsx code like this: onClick={() => {this.onRemove(fileId);}} For simplicity reasons, my this.props.onRemove looks like this: removeFile = (UUID) => { const sleep = milliseconds => new Promise(resolve => setTimeout(resolve, milliseconds)); return sleep(1500).then(() => { console.log('I execute'); }); }; When I run my code, I get this in my console: I execute after I execute Which I am of course assuming is wrong! isn't Promise.all supposed to wait for all promises to resolve before executing what is in the then block? What am I missing, been banging my head against a wall for a while now. Update: I added return to removeFile as comments suggested but the behaviour remains the same. A: The code you provided seems to be working just fine. class ChildComponent extends React.Component { state = { removing: false } onRemove = fileId => { this.setState({ removing: true }); Promise.all([this.props.onRemove(fileId)]).then(() => { console.log('I execute after'); this.setState({ removing: false }); }) .catch(() => { this.setState({ removing: false }); }); }; render() { return ( <button onClick={() => { this.onRemove('fileId');}}> Remove File </button> ); } } const ParentComponent = () => { const removeFile = UUID => { const sleep = milliseconds => new Promise(resolve => setTimeout(resolve, milliseconds)); return sleep(1500).then(() => {console.log("I execute");}); } return <ChildComponent onRemove={removeFile} /> }; ReactDOM.render(<ParentComponent />, document.getElementById('root')); <script src="https://cdnjs.cloudflare.com/ajax/libs/react/16.6.3/umd/react.production.min.js"></script> <script src="https://cdnjs.cloudflare.com/ajax/libs/react-dom/16.6.3/umd/react-dom.production.min.js"></script> <body> <div id='root'></div> </body>
Characterization of protein adsorption on soft contact lenses. IV. Comparison of in vivo spoilage with the in vitro adsorption of tear proteins. Tear protein and gamma-globulin mixtures were adsorbed on soft contact lenses of different chemical composition, surface quality and water content. The adsorption process was followed by Fourier transform infrared-attenuated total reflectance spectroscopy (ATR-FTIR). It was found that gamma-globulin underwent a conformational and orientational change after its adsorption and the extent of structural change appeared to be proportional to the binding strength of the protein with the hydrogel surface. Electrostatic interactions play a major role in the protein adsorption on lenses containing methacrylic acid. Lysozyme is selectively adsorbed on all of the high water content hydrogels and mucin is the major protein component for the pure PHEMA type of lenses. Studies on in vivo spoiled PHEMA and PVP/MMA lenses indicate that lysozyme is the major adsorbed deposit. Papain cleaning of in vivo spoiled lenses shows that although a portion of the deposits is desorbed, the enzyme itself becomes irreversibly adsorbed to the contact lens which may cause harmful effects to the eye.
using System; using System.Runtime.InteropServices; using System.Security; namespace BulletSharp { public class ShapeHull : IDisposable { internal IntPtr _native; ConvexShape _shape; UIntArray _indices; Vector3Array _vertices; public ShapeHull(ConvexShape shape) { _native = btShapeHull_new(shape._native); _shape = shape; } public bool BuildHull(float margin) { return btShapeHull_buildHull(_native, margin); } public IntPtr IndexPointer { get { return btShapeHull_getIndexPointer(_native); } } public UIntArray Indices { get { if (_indices == null) { _indices = new UIntArray(IndexPointer, NumIndices); } return _indices; } } public int NumIndices { get { return btShapeHull_numIndices(_native); } } public int NumTriangles { get { return btShapeHull_numTriangles(_native); } } public int NumVertices { get { return btShapeHull_numVertices(_native); } } public IntPtr VertexPointer { get { return btShapeHull_getVertexPointer(_native); } } public Vector3Array Vertices { get { if (_vertices == null \|\| _vertices.Count != NumVertices) { _vertices = new Vector3Array(VertexPointer, NumVertices); } return _vertices; } } public void Dispose() { Dispose(true); GC.SuppressFinalize(this); } protected virtual void Dispose(bool disposing) { if (_native != IntPtr.Zero) { btShapeHull_delete(_native); _native = IntPtr.Zero; } } ~ShapeHull() { Dispose(false); } [DllImport(Native.Dll, CallingConvention = Native.Conv), SuppressUnmanagedCodeSecurity] static extern IntPtr btShapeHull_new(IntPtr shape); [DllImport(Native.Dll, CallingConvention = Native.Conv), SuppressUnmanagedCodeSecurity] [return: MarshalAs(UnmanagedType.I1)] static extern bool btShapeHull_buildHull(IntPtr obj, float margin); [DllImport(Native.Dll, CallingConvention = Native.Conv), SuppressUnmanagedCodeSecurity] static extern IntPtr btShapeHull_getIndexPointer(IntPtr obj); [DllImport(Native.Dll, CallingConvention = Native.Conv), SuppressUnmanagedCodeSecurity] static extern IntPtr btShapeHull_getVertexPointer(IntPtr obj); [DllImport(Native.Dll, CallingConvention = Native.Conv), SuppressUnmanagedCodeSecurity] static extern int btShapeHull_numIndices(IntPtr obj); [DllImport(Native.Dll, CallingConvention = Native.Conv), SuppressUnmanagedCodeSecurity] static extern int btShapeHull_numTriangles(IntPtr obj); [DllImport(Native.Dll, CallingConvention = Native.Conv), SuppressUnmanagedCodeSecurity] static extern int btShapeHull_numVertices(IntPtr obj); [DllImport(Native.Dll, CallingConvention = Native.Conv), SuppressUnmanagedCodeSecurity] static extern void btShapeHull_delete(IntPtr obj); } }
--- author: - 'T. N. Venkataramana' date: 'August 2, 2002' title: On the gcd of an infinite number of integers --- Introduction {#introduction .unnumbered} ============ In this paper, we consider the greatest common divisor (to be abbreviated gcd in the sequel) of suitable infinite sequences of integers and prove that as the sequences vary, the gcd remains bounded. These questions are motivated by results of [@S] on the congruence subgroup problem. Using these results, we also obtain bounds on the indices of certain congruence subgroups of arithmetic groups in algebraic groups.\ The simplest example of the result on gcd is the following. Let $a$ and $b$ be coprime positive integers and for an integer $n\neq 0$ let $\phi (n)$ be the number of positive integers not exceeding $\mid n\mid$ (the absolute value of $n$) and coprime to $\mid n \mid$. Consider the infinite sequence $$\phi (ax+b)~; x=\cdots,-2,-1,0,1,2,\cdots \leqno (1)$$ and let $g(a,b)$ denote the gcd of the numbers occurring in the sequence $(1)$. Then (see Theorem 1 below), $g(a,b)$ is bounded by $4$ , for all $a$ and $b$. This assertion will be shown to be a simple application of Dirichlet’s Theorem on the infinitude of primes in an arithmetic progression.\ We will also prove an analogue of the above result for arbitrary number fields. Let $S$ be a finite set of places of a number field $F$ containing all the archimedean ones, $a$ and $b$ be coprime elements in the ring of $S$-integers $O_S$ , and for a nonzero ideal $\mathfrak b$ of $O_S$, $\phi({\mathfrak b})$ denote the number of units in the residue class ring $O_S/\mathfrak b$. Write $(y)$ for the principal ideal in $O_S$ generated by the element $y$ in $O_S$. Then we show (see Theorem 2 below) that the gcd $g(a,b)$ of the infinite sequence of numbers $$\phi ((ax+b)); x\in O_S, \leqno (2)$$ is bounded by a constant depending only on the number field $F$. In fact the constant will be shown to depend only on the number of roots of unity in the number field. As in the case of ${{\mathbb{Q}}}$, Theoerm 2 will be shown to be a consequence of the Cebotarev density Theorem.\ This result has an application to algebraic groups. Theorem 2 will be shown to imply that if $\Gamma $ is an $S$-arithmetic congruence subgroup of a linear algebraic group $G$ defined over the number field $F$, then the congruence subgroups $\Gamma (ax+b)$ (of $\Gamma $ for $x$ varying in $O_S$, generate a subgroup $\Gamma '$ of finite index $g$ in $\Gamma $, and the index $g$ is bounded by a constant depending only on the algebraic group $G$ and the number field $F$ (and not on the congruence subgroup $\Gamma $).\ With these notations, we first prove (in $\S$1) the following: Suppose that $a$ and $b$ are coprime rational integers , and let $\phi $ denote the Euler $\phi$ function. Then the gcd $g=g(a,b)$ of the sequence $\{ \phi(ax+b);~x\in {{\mathbb{Z}}}\}$ is bounded by $4$; more precisely, $g$ has the following values. 1. $g=1$ if $b\equiv \pm 1$ (mod $a$) or $\pm 2$ (mod $a$). 2. $g=4$ if $a$ is divisible by four, $b$ is not as in Case 1, $b=\equiv~1$ (mod 4) and $b$ is not a square (mod $a$). 3. $g=2$ in all other cases. Theorem 1 is proved by using Dirichlet’s Theorem on the infinitude of primes in arithmetic progressions.\ Theorem 1 can be generalised to arbitrary number fields. Let $F$ be a number field and $S$ a finite set of places of $F$ including all the archimedean ones. Let $O_S$ denote the ring of $S$-$integers$ of $F$. Given a non-zero ideal $\mathfrak{a}$ of $O_S$, let $\phi (\mathfrak{a})$ denote the number of [units]{} in the quotient ring $O_S/\mathfrak{a}$ (of course, the quotient has only a finite number of elements). Given a non-zero element $x\in O_S$, denote by $\phi (x)$ the number $\phi ((x))$, where $(x)$ is the principal ideal of $O_S$ generated by $x$. Recall that two elements $a$ and $b$ of $O_S$ are said to be coprime, if the ideal generated by $a$ and $b$ is the whole ring $O_S$. Let $\mu _F$ denote the group of roots of unity in the number field $F$.\ Let $a$ and $b$ denote two elements of $O_S$ which are coprime. Let $g$ be the gcd of the numbers $\phi (ax+b)$ where $x$ runs through elements of $O_S$. Then, there is a constant $C$ depending only on the number field $K$ (and not on the elements $a$ and $b$) such that $g\leq C$. In fact, $C$ may be chosen to be $Card (\mu _F)^2$.\ More precisely, $g$ divides $Card (\mu _F)^2$. That is $v_l(g)\leq v_l(Card (\mu _F) ^2)$ where for a prime $l$ and an integer $m$, $v_l(m)$ is the largest power of $l$ which divides $m$.\ In particular, $g$ is divisible only by the primes which divide the order of the group $\mu _F$ of roots of unity in the number field $F$. Theorem 2 has an application to algebraic groups. Indeed, its formulation was suggested by a problem in the arithmetic of algebraic groups. Let $G$ be a linear algebraic group defined over a number field $F$ and let $O_S$ be as before. Let $\Gamma $ be an $S$-congruence subgroup of the group $G(O_S)$ of $O_S$-rational points of $G$. Let $a$ and $b$ be coprime elements in $O_S$ and given $x\in O_S$, let $G(ax+b)$ be the congruence subgroup corresponding to the principal ideal ($ax+b$) of $O_S$. Let $\Gamma '$ be the subgroup of $\Gamma $ generated by the subgroups $\Gamma \cap G(ax+b)$ as $x$ varies through elements of the ring $O_S$.\ There exists an integer $g$ depending only on the group $G$ and the number field $F$ such that for all $\Gamma$ as above, the index of $\Gamma '$ in $\Gamma $ is bounded by $g$. Proof of Theorem 1 ================== As we said before, the proof is a repeated application of Dirichlet’s Theorem on the infinitude of primes in arithmetic progressions. We will prove it by a (small) number of case by case checks.\ \[1\]. Suppose that $b$ is congruent to either $\pm 1$ or $\pm 2$ modulo $a$. Then, there exists an integer $x$ such that $ax+b$ is either $\pm 1$ or $\pm 2$. In either case $\phi (ax+b)=1$; since the gcd $g$ divides each $\phi (ax+b)$, we obtain that $g=1$.\ Let $l$ be a prime and $m$ an integer. Define, as before, $v_l(m)$ to be the largest integer $k$ such that $l^k$ divides $m$.\ \[2\]. We first prove that $$v_l(g)=0$$ if $l$ is an odd prime. Write $a'$ for the l.c.m. of $a$ and $l$. If $b$ is coprime to $l$ and $b \not\equiv 1$ (mod $l$), then, by Dirichlet’s Theorem, the residue class $b$ modulo $a'$ is represented by a prime $p$. Thus, there exist integers $x, y$ such that $p=a'y+b=ax+b$, and $\phi (ax+b)=\phi (p)=p-1\not\equiv 0$ (mod $l$). Therefore, $g$ (which divides $\phi (p)$) is coprime to $l$ as well. That is $v_l(g)=0$. If $b$ is not coprime to $l$, then, by replacing $b$ by $a+b$ we may still assume that $b$ is coprime to $l$, as $a$ and $b$ are coprime. Suppose now that $b\equiv 1$ (mod $l$). Since the group $({{\mathbb{Z}}}/l{{\mathbb{Z}}})^$ of units in the ring ${{\mathbb{Z}}}/l{{\mathbb{Z}}}$ has at least two elements, and $({{\mathbb{Z}}}/a'{{\mathbb{Z}}})^\rightarrow ({{\mathbb{Z}}}/l{{\mathbb{Z}}})^$ is surjective, we may write $b=uv$ modulo $a'$ with $u\not\equiv 1$ and $v\not\equiv 1$ modulo the prime $l$. Moreover, by Dirichlet’s Theorem, $u$ and $v$ modulo $a'$ are represented by (distinct) primes $p$ and $q$. Thus, there exist $x$ and $y$ with $uv=a'y+b=ax+b$ and $p\equiv u$ and $q\equiv v$ modulo $a'$. Moreover, $p-1\not\equiv 0$ (mod $l$) and $q-1\not\equiv 0$ (mod $l$). Thus, $\phi (pq)=(p-1)(q-1)\not\equiv 0$ (mod $l$) whence $v_l(g)=0$. This completes \[2\].\ \[3\]. Now we consider the case when $l$ is even ($l=2$). We show that $$v_2(g)\leq 2.$$ [(3.1)]{}. Suppose that $a$ is even and that $a^$ is the lcm of $a$ and $4$. Now, $b$ is odd since $b$ is coprime to $a$. Thus $b$ defines a class in $({{\mathbb{Z}}}/4{{\mathbb{Z}}})^$. If $b$ is a non-trivial class in $({{\mathbb{Z}}}/4{{\mathbb{Z}}})^$, then, since the class of $b$ modulo $a^$ is represented by a prime $p$, one has $p=ax+b$ for some $x$ with $\phi (ax+b)=\phi (p)=p-1\neq 0$ (mod $4$). Thus, $v_2(\phi (ax+b))\leq 1$ whence $v_2(g)\leq 1$. If $b$ [is]{} the trivial class modulo $4$, then write $b\equiv (-b)(-1)$ (mod $a^$). Both $(-b)$ and $(-1)$ are represented by primes $p$ and $q$ say. Then $p\equiv q\equiv (-1)$ (mod $4$), whence, $p-1$ and $q-1$ are divisible at most by $2$. Thus, there exists an $x$ with $ax+b=pq$, with $\phi (ax+b)=\phi (p)\phi (q)=(p-1)(q-1)\not\equiv 0$ (mod $8$). Hence $v_2(g)\leq v_2(\phi (ax+b))\leq 2$.\ [(3.2)]{}. Suppose $a$ is odd. Let $a^=4a$ denote the lcm of $a$ and $4$. The group $({{\mathbb{Z}}}/a^{{\mathbb{Z}}})^$ of units is a product of $({{\mathbb{Z}}}/a{{\mathbb{Z}}})^$ and $({{\mathbb{Z}}}/4{{\mathbb{Z}}})^$. Hence there exists a prime $p$ such that it represents $b$ modulo $a$ and $-1$ modulo $4$. Thus there exists an $x$ with $p=ax+b$. Moreover $\phi (ax+b)=\phi (p)=p-1\not\equiv 0$ (mod $4$), whence $v_2(g)\leq 1$.\ \[4\]. Suppose that $ax+b$ is at least $3$ in absolute value. Assume also that $a\equiv 0 $ (mod $4$), $b=1$ (mod $4$) and that $b$ is not a square (mod $a$). Write $ax+b=p_1^{e_1}\cdots p_h^{e_h}$, with $p_i$ distinct primes and $e_i$ positive integers. Clearly, the primes $p_i$ are all odd. If $h\geq 2$, then since $\phi (ax+b)$ is divisible by the product $(p_i-1)\cdots (p_h-1)$, it follows that $\phi (ax+b)$ is divisible by $2^h$ and hence by $4$. If $h=1$ and $p_1=3~(mod~4)$, then by passing to congruences modulo $4$ (note that $4$ divides $a$ by assumption), we see that $1\equiv b\equiv p_1^{e_1}\equiv (-1)^{e_1}$ modulo $4$, whence $e_1$ is even, contradicting the assumption that $b$ is not a square modulo $a$. If $h=1$ and $p_1\equiv 1$ (mod $4$), then $\phi (ax+b)=p_1^{e_1-1}(p_1-1)$ is divisible modulo $4$. We have thus proved part (2) of Theorem 1, that for all $x$, $\phi (ax+b)$ is divisible by $4$; that is, $4$ divides $g$. Since we have proved in all cases that $v_2(g)\leq 2$, it follows that $g=4$ if the conditions of Part (2) hold.\ \[5\]. Turn now to the other parts of Theorem 1. If $a\equiv 2~(mod~4)$, then write $a=2a_1$, with $a_1$ odd. By Dirichlet’s Theorem, there exist infinitely many primes $p$ with $p\equiv b$ (mod $a_1$) and $p\equiv 3$ (mod $4$). Note that $b\equiv p\equiv 1$ (mod $2$) since both $b$ and $p$ are odd. Thus, $p\equiv b$ (mod $a$) and $\phi (p)=p-1\not\equiv 0$ (mod $4$) whence $v_2(g)\leq 1$. Since $g$ is always even in this case, it follows that $g=2$.\ If $b$ is $\pm 1$ or $\pm 2$, then, there exists an integer $x$ such that $ax+b=\epsilon$ with $\epsilon =\pm 1$ or $\epsilon = \pm 2$. Clearly, then $\phi (\epsilon )= 1$ whence $g=1$.\ If $a$ and $b$ are as in Part (3) of Theorem 1, then $ax+b$ is at least 3 in absolute value for all $x$ and hence $\phi (ax+b)\geq 2$. If $a$ is divisible by $4$, but $b$ is a square say $c^2$, modulo $a$, then $c$ is represented by a prime $p$ modulo $4$ which (by replacing $c$ by $-c$ if necessary) may be assumed to be congruent to $-1$ modulo $4$. Hence $p^2=ax+b$ for some integer $x$, and $\phi (ax+b)=p(p-1)\not\equiv 0$(mod $4$). Therefore, $v_2(g)\leq 1$ whence $g=2$. The rest of Theorem 1 may be proved in exactly the same way.\ Proof of Theorem 2. =================== Preliminaries. -------------- Denote by $\mu $ the order of the group of roots of unity in the number field $F$. Let $l$ be a prime and $l^e$ the largest power of $l$ which divides $\mu $. Let $\omega $ be a primitive $l^{e+1}$-th root of unity in an algebraic closure of $F$. The Galois group of the extension $F(\omega )/F$ is a subgroup of the group $({{\mathbb{Z}}}/l^{e+1}{{\mathbb{Z}}})^$ of units and is non-trivial, since $l^e$ is the highest power of $l$ which divides $\mu $. Moreover, if ${\mathfrak p}$ is a prime ideal in $O_S$ which is unramified in $F(\omega)$ such that its Frobenius is a non-trivial element in $Gal (F(\omega )/F)$ then, $N({\mathfrak p})-1$ is divisible by $l^e$ but not by $l^{e+1}$.\ Notation. --------- Denote by $F_a$ the ray class field of $F$ corresponding to the ideal $O_S$. Thus, by definition, $F_a/F$ is an abelian extension whose Galois group is isomorphic -under the Artin Reciprocity map- to the quotient $G(F_a/F) ={{\mathbb{A}}}_F^/F^(\prod U_v)$. Here for a commutative ring $R$, we denote by $R^$ the group of units of $R$ and $A_F$ is the ring of adeles of $F$. For each finite place $v$ of $F$, let $O_v$ be the maximal compact subring of the completion $F_v$. If $v\in S$, let $U_v=K_v^$ and if $v\notin S$, let $U_v$ denote the subgroup of elements of $O_v^$ congruent to $1$ modulo the ideal of $O_v$ generated by $a$. Note that $S$ contains all the archimedean primes and that if $v\notin S$ and if $v$ does not divide $a$, then $U_v=O_v^$.\ Given an element $z=\prod (z_v)_v$ of $A_F^$, define its [norm]{} by $\prod (\mid z\mid _v)$ for all $v\notin S$. In particular, its restriction to $\prod O_v^$ (where $v$ runs through all finite places of $F$) is trivial, and hence the norm is a homomorphism on the group of fractional ideals of $O_S^$. Thus, if ${\mathfrak p}$ is a prime ideal in $O_S$ and $v$ the corresponding non-archimedean absolute value on $F$, then the norm is $1/Card (O_S/{\mathfrak p})$.\ By the weak approximation theorem, it is clear that the group $$G(F_a/F)={{\mathbb{A}}}_F^/F^(\prod U_v)$$ is isomorphic to the group $${{\mathbb{A}}}_F(S)^/O_S(a)^(\prod O_v^)$$ where $O_S(a)^$ is the group of units in the ring $O_S$ which are congruent to the identity modulo the principal ideal $a$ of $O_S$ and the product is over all the places $v$ of $F$ not in $S$ and not dividing $a$.\ Proof of Theorem 2. ------------------- Let $E$ be the compositum of the ray class field $F_a$ and the cyclotomic extension $F(\omega )/F$ ($\omega $ being a primitive $L^{e+1}$-th root of unity). The Galois group $G(E/F)$ is abelian and has surjective homomorphisms onto $G(F_a/F)$ and onto $G(F(\omega )/F)$. The group $G(E/F)$ is generated-by the Cebotarev Density Theorem-by the Frobenius elements corresponding to prime ideals ${\mathfrak p}$ of the ring $O_S$ (which may also be assumed to be unramified in the extension $E/F$). In particular, the image of $b\in F$ ($F^$ thought of as a subgroup of ${{\mathbb{A}}}_F(S)^$ (= the group of $S$-ideles)) in $G(E/F)$ is represented by (infinitely many) prime ideals ${\mathfrak p}$. This means that ${\mathfrak p}=(ax+b)O_S$ for some $x\in O_S$. In particular, $\phi ({\mathfrak p})=\phi (ax+b)$.\ Case 1: If moreover, there exists an element $\sigma \in G(E/F)$ such that its image in $G(F_a/F)$ is represented by the element $b$ and its image in $G(F(\omega )/F)$ is non-trivial, then $\sigma$ is represented by a prime ideal ${\mathfrak p}$, with the following properties. By the choice of $\sigma$, one gets an $x\in O_S$ such that $ax+b={\mathfrak p}$. Thus $\phi (ax+b)=\phi ({\mathfrak p})$ and ${\mathfrak p}$ has non-trivial image in $G(F(\omega )/F)$. Hence $\phi ({\mathfrak p})$ is divisible by $l^e$ but not by $l^{e+1}$ (see (2.1)).\ Case 2: If Case 1 is not possible, then this means that the preimage of $b\in G(F_a/F)$ in $G(E/F)$ maps to the trivial element in $G(F(\omega )/F)$. Fix any $\sigma$ in the preimage, and let $\tau \in G(E/F)$ map non-trivially into $G(F(\omega )/F)$ (recall from (2.1) that the latter group is non-trivial). One may write $\sigma =(\sigma \tau)(\tau)^{-1}$. Note that both $\sigma \tau$ and $\tau ^{-1}$ have non-trivial images in $G(F(\omega )/F)$. Represent both elements by prime ideals ${\mathfrak p}$ and ${\mathfrak q}$ respectively. Then $\phi ({\mathfrak p})$ is divisible by $l^e$ but not by $l^{e+1}$ (similarly for $\phi ({\mathfrak q})$). However, ${\mathfrak p}{\mathfrak q}=ax+b$ for some $x\in O_S$. Therefore, $\phi (ax+b)$ is divisible by $l^{2e}$ but by no higher power of $l$. In particular, $v_l(g)\leq 2e$.\ The combination of Cases 1 and 2 proves Theorem 2. A Question ========== In sections 1 and 2 we considered the gcd of $\phi (ax+b)$ as $x$ varies. Here $ax+b$ is a [linear]{} polynomial of degree one, with coprime coefficients. We now replace $ ax+b$ by a polynomial $P(x)=a_nx^n+\cdots+a_0$ where $a_0,\cdots,a_n$ are integers (or S-integers) which are “coprime” i.e. generate the unit ideal. We have the following question, arrived at in conversations with M. S. Raghunathan. Question: --------- Does There exist a constant $C=C(n)$ depending only on the degree $n$ of the polynomial $P$ such that the gcd of the integers $\phi (P(x)): x=0,1,\cdots $ is bounded by $C(n)$ for [all]{} polynomials $P$ of degree $n$ with coprime coefficients ?\ In case the number field $F$ is different from ${{\mathbb{Q}}}$, the question amounts to asking if the constant $C$ depends only on the number field $F$ and on the finite set $S$ of places. Relation to the Congruence Subgroup Problem =========================================== Consider the group $SL_2$ over a number field $F$. Suppose the set $S$ is such that the group $O_S^$ of units is infinite. Given an ideal ${\mathfrak a}$ of $O_S$, let $G({\mathfrak a})$ denote the principal congruence subgroup of $SL_2(O_S)$ of level ${\mathfrak a}$: this is the set of matrices of determinant one, with entries in the ring $O_S$ which are congruent to the identity matrix modulo the ideal ${\mathfrak a}$. Let $E({\mathfrak a})$ denote the normal subgroup of $SL_2(O_S)$ generated by the upper triangular matrices with $1$’s on the diagonal and which are congruent to $1$ modulo the ideal ${\mathfrak a}$. Then, $E({\mathfrak a})$ is a normal subgroup of $G({\mathfrak a})$.\ In the course of proof of the congruence subgroup property for the group $SL_2(O_S)$, Serre (in [@S]) considers the action of the group $T(O_S)\simeq O_S^$ on the quotient $G({\mathfrak a})/E({\mathfrak a})$. Here $T$ is the group of diagonals in $SL_2$. Serre shows that this action is trivial on the subgroup of $T(O_S)$ generated by $\mu $-th powers of elements of $T(O_S)$ (recall that $\mu $ is the number of roots of unity in the number field $F$). This is achieved by proving first that if a coset class $\xi $ in the quotient $SL_2({\mathfrak a})/E({\mathfrak a})$ is represented by a matrix $A=\left (\begin{array}{cc} a & b \\ c & d \end{array} \right)$, then, the group $T(aO_S)$ acts trivially on the element $\xi $. Next, if the element $A$ is replaced by $BA$ with $B=\left (\begin{array}{cc} 1 & x \cr 0 & 1 \end{array} \right )$ with $x\in {\mathfrak a}$, then $BA=\left( \begin{array}{cc} a' & b' \\ c' &d' \end{array} \right)$ with $a'=ax+b$. Consequently, even the group $T((ax+b)O_S)$ acts trivially on the element $\xi $. Thus the group $T_0$ generated by the subgroups $T((ax+b)O_S)$, as $x$ varies, acts trivially on the element $\xi$. By arguments similar to the proof of Theorem 2 (indeed, the proof of Theorem 2 in the present paper is modelled on [@S]), Serre then shows that the group of $\mu $-th powers of $T(O_S)$ is contained in the group $T_0$ and hence acts trivially on $\xi$.\ We now state a generalisation of this result. Let $G\subset GL_n$ be a linear algebraic group defined over a number field $F$. Let $S$ be a finite set of places of $F$ containing all the archimedean ones and let $O_S$ denote the ring of $S$-integers of $F$. Given a non-zero ideal ${\mathfrak a}$ in $O_S$, denote by $G({\mathfrak a})$ the subgroup of $G\cap GL_n(O_S)$ whose entries are congruent to the identity modulo the ideal ${\mathfrak a}$.\ Suppose now that $a$ and $b$ are coprime elements in $O_S$ and that $x\in O_S$. Denote, as before, by $G(ax+b)$, the principal congruence subgroup of level $ax+b $. Let $\Gamma \subset G(F)$ be an arithmetic subgroup and let $\Gamma _{a,b}$ be the group generated by the subgroups $G(ax+b)\cap \Gamma$ for all $x\in O_S$ of $G(O_S)$. \[index\] With the foregoing notation, the group $\Gamma _{a,b}$ has its index in $\Gamma $ bounded by a constant dependent only on $G\subset GL_n$ and the number field $F$, but neither on the arithmetic group $\Gamma $ nor on the elements $a$ and $b$. We begin by noting that for the multiplicative group $G={\bf G}_m$, this is exactly Serre’s Theorem: the index is bounded by $\mu $, the number of roots of unity in the number field.\ The proof of Theorem \[index\] is easy when $G$ is unipotent or semi-simple, since one may appeal to the strong approximation theorem, a version of which implies that if ${\mathfrak a}$ and ${\mathfrak b}$ are coprime ideals, then $G({\mathfrak a})$ and $G({\mathfrak b} )$ generate a subgroup of index bounded by a constant independent of ${\mathfrak a}$ and ${\mathfrak b}$ (see [@R], section 2 for similar considerations). Thus, the proof of Theorem 3 may be reduced easily to that for tori, and hence, by the structure theorem for tori , to that for the groups ${\bf G}_m$ over some [finite extensions]{} $E$ of $F$. Thus, we are reduced to the case of ${\bf G}_m$ over number fields, for which Serre’s result is already available. Acknowledgements ================ The author is grateful to S.D.Adhikari, R.Balasubramanian and to K.Srinivas for their kind invitation to take part and to contribute to the proceedings of a conference in honour of Prof.Subba Rao held at Institute of Mathematical Sciences, Chennai. He is also grateful to the referee for a careful reading of the MS, for making several necessary corrections, and for pointing out a gap (which is now filled!) in the proof of Theorem 1.\ The author acknowledges the help of M. S. Raghunathan in arriving at the question raised in section 3. He is also grateful to J.-P. Serre for suggesting a possible solution through sieve theoretic methods. [JPSH]{} J.-P.Serre, Le Probleme de groupes de congruence pour $SL_2$, Ann. Math. [92]{} (1970), 489-527.\ M.S.Raghunathan, On the Congruence Subgroup Problem II, Invent.Math., [85]{} (1986), 73-117.\ T.N.Venkataramana, On Systems of Generators of Higher Rank Arithmetic Subgroups, Pac. J. Math., [166*]{}, No.1 (1994), 193-212.
Outcome of elastic nailing of diaphyseal forearm fractures in adolescents after failure of conservative management. This is a prospective study to evaluate the efficacy of elastic nails for the treatment of diaphyseal forearm fractures after failure of conservative management. In 35 patients with a mean age of 15.3 years (14-17 years), elastic nails were used for the treatment of diaphyseal forearm fractures after failure of conservative management. In 32 patients (91.4%), we performed closed reduction. In the remaining 3 (8.6%), closed reduction failed and an open reduction, through a minimal approach, was required before nailing. After a mean follow-up of 31 months (range 24-48 months), 20 (60%) patients had an excellent result 10 (34.3%) patients had a good result, and two (5.7%) patients had fair result. The mean time of union was 12 weeks (range 8-15). The mean time in cast was 8.5 weeks (range 7-11). Full range of elbow movement was regained in all cases; however, supination and pronation were limited in two patients. One patient had a superficial infection at the site of entry of the ulnar nail which was successfully treated with oral antibiotics and daily dressing. Neurapraxia affecting superficial branch of the radial nerve in one patient was resolved over a period of time. One case with partial rupture of extensor pollicus longus tendon was reported. There was one case of delayed union. No cases of refracture were reported after removal of the implant. In adolescents, intramedullary fixation by using elastic nail plus cast immobilization provides effective treatment for diaphyseal forearm fracture when closed management has failed. However, it is of special importance to follow the right indication and to pay attention to correct technical procedure.
include ../rules.mk # objects below are generated at compile-time. OTHER_OBJS := lex.yy.o y.tab.o gen-trans.o gen-completion.o # source file below is excluded from compiling. EXCLUDE_SRC := trans.template.c completion.template.c include ../module.mk gen-symbol.h: gen-lexer.l gen-token.h: gen-lexer.l gen-lexer.l: lexer.template.l symbol.template.h token.template.h $(HIGHLIGHT_BEGIN) 5 @ echo "generating $@" $(HIGHLIGHT_END) ./auto-gen.sh $^ gen-trans.c: gen-symbol.h gen-token.h trans.template.c $(HIGHLIGHT_BEGIN) 5 @ echo "generating $@" $(HIGHLIGHT_END) ./trans-gen.sh $^ $@ gen-completion.c: lexer.template.l completion.template.c $(HIGHLIGHT_BEGIN) 5 @ echo "generating $@" $(HIGHLIGHT_END) ./completion-gen.sh $^ $@ lex.yy.c: gen-lexer.l y.tab.h $(COLOR_LEX) $(strip $(DO_LEX)) y.tab.h y.tab.c: grammar.y $(COLOR_YACC) @ echo '$(strip $(DO_YACC))' $(HIGHLIGHT_BEGIN) 3 # highlight conflicts @ $(DO_YACC) $(HIGHLIGHT_END) clean: rm -f .tab.[ch] rm -f lex.yy.c rm -f gen- rm -f *.dot @ echo 'clean'
2015 South Florida Bulls football team The 2015 South Florida Bulls football team represented the University of South Florida (USF) in the 2015 NCAA Division I FBS football season. The 2015 college football season was the 19th season for the Bulls, and their third as a member of the American Athletic Conference (The American), this season joining the newly formed East Division. They played their home games at Raymond James Stadium in Tampa, FL. They were led by Head Coach Willie Taggart, who was in his third year. They finished the season 8–5, 6–2 in American Athletic play to finish in second place in the East Division. They were invited to the Miami Beach Bowl where they lost to WKU. Schedule Source: Game summaries Florida A&M at Florida State at Maryland Memphis Syracuse at UConn SMU at Navy at East Carolina Temple Cincinnati at UCF WKU (Miami Beach Bowl) References Category:South Florida Bulls football seasons South Florida Bulls South Florida Bulls football team
/** * Copyright (c) 2012-2015, Christopher Jeffrey (MIT License) * Copyright (c) 2017, Daniel Imms (MIT License) * * pty.cc: * This file is responsible for starting processes * with pseudo-terminal file descriptors. * * See: * man pty * man tty_ioctl * man termios * man forkpty / /* * Includes / #include <nan.h> #include <errno.h> #include <string.h> #include <stdlib.h> #include <unistd.h> #include <sys/types.h> #include <sys/stat.h> #include <sys/ioctl.h> #include <sys/wait.h> #include <fcntl.h> #include <signal.h> / forkpty / / http://www.gnu.org/software/gnulib/manual/html_node/forkpty.html / #if defined(__GLIBC__) \|\| defined(__CYGWIN__) #include <pty.h> #elif defined(__APPLE__) \|\| defined(__OpenBSD__) \|\| defined(__NetBSD__) #include <util.h> #elif defined(__FreeBSD__) #include <libutil.h> #elif defined(__sun) #include <stropts.h> / for I_PUSH / #else #include <pty.h> #endif #include <termios.h> / tcgetattr, tty_ioctl / / Some platforms name VWERASE and VDISCARD differently / #if !defined(VWERASE) && defined(VWERSE) #define VWERASE VWERSE #endif #if !defined(VDISCARD) && defined(VDISCRD) #define VDISCARD VDISCRD #endif / environ for execvpe / / node/src/node_child_process.cc / #if defined(__APPLE__) && !TARGET_OS_IPHONE #include <crt_externs.h> #define environ (_NSGetEnviron()) #else extern char *environ; #endif / for pty_getproc / #if defined(__linux__) #include <stdio.h> #include <stdint.h> #elif defined(__APPLE__) #include <sys/sysctl.h> #include <libproc.h> #endif / NSIG - macro for highest signal + 1, should be defined / #ifndef NSIG #define NSIG 32 #endif /* * Structs / struct pty_baton { Nan::Persistent<v8::Function> cb; int exit_code; int signal_code; pid_t pid; uv_async_t async; uv_thread_t tid; }; /* * Methods / NAN_METHOD(PtyFork); NAN_METHOD(PtyOpen); NAN_METHOD(PtyResize); NAN_METHOD(PtyGetProc); /* * Functions / static int pty_execvpe(const char , char , char ); static int pty_nonblock(int); static char * pty_getproc(int, char ); static int pty_openpty(int , int , char , const struct termios , const struct winsize ); static pid_t pty_forkpty(int , char , const struct termios , const struct winsize ); static void pty_waitpid(void ); static void pty_after_waitpid(uv_async_t ); static void pty_after_close(uv_handle_t ); NAN_METHOD(PtyFork) { Nan::HandleScope scope; if (info.Length() != 10 \|\| !info[0]->IsString() \|\| !info[1]->IsArray() \|\| !info[2]->IsArray() \|\| !info[3]->IsString() \|\| !info[4]->IsNumber() \|\| !info[5]->IsNumber() \|\| !info[6]->IsNumber() \|\| !info[7]->IsNumber() \|\| !info[8]->IsBoolean() \|\| !info[9]->IsFunction()) { return Nan::ThrowError( "Usage: pty.fork(file, args, env, cwd, cols, rows, uid, gid, utf8, onexit)"); } // file Nan::Utf8String file(info[0]); // args int i = 0; v8::Local<v8::Array> argv_ = v8::Local<v8::Array>::Cast(info[1]); int argc = argv_->Length(); int argl = argc + 1 + 1; char argv = new char[argl]; argv[0] = strdup(file); argv[argl-1] = NULL; for (; i < argc; i++) { Nan::Utf8String arg(Nan::Get(argv_, i).ToLocalChecked()); argv[i+1] = strdup(arg); } // env i = 0; v8::Local<v8::Array> env_ = v8::Local<v8::Array>::Cast(info[2]); int envc = env_->Length(); char *env = new char[envc+1]; env[envc] = NULL; for (; i < envc; i++) { Nan::Utf8String pair(Nan::Get(env_, i).ToLocalChecked()); env[i] = strdup(pair); } // cwd Nan::Utf8String cwd_(info[3]); char cwd = strdup(cwd_); // size struct winsize winp; winp.ws_col = info[4]->IntegerValue(Nan::GetCurrentContext()).FromJust(); winp.ws_row = info[5]->IntegerValue(Nan::GetCurrentContext()).FromJust(); winp.ws_xpixel = 0; winp.ws_ypixel = 0; // termios struct termios t = termios(); struct termios term = &t; term->c_iflag = ICRNL \| IXON \| IXANY \| IMAXBEL \| BRKINT; if (Nan::To<bool>(info[8]).FromJust()) { #if defined(IUTF8) term->c_iflag \|= IUTF8; #endif } term->c_oflag = OPOST \| ONLCR; term->c_cflag = CREAD \| CS8 \| HUPCL; term->c_lflag = ICANON \| ISIG \| IEXTEN \| ECHO \| ECHOE \| ECHOK \| ECHOKE \| ECHOCTL; term->c_cc[VEOF] = 4; term->c_cc[VEOL] = -1; term->c_cc[VEOL2] = -1; term->c_cc[VERASE] = 0x7f; term->c_cc[VWERASE] = 23; term->c_cc[VKILL] = 21; term->c_cc[VREPRINT] = 18; term->c_cc[VINTR] = 3; term->c_cc[VQUIT] = 0x1c; term->c_cc[VSUSP] = 26; term->c_cc[VSTART] = 17; term->c_cc[VSTOP] = 19; term->c_cc[VLNEXT] = 22; term->c_cc[VDISCARD] = 15; term->c_cc[VMIN] = 1; term->c_cc[VTIME] = 0; #if (__APPLE__) term->c_cc[VDSUSP] = 25; term->c_cc[VSTATUS] = 20; #endif cfsetispeed(term, B38400); cfsetospeed(term, B38400); // uid / gid int uid = info[6]->IntegerValue(Nan::GetCurrentContext()).FromJust(); int gid = info[7]->IntegerValue(Nan::GetCurrentContext()).FromJust(); // fork the pty int master = -1; sigset_t newmask, oldmask; struct sigaction sig_action; // temporarily block all signals // this is needed due to a race condition in openpty // and to avoid running signal handlers in the child // before exec* happened sigfillset(&newmask); pthread_sigmask(SIG_SETMASK, &newmask, &oldmask); pid_t pid = pty_forkpty(&master, nullptr, term, &winp); if (!pid) { // remove all signal handler from child sig_action.sa_handler = SIG_DFL; sig_action.sa_flags = 0; sigemptyset(&sig_action.sa_mask); for (int i = 0 ; i < NSIG ; i++) { // NSIG is a macro for all signals + 1 sigaction(i, &sig_action, NULL); } } // reenable signals pthread_sigmask(SIG_SETMASK, &oldmask, NULL); if (pid) { for (i = 0; i < argl; i++) free(argv[i]); delete[] argv; for (i = 0; i < envc; i++) free(env[i]); delete[] env; free(cwd); } switch (pid) { case -1: return Nan::ThrowError("forkpty(3) failed."); case 0: if (strlen(cwd)) { if (chdir(cwd) == -1) { perror("chdir(2) failed."); _exit(1); } } if (uid != -1 && gid != -1) { if (setgid(gid) == -1) { perror("setgid(2) failed."); _exit(1); } if (setuid(uid) == -1) { perror("setuid(2) failed."); _exit(1); } } pty_execvpe(argv[0], argv, env); perror("execvp(3) failed."); _exit(1); default: if (pty_nonblock(master) == -1) { return Nan::ThrowError("Could not set master fd to nonblocking."); } v8::Local<v8::Object> obj = Nan::New<v8::Object>(); Nan::Set(obj, Nan::New<v8::String>("fd").ToLocalChecked(), Nan::New<v8::Number>(master)); Nan::Set(obj, Nan::New<v8::String>("pid").ToLocalChecked(), Nan::New<v8::Number>(pid)); Nan::Set(obj, Nan::New<v8::String>("pty").ToLocalChecked(), Nan::New<v8::String>(ptsname(master)).ToLocalChecked()); pty_baton baton = new pty_baton(); baton->exit_code = 0; baton->signal_code = 0; baton->cb.Reset(v8::Local<v8::Function>::Cast(info[9])); baton->pid = pid; baton->async.data = baton; uv_async_init(uv_default_loop(), &baton->async, pty_after_waitpid); uv_thread_create(&baton->tid, pty_waitpid, static_cast<void>(baton)); return info.GetReturnValue().Set(obj); } return info.GetReturnValue().SetUndefined(); } NAN_METHOD(PtyOpen) { Nan::HandleScope scope; if (info.Length() != 2 \|\| !info[0]->IsNumber() \|\| !info[1]->IsNumber()) { return Nan::ThrowError("Usage: pty.open(cols, rows)"); } // size struct winsize winp; winp.ws_col = info[0]->IntegerValue(Nan::GetCurrentContext()).FromJust(); winp.ws_row = info[1]->IntegerValue(Nan::GetCurrentContext()).FromJust(); winp.ws_xpixel = 0; winp.ws_ypixel = 0; // pty int master, slave; int ret = pty_openpty(&master, &slave, nullptr, NULL, &winp); if (ret == -1) { return Nan::ThrowError("openpty(3) failed."); } if (pty_nonblock(master) == -1) { return Nan::ThrowError("Could not set master fd to nonblocking."); } if (pty_nonblock(slave) == -1) { return Nan::ThrowError("Could not set slave fd to nonblocking."); } v8::Local<v8::Object> obj = Nan::New<v8::Object>(); Nan::Set(obj, Nan::New<v8::String>("master").ToLocalChecked(), Nan::New<v8::Number>(master)); Nan::Set(obj, Nan::New<v8::String>("slave").ToLocalChecked(), Nan::New<v8::Number>(slave)); Nan::Set(obj, Nan::New<v8::String>("pty").ToLocalChecked(), Nan::New<v8::String>(ptsname(master)).ToLocalChecked()); return info.GetReturnValue().Set(obj); } NAN_METHOD(PtyResize) { Nan::HandleScope scope; if (info.Length() != 3 \|\| !info[0]->IsNumber() \|\| !info[1]->IsNumber() \|\| !info[2]->IsNumber()) { return Nan::ThrowError("Usage: pty.resize(fd, cols, rows)"); } int fd = info[0]->IntegerValue(Nan::GetCurrentContext()).FromJust(); struct winsize winp; winp.ws_col = info[1]->IntegerValue(Nan::GetCurrentContext()).FromJust(); winp.ws_row = info[2]->IntegerValue(Nan::GetCurrentContext()).FromJust(); winp.ws_xpixel = 0; winp.ws_ypixel = 0; if (ioctl(fd, TIOCSWINSZ, &winp) == -1) { switch (errno) { case EBADF: return Nan::ThrowError("ioctl(2) failed, EBADF"); case EFAULT: return Nan::ThrowError("ioctl(2) failed, EFAULT"); case EINVAL: return Nan::ThrowError("ioctl(2) failed, EINVAL"); case ENOTTY: return Nan::ThrowError("ioctl(2) failed, ENOTTY"); } return Nan::ThrowError("ioctl(2) failed"); } return info.GetReturnValue().SetUndefined(); } /** * Foreground Process Name / NAN_METHOD(PtyGetProc) { Nan::HandleScope scope; if (info.Length() != 2 \|\| !info[0]->IsNumber() \|\| !info[1]->IsString()) { return Nan::ThrowError("Usage: pty.process(fd, tty)"); } int fd = info[0]->IntegerValue(Nan::GetCurrentContext()).FromJust(); Nan::Utf8String tty_(info[1]); char tty = strdup(tty_); char name = pty_getproc(fd, tty); free(tty); if (name == NULL) { return info.GetReturnValue().SetUndefined(); } v8::Local<v8::String> name_ = Nan::New<v8::String>(name).ToLocalChecked(); free(name); return info.GetReturnValue().Set(name_); } /** * execvpe / // execvpe(3) is not portable. // http://www.gnu.org/software/gnulib/manual/html_node/execvpe.html static int pty_execvpe(const char file, char argv, char envp) { char old = environ; environ = envp; int ret = execvp(file, argv); environ = old; return ret; } / * Nonblocking FD / static int pty_nonblock(int fd) { int flags = fcntl(fd, F_GETFL, 0); if (flags == -1) return -1; return fcntl(fd, F_SETFL, flags \| O_NONBLOCK); } /* * pty_waitpid * Wait for SIGCHLD to read exit status. / static void pty_waitpid(void data) { int ret; int stat_loc; pty_baton baton = static_cast<pty_baton>(data); errno = 0; if ((ret = waitpid(baton->pid, &stat_loc, 0)) != baton->pid) { if (ret == -1 && errno == EINTR) { return pty_waitpid(baton); } if (ret == -1 && errno == ECHILD) { // XXX node v0.8.x seems to have this problem. // waitpid is already handled elsewhere. ; } else { assert(false); } } if (WIFEXITED(stat_loc)) { baton->exit_code = WEXITSTATUS(stat_loc); // errno? } if (WIFSIGNALED(stat_loc)) { baton->signal_code = WTERMSIG(stat_loc); } uv_async_send(&baton->async); } /** * pty_after_waitpid * Callback after exit status has been read. / static void pty_after_waitpid(uv_async_t async) { Nan::HandleScope scope; pty_baton baton = static_cast<pty_baton>(async->data); v8::Local<v8::Value> argv[] = { Nan::New<v8::Integer>(baton->exit_code), Nan::New<v8::Integer>(baton->signal_code), }; v8::Local<v8::Function> cb = Nan::New<v8::Function>(baton->cb); baton->cb.Reset(); memset(&baton->cb, -1, sizeof(baton->cb)); Nan::AsyncResource resource("pty_after_waitpid"); resource.runInAsyncScope(Nan::GetCurrentContext()->Global(), cb, 2, argv); uv_close((uv_handle_t )async, pty_after_close); } /* * pty_after_close * uv_close() callback - free handle data / static void pty_after_close(uv_handle_t handle) { uv_async_t async = (uv_async_t )handle; pty_baton baton = static_cast<pty_baton>(async->data); delete baton; } /** * pty_getproc * Taken from tmux. / // Taken from: tmux (http://tmux.sourceforge.net/) // Copyright (c) 2009 Nicholas Marriott <nicm@users.sourceforge.net> // Copyright (c) 2009 Joshua Elsasser <josh@elsasser.org> // Copyright (c) 2009 Todd Carson <toc@daybefore.net> // // Permission to use, copy, modify, and distribute this software for any // purpose with or without fee is hereby granted, provided that the above // copyright notice and this permission notice appear in all copies. // // THE SOFTWARE IS PROVIDED "AS IS" AND THE AUTHOR DISCLAIMS ALL WARRANTIES // WITH REGARD TO THIS SOFTWARE INCLUDING ALL IMPLIED WARRANTIES OF // MERCHANTABILITY AND FITNESS. IN NO EVENT SHALL THE AUTHOR BE LIABLE FOR // ANY SPECIAL, DIRECT, INDIRECT, OR CONSEQUENTIAL DAMAGES OR ANY DAMAGES // WHATSOEVER RESULTING FROM LOSS OF MIND, USE, DATA OR PROFITS, WHETHER // IN AN ACTION OF CONTRACT, NEGLIGENCE OR OTHER TORTIOUS ACTION, ARISING // OUT OF OR IN CONNECTION WITH THE USE OR PERFORMANCE OF THIS SOFTWARE. #if defined(__linux__) static char pty_getproc(int fd, char tty) { FILE f; char path, buf; size_t len; int ch; pid_t pgrp; int r; if ((pgrp = tcgetpgrp(fd)) == -1) { return NULL; } r = asprintf(&path, "/proc/%lld/cmdline", (long long)pgrp); if (r == -1 \|\| path == NULL) return NULL; if ((f = fopen(path, "r")) == NULL) { free(path); return NULL; } free(path); len = 0; buf = NULL; while ((ch = fgetc(f)) != EOF) { if (ch == '\0') break; buf = (char )realloc(buf, len + 2); if (buf == NULL) return NULL; buf[len++] = ch; } if (buf != NULL) { buf[len] = '\0'; } fclose(f); return buf; } #elif defined(__APPLE__) static char pty_getproc(int fd, char tty) { int mib[4] = { CTL_KERN, KERN_PROC, KERN_PROC_PID, 0 }; size_t size; struct kinfo_proc kp; if ((mib[3] = tcgetpgrp(fd)) == -1) { return NULL; } size = sizeof kp; if (sysctl(mib, 4, &kp, &size, NULL, 0) == -1) { return NULL; } if (size != (sizeof kp) \|\| kp.kp_proc.p_comm == '\0') { return NULL; } return strdup(kp.kp_proc.p_comm); } #else static char * pty_getproc(int fd, char tty) { return NULL; } #endif /* * openpty(3) / forkpty(3) / static int pty_openpty(int amaster, int aslave, char name, const struct termios termp, const struct winsize winp) { #if defined(__sun) char slave_name; int slave; int master = open("/dev/ptmx", O_RDWR \| O_NOCTTY); if (master == -1) return -1; if (amaster) amaster = master; if (grantpt(master) == -1) goto err; if (unlockpt(master) == -1) goto err; slave_name = ptsname(master); if (slave_name == NULL) goto err; if (name) strcpy(name, slave_name); slave = open(slave_name, O_RDWR \| O_NOCTTY); if (slave == -1) goto err; if (aslave) aslave = slave; ioctl(slave, I_PUSH, "ptem"); ioctl(slave, I_PUSH, "ldterm"); ioctl(slave, I_PUSH, "ttcompat"); if (termp) tcsetattr(slave, TCSAFLUSH, termp); if (winp) ioctl(slave, TIOCSWINSZ, winp); return 0; err: close(master); return -1; #else return openpty(amaster, aslave, name, (termios )termp, (winsize )winp); #endif } static pid_t pty_forkpty(int amaster, char name, const struct termios termp, const struct winsize winp) { #if defined(__sun) int master, slave; int ret = pty_openpty(&master, &slave, name, termp, winp); if (ret == -1) return -1; if (amaster) amaster = master; pid_t pid = fork(); switch (pid) { case -1: // error in fork, we are still in parent close(master); close(slave); return -1; case 0: // we are in the child process close(master); setsid(); #if defined(TIOCSCTTY) // glibc does this if (ioctl(slave, TIOCSCTTY, NULL) == -1) { _exit(1); } #endif dup2(slave, 0); dup2(slave, 1); dup2(slave, 2); if (slave > 2) close(slave); return 0; default: // we are in the parent process close(slave); return pid; } return -1; #else return forkpty(amaster, name, (termios )termp, (winsize )winp); #endif } /** * Init */ NAN_MODULE_INIT(init) { Nan::HandleScope scope; Nan::Export(target, "fork", PtyFork); Nan::Export(target, "open", PtyOpen); Nan::Export(target, "resize", PtyResize); Nan::Export(target, "process", PtyGetProc); } NODE_MODULE(pty, init)
Networked Blogs The Naked Truth About Playa del Carmen Posted by Tony & Cheri on August 20, 2011 As owners of the Luna Blue Hotel & Bar, we read a lot of internet chatter about Playa del Carmen. After all, we live and work here and want to keep up with what people are thinking about Playa. We also take note of people’s questions about traveling here. Over the years, we have seen many repeat questions on a few certain topics that never seem to go away or get fully answered. Many people ask about the weather: “My family will be there the second week of August of next year. Will it rain during our vacation?” Others ask about safety: “My brother-in-law’s friend’s boss’ cousin says he heard that people were being machine gunned down in the Walmart. Should I cancel my trip?” But probably our favorite repeat question is…“Are there any nude or topless beaches in Playa del Carmen?” Some folks ask about nude or topless beaches because they want to search them out to do a little au natural sunbathing. Others want to avoid them, worrying their husbands or sons will be scarred for life by exposure to all that flesh. And some are just…curious. So here is the truth about what you can and can’t wear on the beaches of Playa del Carmen (and some other select spots). The Law Many people say that Mexico prohibits all public nudity. And they are right. Mexico federal law prohibits lewd or immoral behavior, including nudity, on public federal lands. All beaches in Mexico including those in the Riviera Maya (Cancun to Tulum) are federal land. However, as in most cases of the law, there are few absolutes and a lot of gray areas about this. Mexico’s federal law on public nudity is enforced by local authorities who have the discretion to decide what constitutes lewd behavior. In Playa del Carmen the local authorities have never enforced the law with regard to topless sunbathing. They do not consider it “lewd conduct.” On Playa’s main resort beach (between Juarez and Constituyentes) and in Playa’s north beach (Playa Norte), topless sunbathing is commonplace and will not draw the attention of any cops, except for perhaps an admiring glance. Topless sunbathing and swimming is also accepted on the beaches in Xpu-ha and in Tulum. The Tradition So why does Playa allow women to go topless on the beach when other places in Mexico don’t? Primarily it is a tradition that predates Playa’s city government and status as a resort town. A couple of decades ago Playa del Carmen was a sleepy little beach town know mostly as a place to catch the ferry to Cozumel. The world and the travel industry paid little attention to it. However, Playa was exactly the unspoiled tropical paradise many people were looking for. European travelers, mostly from Italy, began to visit here. Some never left, and a large Italian expat community began to develop. The Italians brought many traditions to Mexico with them including great pasta and “European style” sunbathing. In other words…topless. Along with the Italian expats, Playa became a destination for American vagabond travelers, i.e. “hippies,” whose lifestyle was based on being free–which included getting naked on the beach. In the beginning, there was no one who cared. The town was too small and remote for anyone to worry about boobs on the beach. By the time the town grew and was discovered as a destination by the travel industry, the existence of topless beaches had become accepted by the local authorities. This is not to say everyone does it. Only a relatively small percentage of visitors to our beaches go topless, but it is still a significant number of women who feel at ease in just a swimsuit bottom on the beach, in the water and occasionally at the beach bars. The All Over Tan While being topless is acceptable on Playa’s beaches, complete nudity is not. In all the years we have been coming to and living in Playa, we have never seen nudity on the town’s main beaches. We suspect that if someone was nude on one of those beaches, with the first complaint from onlookers the police would step in. There was a nude beach in Playa some 10 or 12 years ago. Coco Beach, north of town, was commonly used by those seeking to avoid tan lines. Back then the town ended at Constituyentes, and access to this beach was limited, so no one raised a fuss. However, the famous nude beach disappeared when it was washed away during a particularly bad storm season and then rebuilt as condos and resorts as Playa’s city limits expanded north. As of now, there is no place in Playa’s city limits where public nude sunbathing is allowed. However Tulum has for many years had a reputation for allowing total nudity. A few beach hotel/resorts in Tulum are clothing optional. In addition, while there is no nude beach per se, we have observed over the years that the smaller beach clubs seem to have no objection to nude guests. We have seen a fair number of nude sunbathers on the beaches of Tulum and once observed an entire soccer team from England get off their bus and completely disrobe in the parking lot before running buck naked down to the water! However Tulum has recently grown large enough to create its own local government which by some accounts is very strict about beach club rules. It might be best to ask the beach club employees if it is okay before losing those swimsuits. Beach Etiquette: What do You Say to a Naked Lady? Women who sunbathe or swim topless or nude are doing so for their own enjoyment, not yours. It is not an invitation to stare at them, talk to them, photograph them without permission or comment about them. They may not meet someone’s particular standard of beauty or age…and neither should they have to. The same goes for men who may choose a swimsuit to their liking but not yours. We have seen all ages, shapes and sizes in all stages of undress on the beaches and we have never felt offended. If someone’s attire or lack of attire is bothering you, simply move to another part of the beach. There is no beach so small in the Riviera Maya that you need sit near someone or something that makes you uncomfortable. We regularly relocate when someone near us is smoking heavily. If you do want to get topless or naked on a beach, remember that Mexico is still a conservative Catholic country where many women swim in t-shirts and shorts rather than a skimpy bathing suit. Please limit your expressions of personal freedom to the resort zone beaches which allow such behavior. Avoid the smaller out of the way beaches where local families gather. Tourists are guests in this country and should conduct themselves in away that does not upset the locals. The Final Word A word of warning: If you do find yourself on one of the Riviera Maya’s tropical seashores, and in the heat of the moment you are tempted to expose a little more skin than you normally do back home, we would strongly suggest one little word to make the experience more enjoyable… SUNBLOCK! And lots of it. Have fun on our beautiful beaches no matter what you do or do not wear. Daniellasaid If it’s something you want to try Michelle I say go for it. We visited El Paraiso beach and since it wasn’t all that crowded at the time and with a couple of other topless sunbathers I felt comfortable going topless for the first time and frankly it was less scary than I thought it would be, when families started arriving I put the top back on though. After that I went topless at our resort on the beach only and again there were several others doing the same. I took the advice of Tony and Cheri and tried to keep in mind where I was and who was there so as not to offend. Thanks Tony and Cheri for the great advice as always. Danasaid Well, for the most part it is well written. However, the photos are of very thin young women. Are these the bodies you are saying should only be seen? What about men? what about those with more mature bodies? Sad you talk about acceptance, then show super models. Dana if there is something sad here it is that your self image keeps you from seeing the point of our article…that anyone can enjoy the freedom and beauty of Playa del Carmen’s beautiful beaches. We did in fact talk quite a bit about how no one should be judged by anyone else’s body standards. As for the photos when we talked about “topless” beach goers we assumed most people would figure it applied to women…Mexico doesn’t prohibit men from topless sunbathing. Therefore it was our thought that pictures of men added little to the topic. Secondly, as we pointed out , we don’t think people who go topless or nude on Mexico’s beaches should be photographed without their knowledge. And their pictures should certainly not be circulated on the web without their permission. So, when picking photos for this article we were forced to choose from photos taken by professional photographers of professional models, not “candid shots” where we didn’t know if the subject would appreciate being part of our blog. We specifically avoided “cheesecake” or pin-up type pics. We did try and find some tasteful nude couples pictures but again found none that were publicly available. And we specifically wanted photos taken on the three beaches we were talking about …Playa, Xpu-ha and Tulum…not just any topless photos. So our selection was limited and we went with the three photos we did. Personally we don’t think any of these three photos we used are “super model” variety. We are very sorry if somehow you felt denigrated or left out by the photos we published. That was not our purpose. If next time you are on one of our beautiful Caribe-Mexican beaches and want to pose for a tasteful topless or nude photo we will be happy to post it on an updated version of this blog. Now climb on down from that soap box and head for the beach…and feel free to wear what you want! Rogsaid Petersaid Very well said, we have been traveling to the Playa/Tulum area for 27 years and have seen topless women all those years and all shapes and sizes, it is sad though that as more tourists evolved from the US (where we live) only has being topless become a problem with tourists lashing out about how insulting it is to the people of Mexico and is embarrassing for children to view it, it existed for many years before these tourists, so if you are going to visit the area accept it do not use the excuse it is insulting to the Mexican population because it you who reallt doesn’t want to see it,Mexico does not need your policing, vacation somewhere that it doesn’t exist like the stuffing English Islands thru out the Caribbean!! Arielasaid I will sometimes ask the ‘judgemental’ how it is that they accept/condone the various levels of violence on TV/movies and then allow children to watch. There is usually no connection between the violence and the point at which society has reached. The natural beauty of a nude sunbather hurts no one. We all started nude and will all end nude. Unfortunate that north american society has issue with nudity between the two points. Larry Ratcliffesaid Having lived in Italy, it is of little surprise to me, to see women who sunbath topless. It is, in my belief not a moral issue. It is acceptable on many beaches around the world. Also, I have no problem with it and those that do, need to respect others, maybe this would not be an issue at all.
CNN Tonight turned to ophthalmologist and fiction writer Dr. Robin Cook to hype unsubstantiated fears about the transmission of the Ebola Virus and the CDC's grasp on the situation. Presenting Cook as “The Man Who Wrote The Book On Ebola,” host Don Lemon called Cook's 1987 fiction thriller Outbreak, which details an Ebola outbreak in the U.S.," prophetic." Lemon allowed Cook to speculate that the Centers for Disease Control and Prevention (CDC) cannot adequately protect Americans from Ebola, and that despite the CDC's assertions to the contrary, the virus may live in the air or mutate into a form that can spread as an aerosol. Cook's theories on the transmission of Ebola are out of step with nearly every expert from international health agencies and the CDC. As Vox reported, “basically every health agency in the world agrees” that Ebola cannot be transmitted through the air. The CDC definitively says: “Ebola is not spread through the air or by water, or in general, by food.” Medical experts further agree that it's highly unlikely Ebola could mutate into a form that alters its mode of transmission. That type of mutation would be unprecedented according to Columbia University virologist Vincent Racaniello, who wrote: “We have been studying viruses for over 100 years, and we've never seen a human virus change the way it is transmitted,” and that “There is no reason to believe that Ebola virus is any different from any of the viruses that infect humans and have not changed the way that they are spread.”
Q: Zombies in bash Bash doesn't seem to create zombies. It looks like the processes get immediately reaped when they get killed. Can I make bash make zombies? Why I'm asking: I'd like to be able to safely kill a child process or safely kill -9 it if it doesn't die within a certain period of time but I don't want to accidentally zap a process that isn't my child process. Zombie processes usually make it very easy and race-condition safe. A: To make a zombie process: $ (sleep 1 & exec /bin/sleep 10) This replace the shell which run sleep 1 with /bin/sleep 10 that won't know the sleep 1 process terminated, so creating a zombie for 10 seconds. I'm not sure what do you expect from killing a zombie process. A zombie process was already dead, you can not kill it. Actually, you can make zombie processes disappear, but by killing its parent, not zombie processes themselves. A: Not so interesting answer: $ (A=$BASHPID && ( kill -STOP $A )) [1]+ Stopped ( A=$BASHPID && ( kill -STOP $A ) ) $ ps -C bash PID TTY TIME CMD 29453 pts/0 00:00:00 bash 29593 pts/0 00:00:00 bash 29594 pts/0 00:00:00 bash <defunct>
Slinky Choker Cowl Bodycon Dress Grey Add a dose of slinky into your new season wardrobe. Featuring a sexy shade of grey, bodycon style, and a cowl neck, you'll be raising the temps. Team with lace up heels and a basic clutch for those afterparty vibes.
Donald Trump visited Saudi Arabia where he had a number of meetings. In particular, it became known about a major arms deal between Saudi Arabia and the United States. It’s no exaggeration to call this visit historic for the region. With a request to comment on the significance and consequences of the visit, we turned to Theodore Karasik, Senior Advisor to Gulf State Analytics in Washington DC. How do you think the complicated relations between Iran and Saudi Arabia will develop now? Do you think that Iran will become more tolerant towards the Saudis? The Saudis and their allies want Iran to stop its expansionist activity into Arab lands, halt militaristic behavior with missile production and launches, and cease supporting Shiite extremists groups. This is their point of view basically spelled out by Deputy Crown Prince Mohammed bin Salman in his televised interview on al-Arabiya recently. US President Donald Trump also drove home the point about Iran’s perfidy. Iran, in turn, slammed Saudi Arabia and its allies including the United States for hypocrisy. Tehran is likely to up its game in Arab lands, and make trouble in maritime sealanes and disregard attempts by foreign powers to halt missile tests. Tehran, of course, has learned this stunt from Pyongyang. While Iran is deep into Arab lands and doing business with Saudi allies, Riyadh is encircling Iran through a variety of soft and hard power networks that are in Pakistan (Baluchistan), Tajikistan, Turkmenistan, Afghanistan and Azerbaijan. This is a space to watch. This encirclement idea is not new but now has an added twist with a more aggressive and muscular Saudi foreign and security policy. Overall, sides are being taken on the role Iran is playing in the region and beyond. Saudi Arabia seeks to put Tehran literally out of business. Whether this will become reality or not depends on a number of variables both internal to Iran and outside of the Islamic Republic. Clearly, we are entering an escalation ladder in terms of the Saudi-Iranian competition in the region. With the multi-level civil wars in Libya, Syria, and Yemen, Riyadh and Tehran are likely to battle it out beyond simple rhetoric. Saudi Arabia and allies are establishing the Islamic Military Alliance to Fight Terrorism (IMAFT) to be a NATO-like organization based on organizational and tactical lessons learned from Operation Inherent Resolve. This fact, according to the Riyadh Declaration, is an important step to build up a military and constabulary force of 40,000 troops for deployment. Iran, already heavily vested in the Levant and in Yemen, is unlikely to retreat. Moscow comes into play here and the Kremlin knows that it can be interlocutor on preventing an escalation. However, in a few years, based on the current trajectory, Saudi Arabia and Iran may engage each other in a battlespace instead of by proxy. Twitter @tkarasik
Ready to fight back? Sign up for Take Action Now and get three actions in your inbox every week. You will receive occasional promotional offers for programs that support The Nation’s journalism. You can read our Privacy Policy here. Sign up for Take Action Now and get three actions in your inbox every week. Thank you for signing up. For more from The Nation, check out our latest issue Subscribe now for as little as $2 a month! Support Progressive Journalism The Nation is reader supported: Chip in $10 or more to help us continue to write about the issues that matter. The Nation is reader supported: Chip in $10 or more to help us continue to write about the issues that matter. Fight Back! Sign up for Take Action Now and we’ll send you three meaningful actions you can take each week. You will receive occasional promotional offers for programs that support The Nation’s journalism. You can read our Privacy Policy here. Sign up for Take Action Now and we’ll send you three meaningful actions you can take each week. Thank you for signing up. For more from The Nation, check out our latest issue Travel With The Nation Be the first to hear about Nation Travels destinations, and explore the world with kindred spirits. Be the first to hear about Nation Travels destinations, and explore the world with kindred spirits. Sign up for our Wine Club today. Did you know you can support The Nation by drinking wine? When Congressman Steve Cohen heard Donald Trump’s awful response to Nazi violence in Charlottesville, Virginia, he knew he had to act. “Instead of unequivocally condemning hateful actions by neo-Nazis, white nationalists and Klansmen following a national tragedy,” said the Tennessee Democrat, “the President said ‘there were very fine people on both sides.’ There are no good Nazis. There are no good Klansmen.” Cohen’s conclusion, as a congressman who has accepted responsibility for oversight of constitutional concerns, is that “the president must be impeached and removed from office.” He went on: President Trump has failed the presidential test of moral leadership. No moral president would ever shy away from outright condemning hate, intolerance and bigotry. No moral president would ever question the values of Americans protesting in opposition of such actions, one of whom was murdered by one of the white nationalists. Senator John McCain rightfully tweeted this week that there was ‘no moral equivalency between racists and Americans standing up to defy hate.’ Senator Marco Rubio tweeted, ‘Very important for the nation to hear @potus describe events in #Charlottesville for what they are, a terror attack by #whitesupremacists.’ President Trump has shown time and time again that he lacks the ethical and moral rectitude to be President of the United States. Not only has he potentially obstructed justice and potentially violated the Constitution’s Foreign Emoluments Clause, but he has also shown that he is incapable or unwilling to protect Americans from enemies, foreign and domestic. Neo-Nazis and the KKK are domestic terrorists. If the President can’t recognize the difference between these domestic terrorists and the people who oppose their anti-American attitudes, then he cannot defend us. Cohen is right to address the threat in a smart and serious way, by turning to the remedy that the founders of the American experiment established for dealing with presidents who fail the test of moral leadership: impeachment. In his statement outlining his reasons for proposing articles of impeachment, Cohen quoted Martin Niemöller, the Protestant theologian who famously recalled the rise of Adolph Hitler and German fascism with the lines: First they came for the Socialists, and I did not speak out— because I was not a Socialist. Then they came for the Trade Unionists, and I did not speak out— because I was not a Trade Unionist. Then they came for the Jews, and I did not speak out— because I was not a Jew. Then they came for me—and there was no one left to speak for me. As a Jewish congressman representing a district with a large African-American population, Cohen concluded:
Everyone has been asking, “What did Josh Brown do and say?” Ever since former New York Giants kicker Josh Brown admitted to domestic abuse against then-wife Molly Brown, everyone has been looking up Josh Brown’s wife and looking up terms such as “Josh brown net worth.” So, if you’ve been looking for a Josh Brown wiki, then keep reading, because we have all the details you need. Molly Brown Molly was married to Josh for nine years and they have three kids together. Molly reported to the police that her now-ex-husband Josh physically abused her during their marriage. According to TheNew York Times and police documents released in Washington State, the admissions are part of evidence collected by a detective in King County, Washington after Brown’s arrest last year in a domestic abuse. Molly provided the documents to the police after she made her initial 911 call. Advertisement The charges were dropped after the arrest but Molly told the police that Josh had been physically violent with her many times. The couple had a troubled marriage and were in counseling to try and help deal with their issues but it never worked. The New York Giants After the first domestic abuse allegation, the Giants suspended Josh with pay until further proof was given supporting the abuse claims made by Molly. New York Giants co-owner, John Mara, previously put out a statement supporting the former Giants kicker. “All I can tell you is that we’re aware of all the allegations, and I believe all the facts and circumstances, and we were comfortable with our decision to re-sign him,” Mara said in August. The Giants signed Josh during the last NFL off-season to a two-year, $4.0 million deal, (Josh’s net worth is $2.5 million), but he did not play in the Giants’ opening game this season due to a one-game suspension the league enforced for violating their personal conduct policy. Now Josh has been cut from the team and is no longer affiliated with the Giants, leaving Mara to release a statement, given the evidence. Advertisement “We believed we did the right thing at every juncture in our relationship with Josh,” Mara said. “Our beliefs, our judgments and our decisions were misguided. We accept that responsibility.” Advertisement Although Mara acknowledged the claims made, many still hold him accountable for re-signing Josh in the first place, despite not knowing the full story of his arrest, previously. “Based on the facts and circumstances that we were aware of at that time, we were comfortable with our decision to re-sign him,”Mara said in August. Mara claimed that he was not aware of the extent of the abuse allegations until last week, when the King County Sheriff’s Office in Washington released the details of the police report. Advertisement The Apology Josh brown apologized via ESPN sports analyst, Adam Schefter: “I am sorry that my past has called into question the character or integrity of The New York Giants, Mr. Mara or any of those who have supported me along the way. I have taken measures to get help so that I may be the voice of change, not a statistic. It is important to share that I never struck my wife, and never would. Abuse takes many forms, and is not a gray area. Through the past several years I have worked to identify and rectify my own behaviors. The road to rehabilitation is a journey and a constant modification of a way of life. My journey will continue forever as a person determined to leave a positive legacy and I embrace the opportunities to show and speak about what has helped me to be that man. In the interim, I am cooperating with the Giants and the NFL. Thank you to everyone that has supported me, I will not let you down.” The Giants also released their own statement before letting Josh go, but it wasn’t worded similarly to Josh’s. As a result, Josh has since been relieved by the Giants due to the overwhelming evidence.
Translate Tuesday, August 23, 2016 Ritual Human Sacrifice @ CERN - Wizards and Our Society What does it say about our current society when scientists at CERN perform mock human sacrifices? Sure, the video was a prank, and "without official permission or knowledge” from CERN. People do wonder when the Director for Research and Scientific Computing at CERN says, "Out of this door might come something, or we might send something through it." http://freemantv.com/listen/freeman-t...
Q: Insert a logo in upper right corner of R markdown html document I'm trying to put my company logo on the right corner of my html document Here my code: <script> $(document).ready(function() { $head = $('#header'); $head.prepend('<div class="knitr source"><img src="logo.png" width="220px" align="right" ></div>') }); </script> --- title: "Title" author: "Author" date: "Date" theme: bootstrap output: html_document keep_md: true --- ```{r echo=FALSE, include=FALSE} knitr::include_graphics('./logo.png') ``` <br> ## 1) Header <br> Lorem ipsum dolor sit amet, consectetuer adipiscing elit. Aenean commodo ligula eget dolor. Aenean massa. Cum sociis natoque penatibus et magnis dis parturient montes, nascetur ridiculus mus. Donec quam felis, ultricies nec, pellentesque eu, pretium quis, sem. Nulla consequat massa quis enim. Donec pede justo, fringilla vel, aliquet nec, vulputate eget, arcu. In enim justo, rhoncus ut, imperdiet a, venenatis vitae, justo. However, because the logo.png is a local file when sharing the html document people are not able to see it. Additionally, I tried the following approach --- title: "Title" author: "Author" date: "Date" output: html_document: css: markdown.css includes: in_header: extLogo.html --- where extLogo.html <div class="logos"><img src="logo.png" width="220px" align="right"></div> But it creates a div outside the div where the Title is (<div class="container-fluid main-container">). Can anyone help on this? A: You can use htmltools::img with a little inline CSS for positioning. src can take a path directly, but when images aren't just handled like plots, sometimes knitting fails to convert images to a URI properly, which in turn causes them to fail to render. Using self_contained: false in the YAML is a quick solution, but it's not much harder to use knitr::image_uri to manually convert the image: --- title: "Title" author: "Author" output: html_document --- ```{r, echo=FALSE} htmltools::img(src = knitr::image_uri(file.path(R.home("doc"), "html", "logo.jpg")), alt = 'logo', style = 'position:absolute; top:0; right:0; padding:10px;') ``` --- # 1. Header Lorem ipsum dolor sit amet, consectetuer adipiscing elit. Aenean commodo ligula eget dolor. A: The accepted answer works if you are using classical html output. If like me, you also work with bookdown, the logo need to appear on every pages. So, in case somebody find this answer but want to add a logo with bookdown, I give my proposition: We need to create an external file with a script to be called in header, thankfully we can create it directly in the rmarkdown script. We also use htmltools::img to allow including the image without external image file. Here is my rmarkdown script to be used as an example: --- title: "Logo with Bookdown" author: "Author" date: '`r format(Sys.time(), "%d %B, %Y")`' output: bookdown::gitbook: includes: in_header: header.html --- ```{r setup, include=FALSE} knitr::opts_chunk$set(echo = TRUE) ``` ```{r htmlTemplate, echo=FALSE} # Create the external file img <- htmltools::img(src = knitr::image_uri(file.path(R.home("doc"), "html", "logo.jpg")), alt = 'logo', style = 'position:absolute; top:50px; right:1%; padding:10px;z-index:200;') htmlhead <- paste0(' <script> document.write(\'<div class="logos">',img,'</div>\') </script> ') readr::write_lines(htmlhead, path = "header.html") ``` # Page 1 This is an R Markdown document. Markdown is a simple formatting syntax for authoring HTML, PDF, and MS Word documents. For more details on using R Markdown see <http://rmarkdown.rstudio.com>. When you click the Knit button a document will be generated that includes both content as well as the output of any embedded R code chunks within the document. You can embed an R code chunk like this: ```{r cars} summary(cars) ``` # Page 2 You can also embed plots, for example: ```{r pressure, echo=FALSE} plot(pressure) ``` Note that the `echo = FALSE` parameter was added to the code chunk to prevent printing of the R code that generated the plot.
--- -api-id: M:Windows.Devices.Gpio.GpioChangeCounter.Reset -api-type: winrt method --- <!-- Method syntax. public GpioChangeCount GpioChangeCounter.Reset() --> # Windows.Devices.Gpio.GpioChangeCounter.Reset ## -description Resets the count to 0 and returns the previous count. ## -returns A [GpioChangeCount](gpiochangecount.md) structure containing a count and an associated timestamp. ## -remarks The following exception can be thrown by this method: * HRESULT_FROM_WIN32(ERROR_INVALID_HANDLE) - the change counter or the associated pin has been disposed. ## -see-also ## -examples
extends Control signal delete_save(name) signal select_save(name, page_index) signal set_screenshot(screenshot) signal set_datetime(datetime) signal set_save_name(save_name) signal set_delete_button(visibility) var file := File.new() var save_name:String = "" var save_page_index:Vector2 = Vector2.ZERO var screenshot:Texture = null func init(path:String, name:String, page_index:Vector2, save_ext:String, hide_delete:bool = false): save_name = name save_page_index = page_index var filename = name if page_index: filename = "%s_%s_%s" % [str(save_page_index.x), str(save_page_index.y), save_name] if not hide_delete: var png_path = path.plus_file(filename + ".png") if file.file_exists(png_path): Rakugo.debug("slot exist, loading image") set_screenshot(load(png_path)) else: hide_delete_button() set_save_name(name) if name == "empty": set_datetime(0) else: set_datetime(file.get_modified_time(path.plus_file(filename + "." + save_ext))) func _on_save_select(): emit_signal("select_save", save_name, save_page_index) func _on_save_delete(): if save_page_index: emit_signal("delete_save", "%s_%s_%s" % [str(save_page_index.x), str(save_page_index.y), save_name]) else: emit_signal("delete_save", save_name) func set_screenshot(texture): self.screenshot = texture emit_signal("set_screenshot", texture) func set_datetime(datetime): emit_signal("set_datetime", datetime) func set_save_name(savename): emit_signal("set_save_name", savename) func hide_delete_button(): emit_signal("set_delete_button", false)
That's interesting coming from a person who helped re-elect the Bush/Cheney team and in my eyes is just as responsible for the GOP "soul" problem as anyone else. It was Peggy that said back in 2000: "we can’t afford another famous liar in the White House." Lying a country into war hasn't seemed to bother her all that much. Noonan carefully frames her criticism of BushCo starting in 2004 ---as if they suddenly changed after that election. Download Download Robert Elisberg called Peggy out on HuffPo: Unfortunately, Ms. Noonan, there is little hidden intelligence that Democrats haven't been yelling about publicly for years. There publicly were no WMDs in Iraq when we went to war - yet you made your "grand bargain" and still supported George Bush. The budget deficit and national debt were massive - and public - yet you and your Republican party made its "grand bargain" and supported tax cuts for the wealthiest Americans. It was public that there were no links between Iraq and 9/11, but you made your "grand bargain" to support George Bush and blast as traitors and cowards anyone who dared say otherwise. And when an agent whose job was specifically to know more than others - and tell her superiors about that deep inside intelligence - was outed by people even George Bush last Thursday acknowledged were "probably" in his Administration - you Republicans had long-since made your "grand bargain" and defended the White House. And then she complains about dynasties. Once again she forgets her role in perpetuating the Bush family dynasty. Peggy, if you think the Republican party does indeed have a soul problem, then I'd suggest you lead the way and if it's possible find your own soul first. MSNBC: MTP Transcript MS. NOONAN: May I just throw in here that I think the Republicans have a tough time this year. The Democratic Party is trying to figure out of two candidates which one will take them to success, take them to the White House. The Republican Party is trying to refind its soul. And in looking at each state, at each of these guys, they're thinking "is this the guy who reflects what conservatism is--what modern conservatism is, what this party is, and the next day they think, "maybe it's this guy." It is a much tougher thing to find your soul than it is to find success. So I think the Republicans are really going to be struggling for a while. I also think, Jon, I must say, I think what has happened with the conservative coalition is that it has been sundered. I think it was sundered by this administration from 2004 on through a series of decisions that were not just at odds with, but deeply defined of and rejecting of the feelings, thoughts and views of Republicans and conservatives. And to make it even worse, the Congress, when it was under Republican hands and now Democratic hands, was just as defiant, just as at odds with the feelings of so many people about what it is that is most reflective of conservatism in the Republican Party. So I think Republicans have taken a beating in a way and they--I mean, almost a psychic beating, and they are trying really hard to redefine and come back. It's going to be a tough job. MR. BROKAW: Republicans and Democrats alike. I have never heard as many Republicans, gold-star, born and bred Republicans, so unhappy with the management of this country by a Republican president now. MS. NOONAN: Totally true. MR. BROKAW: And I think that when she played the competence card and the experience card, it's measured against that. MS. GOODWIN: Right. MR. BROKAW: We don't want to go back into an unknown again. Here is somebody who does know what she's doing. That does pop up in the polls. But the counterweight to it, of course, is still not entirely comfortable with her. I have questions about her character and concern about whether she can win. MS. NOONAN: May I say, dynasticism is part of this, too? MS. GOODWIN: Oh, yeah. MS. NOONAN: We haven't mentioned it, but there is this Bush, Clinton, Bush, Clinton--I've called it a sickness. It is an odd way for a great democracy to comport itself in this strange--we have dynasties now backed by lobbyists, backed by machines and machinery. The fact that America's doing this is giving so many people pause. It us unlike us. And I cannot help but think, as some people come forward and endorse on the Democratic side Mrs. Clinton, they must be thinking stop the dynasty. I know Republicans are thinking stop the dynasties. MR. BROKAW: But on NBC, you'd be happy with Russert, Brokaw, Russert, Brokaw. That would be OK? MS. NOONAN: Forever, Tom. Forever.
Gastroenteritis is a major public health issue worldwide. Noroviruses are now considered emerging pathogens ([@R1]) and are recognized as the leading cause of nonbacterial, acute gastroenteritis in humans ([@R2]). The 2 genera, Norovirus and Sapovirus, are members of the family Caliciviridae and have a positive-sense, single-stranded RNA genome ≈7.5 kb long. Because no readily available cell culture system exists, characterization and classification of noroviruses are based on reverse transcription (RT)--PCR, genomic sequencing, and phylogenetic analysis ([@R2]--[@R5]). According to the latest scheme for norovirus nomenclature, the 29 genetic norovirus clusters or genotypes are classified into 5 genogroups (GI--V) ([@R6]). GI and II infect humans, and GII.4 has been the most highly prevalent genotype worldwide during the past decade ([@R2],[@R5],[@R7]). The saying "Madagascar is not an island, but an archipelago" captures an important aspect of the country, whose geography and history have combined to produce a society of considerable diversity and uniqueness ([@R8]). In recent years, many studies have investigated the role of human noroviruses in childhood diarrhea and found worldwide distribution ([@R4],[@R7],[@R9],[@R10]). However, no studies have reported the prevalence and molecular epidemiology of noroviruses in Madagascar, which we report here. The Study ========= From May 2004 to May 2005, a study of acute gastroenteritis in children [\<]{.ul}16 years of age was undertaken by the Institut Pasteur, Antananarivo, Madagascar. Children with a diagnosis of acute dehydrating watery diarrhea who were seen at the rehydration clinics and hospitals of Antananarivo were eligible for the study. Antananarivo, the capital city of Madagascar, has a population of ≈4 million. The study was approved by the Ethical Review Board of the Institut Pasteur, Antananarivo, Madagascar. Fecal samples were collected from the children and stored at --80°C until analysis was undertaken at the University of Liverpool, UK. There, viral RNA was extracted from 150 μL of 10%--20% fecal suspensions in phosphate-buffered saline by using a guanidine and silica method ([@R11]). Sapoviruses were not sought in the initial screening. RT-PCR was performed in a 50-μL reaction mixture with primers that targeted the capsid N terminus/shell gene. For GI, forward primer G1SKF (5′-CTGCCCGAATTYGTAAATGA-3′) and reverse primer G1SKR (5′-CCAACCCARCCATTRTACA-3′) were used, yielding a PCR product of 330 bp. For GII, the primers used were forward primer G2SKF (5′-CNTGGGAGGGCGATCGCAA-3′) and reverse primers G2SKR (5′-CCRCCNGCATRHCCRTTRTACAT-3′) and G2ALSKR (5′-CCACCAGCATATGAATTGTACAT-3′), yielding a 344-bp product ([@R12]). The PCR was performed with an initial denaturation at 94°C, followed by 40 cycles of 60-sec denaturation at 94°C, 60-s primer annealing at 50°C, an extension for 2 min at 72°C, followed by a final extension stage of 15 min at 72°C. Amplification products were examined under ultraviolet light after electrophoresis through a 2% agarose gel with ethidium bromide staining. Products were extracted by using the QIAquick PCR purification kit (QIAGEN, Basingstoke, UK) and were sequenced by Macrogen Inc. (Seoul, South Korea). Phylogenetic relationships were examined by aligning sequences with the ClustalW multiple alignment program (European Molecular Biology Laboratory, Heidelberg, Germany). A phylogenetic tree was constructed according to the neighbor-joining method by using ClustalX (version 1.83) and the alignment file obtained by analysis with ClustalW. Bootstrap values on a scale from 1 to 1,000 were also calculated. An unrooted phylogram of norovirus isolates from the present study and prototype strains was plotted in the PHYLIP format (<http://evolution.genetics.washington.edu/phylip.html>) output by using TreeView software, version 3.1 (<http://taxonomy.zoology.gla.ac.uk/rod/treeview.html>). Assignment of norovirus to genotype was made according to the scheme proposed by Zheng et al. ([@R6]). The nucleotide sequences of the Malagasy strains have been deposited at GenBank (accession nos. EF213624--EF213635, EF213638, and EF213640.) Norovirus-positive samples were screened for other viruses by negative-stain electron microsopy and by RT-PCR for rotavirus and astrovirus ([@R13],[@R14]). During this 12-month study, 258 children with acute gastroenteritis in Madagascar were screened for norovirus infection. Because 21 samples contained insufficient stool, 237 samples were analyzed (142 from boys and 95 from girls). Overall, 85% of children were \<3 years of age, 77% were \<2 years, 43% were \<1 year, and 3% were newborns. The median age of the study population was 20 months (range 1 day to 16 years). Fourteen noroviruses (5.9%) were detected in 237 children ([Table 1](#T1){ref-type="table"}). Noroviruses were found in all age groups. Infection rates did not differ between boys and girls (6.3% and 5.2%, respectively, p\>0.1). No coinfections with other viruses (rotavirus, astrovirus, and adenovirus) were detected. Ten (71%) of the noroviruses detected were identified as belonging to genogroup GII; the remaining 4 (29%), to GI. Most GII noroviruses belonged to a potentially novel cluster ([Figure 1](#F1){ref-type="fig"}). GI noroviruses were further classified into 3 genotypes: GI.1 (1 isolate), GI.4 (1 isolate), and GI.3 (2 isolates). ###### Characteristics of viruses from children with acute gastroenteritis in Madagascar\* Identification no. GenBank accession no. Sample† date Age, mo Sex Norovirus PCR Norovirus sequencing EM for NoV, RV, AV‡ -------------------- ----------------------- -------------- --------- ----- --------------- ---------------------- --------------------- DG6004-Madag04 EF213640 May 2004 14 M GI pos GI-1 Neg DC2022-Madag04 EF213626 July 2004 14 F GII pos GII novel Neg DG6003-Madag04 EF213634 Oct 2004 44 M GII pos GII novel Neg DR0011-Madag04 EF213628 Nov 2004 12 M GII pos GII novel Neg DR0025-Madag04 EF213625 Nov 2004 17 M GI pos GI-4 Neg DC2048-Madag04 EF213624 Nov 2004 3 M GI pos GI-3 Neg DR0023-Madag04 EF213638 Nov 2004 9 F GI pos GI-3 Neg DR0045-Madag04 EF213627 Nov 2004 19 F GII pos GII novel Neg DC2054-Madag04 EF213629 Dec 2004 16 M GII pos GII novel Pos (putative NoV) DG6020-Madag04 EF213630 Dec 2004 30 M GII pos GII novel Neg DR0046-Madag04 EF213631 Dec 2004 14 F GII pos GII novel Neg DT1020-Madag04 EF213632 Dec 2004 12 F GII pos GII novel Neg DT1032-Madag04 EF213633 Dec 2004 8 M GII pos GII novel Neg DM4025-Madag05 EF213635 Mar 2005 51 M GII pos GII novel Neg \EM, electron microscopy, NoV, norovirus; RV, rotavirus; AV, astrovirus; pos, positive; neg, negative. †Fecal samples. ‡All norovirus-positive samples were negative for AV and RV when tested by reverse transcription--PCR. ![Phylogenetic tree of noroviruses based on the 330-bp region (for GI) and 344-bp region (for GII) of the capsid N terminus/shell gene. Fourteen novel sequences were included, designated according to isolate code, place, and year (e.g., DR001-Madag04); 25 sequences of reference norovirus strains ([@R6]) were included, designated according to genogroup-genotype, place, country, and year (e.g.,GII-2/Melksham-GRB1994). Comparative strains are GI-1/NV-USA1968 (Norwalk, M87661), GI-2/SOV-GBR1993 (Southampton, L07418), GI-3/DSV-USA1993 (Desert Shield, U04469), GI-4/Chiba-JPN2000 (AB042808), GI-5/Musgrov-GBR1989 (Musgrove, AJ277614), GI-6/Hesse-DEU1998 (AF093797), GI-7/Wnchest-GBR1994 (Winchester, AJ277609), GI-8/Boxer-USA2001 (AF538679), GII-1/Hawai-USA1971 (U07611), GII-2/Melksham-GBR1994 (X81879), GII-3/Toronto-CAN1993 (U02030), GII-4/Bristol-GBR1993 (X76716), GII-5/Hillingd-GBR1990 (Hillingdon, AJ277607), GII-6/Seacrof-GBR1990 (Seacroft, AJ277620), GII-7/Leeds-GBR1990 (AJ277608), GII-8/Amstdam-NLD1990 (Amsterdam, AF195848), GII-9/VABeach-USA1997 (AY038599), GII-10/Erfurt-DEU2000 (AF427118), GII-11/SW918-JPN1997 (AB074893), GII-12/Wortley-GBR1990 (AJ277618), GII-13/Faytvil-USA1998 (Fayetteville, AY113106), GII-14/M7-USA1999 (AY130761), GII-15/J23-USA1999 (AY130762), GII-16/Tiffin-USA1999 (AY502010), and GII-17/CSE1-USA2002 (AY502009). Bootstrap values based on 1,000 generated trees are displayed at the nodes. The scale bar represents nucleotide substitutions per site.](07-0215-F1){#F1} The median age of children with norovirus infection was 18 months (range 3--51 months). Most infections (≈86%) occurred in children \<36 months of age. No infections were recorded in newborns or children \>5 years of age. All infections with genogroup GI noroviruses were found in children \<24 months of age ([Table 2](#T2){ref-type="table"}). Noroviruses were detected throughout the year; however, infections peaked during the wet season in Madagascar. November and December were the months of major norovirus prevalence (35.7% each month). GI noroviruses preceded GII infections by a few days ([Figure 2](#F2){ref-type="fig"}). ###### Distribution of viruses and norovirus genogroups in children with acute gastroenteritis, by age, Madagascar, May 2004--May 2005 Virus Age group, mo ---------------------- --------------- ---- ---- ---- Other than norovirus 96 75 18 34 Norovirus GI 2 2 0 0 Norovirus GII 3 4 1 2 ![Seasonality of GI and GII norovirus infections, Antananarivo, Madagascar, May 2004--May 2005.](07-0215-F2){#F2} Conclusions =========== To our knowledge, ours is the first study that has used molecular detection methods to investigate the role of noroviruses in pediatric gastroenteritis in Madagascar. We showed that infections with GI and GII noroviruses are relatively common. In a 1-year collection of stool samples, we detected noroviruses by RT-PCR in ≈6% of children with acute gastroenteritis in Antananarivo. This rate establishes norovirus as the second most commonly detected enteric virus in this population, behind rotavirus (38%) and followed by astrovirus (2.5%) (data not shown). These findings are consistent with those of studies elsewhere ([@R7],[@R10]). The median age of children with norovirus infection (18 months) was higher than previously reported ([@R7]) and higher than that of the rotavirus-infected group (median 10 months, range 1 day to 48 months) and that of the astrovirus-infected group (median 10 months, range 5--20 months) (data not shown). Noroviruses were detected throughout the year, but the number peaked in November and December. Such seasonality in a tropical country is not really expected, as year-round circulation has been previously documented ([@R15]). Our findings confirm the finding of previous studies that GII is the predominant norovirus genogroup circulating in communities worldwide. Considerable genetic diversity was observed among the norovirus GII isolates, and some were identified as belonging to a potentially novel cluster. The closest reference strain to the potentially novel cluster was the recombinant Hu/NoV/GII.1/Hawaii/1971/US. In contrast, norovirus GI isolates were clustered with prototype strains; Hu/NoV/GI.3/DSV395/1990/SA (Desert Shield) was predominant (2 strains), followed by Hu/NoV/GI.1/Norwalk/1968/US (Norwalk) and Hu/NoV/GI.4/Chiba407/1987/JP (1 each). This study has several limitations. First, it is a preliminary study. The sample size was small, and we examined samples collected over a 13-month period. Longer, longitudinal studies are required to address issues such as norovirus seasonality and temporal genetic variability. In addition, we restricted our analysis to specimens collected from patients at rehydration clinics and hospitals, so prevalence of norovirus infections in the general population may have been underestimated. Furthermore, the use of short conserved sequences, although successful for diagnosis of norovirus infection, should be used with caution for classification and phylogenetic analyses. Further analysis by full capsid sequencing might be required. Nevertheless, continued norovirus surveillance is needed to monitor the spread and persistence of the various genotypes infecting children in Madagascar. Suggested citation for this article: Papaventsis DC, Dove W, Cunliffe NA, Nakagomi O, Combe P, Grosjean P, et al. Norovirus infection in children with acute gastroenteritis, Madagascar, 2004--2005. Emerg Infect Dis \[serial on the Internet\]. 2007 Jun \[date cited*\]. Available from <http://www.cdc.gov/eid/content/13/6/908.htm> We are grateful to P. Mauclere, for providing the opportunity to work with these samples. The study was funded internally by the University of Liverpool. Dr Papaventsis is an honorary clinical lecturer in medical microbiology and genitourinary medicine, Department of Host Defense and Infection, Faculty of Medicine, University of Liverpool, UK. His main research interests include the molecular epidemiology of enteric viruses.
Mick Mulvaney, acting director of the Consumer Financial Protection Bureau (CFPB), announced Wednesday that the federal watchdog will effectively shutter its student loan division and shift its responsibilities to another office, a move that critics warn will lead to "open season on borrowers." The restructuring is part of Mulvaney master plan to, as the New York Times notes, "refocus the agency away from its consumer finance enforcement and rule-writing mission and more toward providing consumers with information about their legal rights"—in other words, to "defang" the CFPB, a long-time target of the acting director as well as President Donald Trump. While a CFPB spokesman framed the shift as "modest," insisting that agency personnel are "working on the same material as they were before," career officials told the Times they fear it "will sidetrack a major enforcement case the agency is pursuing against Navient, the nation's largest student loan collector." The move was also sharply criticized beyond the agency, by consumer advocates and at least one member of Congress. Pointing out that "student loan debt is exploding," Sen. Elizabeth Warren (D-Mass.)—one of the driving forces behind the creation of the CFPB—said that "it's clear" the Trump administration "has declared war on students." Student loan debt is exploding, but @MickMulvaneyOMB is planning to shut down the only federal office fully focused on protecting student borrowers from predatory companies. Add this to @BetsyDeVosED's anti-student work, & it's clear the Trump Admin has declared war on students. https://t.co/xLrhKHDmsS SCROLL TO CONTINUE WITH CONTENT Never Miss a Beat. Get our best delivered to your inbox. — Elizabeth Warren (@SenWarren) May 9, 2018 "At a time when the number of and the size of student loans are spiraling out of control, it's simply appalling to me that the administration is deciding to close the one office in the United States government that is exclusively focused on promoting fairness in student lending," Christopher Peterson, a senior fellow at the Consumer Federation of America, told MarketWatch. "Previously, the unit interacted with state law enforcement officials on student loan issues," MarketWatch explained. "The agency also collected complaints, pushed companies to respond to them, and held firms accountable for inappropriate practices. Now it will likely focus more on simply providing information to borrowers." Challenging the CFPB's new priorities under Mulvaney, Whitney Barkley-Denney, senior policy counsel with the Center for Responsible Lending, told the Associated Press, "Education alone cannot stop predatory behaviors on the part of for-profit schools and servicers, nor can it help hundreds of thousands of Americans in serious debt because of these practices." Wednesday's announcement comes as Mulvaney, who also runs the Office of Management and Budget (OMB), faces mounting charges of corruption and calls for his resignation.
Introduction ============ Osteoarthritis (OA) is the most common musculoskeletal disease causing chronic pain and joint disability. OA is characterized by the loss of articular cartilage, involving increased subchondral bone remodeling, osteophyte formation, weakening of the periarticular muscles, and thickening of the capsule and synovial membrane, which lead to functional joint limitations (Guilak, 2011\[[@R17]\]; Mobasheri, 2013\[[@R43]\]; Speziali et al., 2015\[[@R49]\]). In particular, OA is the result of mechanical and biological events that cause the degradation of articular cartilage. These processes are mediated by excessive synthesis and release of catabolic tissue proteinases, such as matrix metalloproteinases (MMPs), collagenases and aggrecanases, that are upregulated by inflammatory stimuli and oxidative stress, including inflammatory cytokines and mediators, and reactive oxygen species (Goldring and Otero, 2011\[[@R15]\]; Makki and Haqqi, 2015\[[@R39]\]; Lepetsos and Papavassiliou, 2016\[[@R35]\]). Currently, pharmacological treatment for patients with OA is based on some steroidal and non-steroidal anti-inflammatory drugs for alleviation of pain as well as inflammation. However, they can not perfectly prevent the progressive cartilage degradation and repair the impaired cartilage of OA patients, and long-term use of these drugs can lead to severe side effects or toxicity, including gastrointestinal disturbances and cardiovascular risk (Mobasheri, 2013\[[@R43]\]; Goldring and Berenbaum, 2015\[[@R14]\]). Therefore, ideal agents that inhibit cartilage degradation with better safety and efficacy may represent an attractive strategy to treat OA. Herbal sources have been widely and safely consumed for centuries. Many studies indicate that these herbs have a wide range of diverse biological activities with few side effects (Chen et al., 2015\[[@R7]\]; Hou et al., 2015\[[@R18]\]). Therefore, traditional herbal medicinal sources have been investigated widely as adjuvant therapeutic agents in the treatment of OA (Cameron and Chrubasik, 2013\[[@R6]\]; Dhippayom et al., 2015\[[@R10]\]). Schisandrae Fructus, the dried fruit of Schisandra chinensis (Turcz.) Baill. (Magnoliaceae), has been used in traditional medicine for the treatment of various medicinal purposes (Panossian and Wikman, 2008\[[@R45]\]; Chun et al., 2014\[[@R9]\]). The diverse pharmacological effects of Schisandrae Fructus include antioxidant (Kang et al., 2014\[[@R23]\]), anti-tumor (Lv et al., 2015\[[@R37]\]), hepatoprotective (Wat et al., 2016\[[@R54]\]), anti-septic (Kook et al., 2015\[[@R30]\]), neuroprotective (Lee et al., 2012\[[@R33]\]), anti-inflammatory (Bae et al., 2012\[[@R3]\]; Kang et al., 2014\[[@R24]\]), anti-atherosclerotic (Jeong et al., 2015\[[@R20]\]), and anti-atrophic (Kim et al., 2015\[[@R27]\]\[[@R28]\]), and anti-diabetic effects (Kwon et al., 2011\[[@R31]\]). Recently we reported that Schisandrae Fructus possessed potential chondroprotective effects of the collagen matrix breakdown in a pro-inflammatory cytokine interleukin (IL)-1β-induced model in vitro (Jeong et al., 2015\[[@R21]\]). However, to our knowledge, the in vivo therapeutic effects of this compound and its effects on the molecular mechanisms of OA have not been investigated. Therefore, as a part of our on-going research program for finding novel anti-osteoarthritic substances from traditional medicinal sources, the present study investigated the anti-osteoarthritic potential and underlying mechanism of an ethanol extract of Schisandrae Fructus (SF) in a rat model of metabolic-inhibitor-monosodium iodoacetate (MIA)-induced OA. Materials and Methods ===================== Preparation of SF ----------------- The dried fruits of S. chinensis were collected from Mungyeong city (Gyeongsangbuk-do, Republic of Korea) and washed three times with tap water before storage at -80 °C. Frozen samples were lyophilized and homogenized using a grinder before extraction with 20 % ethanol at room temperature for 4 h, filtered, and concentrated using a rotary vacuum evaporator (BÜCHI Labortechnik, Flawil, Switzerland). The extract (SF) was dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich Chemical Co., St. Louis, MO, USA) as a 50 mg/mL stock solution and stored at 4 °C and diluted with physiological saline to the desired concentration prior to use. Animals ------- Male Sprague-Dawley rats weighing 180\~240 g (5 weeks of age) at the start of the experiment were purchased from Samtako Inc. (Osan, Republic of Korea). Two animals were housed per polycarbonate cage in a room under controlled-temperature conditions (20\~24 °C, humidity 40\~70 %) with controlled lighting (12 h light and/or 12 h dark cycle) and had access to sterile food and R/O water (Lee et al., 2016\[[@R34]\]). This study was carried out in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. In addition, the animal protocol used in this study was reviewed by the Dongeui University - Institutional Animal Care and Use Committee on their ethical procedures and scientific care, and it has been approved (Approval Number: A2015-019). Development of OA with MIA injection and administration with SF --------------------------------------------------------------- The rats were randomized and assigned to treatment groups before the initiation of the study (n = 8 per group). For induction of OA, rats were anesthetized using isoflurane and then given a single injection of 50 μL sterile 0.9 % saline containing 3 mg/kg MIA (Sigma-Aldrich Chemical Co.) using a 0.3 mL insulin syringe (BD Medical-Diabetes Care, Franklin Lakes, NJ, USA) through the patellar ligament into the articular cavity of the right knee. Control rats were injected with an equivalent volume of saline. SF was administered orally once per day for 3 weeks at a dose of 100 mg/kg. Measurement of knee joint swelling ---------------------------------- After the rats were killed at 3 weeks post-MIA injection, the right knee was isolated, and the femur, tibia, and patella were dissected free of muscle. Knee diameter was measured using a calibrated digital caliper (Mitutoyo, Kawasaki, Japan) to assess the developmental stages of OA on 3 weeks post-MIA injection (Fernihough et al., 2004\[[@R12]\]). Serum analysis -------------- At the end of the 3 weeks, the samples of whole blood were collected from the abdominal vein. Blood was allowed to clot for 30 min. Then, the serum was separated via centrifugation at 1,500 g for 10 min and stored at -80 °C. Concentrations of nitric oxide (NO) in the serum samples were determined by measuring nitrite, which is a major stable product of NO, using the Griess reagent. Briefly, 50 μL of serums were mixed with 50 μL of Griess reagent (Sigma-Aldrich Chemical Co.), followed by incubation for 10 min at 37 °C. Optical density was measured at 540 nm using an enzyme-linked immunosorbent assay (ELISA) reader (Dynatech Laboratories, Chantilly, VA, USA) (Kwon et al., 2016\[[@R32]\]). Serum levels of prostaglandin E~2~ (PGE~2~) were determined according to the manufacturer\'s instructions (ELISA kit, R&D Systems, Minneapolis, MN, USA) (Kim et al., 2016\[[@R29]\]). The pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α, and cartilage degeneration mediators such as cartilage oligomeric matrix protein (COMP) and C-telopeptide of type II collagen (CTX-II) were also determined using ELISA kits (R&D Systems, Minneapolis, MN, USA) according to the manufacturer\'s recommendations. Joint histological examination ------------------------------ Histological changes were assessed to confirm the effects of SF on cartilage degeneration in the knee joints of MIA-induced OA rats. After the rat sacrifice at 3 weeks, each knee joint was resected, fixed in 10 % formalin (Sigma-Aldrich Chemical Co.) for 24 h at 4° C, and decalcified with 5 % hydrochloric acid (Sigma-Aldrich Chemical Co.) for 4 days at 4° C. After decalcification, the specimens were embedded in paraffin. Sections (2\~3 μm) were stained with hematoxylin and eosin (H&E), safranin O-fast green and toluidine blue (Sigma-Aldrich Chemical Co.), respectively, and then observed under Carl Zeiss Axio-plan 2 imaging microscope (Carl Zeiss, Deisenhofen, Germany). All stained slides were histologically evaluated and statistically graded on a scale of 0\~13 by double-blind observation, according to the modified Mankin scoring system (Mankin et al., 1971\[[@R40]\]). Immunohistochemical analysis ---------------------------- The sections were depleted of endogenous peroxidase activity by treatment with 3 % H~2~O~2~ for 15 min. They were then were blocked with normal goat serum (Sigma-Aldrich Chemical Co.) for 30 min and incubated at 4 °C overnight with primary antibodies followed by the appropriate biotinylated secondary antibodies and horseradish peroxidase-conjugated streptavidin-biotin staining, and finally with a 3,3′-diaminobenzidine (DAKO, Glostrup, Denmark). Primary antibodies against the following proteins were used: inducible NO synthase (iNOS, 1:100; SC-7271, mouse monoclonal, Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA), cyclooxygenase-2 (COX-2, 1:50; SC-19999, mouse monoclonal; Santa Cruz Biotechnology, Inc.), MMP-13 (1:50; ab51072, rabbit monoclonal; Abcam, Cambridge, UK), COMP (1:50; ab11056, rabbit monoclonal; Abcam) and CTX-II (1:50; PAA686Hu01, rabbit polyclonal; Cloud-Clone Corp., Houston, TX, USA ). Histological changes were examined by a Carl Zeiss Axio-plan 2 imaging microscope (Carl Zeiss) and photographed. Statistical analysis -------------------- Data were expressed as mean ± standard deviation (SD) for at least three separate determinations for each group. The differences between the groups were examined for statistical significance using the Student\'s t-test and one-way ANOVA with GraphPad software (GraphPad Inc., La Jolla, CA, USA). A value of p \< 0.05 was considered as being significant. Results ======= SF reduced MIA-induced knee swelling in rats -------------------------------------------- Knee diameters were measured to determine the degree of joint swelling, an index of inflammation that occurred after intra-articular injection of MIA. As shown in Figure 1[(Fig. 1)](#F1){ref-type="fig"}, the knee diameter of in MIA groups increased significantly after an intra-articular injection of MIA as compared with normal control group. However, SF treatment significantly reduced the joint swelling at 3 weeks after MIA injection. SF ameliorated the histological evaluation of the articular damage in MIA-induced OA rats ----------------------------------------------------------------------------------------- Because, the cartilage degeneration is the main histologic feature of OA, we investigated the effects of SF on the morphological changes and severity of the particular damage using H&E, Safranin O-fast green, and toluidine blue staining in the MIA-induced OA rat. Our findings showed that MIA-injected group showed the severity of surface irregularity and surface cleft, and matrix loss of articular cartilage associated (Figure 2A[(Fig. 2)](#F2){ref-type="fig"}). However, SF alone had little effect on the structural, morphological changes in the joints, and administration with SF attenuated damages in the articular cartilages compared with those of the MIA-treated group. Therefore, the severity of OA lesion was graded using the modified Mankin scoring system, and we found that the overall modified Mankin\'s scores were significantly recovered by SF treatment compared with a MIA-treated group (Figure 2B[(Fig. 2)](#F2){ref-type="fig"}). SF inhibited the production of pro-inflammatory cytokines in MIA-induced OA rats -------------------------------------------------------------------------------- Pro-inflammatory cytokines have important roles in the development and progression of OA (Kapoor et al., 2011\[[@R25]\]; Mabey and Honsawek, 2015\[[@R38]\]). We, therefore, determined whether SF had any inhibitory effects on the production of inflammatory cytokines associated with OA, such as IL-1β, IL-6, and TNF-α. As illustrated in Figure 3[(Fig. 3)](#F3){ref-type="fig"}, the serum levels of the cytokines significantly increased in the serum of MIA group compared with those in the saline group; however, the group treated with SF effectively inhibited the production of IL-1β, IL-6, and TNF-α when compared to MIA alone. SF protected the production on NO and PGE~2~, and expression of iNOS and COX-2 in MIA-induced OA rats ----------------------------------------------------------------------------------------------------- Because overproductions of pro-inflammatory mediators such as NO and PGE~2~ also have been correlated to the pathophysiology of OA (Amin et al., 2000\[[@R1]\]; Martel-Pelletier et al., 2003\[[@R42]\]), we investigated the effects of SF on NO and PGE~2~ release in MIA-induced OA rats. As indicated in Figure 4A and B[(Fig. 4)](#F4){ref-type="fig"}, a substantial increase in the NO and PGE~2~ levels were detected in MIA-induced OA rats when compared to normal control group; however, these levels were significantly decreased following SF administration. We subsequently investigated whether the inhibitory effects of SF on NO and PGE~2~ production were related to the regulation of the expression of their synthesis enzymes, iNOS, and COX-2, in knee joints by immunohistochemical analysis. The results showed that compared to the control group, MIA remarkably induced the expression of iNOS and COX-2, while, SF obviously suppressed elevated expression levels of iNOS and COX-2 in the cartilaginous tissues of the MIA-induced OA rats (Figure 4C and D[(Fig. 4)](#F4){ref-type="fig"}). SF down-regulated the MMP-13 expressions in MIA-induced OA rats --------------------------------------------------------------- The progressive destruction of cartilage degradation in OA is caused by several matrix-degrading enzymes including MMPs produced by the chondrocytes and synovium (Burrage et al., 2006\[[@R5]\]; Troeberg and Nagase, 2012\[[@R51]\]). Because, among the MMPs family, MMP-13 play a most important role in degrading cartilage (Takaishi et al., 2008\[[@R50]\]; Li et al., 2011\[[@R36]\]), we examined the effects of SF on the expression of MMP-13 in MIA-stimulated OA cartilage. Our results demonstrated that the number of chondrocytes staining positive for MMP-13 was increased after MIA injection, with significantly lower percentages of MMP-13-positive chondrocytes evident in the SF-administered group relative to saline-treated controls (Figure 5[(Fig. 5)](#F5){ref-type="fig"}). SF diminished the production of COMP and CTX-II in MIA-induced OA rats ---------------------------------------------------------------------- We next investigated the effects of SF on the levels of COMP and CTX-II, well-established biomarkers for diagnosis and OA progression (Goode et al., 2012\[[@R16]\]; Saberi Hosnijeh et al., 2016\[[@R48]\]), which play key roles during subsequent progressive osteophytes in multiple knee compartments. Our ELISA data indicated that excessive production of COMP and CTX-II were evident in the serum of MIA-induced OA rats; these levels were significantly diminished following SF administration (Figure 6A and B[(Fig. 6)](#F6){ref-type="fig"}). Consistent with the results of ELISA, immunohistochemistry assay showed that oral administration with SF caused a significant decrease in expression of COMP as well as CTX-II compared with that in the normal control group (Figure 6C and D[(Fig. 6)](#F6){ref-type="fig"}). Discussion ========== In this study, we investigated whether or not SF exerts a chondroprotective effect in a rat OA model by injection with MIA, which is known to induce OA through interruption of chondrocyte metabolism (Barve et al., 2007\[[@R4]\]). Our data showed that oral administration of SF led to a significant decrease of structural changes such as joint space narrowing and cartilage destruction in MIA-induced OA rats, which was associated with a reduction of pro-inflammatory molecules, MMP-13 and both biomarkers of cartilage and bone metabolism such as COMP and CTX-II. The compelling evidence demonstrated that pro-inflammatory cytokines are significantly elevated in synovial fluid from OA patients and play critical roles in the promotion of the catabolic processes in OA, causing cartilage degradation (Kapoor et al., 2011\[[@R25]\]; Rahmati et al., 2016\[[@R47]\]). High levels of pro-inflammatory cytokines have been found in synovial fluid from OA patients and several models of cartilage degradation (Goldring and Otero, 2011\[[@R15]\]; Kellesarian et al., 2016\[[@R26]\]). Among these cytokines, IL-1β is highly over-expressed in the cartilage as well as in the synovial tissue while the expression of IL-1Rα, a receptor antagonist of the IL-1 family (Jotanovic et al., 2012\[[@R22]\]). This cytokine inhibits proliferation and triggers apoptosis of chondrocytes and blocks the extracellular matrix (ECM) structural compounds synthesis by activating MMPs including MMP-13 (Mabey and Honsawek, 2015\[[@R38]\]; Rahmati et al., 2016\[[@R47]\]). IL-6 has also been reported to act as one of the main pro-inflammatory cytokines involved in the pathophysiology of OA. IL-6 induces destruction of joint and cartilage by stimulating the activation of osteoclasts and differentiation of mesenchymal cells into chondroblasts (Doss et al., 2007\[[@R11]\]; Jotanovic et al., 2012\[[@R22]\]). In addition, previous studies revealed that TNF-α has similar to or synergistic with IL-1β and IL-6 in the production of matrix-degrading enzymes and inhibition of proteoglycan synthesis, resulting in loss of cartilage and bone resorption during the process of OA development (Jotanovic et al., 2012\[[@R22]\]; Kellesarian et al., 2016\[[@R26]\]). In accordance with, many studies demonstrated that anti-inflammatory agents capable of inhibiting the production of those cytokines may have the potential to control or treatment of OA (Kapoor et al., 2011\[[@R25]\]; Mabey and Honsawek, 2015\[[@R38]\]). Hence, we investigated the anti-inflammatory effects of SF by measurements of the serum levels of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, in MIA-induced OA rats, and found that SF administration decreased these cytokines, the MIA increased these parameters. Taken together, the present results indicate that SF has a potential of prevention against inflammatory responses, and subsequently might reduce the damage of articular cartilage. In addition to the roles of inflammatory cytokines, pro-inflammatory mediators such as NO and PEG~2~ plays an extremely important role in the development of inflammation in OA (Amin et al., 2000\[[@R1]\]; Rahmati et al., 2016\[[@R47]\]). These pro-inflammatory mediators can induce cell death of chondrocytes and loss of cartilage matrix in the pathogenesis of OA, and they are also significantly elevated in cartilage and synovial tissues from OA patients (Notoya et al., 2000\[[@R44]\]; Park et al., 2006\[[@R46]\]). Moreover, the pro-inflammatory cytokines can stimulate the production of pro-inflammatory mediators, such as NO and PEG~2~, through activation of chondrocytes (Martel-Pelletier et al., 2006\[[@R41]\]; Rahmati et al., 2016\[[@R47]\]). Therefore, we next investigated the effects of SF on the release of NO and PEG~2~ in MIA-induced OA rat model. Our results clearly demonstrated that the serum levels of NO and PEG~2~were significantly higher in the MIA group compared with the control group. However, SF effectively reduced MIA-induced elevation of NO and PEG~2~ production by suppressing upstream molecules iNOS and COX-2 expression, consistent with a previous our report that SF reduced production of NO and PEG~2~ in IL-1β-stimulated human chondrocytes (Jeong et al., 2015\[[@R21]\]) and lipopolysaccharide-activated murine macrophage (Kang et al., 2014\[[@R24]\]). Accumulated evidence suggested that MMPs are important metalloproteases involved in tissue remodeling including the turnover, catabolism, and degradation of the ECM (Burrage et al., 2006\[[@R5]\]; Troeberg and Nagase, 2012\[[@R51]\]). MMPs expression could be up-regulated by pro-inflammatory cytokines in a variety of tissues and cell types, including articular chondrocytes (Goldring and Otero, 2011\[[@R15]\]; Takaishi et al., 2008\[[@R50]\]). Among the MMPs, MMP-13 is critical for degrading collagens, proteoglycans and other ECM macromolecules in the osteoarthritic pathological process (Takaishi et al., 2008\[[@R50]\]; Li et al., 2011\[[@R36]\]). We then analyzed the expression of MMP-13, to assess the effects of SF on the catabolic activity of chondrocytes. Consistent with previous studies (Andereya et al., 2006\[[@R2]\]; Barve et al., 2007\[[@R4]\]), the serum levels of MMP-13 and the percentages of MMP-13-positive chondrocytes were significantly higher in the MIA-treated group than in the saline-treated controls. However, our results demonstrated that the SF-administrated rats had fewer MMP-13-producing cells than did the MIA-treated rats, which was connected with lowering MMP-13 production. These observations support the fact that SF might have a chondroprotective effect by reducing the production and activation of MMP-13. Several clinical studies in OA patients and OA animal models demonstrated that the elevated levels of COMP and CTX-II are correlated with increased risk and progression of OA. COMP, a pentameric glycoprotein, is one of the essential components of the extracellular matrix of the cartilage (Goode et al., 2012\[[@R16]\]; Saberi Hosnijeh et al., 2016\[[@R48]\]). COMP functions as a regulator in governing the assembly of type II collagen fibers in cartilage, thereby this glycoprotein stabilizes the collagen network in cooperation with other matrix proteins (Christgau et al., 2001\[[@R8]\]). However, its levels during the development of OA and under inflammatory condition are obviously increased in serum and synovial fluid and positively correlated with joint damage in knee OA (Vilím et al., 2002\[[@R53]\]; Verma and Dalal, 2013\[[@R52]\]). In addition, CTX-II is produced by degradation of type II collagen through the action of proteases with cartilage injury or degeneration and finally excreted in the urine (Christgau et al., 2001\[[@R8]\]; Freeston et al., 2011\[[@R13]\]). CTX-II contents were also elevated in OA patients as compared with normal individuals, which levels are associated with both the prevalence and progression of OA (Jansen et al., 2009\[[@R19]\]; Freeston et al., 2011\[[@R13]\]). These observations indicated that these two factors have the potential to be prognostic biomarkers for monitoring cartilage degradation in patients with OA (Goode et al., 2012\[[@R16]\]; Saberi Hosnijeh et al., 2016\[[@R48]\]). In our ELISA study, both serum COMP and CTX-II levels in the MIA-induced OA group were highly increased compared to the control group; however, treatment with SF significantly prevented the increase. In agreement with the result, the immunohistochemistry data also showed that rats injected with MIA dramatically increased COMP and CTX-II expression in articular cartilage, and besides administration with SF significantly reduced their expression in MIA-induced OA rats. Therefore, it is possible that the reduction in COMP and CTX-II serum levels by SF most likely represents suppressed MIA-induced degradation of cartilage, as cartilage is a major contributor to circulating COMP and CTX-II levels. Conclusions =========== In conclusion, we demonstrated that administration with SF effectively attenuated the severity of articular cartilage destruction in MIA-induced OA of the knee joint in rats. To the best of our knowledge, this is the first report to demonstrate the antiarthritic effects of SF on MIA-induced OA model. The antiarthritic effects of SF were associated with the decreased production of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α, and mediators including NO and PGE~2~through reducing their corresponding genes expression. SF also protected the articular cartilage damage by suppression of MMP-13 and two representative biomarkers for diagnosis of OA, COMP, and CTX-II, in the OA animal model induced by MIA. Based on the results of this study, we suggest that Schisandrae Fructus has excellent potential as a therapeutic modality for treating OA. Conflicts of interest ===================== The authors declare that there is no conflict of interest. Acknowledgement =============== This work was supported by the High Value-added Food Technology Development Program (314043-3), Ministry of Agriculture, Food and Rural Affairs, Republic of Korea ![Effects of SF on knee joint swelling in MIA-induced OA rats. (A) Photographs of the hind knee joint at 3 weeks after the model of MIA-induced OA rats. (B) The severity of osteoarthritis during the course of MIA was determined by measuring the volume of the hind knee joint using calibrated digital caliper. Data were expressed as mean ± SD (n = 8) (\\p \< 0.01 MIA group vs. control group;^\#\#\#^p \< 0.001 SF+MIA treatment groups vs. MIA group)](EXCLI-16-265-g-001){#F1} ![Histological evaluation of joints activity after administration with SF in MIA-induced OA rats. Rats were injected with 3 mg MIA in the right knee. SF was administered orally daily for 3 weeks after MIA injection. (A) The knee joints of OA rats treated with either SF or vehicle control were stained with H&E, Safranin O and toluidine blue. (B) The joint lesions were graded on a scale of 0-13 using the modified Mankin scoring system, giving a combined score for cartilage structure, cellular abnormalities, and matrix staining. Data were expressed as mean ± SD (n = 8) (\p \< 0.05 MIA group vs. normal control group;^\#^p \< 0.05 SF+MIA treatment groups vs. MIA group)](EXCLI-16-265-g-002){#F2} ![Effects of SF on the cytokines (IL-1β, IL-6, and TNF-α) production in the serum of MIA-induced OA rats. Rats were injected with 3 mg MIA in the right knee. SF was administered orally daily for 3 weeks after MIA injection. (A) The concentrations of IL-1β, (B) IL-6 and (C) TNF-α in serum collected from MIA-induced OA rats treated with or without SF. Data were expressed as mean ± SD (n = 8) (\p \< 0.05 and \\p \< 0.01 MIA group vs. normal control group; ^\#^p \< 0.05 and ^\#\#^p \< 0.01 SF+MIA treatment groups vs. MIA group)](EXCLI-16-265-g-003){#F3} ![Effects of SF on the production of NO and PGE~2~, and expression of iNOS and COX-2 in MIA-induced OA rats. The contents of NO (A) and PGE~2~ (B) were measured in the serum of MIA-induced OA rat using Griess reaction and commercial ELISA kit, respectively. (C and D) Immunohistochemical staining was used to identify the expression of iNOS and COX-2 in the articular cartilage. Data were expressed as mean ± SD (n = 8) (\p \< 0.05 MIA group vs. normal control group; \\p \< 0.01 MIA group vs. normal control group; ^\#^p \< 0.05 SF+MIA treatment groups vs. MIA group; ^\#\#^p \< 0.01 SF+MIA treatment groups vs. MIA group)](EXCLI-16-265-g-004){#F4} ![Effects of SF on the expression of MMP-13 in MIA-induced OA rats. (A) The immunohistochemical staining was used to identify the expression of MMP13 in the articular cartilage. (B) Data were expressed as mean ± SD (n = 8) (\p \< 0.05 MIA group vs. normal control group; ^\#^p \< 0.05 SF+MIA treatment groups vs. MIA group)](EXCLI-16-265-g-005){#F5} ![Effects of SF on production and expression of COMP and CTX-Ⅱ in MIA-induced OA rats. (A and B) The COMP and CTX-II production were measured in the serum of MIA-induced OA rat using a commercial ELISA kits. (C and D) Immunohistochemical staining was used to identify the expression of COMP and CTX-II in the articular cartilage. Data were expressed as mean ± SD (n = 8) (\p \< 0.05 MIA group vs. normal control group; \\*p \< 0.01 MIA group vs. normal control group; ^\#^p \< 0.05 SF+MIA treatment groups vs. MIA group)](EXCLI-16-265-g-006){#F6}
The 250PFNT series Portable Fuel Nozzle Tester provides helicopter and fixed wing operators with a means of flow testing the turbine engine fuel nozzles of Allison Model 250 engines. The tester enables periodic field level flow patternization testing to be accomplished on site rather than having to send the items to an overhaul facility thereby reducing costs and turnaround time.
Q: linking one component to another in react with if else condition. (without react-router) I am new to react, i am trying to link another page with if the condition is true My code is like this checkCred(){ for(var i=0; i < details_array.length; i++){ var currentObject = details_array[i]; if (this.email.value === currentObject.username){ console.log('yes done it'); // link to another component named as Index. if the above statement is true then only // } else{ //Sorry your credentials were wrong } } } here is button which is connected to this link. <span onClick={this.checkCred.bind(this)} className="button1" bsStyle="primary" bsSize="large" > BLOCK </span> I dont know how to connect to another page, when i am using react-router. it is directly going to another page without checking condition. A: Thus problem can be solved by {withRouter} Code will look like this. for(var i=0; i < details_array.length; i++){ var currentObject = details_array[i]; if (this.email.value == currentObject.username && this.password.value == currentObject.password){ console.log('yes done it'); this.props.router.push('Index'); } I hope this will help everyone!!! Thanks
Introduction ============ The term post polio syndrome (PPS) was introduced in 1985 by Halstead. It is characterized by a sudden or progressive loss of muscle strength, new muscle atrophy, muscle pain, fatigue, functional impotence, intolerance to cold after a period of at least 15 years from acute polio virus infection, a period of neurological and functional stability, in the absence of other medical explanation \[[@b1-cm-86-150]\]. The reported prevalence of PPS is between 15% and 80% of all patients with previous poliomyelitis virus infections \[[@b2-cm-86-150],[@b3-cm-86-150]\]. The few studies available regarding drug therapy have reported no efficiency of the studied drug agents: steroids, pyridostigmine, amantadine in the management of fatigue and muscle strength \[[@b4-cm-86-150],[@b5-cm-86-150],[@b6-cm-86-150]\]. Non-randomized studies with kinesitherapy programs with a duration between 6 weeks and 7 months, involving isokinetic and isometric endurance muscle training, demonstrated an increase of muscle strength in patients with mild and moderate loss of muscle strength and a reduction of muscle fatigue \[[@b7-cm-86-150],[@b8-cm-86-150],[@b9-cm-86-150]\]. In a randomized study, a significant reduction in pain, depression, fatigue, as well as an improvement of walking following hydrothermotherapy were described \[[@b10-cm-86-150]\]. Rehabilitation programs through physical-kinetic therapy are the only way to limit functional deficit, playing an important role in the long-term management and care of patients. The aim of the study is to clinically and functionally assess the efficiency of an individualized rehabilitation program in the case of a patient with PPS. Material and method =================== DV, aged 57 years, with a history of poliomyelitis since the age of 2, had walked with crutches with armpit support since the age of 5. In October 2012, he sought medical attention for a progressive loss of muscle strength, particularly in the lower limbs, fatigue, muscle atrophy, intolerance to cold, impossible standing and walking, symptoms occurring a year before, and worsening in the last month. At the age of 30, he had a right tibial fracture, operated with osteosynthesis material. Since the age of 50, he had had high blood pressure values, currently receiving drug treatment and a low sodium diet. The objective examination of the osteoarticular system revealed marked dorso-lumbar scoliosis, scapula alata, scapulo-humeral (SH) pain, left SH stiffness (joint testing shows 120° flexion, 30° extension, 90° abduction, 50° internal rotation, 50° external rotation), reducible flexum of the knee, bilateral hollow foot, lower limb muscle atrophy, impossible orthostatism and walking. Active segmental movements absent in the right lower limb, diminished to the left. Muscle strength: 1/5 right lower limb, 3/5 left lower limb, 4/5 bilateral upper limbs. Loss of osteotendinous reflexes, normal sensory examination, imperative micturition and dyspnea were observed. Paraclinical investigations showed biological tests within normal limits, moderate restrictive ventilatory dysfunction at functional respiratory tests. EKG was normal. EMG examination evidenced chronic denervation and rare fasciculations, without any nervous conduction abnormalities. X-rays of the cervico-dorso-lumbar spine showed spondylarthrosis changes. Computed tomography (CT-scan) of the cervical spine showed cervical arthrosis without stenosis. Drug treatment used included NSAIDs, antispastics, vitamins. Clinical and functional assessment were performed at the beginning of the rehabilitation treatment and after the two weeks of treatment. Pain on the visual analogue scale (VAS), articular mobility using joint evaluation, muscle strength using muscle testing, and transfers were monitored. Rehabilitation treatment consisted of sedative paravertebral massage and toning massage of the upper and lower limbs, posturing with the upper limbs in slight abduction, the elbows and knees in extension, in order to prevent tendinous retractions and joint stiffness. Paraffin packing with analgesic and myorelaxant effect was used for the left shoulder. Passive mobilizations of the lower limbs were performed in order to prevent potential complications of the immobilization syndrome, such as joint stiffness, increase in muscle hypotrophy, immobilization osteoporosis and thrombophlebitis; active mobilizations of the upper limbs were aimed at increasing the range of joint motion. Transfers in bed, as well as from bed to wheelchair, postures facilitating respiration, and respiratory gymnastics for the improvement of respiratory function were also carried out. Isotonic and isometric muscle training for preventing the loss of muscle strength was monitored for exercise duration and the rest period. Stretching exercises and muscle relaxing exercises were also performed. The ergotherapy program consisted of techniques for the improvement of ADLs. The agreement of Ethic Commission of research of the Clinical Rehabilitation Hospital Cluj-Napoca was obtained. Results ======= After two weeks of drug treatment and rehabilitation, the intensity of pain in the shoulder decreased (VAS before treatment 9 and after treatment 5). The patient was able to perform by himself transfers in bed and also, from bed to wheelchair, having a higher degree of independence in the wheelchair. Mobility in the left scapulo humeral joint significantly improved (150° flexion, 70° extension, 120° abduction, 70° external rotation, 70° internal rotation). Muscle testing also improved: 2/5 right lower limb, 3/5 left lower limb, 4/5 bilateral upper limbs. Discussion ========== Post-polio syndrome (PPS) may be difficult to diagnose in some people because both neurological diseases and other medical conditions can explain aggravation of a previous stable motor deficit. It is important to clearly establish the origin and potential causes for declining strength and to assess progression of weakness not explained by other health problems. Magnetic resonance imaging (MRI) and computed tomography (CT) of the spinal cord, electrophysiological studies, and other tests (muscle biopsy or a spinal fluid analysis) are frequently used for the differential diagnosis. Neurological conditions that involve progressive aggravation of a motor deficit are cervical myelopathy, syringomyelia, amyotrophic lateral sclerosis, motor neuropathies and myopathies. In our case, the CT scan of the cervical spine (MRI could not be performed due to metallic implants) ruled out the spinal cord compression; the lack of sensory signs at clinical and electrophysiological studies excluded radiculo- and neuropathies, and also myopathies, which have a typical EMG aspect. Other medical conditions can mimic motor deficit with fatigue: shoulder osteoarthritis from walking with crutches, a chronic rotator cuff tear, or a progressive scoliosis causing breathing insufficiency. Pain, weakness, and fatigue can result from the overuse or disuse of muscles and joints. Rehabilitation treatment's complexity depends on the goals established after osteoarticular and muscular system examination. To obtain the best efficacy, association between different physical methods of treatment is necessary (massage, kinetotherapy, hydrothermotherapy and occupational therapy). The study reveales the benefits of physical-kinetic therapy for the maintenance and increase of joint mobility, the improvement of pain, muscle strength and respiratory function. The data in literature show that the excessive use of muscles and training can aggravate PPS symptoms and decrease muscle strength \[[@b11-cm-86-150]\]. However, there are no prospective studies demonstrating that increased muscle activity or training can induce a decrease of muscle strength compared to no training or minimal muscle activity. Patients with regular physical exercise had fewer symptoms and an increased functional level compared to physically inactive patients. The majority of the studies based on physical exercise were conducted under monitoring, with submaximal exercise, intermittent pauses and rest periods in order to prevent overstrain effects \[[@b11-cm-86-150],[@b12-cm-86-150]\]. Conclusions =========== Rehabilitation programs through physical-kinetic therapy: massage, kinesitherapy, thermotherapy, hydrothermotherapy, occupational therapy are the only way to limit functional deficit, playing an important role in the long-term management and care of patients. Long-term prognosis is unfavorable, and the regular follow-up of patients and their inclusion in complex medical rehabilitation programs are important for ensuring the highest possible autonomy and increasing the quality of life of these patients. Rehabilitation is a complex process, which involves high costs at an individual, psycho-emotional level, as well as at the social level. ![CT-scan cervical spine - Cervical arthrosis.](cm-86-150f1){#f1-cm-86-150} ![CT-scan cervical spine - Cervical arthrosis.](cm-86-150f2){#f2-cm-86-150}
1904 Nemzeti Bajnokság I Statistics of Nemzeti Bajnokság I for the 1904 season. Overview It was contested by 9 teams, and MTK Hungária FC won the championship. League standings References Hungary - List of final tables (RSSSF) Category:Nemzeti Bajnokság I seasons Category:1904 in Hungarian football Hun Hun
French economy - Accounts and files2014 Edition “French economy - Accounts and files” presents every year a summary of the evolutions of French and international economies. Based on national accounts, this book analyses the main events which happened in 2013. Wage resilience in France since the Great Recession From 2009 onwards, the slowdown in French real wages was less acute than that in labour productivity, which pulled French firms'margin rate down, falling to its lowest level since 1985. How can this resilience of wages be explained? Econometric models of wages show that it is usual for a slowdown in labour productivity not to be passed on in full to wages, but also that this mechanism is not sufficient in itself to explain the recent disconnection between real wages and productivity. Two potential explanatory hypothesis are sometimes proposed for this disconnection: a change in the labour force structure driven by greater job losses among lower-paid workers, and downward nominal wage rigidities for those employees who have not changed companies. At the end of 2008 and in 2009, the fall in employment was accompanied by a change in the labour force structure. With a decline in the proportion of less qualified employees, job separation among those earning the lowest wages thus contributed to buoying up the average wage. Excluding employed population structure changes during the crisis, average wage would have grown by 0.7 points less each year between 2009 and 2012. However, the rise in the qualification level of the working population was already making a positive contribution towages of 0.4 points per year prior to the recession. The effect of the change in composition due to the recession therefore seems quite weak. In parallel, almost no downwardwage rigidities were observed. For those persons remaining in the same firm, a significant amount of wage dropped, while wage freezes are rare. In addition to this, those enterprises that suffered a specific fall in their activity in 2009 adjusted wages downwards and these reductions were greater in scale, on average, than the price rises granted by companies whose activity improved. Nominal rigidities therefore cannot explain the inertia in wage dynamics, as shown by a macroeconomic analysis of wages.
The Kingston Whig-Standard, Tuesday, November 30, 1999 Province battles pollution charges Annette Phillips One year after she helped convict the City of Kingston on pollution charges, environmentalist Janet Fletcher was back in court yesterday to see the Ontario government defend itself against charges of allowing toxic contaminants to leak into the water system near Belleville.It’s the first known time in Canadian history a provincial government has had to defend itself in court against pollution charges. Fletcher, along with the Environmental Bureau of Investigation (EBI), laid the charges. She is gravely concerned about the government’s failure to clean up the abandoned Deloro mine site. “If I lived in Deloro, I would be scared to death,” Fletcher said in an interview last night. Deloro, north of Belleville, is believed to be the most toxic dump site in Ontario. Tests dating back to 1995 identify continuous discharges of arsenic, cadmium, cobalt, copper, nickel and zinc from the abandoned gold mine into Young’s Creek and the Moira River. The Moira flows into the Bay of Quinte, which has been designated an area of concern under the Canada-U.S. Great Lakes Water Quality Agreement due to high concentrations of arsenic from the site. FLETCHER AND EBI DISAGREE The Ministry of the Environment says the village of Deloro, just outside the mine site, is a safe place to live. Fletcher and the EBI disagree. In May 1999, samples collected from the vacuum cleaner of a Deloro resident showed arsenic levels above the allowable standard. “This was inside her home,” said Fletcher. “Her kids were crawling around on the floor in that.” Fletcher accuses ministry officials of misleading the citizens of Deloro with the results of health risk studies released earlier this year. A clinical researcher at Queen’s University, Fletcher says the government’s health study “was not based on reality.” She refuses to accept the government’s assertion that Deloro is a safe place to live and says village residents were never told of a 10-year-old study that found the area severely contaminated. “How safe would you feel with all that arsenic dust blowing in from those tailings?” Fletcher asks. The Ontario government inherited the dump and its toxic contaminants in 1980, after the landowners went bankrupt. Following 11 provincially-funded studies, the Ministry of the Environment has made scant progress in cleaning up the site or stopping the leakage, EBI alleges. Brian Ward, regional director for the ministry, says $13 million has been spent to date containing the leaking dump site. In addition to filling in 20 to 30 mine shafts and covering arsenic-coated tailings, the ministry has installed a treatment plant that has been more than 99-per-cent effective in removing arsenic from the water. A system to contain contaminated groundwater has also been put in place. The government is prepared to spend millions more to seal up the site so toxins can’t escape. Some small patches of contaminated earth in the village of Deloro will also be excavated and moved to the containment site. “We are committed to the final clean-up,” Ward said in an interview from Ottawa last night. “There is major progress under way to finalize our plan and clean up the site.” ONLY THE BEGINNING The trial that began yesterday in Ottawa is only the beginning. The EBI laid a second set of charges last year when it discovered radioactive waste leaking from the same mine site. As recently as last November, EBI tests at the Deloro mine site showed uranium, radium and cobalt contaminating land to which the public has unrestricted access. Court dates have not yet been set for the radioactive waste charges. The EBI is a project of the Energy Probe Research Foundation. In conjunction with partners like the Sierra Legal Defence Fund, EBI investigates and prosecutes environmental charges.
Introduction {#Sec1} ============ Camptocormia is often associated with Parkinson's disease (PD) and is indicated by excessive spinal anteflexion, with exacerbation of symptoms when the patient is in an upright position and amelioration when in a recumbent position \[[@CR1]\]. Long duration of PD, vertebral surgery, and dopamine agonists are representative cumulative factors leading to camptocormia \[[@CR2]\]. The mechanisms of camptocormia are hypothesized to be dystonia, paravertebral myopathy, and disturbance of vertical perception; however, this has not been clarified \[[@CR3]\]. Camptocormia is often refractory to treatment, including medication, physical therapy, and surgery \[[@CR3], [@CR4]\]. As a treatment for camptocormia, local injection of botulinum toxin (BT) was first reported in 2005 in patients with parkinsonism and/or dystonia \[[@CR5]\]. In the report, a single injection into the rectus abdominis (RA) muscle was effective for approximately 3 months. Following studies examined the efficacy of BT into the RA and iliopsoas muscles for camptocormia in PD; however, they failed to show significant improvement \[[@CR6]--[@CR8]\]. Using intramuscular injection of lidocaine, the external oblique (EO) muscle was first reported in 2012 as a therapeutic target for camptocormia in PD when the flexion point of the spine was between the lower thoracic and the upper lumbar level \[[@CR9]\]. The same authors later showed that repeated lidocaine injection into the EO maintained improvement of camptocormia over 90 days of observation \[[@CR10]\], and hyperactivity of the EO when tilting up could contribute to camptocormia by a dystonic mechanism \[[@CR11]\]. In 2014, the first case of BT injection into unilateral EO and RA was reported \[[@CR12]\]. In this report, a patient with PD received an injection of 200 units of onabotulinum toxin A into the right RA and left EO due to past excision of the left RA. The painful abdominal contraction, which was considered dystonia because of palpable abdominal contraction and hyperactivity in needle electromyography (nEMG), was ameliorated, as was the angle of camptocormia. Repeated injection of BT at intervals of 3--4 months successfully maintained the amelioration for 1 year or more. Apart from these reports, we found no published evidence of local injection into the EO for camptocormia in PD. Therefore, in this study we evaluated the therapeutic efficacy of BT injection into the bilateral EO muscle for camptocormia in multiple cases. The aim of this study is an exploratory examination whether BT can attenuate the angle of camptocormia and disabling symptoms which are originated from camptocormia, and if any, whether clinical backgrounds (e.g. spinal degeneration) affect to the efficacy of BT. Methods {#Sec2} ======= Six patients with PD and camptocormia (four females and two males, 54--79 years old, 134--170 cm in height, 37.8--59.2 kg in weight) were enrolled in this prospective cohort study from June 2016 to February 2018. This study was approved by the local ethics committee of Hyogo-Chuo National Hospital and the patients provided written informed consent. This trial was registered in the Japan Medical Association Center for Clinical Trials Clinical Trial Registry (ID: JMA-IIA00371). Inclusion criteria were: meeting the UK Brain Bank criteria of PD \[[@CR13]\], presence of debilitating symptoms or difficulty due to camptocormia, exacerbation of camptocormia in an upright position with amelioration in a recumbent position, and the flexion point in thoracic vertebrae. Exclusion criteria were: a family history of parkinsonism, presence of cognitive dysfunction (Mini-Mental State Examination score ≤ 25), overlap of latero- or retro-flexion of the spine, and exhibiting diurnal or on/off fluctuation of camptocormia. Camptocormia angle (CA) was defined as the angle between a vertical line and the line connecting the acromion with the greater trochanter, as defined in a prior study \[[@CR2]\]. CA was evaluated in the lateral view on digital photographs taken at a distance of 2 m and a height of 1 m, without any effort by the patients to correct their posture. We did not exclude patients with spinal lesions if the flexion angle of the spinal deformity was clearly milder than the observed CA. When the patient had painful abdominal contraction, the severity of the pain was evaluated using the visual analog scale (VAS) for painful abdominal contraction (range 0--100; 100 points being the worst) \[[@CR14]\]. Objective stiffness of abdominal muscles \[[@CR5], [@CR12]\] was defined in this study as pathological contraction of abdominal muscles (including EO and RA) at inspection and/or palpation in a relaxed spine position. Muscle hyperactivity (MH) in nEMG of abdominal muscles \[[@CR12]\] was defined here as the presence of pathological involuntary discharges in a relaxed spine position. Tilt-table EMG \[[@CR11]\] was not available in our institution and thus, was not used. Onabotulinum toxin-A (Botox^®^; Allergan Plc, Dublin, Ireland) was injected into the bilateral EO muscle at a symmetrical dose under sonographic guidance. The injection site in each EO was the intersection point of the anterior axillary line and the transverse line through the umbilicus; therefore, each patient received two injections as a single treatment. Seventy-five (case 1) or 90 (cases 2--6) units of BT were injected into each EO (i.e. 150 or 180 units per patient) at a concentration of 100 units BT per 4 mL normal saline, since this dilution was our practice for the injection into large or wide muscles to gain widespread diffusion of BT. Using a previous report on cervical dystonia to help determine dosage, we limited the first dose to less than 180 units per patient \[[@CR14]\]. Case 1 received a smaller dose of BT than the others because they were the first to receive BT in the EO in our institution. For statistical analysis, Shapiro--Wilk testing was used to examine the normality of data distribution, and when the normality was not confirmed, the Wilcoxon signed-rank test was used to compare CA before and 2 weeks after the dose of BT by using analytic software, Excel-Toukei Version 2018 (SSRI Co. Ltd., Tokyo, Japan). A p value \< 0.05 obtained in a two-tailed test was considered as statistically significant. Long-term effects were sustained using maintenance doses of 100 units (case 1) or 120 units (cases 2--6) per EO, plus 30% of the original dose, in adequate intervals for each patient when the efficacy of BT had worn off. Antiparkinsonian medications were not changed during the observation period. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Results {#Sec3} ======= The profiles of the patients are shown in Table [1](#Tab1){ref-type="table"}. The exacerbating factor of camptocormia was forward bending for the housework in case 2, and spinal compressive fracture or surgery in other cases. The most disabling symptoms relevant to camptocormia were painful abdominal contractions in cases 1 and 2, dysbasia in case 3, and difficulty in facing upward in cases 4--6. Except case 2, who had comorbid blepharospasm, none of the enrolled patients had dystonia or dystonia-associated pathologies other than camptocormia. Antiparkinsonian medications, including dopamine agonists (daily dose of pramipexole, 1.125 mg in case 2 and 1.5 mg in case 4 and 6; rotigotine, 27 mg in case 1 and 4.5 mg in case 3), were not changed during the observation in this study. Antiparkinsonian medications in the patients were unlikely to have induced or exacerbated camptocormia in daily examinations. The flexion point was medium (fifth--eighth) thoracic vertebrae in cases 1 and 5 and lower (ninth--twelth) thoracic vertebrae in the remaining cases. Objective stiffness of EO and RA and MH and/or continuous repetitive discharge (CRD) in nEMG were present in all cases; however, only cases 1 and 2 claimed pain due to abdominal contraction. CRD in EO has not been documented in any previous published reports. The patients had variable severity of spinal pathologies, and the deformity of the spine was severe in cases 4 and 6, featured by lumbar herniation and lumbar canal stenosis. Atrophy of the paraspinal muscle in computed tomography was mild (i.e. can be explained by normal aging) in cases 1, 2, and 6 and moderate (i.e. considered as pathologic, but a certain amount of the muscle was remaining) in cases 3--5. No adverse events were observed with the injection of BT. The efficacy of BT was noted, by subjective claim and/or objective inspection, 7--10 days after the injection. Two weeks after injection, CA was attenuated in all the six cases, as shown in Table [1](#Tab1){ref-type="table"}. The normality of the distribution of CA was not confirmed as significant (p \> 0.05). The median (interquartile range) of CA showed significant attenuation \[38° (23.5°) vs. 18° (21°), p = 0.028\], comparing before and 2 weeks after the botulinum injection. Camptocormia-related symptoms were subjectively relieved in cases 1--3 and 6; however, cases 4 and 5 did not perceive the amelioration, hence cases 4 and 5 rejected the maintenance doses of BT. Patient 6 also declined the maintenance dose because he needed to care for his wife. The VAS of painful abdominal contraction in cases 1 and 2 improved from 84 and 98 to 4 and 77, respectively. In case 3, the time to walk a 10-m straight line and their stride improved from 16.1 s with 29 steps, to 11.0 s with 22 steps after BT. Objective abdominal stiffness and nEMG findings persisted even after camptocormia was attenuated. Cases 1--3 received maintenance doses of 100 (case 1) or 120 (cases 2--3) units of BT per EO (i.e. 200 or 240 units per patient), and they obtained the same efficacy as the initial dose. By observing the decline of the effectiveness of each injection of BT, the interval of the maintenance dose was 4 months in case 1, because the effectiveness of BT tapered off at 3 months. The therapeutic interval was 3 months in cases 2 and 3 because the effectiveness tapered off at 2 months. In the long term, cases 1 and 2 had good maintenance of amelioration of camptocormia for 1 year or more (CA 1 year after the BT injection was 9° and 7°, and VAS of abdominal pain 1 year after was 21 and 74 in cases 1 and 2, respectively). However, several falls without spinal compressive fracture in case 3 re-exacerbated camptocormia, such that attenuation of CA remained suboptimal (CA at 1 year was 48°).Table 1Clinical features of the patientsCase123456Age (years)547376797677SexMaleFemaleFemaleFemaleFemaleMaleHoehn & Yahr scale434333PD duration (years)181661059Camptocormia duration (years)323213Dopamine agonist (mg/day)RTG 27PPX 1.125RTG 4.5PPX 1.5Not usedPPX 1.5Exacerbating factors of camptocormiaLH surgeryHouseworkSCFSCFSCFLCS surgeryHeight (cm)165142144134138170Body weight (kg)54.340.639.640.037.859.2Flexion point of the spineMedium ThLower ThLower ThLower ThMedium ThLower ThSpinal x-ray or MRILH Th11 fractureMild LCSSC fracture, mild LCS, mild LHL2,and L3 fracture, severe LCS, severe LHL2 fracture, moderate LCS, mild LHTh11 fracture, severe LCS, severe LHParaspinal muscle atrophyMildMildModerateModerateModerateMildnEMGMH in EOMH in EO, CRD in EO & RACRD in EOCRD in EO & RAMH in EOMH in EO & RADose of BT (units per EO)759090909090CA (degrees, before vs. 2 weeks after BT)49 vs. 921 vs. 483 vs. 3033 vs. 2719 vs. 843 vs. 37BT botulinum toxin, CA camptocormia angle, CRD continuous repetitive discharge, CT computed tomography, EO external oblique, L lumbar (L2 and L3 show the vertebrae with fracture), LCS lumbar canal stenosis, LS lumbar spondylosis, LH lumbar herniation, MH muscle hyperactivity, MRI magnetic resonance imaging, MUP motor unit potential, nEMG needle electromyography, PPX pramipexole, PSM paraspinal muscle, RA rectus abdominis, RTG rotigotine, SC sacrococcygeal, SCF spinal compressive fracture, Th thoracic vertebrae (Th11 shows the vertebrae with fracture) Discussion {#Sec4} ========== We observed attenuation of CA in six patients with PD who suffered from thoracic-level camptocormia, when comparing before treatment and 2 weeks after the botulinum injection into bilateral EO. Although the number of patients is small, this report is the first to show efficacy of BT in bilateral EO with statistically significant improvement in the angle of camptocormia; however, there are several limitations and points for discussion. Due to the study design of an open-label and non-blinded trial, the possibility of a placebo effect cannot be eliminated. However, the latency from the injection of BT to the emergence of efficacy (7--10 days) and duration of efficacy (2--3 months) was considered to be the effect of BT because this treatment effect curve is also generally observed with botulinum therapy \[[@CR15], [@CR16]\]. In a previous report using lidocaine, consecutive injections were performed every 4--5 days due to the shortness of drug action (the effect of a single dose lasted for several days), to obtain efficacy in 90 days \[[@CR10]\]. Both the previous report of BT into unilateral EO \[[@CR12]\] and our results show that a single injection of BT had therapeutic efficacy for several months; however, a direct comparison between BT and lidocaine is needed for conclusive evidence of a difference in their effectiveness. We used doses of 75--90 units per single EO, i.e. 150--180 units per patient, of onabotulinum toxin A as the initial dose, for the safety of our light-weight patients. Considering the doses of onabotulinum toxin A used in previous studies of 300--600 units per patient \[[@CR5]\] and 200 units in unilateral EO \[[@CR12]\], our doses may have been insufficient. However, given that the escalation of doses in the maintenance injections did not lead to further amelioration, our doses may have reached supramaximal levels. We selected a relatively low concentration of BT to obtain a broad spread because of the width of EO; however, actual spread of BT is difficult to determine and varies between individuals \[[@CR15], [@CR16]\]. In addition, more exploration is needed to determine the optimal site of injection in the EO, and the best method of evaluating the CA. Considering the individual variability in the therapeutic efficacy of BT, the fact that cases 4 and 6 had severe spinal degeneration and very limited efficacy for BT suggests that modification only in dystonia of the EO muscle is suboptimal to attenuate camptocormia comprehensively. As suggested in a previous report of surgical intervention for camptocormia, poor quality of the spine can limit the therapeutic effect \[[@CR4]\]. Moreover, the maximal effect of BT in case 3 could not be maintained due to re-exacerbation of symptoms due to falls. Therefore, to modify exacerbating factors of camptocormia it may be necessary to provide long-term treatment. In terms of subjective relief of symptoms, cases 4 and 5 did not perceive the attenuation of the CA; therefore, CA alone may be an insufficient marker to evaluate amelioration of camptocormia. As case 3 achieved the ability to walk faster and with a larger stride, similar to a recent report that showed a relationship between camptocormia and gait \[[@CR17]\], marginal symptoms/signs associated with camptocormia (i.e. painful contraction of abdominal muscles in cases 1 and 2, and dysbasia in case 3) might need intensive examination for the correct evaluation of therapeutic efficacy. We expected objective stiffness of abdominal muscles, MH and/or CRD to act as biomarkers of camptocormia; however, this was not the case. We speculate that the cause of CRD is secondary muscle injury from excessive contraction due to dystonia, although CRD is a nonspecific sign of injury in motor neurons or muscles \[[@CR18]\]. Other limitations of this study are heterogeneity in the duration of PD, in the severity of CA, in the exacerbating factors of camptocormia and other backgrounds of patients, the coexistence of spinal degeneration, dropout of cases 4--6 to examine the long-term effect of BT, and a smaller dose of BT in case 1 than the others. Limitations are small sample size, open-label and non-blinded trial, heterogeneity of the backgrounds of patients, unexamined validity of the maneuver of botulinum injection (i.e. the injection site and dilution), not thorough evaluation of walking ability, and dropout of three patients in the long term. Conclusions {#Sec5} =========== To conclude, BT into the bilateral EO muscle attenuated the angle of thoracic-level camptocormia in six patients with PD over the observation period of 2 weeks. The reproducibility of results, long-term efficacy, and subjective relief of symptoms requires further examination. Enhanced digital content To view enhanced digital content for this article, go to 10.6084/m9.figshare.6901976. The authors thank the participating patients for their involvement. The authors disclosed the study design and results for the involved patients after the closure of this study, without violating the anonymity of the patients. Funding {#FPar1} ======= No funding or sponsorship was received for this study or publication of this article. The article processing charges were funded by the authors. Authorship {#FPar2} ========== All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Author Contribution {#FPar3} =================== HT developed the concept and design of the study and analyzed the data. HT, HY, NK, and IF performed data collection. HT and OG performed and evaluated nEMG. HT drafted and others critically revised the manuscript. NF evaluated radiologic features of the patients. IF approved the final manuscript. Disclosures {#FPar4} =========== Hiroyuki Todo, Hiroshi Yamasaki, Go Ogawa, Katsuya Nishida, Naonobu Futamura, and Itaru Funakawa have nothing to disclose. Compliance with Ethics Guidelines {#FPar5} ================================= All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Data Availability {#FPar6} ================= All the data used in the analysis are presented in Table [1](#Tab1){ref-type="table"}. The datasets generated during and/or analyzed during the current study are not publicly available due to privacy protection of the participating patients, but are available from the corresponding author on reasonable request. Open Access {#d29e876} =========== This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (<http://creativecommons.org/licenses/by-nc/4.0/>), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
'Gremlins' Meets 'Hot Fuzz' in Early 'Cute Little Buggers' Photos The creatures of Cute Little Buggers aren't as cuddly as they look — and they are soon to be invading theaters. Heat Vision has an early look at the comedy-horror pic, which is described as Hot Fuzz meets Gremlins. Uncork’d will distribute the film the U.S. and Canada, while High Octane has acquired rights for the rest of the world. Tony Jopia is directing Cute Little Buggers, in which aliens crash-land in the English countryside and kidnap women from a local ball. The villagers and an out-of-town hero named Melchior must rescue the women and restore peace. "Tony knows how to give audiences a good time — and his latest is no exception. Cute Little Buggers will spook you – there’s moments in this that will make the goosebumps rise and then some — but it will also give audiences belly laugh after belly laugh," said Uncork’d president Keith Leopard. "At its core it’s a real throwback to the golden-age creature features.” High Octane Pictures founder Galen Christy also had high praise for the film, adding, "Not many films can immediately hook you from the first frame … but this sure does! Cute Little Buggers is infused with an infectious energy, some high-spirited performances, and a unique premise — I defy anyone not to really enjoy it!"
FIRE WARNING: Beware what you put near your windows Damage from a fire in Weston, Nottinghamshire, caused by a magnifying mirror. Danielle Hayden Published:11:00Tuesday 15 March 2016 Share this article The fire service is urging Nottinghamshire residents to be careful putting magnifying objects near windows following a recent fire. The warning comes after firefighters were called to a fire in Weston recently which was started by a magnifying make-up mirror. Sun rays hit the mirror, creating an “intense beam of heat” which set alight some nearby curtains. This incident was dealt with quickly and nobody was hurt, however Nottinghamshire Fire and Rescue Service is keen to stress that these types of fires can happen any time but can be more common in spring and autumn due to the low sun - and can be avoided as long as people are careful with what they place on windowsills and near to windows. Magnifying items can include fish bowls, glass ornaments, paperweights and glasses of water, as well as mirrors. Crew Manager Andy Oxnard, who works as part of the team, said: “We would strongly advise that people avoid placing these types of objects near windows as they can potentially concentrate the sun’s rays and set fire to nearby items such as curtains, paper or clothes. “Fortunately there was nobody injured at the fire in Weston recently, and the damage was only small, however it could have been a lot worse.” The same crew from Newark also attended another similar incident towards the end of last year. This fire, which was at a property in Muskham, started after rays from the sun were accidentally concentrated by a mirror onto some paper - which then set alight. Andy is also advising that people have a general look at their windowsills to see if they currently have any magnifying objects on there and, if so, that they take them off where possible. “We would also urge people to make sure they have working smoke alarms in their homes in case something like this does happen and that, in such a situation, they get out, stay out and call 999,” he added. Trending Nottinghamshire in the snow - click to see a gallery of the best photos Egyptian student dies three weeks after being attacked by girl gang in Nottinghamshire WEATHER ALERT: Snow to return to Nottinghamshire THIS WEEKEND Massive solar storm set to hit Earth tomorrow could bring power cuts and Northern Lights to Nottinghamshire LIVE UPDATES: Road closures, weather warnings and advice for motorists
In 1941, oestrogen therapy became the first reported hormonal manipulation for men with advanced prostate cancer ([@bib10]), but was superseded by surgical and medical castration ([@bib22]; [@bib16]). Diethylstilboestrol (DES) is a synthetic non-steroidal oestrogen that has been widely used in men with castration-resistant prostate cancer (CRPC). Several mechanisms have been proposed to explain DES activity, including reduction of luteinizing hormone, testosterone and androgenic steroid levels ([@bib3]), inhibition of telomerase activity ([@bib9]); direct binding of the androgen receptor (AR) ([@bib25]) and suppression of β-tubulin isotypes ([@bib14]). High-dose (5 mg daily) DES was associated with cardiovascular toxicity ([@bib12]), but low-dose DES 1 mg daily had a more acceptable therapeutic ratio, with reported activity including ⩾50% PSA declines in 23--43% of patients ([@bib24]; [@bib13]; [@bib5]; [@bib26]) and time to PSA progression of 4--4.6 months ([@bib5]; [@bib26]). Combined with dexamethasone, DES treatment resulted in ⩾50% PSA declines in 64--68% of patients in a small randomised study ([@bib23]), but venothromboembolic events occurred in 22% of patients in the combination arm. Diethylstilboestrol continues to be used in men with CRPC in several countries. Furthermore, a clinical trial randomising patients between LHRH analogue treatment or transcutaneous oestrogen patches is currently in progress (PATCH trial, NCT00303784). Abiraterone is an irreversible, selective, CYP17A1 inhibitor that blocks steroidal conversion to androgens and oestrogens. Large Phase III studies confirmed abiraterone as an effective treatment in CRPC ([@bib6]; [@bib18]). With six survival-prolonging treatments for CRPC, understanding the activity of treatments administered sequentially has become critically important for physicians. This is particularly relevant given the current financial pressures on healthcare budgets and the hypothesis that sequential therapies may impact the efficacy of later-line treatments acting on similar pathways of tumour growth. We therefore sought to evaluate the antitumour activity of abiraterone after DES therapy. Patients and Methods ==================== This was a retrospective analysis of all patients treated with abiraterone at the Royal Marsden NHS Foundation Trust (RM) hospital in Chelsea, London and Sutton, Surrey, UK. Patients were identified from the pharmacy dispensing records and received abiraterone with concomitant prednisolone 10 mg daily or dexamethasone 0.5 mg daily in the settings of Phase I, II or III clinical trials reported previously ([@bib2]; [@bib4]; [@bib1]; [@bib17]; [@bib6]; [@bib18]) (N=123) and expanded access programs or post approval (N=151). All clinical trial patients underwent baseline and three-monthly imaging by computed tomography (CT) and bone scan. Patients treated outside of trials had CT and bone scan imaging at baseline and every 6 months as per local practice guidelines. Demographic and treatment-related data were collected using the electronic hospital record. The objective of this analysis was to report the response rate and survival of patients treated with abiraterone, taking into account prior treatment with DES and docetaxel. This analysis was approved by the RM Clinical Audit Committee (SE143). Prostate-specific antigen and soft tissue responses were assessed using Prostate Cancer Working Group 2 criteria ([@bib21]). Prostate-specific antigen progression was defined as a confirmed ⩾25% rise from nadir in patients with a ⩾50% PSA decline and as a confirmed ⩾25% rise from baseline in the remaining patients, disregarding progression prior to 12 weeks of therapy. Due to the impact of patient censoring, time to PSA progression in the post-docetaxel groups was calculated using bootstrap analysis. Radiographic responses and progression were assessed using RECIST 1.1 in patients with measurable soft tissue disease ([@bib7]). Date cut-off for follow-up was 31 December 2012 and patients still alive or lost to follow-up were censored. Descriptive statistics and Kaplan--Meier survival analyses were performed using IBM SPSS Statistics v20 (IBM). Results ======= Patient characteristics ----------------------- Between January 2006 and October 2012, a total of 274 patients received abiraterone. The patient population is described in [Table 1](#tbl1){ref-type="table"}. Of these, 114 were treated with DES prior to abiraterone at doses of 1 to 3 mg per day with or without aspirin and/or dexamethasone as per institutional standards. The majority of patients (106, 96.3%, 4 patients not known) received at least 30 days of DES. Diethylstilboestrol was discontinued in 86 (75.4%) men due to progressive disease, whereas 18 (15.8%) discontinued due to toxicity (reason unknown in 10 patients). A total of 68 patients were treated with abiraterone prior to chemotherapy, whereas 206 patients were treated with abiraterone after docetaxel (see [Table 2](#tbl2){ref-type="table"}). The median follow-up for the overall cohort was 58 months. The antitumour activity of abiraterone is lower in docetaxel-treated compared with docetaxel-naïve patients ([@bib1]; [@bib17]; [@bib19]; [@bib6]; Ryan et al, 2013), and we have therefore reported the activity of abiraterone post-DES in these two settings separately. Of the 68 docetaxel-naïve patients treated with abiraterone, 27 had previously received DES. Of the 206 docetaxel-treated patients who received abiraterone, 87 had been treated with DES. Abiraterone administered prior to docetaxel ------------------------------------------- Activity measures for the 27 men treated with abiraterone following DES are shown in [Table 2](#tbl2){ref-type="table"} and [Figure 1](#fig1){ref-type="fig"}, including ⩾50% PSA declines in 20 patients (74.1%), a median time to PSA progression of 8.5 months and median duration of treatment of 11.4 months. Median survival from start of abiraterone was 36.7 months (95% CI 11.1--62.4). In comparison, ⩾50% PSA declines occurred in 35 of the 41 patients (85.4%) who received abiraterone without prior DES exposure, with median time to PSA progression of 9.2 months and median treatment duration of 16.6 months. In these patients, the median survival from start of abiraterone was 40.5 months (95% CI 27.8--53.2). Abiraterone administered after docetaxel ---------------------------------------- A total of 87 men were treated with abiraterone after DES and docetaxel. Maximum PSA declines of ⩾50% occurred in 23 of the 81 evaluable patients (28.4%) and median time to PSA progression was 4.3 months (16 patients discontinued therapy prior to 12 weeks and were not included in progression analysis). Patients remained on treatment with abiraterone for a median of 5.5 months. Median survival was 13.4 months (95% CI 9.8--17.0). A total of 119 patients received abiraterone after docetaxel with no prior DES exposure. Declines of PSA ⩾50% occurred in 40 of 113 patients evaluable for PSA response (35.4%) with a median time to PSA progression of 4.3 months (28 patients discontinued therapy prior to 12 weeks). Patients received abiraterone for a median of 4.3 months and the median survival was 13.4 months (95% CI 9.8--16.7). Diethylstilboestrol administered after abiraterone -------------------------------------------------- A total of 31 patients received DES after abiraterone. In this cohort, 28 (90.3%) patients had also received docetaxel and one patient had been treated with cabazitaxel chemotherapy. The median duration of abiraterone prior to DES was 11.2 months (see [Table 2](#tbl2){ref-type="table"}). The median duration of DES treatment was 2.7 months (range 0.1--31.2). Diethylstilboestrol was discontinued due to progression in 18 (62%) and toxicity in four (13.8%) patients (reason unknown in five patients and patient death in three patients). Prostate-specific antigen declines of ⩾50% occurred in 8.7% (2/23) evaluable patients. No objective soft tissue responses were seen in the six evaluable patients. The majority of patients did not have follow-up scans due to declining performance status. Of 14 patients who received DES for \>3 months, four were docetaxel-naïve at start of DES treatment (three of these patients, however, received docetaxel after DES) and seven (50%) had ⩾90% PSA declines on abiraterone. Another patient discontinued abiraterone after 27 days of treatment due to an acute pulmonary embolism; abiraterone was not re-started because it was impossible to exclude a causal relationship. This patient had a subsequent 80% PSA decline on DES and remained on treatment for 31.3 months. Discussion ========== In this large, single-centre cohort of CRPC patients, abiraterone retained significant and clinically important activity after DES treatment. Prior DES exposure appeared to have minimal impact on overall abiraterone activity. We also report the activity of DES after abiraterone, which was prospectively collected for our patients. In these patients, DES was primarily used in the end-stage setting when no other treatment was possible due to availability or patient fitness and its activity in this setting was very modest. Patients who received \>3 months DES treatment were mainly patients who had substantial PSA declines and long durations of treatment on abiraterone or those who stopped abiraterone prematurely. The short treatment duration and survival on DES after abiraterone and docetaxel reflect the advanced state of these patients and may therefore have underestimated the activity of DES post abiraterone. Recent reports suggest both abiraterone and enzalutamide have lower activity in patients with poorer performance status ([@bib6]; [@bib20]; [@bib11]; [@bib15]). We did not have robust data available to evaluate the activity of DES treatment prior to abiraterone. These data are retrospective in nature. The sample size of the cohorts, especially in chemotherapy-naïve patients, is limited. Furthermore, we assessed abiraterone activity using PSA endpoints, which are commonly used activity endpoints, but not robust surrogates of overall survival([@bib8]). Of note, the median time on DES in our pre-chemotherapy cohort was considerably longer than previously reported ([@bib26]). It is likely that patients with a good response to prior hormonal manipulations and no clinical indication for cytotoxic chemotherapy were positively selected in the Phase II trials of abiraterone pre-chemotherapy. The landscape of treatments for CRPC is changing rapidly and abiraterone was recently approved in the pre-chemotherapy setting. This analysis demonstrates that abiraterone remains an active treatment in patients after prior DES treatment. Given the efficacy of abiraterone and the toxicity of DES, abiraterone will increasingly be used prior to DES, although financial constraints may limit the use of abiraterone in certain settings. The antitumour activity of DES after abiraterone in this cohort of patients was limited, indicating that other treatment options or clinical trials should be considered in fit abiraterone-resistant patients. Similarly, our data suggest very limited activity with DES in poor performance, end-stage patients who previously received abiraterone. The authors are employees of the Section of Medicine that is supported by a Cancer Research UK programme grant and an Experimental Cancer Medical Centre (ECMC) grant from Cancer Research UK and the Department of Health (Ref: C51/A7401). GA is supported by a Cancer Research UK Clinician Scientist Fellowship. The authors acknowledge NHS funding to the Royal Marsden NIHR Biomedical Research Centre. AO is recipient of a 2-year bursary from the Swiss Cancer League (No. BIL KLS-02592-02-2010). Abiraterone acetate was developed at The Institute of Cancer Research, which therefore has a commercial interest in the development of this agent. CP received lecture fees from Sanofi-Aventis and travel support from Sanofi-Aventis and Janssen-Cilag. DD received honoraria for advisory boards and served as a consultant for Takeda, Amgen, Astellas Pharma and Succinct Healthcare. JSdB received consulting fees from Ortho Biotech Oncology Research and Development (a unit of Cougar Biotechnology), consulting fees and travel support from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Supergen and Takeda, and grant support from AstraZeneca and Genentech. GA received consulting fees and travel support from Janssen-Cilag, Veridex, Roche/Ventana and Millennium Pharmaceuticals, lecture fees from Janssen-Cilag, Ipsen, Takeda and Sanofi-Aventis and grant support from AstraZeneca and Genentech. GA and DD are on The ICR rewards to inventors list of abiraterone acetate. ![Waterfall plots of maximum PSA decline on abiraterone. PSA increases of \>50% were capped. Abbreviation: Pts=patients.](bjc2013446f1){#fig1} ###### Patient characteristics AA pre-docetaxel DES pre-treated (*N*=27) AA pre-docetaxel DES naïve (*N*=41) AA post-docetaxel DES pre-treated (*N*=87) AA post-docetaxel DES naïve (*N*=119) ------------------------------------------------------- ------------------------------------------------------- ------------------------------------------------- -------------------------------------------------------- --------------------------------------------------- Median age at diagnosis (years) 63.2 64.1 63.1 62.5 Range 45.3--80.7 44.8--79.6 43.9--77.7 41.8--77.3 Median Gleason score 8 8 7 8 Range 6--10 6--10 2--10 4--10 Median time from diagnosis to CRPC (years) 3.3 3.6 3.8 2.3 Range 0.3--13.7 0.6-- 16.2 0.7--14.3 0.1--14.6 *Treatments prior to DES (or abiraterone), N* (%)** Antiandrogens 24 (89) 40 (98) 83 (95) 116 (97) Single-agent steroids 5 (19) 13 (32) 12 (14) 53 (45) DES administered with steroids, N (%) 5 (19) NA 21 (24) NA Docetaxel prior to DES, N (%) NA NA 25 (29) NA ECOG performance status at AA, N (%) (NA: 3) (NA: 3) 0 15 (56) 25 (61) 18 (21) 25 (21) 1 12 (44) 16 (39) 52 (60) 74 (62) 2 14 (16) 17 (14) *Metastases at AA, N* (%)** Bone 22 (81) 33 (80) 81 (93) 107 (90) Nodal 9 (33) 18 (44) 38 (44) 59 (50) Visceral 5 (19) 2 (5) 13 (15) 20 (17) Median PSA at AA (μg l^−1^) 193 39.9 435 213 Range 14.8--2642 3.5--870 10--8580 2.3--10 335 Median haemoglobin at AA (g l^−1^) 12.7 12.7 11.5 11.2 Range 9.7--15.4 10.0--15.1 8.1--14.7 8.0--16.5 Median alkaline phosphatase at AA (U l^−1^) 87 96 158 147 Range 41--518 43--642 23--2044 34--2163 Median albumin at AA (g l^−1^) 36 37 34 35 Range 27--42 31--48 23--41 24--47 Median lactate dehydrogenase at AA (U l^−1^) 172 174 205 217 Range 78--576 110 --298 72--2490 119--1659 Abbreviations: AA=Abiraterone acetate; CRPC=castration-resistant prostate cancer; DES=diethylstilboestrol; ECOG=Eastern Cooperative Oncology Group; PSA=prostate-specific antigen. ###### Activity of abiraterone grouped by DES exposure AA pre-docetaxel DES pre-treated (*N*=27) DES naïve (*N*=41) --------------------------------------------------------------- ---------------------------------------- --------------------------------- Median duration of AA treatment (months, m) 11.4 16.6 95% CI 7.6--16.8 12--21.7 Median duration of DES treatment (m) 11.4 95% CI 8--15 *N*(%) *N*(%) ⩾50% PSA decline 20 (74.1) 35 (85.4) ⩾30% PSA decline 22 (81.5) 37 (90.2) Soft tissue response 4/10 (40) 9/18 (50) Median survival from start of AA (m) 36.7 40.5 95% CI 11.1--62.4 27.8--53.2 Median time to PSA progression on AA (m) 8.5 9.2 95% CI 3.0--14.1 5.7--12.7 Number of evaluable patients 24 39 Median time to radiographic soft tissue progression on AA (m) 11.9 13.8 95% CI 0--30.6 8.3--19.3 Number of evaluable patients 10 18 Abiraterone (AA) post-docetaxel DES pre-treated (*N*=87) DES naïve (*N*=119) Median duration of AA treatment (m) 5.5 4.3 95% CI 4.4--6.5 3.7--5.6 Median duration of DES treatment (m) 9 95% CI 5.8--15 *N*(%) *N*(%) ⩾50% PSA decline 23/81 (28.4) 40/113 (35.4) ⩾30% PSA decline 34/81 (42) 55/113 (48.7) Soft tissue response 9/36 (25) 6/40 (15) Median survival from start of AA (m) 13.4 13.4 95% CI 9.8--17 9.8--16.7 Median time to PSA progression on AA (m) 4.3 4.3 95% CI 3.5 --5.5 3.7--5.5 Number of evaluable patients 71 91 Median time to radiographic soft tissue progression on AA (m) 2.9 2.7 95% CI 1.6--4.2 2.5--2.9 Number of evaluable patients 36 40 *DES post abiraterone, N=31* *Performance status at start of DES, N* (%)** 0 4 (13) 1 10 (32) 2 13 (42) 3 4 (13) Median PSA at start of DES (μg l^−1^) 399 Range 13.8--22\'299 DES (PSA evaluable *N*=23) Prior abiraterone Median time on treatment (m) 2.7 11.2 95% CI 1.8-- 4.4 Range 0.1--31.2 0.9--32.7 ⩾50% PSA decline, N (%) 2/23 (9) 17/31 (55) Median survival from start of DES (m) 4.8 Range 0.2--46.4 Abbreviations: AA=abiraterone acetate; CI=confidence interval; DES=diethylstilboestrol; PSA=prostate-specific antigen. [^1]: These authors contributed equally as first authors. [^2]: Co-senior authors.
Q: GridserachCV, make_scorer in python, for class specific F1 I am working with a highly imbalanced dataset (more values in class 0 and few in class 1). To analyse the performance of the classifier I am using the F1 metric. I set average = None in the F1 function from scikitlearn, this is because I want to check its performance on class 0 and 1 separately and am only concerned about the classifier's performance on class 1. value = f1_score(yTest, y_scores, average=None) value[1] gives me the required value Now for hyperparameter tuning using gridserachcv, I create the F1 score in the following way f1_scorer = make_scorer(f1_score, average=None) However this gives an array which is not accepted by GridSearchCV(svc_clf, param_grid, cv=nfolds, error_score=0.0, scoring=f1_scorer2) How do I extract the value at index 1 to be used as the metric in the scoring parameter. This is because I want to place focus on the classifier's performance on class 1 during hyperparameter tuning. I did try some naive ways of writing f1_scorer2[1] etc but it says '_PredictScorer' object is not subscriptable A: If you only care about the f1 score for the positive class, then the defaults average='binary' and pos_label=1 should be fine. If you needed to in another situation, you should be able to define a thin wrapper function: def pos_f1_score(estimator, X, y): y_pred = estimator.predict(X) f1s = f1_score(y, y_pred, average=None) return f1s[1] Finally, a number of common metrics have already been made into scorers that you can invoke with a string for scorer; see a list here.
Abstract/Summary ? NExT Core The overall objective of the Nutrition, Exercise and phenotype Testing (NExT) core of MNORC (formerly the ?Human Phenotyping Core? (HPC) is to enhance and expand the research capabilities of MNORC investigators performing clinical and translational studies related to nutrition, obesity, and/or obesity-related disorders in humans. The NExT core accomplishes this goal by: 1) Provide consultation services to translational, clinical and population-based investigators regarding appropriate assessment, testing and/or intervention approaches for their studies related to nutrition, physical activity/exercise, obesity, or obesity-related cardio- metabolic disorders, 2) offering expertise and infrastructure for sophisticated and standardized physiologic testing of human subjects, including children and adults 3) providing services to directly assist researchers to conduct their nutritional and/or physical activity/exercise interventions in human subjects, and 4) assisting in the development of new techniques or acquire new technologies for human metabolic phenotyping. In addition to offering a wide array of relatively ?standard? phenotypic measurements (e.g., anthropometry and body composition (DXA, PeaPod), blood pressure, fasting blood work, oral glucose tolerance, nutritional and physical activity assessments via self reports and objective methods (test meals, accelerometry), and aerobic fitness assessments) the NExT core also offers several more involved procedures to more thoroughly assess the metabolic phenotype (e.g., hyperinsulinemic-euglycemic clamp, isotope-tracer metabolic studies, resting energy expenditure, skeletal muscle and adipose tissue biopsies). Before beginning their studies, MNORC investigators may consult with expert NExT core personnel to gain insights on how the available methodologies may help them to test their hypotheses, and potentially expand their research questions using the tools made available to them through the Core. NExT core personnel also consult with MNORC investigators to help optimize their study designs and their research intervention strategies/approaches. The NEXT core also directly assists MNORC investigators to conduct their obesity/nutritional interventions by providing services such as: nutritional consultations with study participants, supervision of exercise training interventions, assessment of physical activity and dietary behaviors during an intervention, as well as assistance with conducting interventions specifically tailored to each research participant. Overall, the services of the NExT core provide well-controlled and standardized phenotypic testing, state-of-the-art techniques for ?deeper? phenotype assessment, as well as assistance to conduct well-controlled research interventions, all of which greatly enhance and expand on existing approaches used by researchers in the areas of nutrition and obesity in children and adults.
Q: how can we validate duplicate in database table while inserting data from excel I have created a sql table which contains 38 columns and I am importing data from excel to sql table for inserting I have used bulkcopy option while importing once data is imported and while we insert again data is inserted again duplicates are coming so please give me the solution for validate and insert A: I have done the same thing for my project. I have many files but with different names and all files have different data. So I used filename as unique ID and inserted the filename as a value in a new column in Table. Before uploading I check if the same filename is listed in Table or not. Look for something unique in your excel files, may be name, or anything you see is unique.
[Anonymity and gamete donation]. In France the gamete donation is based on the major principles: anonymity, no payment, solidarity and this mode of procreation can be used only if a medical indication is present in recipient couples. In prerequisite and during the revision of the law of bioethics, a wide debate took place about the anonymity of gamete donation. The objectives of this article is to review the concept of the anonymity and its links with the questions of the origin, the secret of the modalities of the conception and the mourning of the fertility, children, donors and the recipient couples waiting for gamete donation. The international situation is also addressed. The contribution of the CECOS, the centers which practice the sperm and the egg donations is highlighted. The anonymity cannot be discussed without addressing all these links and the complexity of this particular mode of conception. To date, the French society has maintained the anonymity in the new law of bioethics.
Q: Why is a button clickable when theres another layout overlaying it? I got a Layout which is relatively positioned. In it I got (by now) two things: A Clickable Button which is bound to an onClick-Event A LinearLayout which is overlaying the full screen Although the LinearLayout is overlaying the button, the button is still clickable. Even if there's another button in the overlay. How can I avoid this? A: The overlaying views (and layouts) have to implement an onClick listener to catch the event, otherwise the event is dispatched on the underlaying views. A: Alright I found an approach that works together with animation: The Layout (shortened): <RelativeLayout ...> <Button ... /> <LinearLayout android:id="@+id/underlay" android:background="#00ffffff" /> <LinearLayout android:id="@+id/overlay" ... /> </RelativeLayout> Now when Fading In "overlay" it seems to be the best to have an invisible "underlay" which is immediately put to VISIBLE: LinearLayout underlay = (LinearLayout)findViewById(R.id.underlay); underlay.setVisibility(View.VISIBLE); underlay.setOnClickListener(...); //now animate the overlay
L.S. Harrington and G.M. Findlay contributed equally to this paper. Abbreviations used in this paper: IRS, insulin receptor substrate; MEF, mouse embryo fibroblast; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-OH kinase; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PTB, phosphotyrosine-binding domain; siRNA, small interfering RNA; TSC, tuberous sclerosis complex. Introduction ============ The signal transduction mechanisms operating downstream of insulin receptor ligation have highlighted the importance both of the receptor tyrosine kinase substrates (insulin receptor substrates, IRS-1 and IRS-2) and the lipid kinase phosphoinositide 3-OH kinase (PI3K; [@bib40]; [@bib41]; [@bib2]; [@bib54]). Activation of PI3K occurs via recruitment to IRS proteins, and is critical in generating many of the cell\'s responses to insulin ([@bib43]). The insulin--PI3K pathway also plays a conserved role in regulating cell and organism size. Mice deficient in effectors of PI3K, PDK1 and S6K1, exhibit growth defects ([@bib44]; [@bib24]), whereas activation of PI3K leads to increases in cell and organ growth ([@bib25]; [@bib3]; [@bib45]). The growth response to insulin-like growth factors involves the S6 kinases and leads to increased translation of 5′-terminal oligopyrimidine track mRNAs ([@bib19]), many of which encode ribosomal proteins. By increasing ribosome biogenesis, activation of S6K is thought to lead to an increase in protein synthesis ([@bib53]). Two S6K genes, S6K1 and S6K2, together encode four kinase isoforms, three of which are present in the nucleus ([@bib39]; [@bib11]). Two signaling pathways have been shown to positively regulate S6K: the insulin--PI3K pathway ([@bib38]; [@bib29]) and a nutrient pathway involving the mammalian target of rapamycin (mTOR; [@bib1]; [@bib31]). A genetic regulator of S6K1 activity has also been identified---the tumor suppressor tuberous sclerosis complex (TSC1-2), a complex of the TSC1 and TSC2 gene products, hamartin and tuberin ([@bib52]). Inactivation of TSC1-2 leads to constitutive S6K1 activity ([@bib18]; [@bib22]) and growth in Drosophila ([@bib17]; [@bib7]; [@bib33]; [@bib49]). An inhibitory target of TSC1-2 action has been identified as Rheb, a small GTPase ([@bib8]; [@bib42]; [@bib47]; [@bib55]) with Rheb overexpression resulting in activation of S6K (for review see [@bib27]). A key unresolved question is how S6K activation and growth stimulated by insulin-like growth factors is appropriately coordinated with the other responses downstream of PI3K that include cell proliferation and survival. Negative feedback loops relating a downstream response of insulin--PI3K signaling to the overall level of pathway activation would be a potential means of accomplishing this type of coordination. Here, we show that by suppressing such a negative feedback loop, TSC1-2 is a key positive regulator of PI3K signaling. TSC1-2 promotes PI3K signaling by suppressing S6K, thereby preventing S6K-dependent inactivation of IRS-1 and IRS-2. As a result of IRS inactivation, TSC2-deficient cells exhibit a profound defect in PI3K signaling and fail to activate the serine-threonine kinase PKB or respond to the migration and pro-survival activities of IGF-1. We show that for IRS-1, the inactivation is exerted through S6K-dependent suppression of gene transcription and by direct phosphorylation by S6K1 in a region critical for IRS-1 adaptor function. We suggest that although TSC1-2 loss of function promotes hamartomatous growth in TSC, a failure to activate insulin--PI3K signaling may explain the low malignant potential of such tumors. Results ======= TSC1-2 specifically regulates insulin signaling to PI3K ------------------------------------------------------- Insulin-stimulated activation of the PI3K-regulated serine-threonine kinase PKB (also known as AKT) is defective in cells deficient in TSC2 ([@bib18]) or TSC1 ([@bib22]). To determine whether there is a specific impairment of insulin-like growth factor signaling, we assayed PKB activity after stimulation of cells with insulin, IGF-1, or EGF. In control TSC2 ^+/+^ mouse embryo fibroblasts (MEFs) or TSC2 ^−/−^ MEFs in which wild-type TSC2 has been reintroduced ([@bib18]), PKB is activated by insulin, IGF-1, and EGF ([Fig. 1](#fig1){ref-type="fig"} A). In contrast, in TSC2 ^−/−^ MEFs or TSC2 ^−/−^ MEFs in which a pathogenic TSC2 mutant is reintroduced, PKB is activated strongly only by EGF. Similarly, a downstream effector of PKB, GSK3α/β, is robustly phosphorylated in response to stimulation by all three growth factors in control MEFs, but only strongly by EGF in TSC2 ^−/−^ MEFs ([Fig. 1](#fig1){ref-type="fig"} B). ![PI3K activation by insulin-like growth factors is dependent on functional TSC2 . (A) PKB activation in cells expressing or lacking functional TSC2. PKB activation in isogenic TSC2 ^+/+^, TSC2 ^−/−^ MEFs, and TSC2 ^−/−^ MEF lines in which wild-type (−/− (+WT)) or a pathogenic mutant TSC2 (−/− (+N1643K)) has been reintroduced were starved and stimulated with the indicated growth factors for 10 min. The ability of insulin, IGF-1, and EGF to activate PKB is demonstrated by phosphorylation of Ser-473 (S473-P). (B) Phosphorylation of GSK3α/β, at GSK3α Ser-21 (top) and GSK3β Ser-9 (middle) after insulin, IGF-1, or EGF stimulation. Bottom: total GSK3α/β. (C) PI3K activity in TSC2 ^+/+^ or TSC2 ^−/−^ MEFs, or TSC2 ^−/−^ MEFs reconstituted with wild-type TSC2 (+WT) or a disease-causing mutant TSC2 (+N1643K) after stimulation with IGF-1. Results are expressed as values relative to unstimulated controls. (D) PIP3 levels in TSC2 ^+/+^ or TSC2 ^−/−^ MEFs, or TSC2 ^−/−^ MEFs reconstituted with wild-type TSC2 (+WT) or a disease-causing mutant TSC2 (+N1643K) after stimulation with IGF-1 or EGF. The results (means and SD of triplicate determinations) are expressed relative to control unstimulated cells.](200403069f1){#fig1} Because PKB activation generally requires PI3K activation and the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3) at the membrane ([@bib2]), we assayed PI3K activity and measured levels of PIP3 after stimulation with IGF-1 or EGF. TSC2 ^−/−^ MEFs neither activate PI3K ([Fig. 1](#fig1){ref-type="fig"} C) nor elevate levels of PIP3 in response to IGF-1 stimulation ([Fig. 1](#fig1){ref-type="fig"} D), whereas PIP3 generated after stimulation with EGF is similar to that of control TSC2-expressing MEFs ([Fig. 1](#fig1){ref-type="fig"} D). Thus, the failure to activate PKB after stimulation with insulin or IGF-1 in TSC2-deficient cells is due to a general failure to activate PI3K and generate its lipid product, PIP3. TSC1-2 regulates IRS-1 mRNA via S6K --------------------------------------- The basis of the insulin signaling defect in cells lacking TSC2 could be either at the level of expression of the insulin/IGF-1 receptors or IRS proteins, or at the level of their activation. Therefore, we performed a microarray analysis of gene expression differences between TSC2 ^+/+^ and TSC2 ^−/−^ MEFs, which shows that the level of the IRS-1 mRNA is significantly reduced in TSC2 ^−/−^ MEFs ([Fig. 2](#fig2){ref-type="fig"} A). To confirm this result, we analyzed IRS-1 mRNA. IRS-1 mRNA abundance is significantly reduced in TSC2 ^−/−^ MEFs ([Fig. 2](#fig2){ref-type="fig"} B). Importantly, this reduction is fully reversed by stable retroviral introduction of wild-type TSC2 ([Fig. 2](#fig2){ref-type="fig"} B). Interestingly, the level of IRS-2 mRNA is unaffected by the absence of functional TSC2. A similar result is obtained comparing the levels of IRS-1 protein in these cells by Western blotting, whereas the levels of IRS-2 protein or of the insulin or IGF receptors is unaffected by TSC2 expression ([Fig. 2](#fig2){ref-type="fig"} C). Thus, IRS-1 expression is maintained by the presence of functional TSC2. ![IRS-1 mRNA and protein expression is dependent on TSC2. (A) Microarray analysis of TSC2 ^+/+^ and TSC2 ^−/−^ MEFs. IRS-1 mRNA is more abundant in TSC2 ^+/+^ MEFs (green) compared with TSC2 ^−/−^ MEFs (red). (B) Northern blotting of IRS-1 (top) or IRS-2 (middle) mRNAs in isogenic TSC2 ^+/+^, TSC2 ^−/−^ MEFs, and a TSC2 ^−/−^ MEF line in which wild-type TSC2 has been reintroduced (−/− +WT). Aliquots of these samples were run on a separate gel and probed for β-actin as a control for RNA content (bottom). White line indicates that intervening lanes have been removed. (C) IRS-1 (first panel), IRS-2 (second panel), InR (third panel), and IGF1-R (fourth panel) protein levels in TSC2 ^+/+^, TSC2 ^−/−^, and a TSC2 ^−/−^ MEF line in which wild-type TSC2 has been reintroduced (−/− +WT). A blot was reprobed for ERK1/2 as a control for protein loading (bottom panel).](200403069f2){#fig2} IRS-1 protein levels have previously been shown to be rapamycin sensitive ([@bib14]). Because mTOR/S6K signaling is hyperactivated in TSC2-deficient cells ([@bib18]), we sought to examine the effect of rapamycin on IRS-1 mRNA abundance. Rapamycin treatment of TSC2 ^−/−^ MEFs relieves the suppression of IRS-1 mRNA abundance after ∼24 h of treatment ([Fig. 3](#fig3){ref-type="fig"} A). This restoration of IRS-1 mRNA abundance by sustained rapamycin treatment is reversed by actinomycin D ([Fig. 3, B and C](#fig3){ref-type="fig"}), indicating that mTOR/S6K1 signaling likely reduces IRS-1 mRNA abundance primarily at the level of gene transcription. ###### Inhibition of S6K restores IRS-1 mRNA. (A) IRS-1 mRNA levels (top) in serum-starved TSC2 ^+/+^ or TSC2 ^−/−^ MEFs in untreated cells or after the addition of 20 nM rapamycin for various times. The blot was reprobed for β-actin as a control for mRNA loading (bottom). White line indicates that intervening lanes have been removed. (B) IRS-1 mRNA levels (top) in TSC2 ^−/−^ MEFs treated with 20 nM rapamycin alone, or in the presence of 10 μg/ml actinomycin D for the final 10 h of a 24-h treatment. The blot was reprobed for β-actin as a control for mRNA loading (bottom). (C) Quantitative RT-PCR analysis of untreated, rapamycin-treated, and rapamycin plus actinomycin D--treated TSC2 ^−/−^ MEFs. Left, β-actin; right, IRS-1. A single graph from triplicate determinations showing identical results is shown. (D) RNAi-mediated inhibition of S6K1 and S6K2. Western blotting of extracts from TSC2 ^+/+^ or TSC2 ^−/−^ MEFs transfected with a combination of scrambled siRNAs (C) or S6K1, S6K2, or S6K1 plus S6K2 siRNAs. Top, S6K1; middle, S6K2; bottom, anti-pS6 (Ser240/244). Where indicated, cells were stimulated for 10 min with insulin or treated with 20 nM rapamycin for 1 h. (E) IRS-1 mRNA levels in TSC2 ^+/+^ MEFs or TSC2 ^−/−^ MEFs transfected with a combination of S6K1 and S6K2 scrambled siRNAs (C), S6K1, or S6K2 siRNAs, or treated for 24 h with 20 nM rapamycin. Top, IRS-1 mRNA; The blot was also reprobed for β-actin as a control for mRNA loading (bottom). (F) Quantitative RT-PCR analysis of untreated TSC2 ^+/+^, TSC2 ^−/−^, or TSC2 ^−/−^ treated with 20 nM rapamycin or RNAi to S6K1 or S6K2. Left, β-actin; right, IRS-1. A single graph from triplicate determinations showing identical results is shown. ![](200403069f3ac) ![](200403069f3df) Next, we asked whether the suppression of IRS-1 mRNA was mediated by either S6K1 or S6K2, both of which are rapamycin-sensitive kinases, using a small interfering RNA (siRNA) approach. A near complete knock-down of S6K1 and a 70--80% knock-down of S6K2 is observed ([Fig. 3](#fig3){ref-type="fig"} D). Suppression of either S6K1 or S6K2 mimics the effect of rapamycin treatment and restores IRS-1 mRNA to a level approaching that of TSC2 ^+/+^ MEFs ([Fig. 3, E and F](#fig3){ref-type="fig"}). We conclude that the suppression of IRS-1 mRNA we observe in TSC2-deficient cells is mediated by both forms of S6K---S6K1 and S6K2. TSC1-2 promotes insulin signaling by inhibiting S6K action on IRS-1 --------------------------------------------------------------------- IRS-1 and IRS-2 proteins extracted from TSC2 ^−/−^ MEFs exhibit reduced migration on SDS-PAGE gels ([Fig. 2](#fig2){ref-type="fig"} C). Treatment of IRS-1 immunoprecipitates with λ-phosphatase indicates that the reduced migration of IRS-1 in TSC2 ^−/−^ MEFs is due to differences in phosphorylation, with the protein exhibiting a larger change in mobility than IRS-1 from TSC2 ^+/+^ MEFs after phosphatase treatment ([Fig. 4](#fig4){ref-type="fig"} A). To determine if this change in IRS-1 phosphorylation is caused by mTOR/S6K signaling, we treated TSC2 ^+/+^ or TSC ^−/−^ MEFs for various times with rapamycin and examined IRS-1 and IRS-2 protein levels. Both IRS-1 and IRS-2 migrate as slower species in TSC2-deficient cells. After the addition of rapamycin to TSC2 ^−/−^ MEFs for 1 h, both IRS-1 and IRS-2 migrate as faster migrating species with no increase in protein levels. However, after 24 h treatment with rapamycin, the migration and level of IRS-1 protein in TSC2 ^−/−^ MEFs is similar to that of untreated TSC2 ^+/+^ MEFs ([Fig. 4](#fig4){ref-type="fig"} B). In contrast, the level of IRS-2 is largely unaffected by rapamycin treatment in either TSC2 ^+/+^ or TSC2 ^−/−^ MEFs. PKB activation in TSC2 ^−/−^ MEFs is partially restored after 1 h of rapamycin treatment, and is fully restored after 24 h of treatment ([Fig. 4](#fig4){ref-type="fig"} C). Consistent with the rescue of PKB activation, the elevation of PIP3 after IGF-1 stimulation of TSC2 ^−/−^ MEFs pretreated with rapamycin for 24 h is similar to that produced in stimulated TSC2 ^+/+^ MEFs ([Fig. 4](#fig4){ref-type="fig"} D). ###### Inhibition of S6K restores insulin signaling. (A) Treatment of IRS-1 immunoprecipitates with λ-phosphatase indicating that reduced migration of IRS-1 in TSC2 ^−/−^ MEFs is due to increased phosphorylation. (B) Treatment of serum-starved TSC2 ^+/+^ or TSC2 ^−/−^ MEFs for various times with rapamycin followed by immunoblotting for IRS-1 (top) or IRS-2 (bottom). The slower migrating, more heavily phosphorylated IRS-1 or IRS-2 present in TSC2 ^−/−^ MEFs is indicated with an arrow; the faster migrating IRS-1 or IRS-2 present in TSC2 ^+/+^ cells or after rapamycin treatment is indicated with an arrowhead. (C) PKB activation by insulin or IGF-1 after treatment of TSC2 ^+/+^ or TSC2 ^−/−^ MEFs with rapamycin for the indicated times. Top, Ser473-phosphorylated PKB; bottom, level of total PKB. (D) PIP3 levels in TSC2 ^+/+^ (gray bars) or TSC2 ^−/−^ (white bars) MEFs after IGF-1 stimulation in untreated cells or cells pretreated for 24 h with 20 nM rapamycin. Results from triplicate determinations (means and SDs) are shown normalized to control unstimulated samples and are representative of three independent experiments. (E) PKB activation after RNAi-mediated inhibition of IRS-1, IRS-2, IRS-1 plus IRS-2, or a combination of scrambled IRS-1 and IRS-2 siRNA (Scrambled) in TSC2 ^−/−^ MEFs stimulated by insulin for 10 min after treatment with 20 nM rapamycin for 1 h. First panel, IRS-1; second panel, IRS-2; third panel, Ser473-phosphorylated PKB; bottom panel, total PKB. (F) Rescue of PKB activation in TSC2 ^−/−^ MEFs after overexpression of IRS-1 or IRS-2. Extracts from mock-transfected TSC2 ^−/−^ MEFs (C) or MEFs transfected with expression constructs expressing myc-IRS-1 or IRS-2 were starved for 24 h after transfection and were treated with 20 nM rapamycin for 1 h before stimulation with insulin for 10 min. Where indicated, mock-transfected cells were also treated with 20 nM rapamycin for 24 h before stimulation. First panel, myc-IRS-1 detected with 9E10 monoclonal; second panel, IRS-2; third panel, Ser473-phosphorylated PKB; bottom panel, total PKB. (G) PKB activation in TSC2 ^−/−^ MEFs after RNAi-mediated inhibition of S6K1, S6K2, S6K1 plus S6K2, or a mixture of S6K1 and S6K2 scrambled siRNAs (Scrambled) after insulin stimulation for 10 min. Scrambled siRNA-transfected cells were also treated with 20 nM rapamycin for 24 h before insulin stimulation where indicated. ![](200403069f4ad) ![](200403069f4eg) To examine whether the rescuing effect of rapamycin upon insulin signaling is mediated via effects on IRS-1 or IRS-2, we again used siRNAs. The partial rescue of PKB activation we observe with 1 h of rapamycin treatment is diminished by suppression of either IRS-1 or, to a lesser extent, IRS-2, with a more pronounced effect observed when both proteins are suppressed ([Fig. 4](#fig4){ref-type="fig"} E). To determine whether perturbation of IRS function is the critical lesion responsible for diminished insulin signaling in TSC2 ^−/−^ MEFs, we then asked whether insulin signaling could be rescued in TSC2 ^−/−^ MEFs after overexpression of IRS-1 or IRS-2. We find that overexpression of either IRS-1 or IRS-2 results in an increase in PKB activation, which when combined with short-term inhibition of mTOR/S6K signaling using rapamycin leads to a phenocopy of the effect of sustained (24 h) treatment with rapamycin ([Fig. 4](#fig4){ref-type="fig"} F). Then, we asked whether the enhanced effect on signaling we observe after rapamycin is due to inhibition of S6K, using siRNAs. The results indicate that suppression of either S6K1 or S6K2 in TSC2 ^−/−^ MEFs leads to an increase in PKB activation, with a larger increase elicited by suppression of S6K1 ([Fig. 4](#fig4){ref-type="fig"} G). Suppression of either kinase leads to an equivalent increase in the level of IRS-1 protein, with no effect on IRS-2. Together, these results show that the reduced insulin signaling we observed in TSC2 ^−/−^ MEFs is caused by effects on both IRS-1 and IRS-2. In the case of IRS-1, the effects appear to be partially mediated by S6K, with both S6K1 and S6K2 contributing to reduced insulin signaling. IRS-1 is a novel substrate for S6K ---------------------------------- We reasoned that IRS-1 may also be a novel substrate for S6 kinases, and tested the ability of GST-tagged IRS-1 fragments covering the entirety of the protein to be phosphorylated in vitro by S6K, in comparison to S6. A fragment encompassing residues 108--516 (IRS-1^108--516^) is efficiently phosphorylated by S6K in vitro ([Fig. 5](#fig5){ref-type="fig"} B). Comparison of the S6K phosphorylation site in S6 with IRS-1^108--516^ reveals three potential phosphorylation sites in which an RxRxxS is followed by distal serines as occurs in S6 ([Fig. 5](#fig5){ref-type="fig"} A). We mutagenized both the proximal (RxRxx[S]{.ul}) and distal serines in each of these potential sites and asked whether such mutants could be phosphorylated in vitro. The results show that only in IRS-1^108--516^ in which serines 302, 307, and 310 are mutated ([Fig. 5](#fig5){ref-type="fig"} A, site 2) is IRS-1 not phosphorylated in vitro by S6K1 ([Fig. 5](#fig5){ref-type="fig"} C, left panels). Individual mutagenesis of serines 307 and 310 has little effect on IRS-1^108--516^ phosphorylation, indicating that this site is not phosphorylated at multiple serines like that of S6, whereas mutagenesis of serine 302 to alanine ablates phosphorylation ([Fig. 5](#fig5){ref-type="fig"} C, right panels). This result was confirmed using Western blotting with a phospho-Ser302 antibody that only recognizes wild-type IRS-1 after in vitro phosphorylation by S6K ([Fig. 5](#fig5){ref-type="fig"} D). To confirm that this phosphorylation detected in vitro is sensitive to TSC2 in vivo, we probed extracts with this antibody. Although the level of IRS-1 is reduced in TSC2-deficient MEFs compared with TSC2-expressing MEFs ([Fig. 2](#fig2){ref-type="fig"} C and [Fig. 5](#fig5){ref-type="fig"} E), the level of Ser302-phosphorylated IRS-1 is greatly increased ([Fig. 5](#fig5){ref-type="fig"} E) and rapamycin sensitive ([Fig. 5](#fig5){ref-type="fig"} F). We again used S6K siRNAs to determine whether IRS-1 Ser302 phosphorylation is through S6K in vivo. The result indicates that IRS-1 Ser302 phosphorylation is decreased after siRNA-mediated suppression of S6K1, but is unaffected by suppression of S6K2 ([Fig. 5](#fig5){ref-type="fig"} G). Thus, in TSC2 ^−/−^ MEFs cells, IRS-1 Ser302 phosphorylation is regulated primarily by S6K1, and not S6K2, although the less effective knock-down of S6K2 expression leaves open the formal possibility of some contribution from this kinase also. ###### IRS-1 is a novel S6K substrate. (A) Domain structure of IRS-1 indicating regions of GST fusions (aa numbering based on murine IRS-1) used for in vitro kinase assays and comparison of the S6 phosphorylation site with candidate S6-like phosphorylation sites present in IRS-1^108--516^. Conserved arginines are shown in bold, serines phosphorylated by S6K in S6 and potentially phosphorylated in IRS-1^108--516^ are shown in red, and serines mutated to alanines in mutants of sites 1--3 are underlined. Also shown is the homologous site to site 2 in murine IRS-2. (B) In vitro kinase assay of GST-IRS-1 fragments with purified S6K2. Full-length GST fusion proteins (1--4, as indicated in A) and 40S ribosomal proteins containing S6 (40S) in these preparations are indicated with asterisks in the Coomassie blue--stained gel (right), and the ^32^P-labeled proteins after the kinase assay and autoradiography are shown on the left. Two phosphorylated bands are noted in kinase assay with IRS-1^108--516^, the lower of which represents a poorly resolved doublet of cleaved forms of the protein. An arrow indicates ^32^P-labeled S6 present in the 40S ribosome preparation. (C) In vitro kinase assay of IRS-1 site-directed mutants by S6K1. Top panels, autoradiographs; bottom panels, Coomassie blue--stained gels; left panels, phosphorylation of IRS-1^108--516^ (WT) and site 1--3 compound mutants as indicated in [Fig. 4](#fig4){ref-type="fig"} A; right panels, phosphorylation of IRS-1^108--516^ and individual serine-to-alanine mutants of the serine residues within site 2. (D) Ser302 phosphorylation of IRS-1^108--516^ wild-type (WT) or IRS-1^108--516^ with Ser302 mutated to alanine (S302A) detected with a phosphospecific antibody to IRS-1 Ser302 after in vitro phosphorylation by S6K1. (E) IRS-1 Ser302 phosphorylation is elevated in vivo. Top, Ser302-phosphorylated IRS-1 detected by a phosphospecific Ser302 antibody in extracts from serum-starved isogenic TSC2 ^+/+^ and TSC2 ^−/−^ MEFs, and TSC2 ^−/−^ MEFs lines in which wild-type (−/− (+WT)) or a pathogenic mutant TSC2 (−/− (+N1643K)) has been reintroduced; top, Ser302-phosphorylated IRS-1; bottom, total IRS-1. (F) IRS-1 Ser302 phosphorylation is inhibited by mTOR/S6K inhibition with rapamycin in serum-starved TSC2 ^−/−^ MEFs. Top, Ser302-phosphorylated IRS-1; bottom, total IRS-1. Where indicated, MEFs were also stimulated with insulin for 10 min. (G) IRS-1 Ser302 phosphorylation is diminished in TSC2 ^−/−^ MEFs after siRNA-mediated inhibition of S6K1. Top, Ser302-phosphorylated IRS-1; bottom, total IRS-1. Where indicated, MEFs were also stimulated with insulin for 10 min. ![](200403069f5ad) ![](200403069f5eg) Phosphorylation by S6K inhibits IRS-1 function ---------------------------------------------- Next, we asked whether IRS-1 could be tyrosine phosphorylated and associate with PI3K in TSC2 ^−/−^ MEFs after stimulation with insulin. The results show that in TSC2 ^−/−^ MEFs, IRS-1 is both poorly tyrosine phosphorylated and associated with PI3K after stimulation of cells with insulin. Rapamycin treatment for 1 h results in a partial restoration of both IRS-1 tyrosine phosphorylation and association with the p85 subunit of PI3K in TSC2 ^−/−^ MEFs ([Fig. 6, A and B](#fig6){ref-type="fig"}). Importantly, this short-term treatment does not significantly alter IRS-1 protein levels ([Fig. 4, B and E](#fig4){ref-type="fig"}), which argues that the reduction in signaling capacity is attributable to impaired function as well as a reduction in the pool of available IRS-1. Sustained inhibition of S6K signaling by rapamycin treatment of TSC2 ^−/−^ MEFs restores both tyrosine phosphorylation and PI3K association to levels approaching that of TSC2 ^+/+^ cells ([Fig. 6](#fig6){ref-type="fig"} A). Then, we asked whether phosphorylation of IRS-1^108--516^ by S6K directly inhibits its association with activated insulin receptors. We phosphorylated in vitro a GST fusion protein containing the phosphotyrosine-binding domain (PTB) of IRS-1 with S6K, and determined the amount of activated insulin receptor that associated with unphosphorylated or phosphorylated IRS-1 in a pull-down assay. The result shows that phosphorylation of the IRS-1 PTB domain by S6K markedly decreases its association with insulin receptor ([Fig. 6, C and D](#fig6){ref-type="fig"}), whereas a Ser302-glutamic acid mutant, which may mimic the effect of phosphorylation at this site, exhibits impaired binding to the insulin receptor ([Fig. 6, E and F](#fig6){ref-type="fig"}). Thus, S6 kinases directly phosphorylate IRS-1 at Ser302, and the resulting reduction of binding to insulin receptors is likely to play a major role in the inability of IRS-1 to signal to PI3K. ###### S6K phosphorylation blocks IRS-1 function. (A) IRS-1 tyrosine phosphorylation and association with PI3K is suppressed in TSC2 ^−/−^ MEFs and rescued by inhibition of S6K. IRS-1 immunoprecipitates in unstimulated or insulin-stimulated TSC2 ^+/+^ or TSC2 ^−/−^ MEFs after rapamycin treatment for the indicated times, immunoblotted for phosphotyrosine (panel 1), or the coimmunoprecipitation of the p85 subunit of PI3K (panel 2). The total levels of IRS-1 and p85 in cell lysates are indicated in panels 3 and 4, respectively. (B) Quantitation of insulin- stimulated IRS-1 tyrosine phosphorylation in untreated TSC2 ^−/−^ MEFs or the same cells after rapamycin treatment for the indicated times. An arbitrary value was obtained representing the difference between unstimulated and the corresponding insulin-stimulated level of phosphotyrosine in IRS-1 immunoprecipitations as detected on scanned autoradiographs. The values from three independent experiments were averaged and plotted on a bar chart, with the error bars showing the SEM. (C) Phosphorylation of immobilized GST-IRS-1^108--516^ PTB domain by S6K2 inhibits insulin receptor (InR) interaction. The interaction with tyrosine-phosphorylated InR (top) was determined in vitro by the addition of glutathione beads containing the indicated amounts of S6K2-phosphorylated or unphosphorylated GST-IRS-1^108--516^ or GST to lysates prepared from insulin-stimulated CHO-IR cells. An immunoblot of the level of GST-IRS-1 fusion protein or GST is indicated on the bottom. DP indicates degradation products of the GST-IRS-1 protein. (D) Quantitation of InR binding to GST-IRS-1^108--516^ (WT) or a mutant GST-IRS-1^108--516^ in which serine 302 is mutated to alanine (S302A) after in vitro phosphorylation by S6K2. Error bars show the SEM from three experiments. (E) InR binding of wild-type GST-IRS-1^108--516^, or S302A and S302E mutants in a pull-down assay. Top, InR; bottom, anti-GST. (F) Quantitation of InR binding to GST-IRS-1^108--516^ (WT) or S302A and S302E mutants. An arbitrary value of 100 was assigned for the binding of wild-type GST-IRS-1^108--516^, and the binding of the mutant IRS-1 proteins was expressed relative to this value. Error bars show the SEM from three experiments. ![](200403069f6ad) ![](200403069f6ef) Impaired PI3K signaling abrogates IGF-1--mediated chemotaxis and survival ------------------------------------------------------------------------- PI3K activation by insulin or IGF-1 is required for migration/chemotaxis and survival. Survival is known to involve activation of PKB ([@bib23]), whereas chemotaxis requires PI3K activity ([@bib35]). Therefore, we tested the responses of TSC2 ^+/+^ or TSC2 ^−/−^ MEFs to IGF-1 in chemotaxis and survival assays. We observe a similar basal and EGF-stimulated rate of migration for both TSC2 genotypes, but a pronounced impairment in IGF-1--stimulated chemotaxis in TSC2 ^−/−^ MEFs. Pretreatment with rapamycin for 24 h has little effect on migration of TSC2 ^+/+^ MEFs, but restores IGF-stimulated migration of TSC2 ^−/−^ MEFs ([Fig. 7, A and B](#fig7){ref-type="fig"}). ###### IGF-1--mediated migration and survival are impaired in TSC2 -deficient MEFs. (A) A chemotaxis assay indicating the migration of TSC2 ^+/+^ or TSC2 ^−/−^ MEFs in the absence or presence of 50 ng/ml IGF-1 or 20 ng/ml EGF as a chemotactic factor in a Transwell assay. The pictures show fluorescently labeled cells that have traversed a fluorescently inert filter, such that only the cells that have crossed the filter are photographed. Basal migration (left-hand panels) in the presence of 0.5% FCS present in both chambers and IGF-1--stimulated migration (middle panels) or EGF-stimulated migration (rightmost two panels) is shown in untreated cells (top six panels) or cells pretreated with 20 nM rapamycin for 24 h (bottom four panels). (B) Quantitation of IGF-1-- or EGF-mediated chemotaxis in the chemotaxis assay of TSC2 ^+/+^ (gray bars) or TSC2 ^−/−^ (white bars) MEFs. The results are expressed as a percentage of that of IGF-1--stimulated chemotaxis of TSC2 ^+/+^ MEFs not treated with rapamycin (100%) from four random 10× fields of two duplicate wells. Error bars show the SEM values. (C) Cell survival assay in the absence of serum. A quantitative analysis of the percentage of TUNEL-positive nuclei is shown for TSC2 ^+/+^ (gray bars) and TSC2 ^−/−^ (white bars) MEFs after 8 h in serum-free medium alone (−) or supplemented with 200 ng/ml IGF-1 (+) in untreated MEFs or MEFs pretreated for 36 h with 20 nM rapamycin. The results are from four random 10× fields and are typical of experiments performed twice. (D) Relative cell survival of TSC2 ^+/+^ (gray bars) or TSC2 ^−/−^ (white bars) MEFs. The results were obtained by dividing the means of the percentages of TUNEL-positive nuclei in the absence of IGF-1 by the means of those in the presence of IGF-1. ![](200403069f7ab) ![](200403069f7cd) Next, we tested the ability of IGF-1 to act as a survival factor for TSC2 ^+/+^ or TSC2 ^−/−^ cells. We assessed survival after serum removal, an assay in which IGF-1 is known to act as a survival factor ([@bib48]). IGF-1 significantly protects TSC2 ^+/+^ MEFs from apoptosis, but has little protective effect on TSC2 ^−/−^ cells ([Fig. 7](#fig7){ref-type="fig"}). TSC2 ^−/−^ MEFs exhibit a higher basal rate of survival in the absence of serum, raising the possibility that additional pro-survival pathways may be activated in these cells. Because rapamycin has been shown to lead to increased apoptosis of TSC2-deficient tumor cells in vivo ([@bib21]) and S6K1 phosphorylation has been implicated in inactivation of the pro-apoptotic factor Bad ([@bib13]), we assessed basal and IGF-1--mediated survival after treatment of cells with rapamycin. The results show that rapamycin treatment has little effect on the survival of TSC2 ^+/+^ MEFs. However, rapamycin has two effects on TSC2 ^−/−^ MEF survival, decreasing basal survival in the absence of IGF-1 while increasing survival in the presence of IGF-1 ([Fig. 7, C and D](#fig7){ref-type="fig"}). We conclude that under the conditions of serum withdrawal, IGF-1 does not activate pro-survival signaling in TSC2-deficient cells, and that a weaker pro-survival signal is instead provided by mTOR/S6K signaling. Discussion ========== The insulin--PI3K pathway controls cell number (through promoting cell cycle progression and survival via PKB/AKT; [@bib23]) and cell growth (via activation of the S6Ks; [@bib5]). How, then, do cells and tissues coordinate these activities, given that different relative amounts of cells and growth may normally be required to obtain a given organ size, or to modulate this size during development or in the adult? Regulators of coordination may be inferred from human pathologic overgrowth conditions in which such coordination is lost, or in model organisms such as Drosophila where loss-of-function mutations can be analyzed for their effect on organ growth. Both PTEN ([@bib30]) and TSC1-2 (mutated in TSC; [@bib6]; [@bib51]) may play coordinating roles in organ size control ([@bib10]; [@bib49]). However, PTEN (but not thus far TSC1-2) mutations are known to promote tumorigenesis, with the gene frequently mutated or lost in advanced neoplasms ([@bib26]). A connection between PTEN and TSC1-2 has also been proposed via PTEN loss of function leading to hyperactivation of the protein kinase PKB/AKT, which phosphorylates tuberin ([@bib16]; [@bib28]). Tuberin phosphorylation has been suggested to negatively regulate the TSC1-2 protein complex, allowing activation of S6K and cell growth ([@bib34]). In this paper, we have explored the failure of insulin to activate PKB in TSC2 ^−/−^ cells ([@bib18]). However, the absence of TSC1-2 complex function leads not to a specific failure in PKB activation, but rather to a general failure in insulin\'s ability to activate PI3K. As a result of TSC1-2 loss of function, insulin-like growth factors do not activate PI3K due to S6K inactivating the adaptor proteins IRS-1 and IRS-2. S6K activation appears to attenuate PI3K signaling through suppressing the adaptor protein IRS-1, both at the level of gene transcription and at the level of its function in coupling activated receptors to PI3K. The former mechanism is unexpected, and is mediated by S6K1 and S6K2, indicating that these protein kinases have a direct role in regulating IRS-1 transcription. A transcription factor, CREM, has already been shown to be a substrate for S6K1 ([@bib4]). Although the full range of consequences of activation of the mTOR/S6K pathway remain to be determined, it appears that a reduced responsiveness to growth factors may not be restricted to insulin signaling ([@bib56]). Future experiments will help clarify whether such "indirect" inhibitory consequences of aberrant mTOR/S6K activation on cell signaling play a role in the distinctive pathology of hamartoma development in TSC. A second major mechanism of IRS-1 inactivation by S6K is through phosphorylation. We have identified a site (Ser302) proximal to the IRS-1 PTB domain that we show is phosphorylated by S6K in vitro, which shows increased phosphorylation in TSC2-deficient cells and is sensitive to inhibition of mTOR/S6K signaling. Our data indicate that, at least in TSC2 ^−/−^ MEFs, the major kinase responsible for phosphorylating IRS-1 Ser302 is S6K1 and that phosphorylation of this site may disrupt the ability of the PTB domain to interact with activated insulin receptors. Reversal of this phosphorylation by short-term treatment with rapamycin, or inhibition of S6K1 by RNAi, partially rescues activation of PKB, arguing that phosphorylation by S6K may be a major mechanism to inactivate IRS-1 function. However, the extent of the band shift we observe in both IRS-1 and IRS-2 extracted from TSC2-deficient cells might suggest that more than one site is phosphorylated by S6K (or perhaps other mTOR-regulated kinases) in vivo; our data support the argument that the direct phosphorylation of the PTB domain site could account for the profound inhibition of IRS-1 function in these cells. [@bib9] have also reported that IRS-1 is phosphorylated at Ser302, by an unidentified nutrient- and rapamycin-sensitive kinase. However, using a Ser302-alanine mutant in 32D cells, these workers report that Ser302 phosphorylation may be necessary for association with PI3K p85 and for a restricted set of insulin--PI3K-regulated responses including activation of S6K and DNA synthesis. Surprisingly, their work indicates that activation of PKB is largely unaffected by preventing phosphorylation at this site, suggesting that PIP3 generation is unaffected by preventing Ser302 phosphorylation. However, they did not examine the consequences upon insulin signaling of a phosphomimic of Ser302 (which may reflect the situation occurring upon activation of mTOR/S6K signaling reported here), rendering it difficult to determine what the consequences of increased phosphorylation of this site may be. However, our finding that regulation of IRS by S6K occurs by both long-term (transcriptional) and acute (phosphorylation) mechanisms, and that both these mechanisms act in the same manner (i.e., inhibitory) toward insulin--PI3K activation, is consistent with what we observe in TSC2 ^−/−^ cells where S6K is hyperactive and PI3K activation is defective. We suggest that TSC1-2, S6K, and S6K-regulated inactivation of IRS proteins is a negative feedback sensor that may be designed to relate the amount of nutrient/S6K-dependent growth to the magnitude of insulin\'s activation of PI3K. The contribution of unregulated S6K activity to tumorigenesis is currently unknown. Some TSC1-2--deficient lesions have increased levels of phosphorylated S6, indicating elevation of S6K activity ([@bib22]; [@bib20]). Treatment of Eker rat tumors, in which TSC2 is inactivated, with the mTOR inhibitor rapamycin leads to increased apoptosis of these cells, indicating that mTOR/S6K signaling may be important here ([@bib21]). However, it is also clear that mice rendered TSC-null by genetic means do not develop beyond mid-gestation ([@bib22]), whereas in TSC, hamartomatous growths are generally slow or normally growing, and have a low malignant potential. This contrasts with PTEN inactivation in Cowden disease, in which predisposition to malignancy is evident ([@bib46]). Our model ([Fig. 8](#fig8){ref-type="fig"}) suggests that an explanation for the low level of malignancy observed in TSC1-2--deficient tumors may be that insufficient pro-tumorigenic PIP3-dependent signals (such as PKB activation) are generated in TSC1-2--deficient tumor cells, and that such signals may be required for malignant conversion. Our data also suggest a paradigm of how appropriate organ size control may be achieved: cell growth through S6 kinases may be either coordinated with PI3K-regulated cell number control or uncoupled from it, depending on the presence or absence of a functional TSC1-2 complex. ![A model for TSC1-2 regulation of insulin signaling to PI3K. The elevated production of the inositol phospholipid PIP3 by PI3K and its antagonism by PTEN (and 5-phosphatases; not depicted) determines the activation of downstream responses such as activation of PKB. A further downstream response to PKB activation may be the inactivation of TSC1-2 via phosphorylation of tuberin, resulting in S6K activation. In our model, TSC1-2 promotes insulin-like growth factor signaling to PI3K by repressing a negative feedback loop from mTOR/S6K to the adaptor molecule IRS-1. This negative regulation by TSC1-2 may be on mTOR effectors ([@bib18]) or on mTOR directly ([@bib50]). A similar negative feedback involving S6K repression of PKB activation has also been described in Drosophila ([@bib36]), although the target of dS6K\'s inhibitory action here is not known. Repression of IRS-1 by mTOR/S6K occurs via both a transcriptional repression of IRS-1 gene expression mediated by both S6K1 and S6K2 and by direct phosphorylation of IRS-1 protein close to the PTB domain by S6K1. Therefore, failure to activate PI3K may restrict the malignant potential of TSC-defective cells.](200403069f8){#fig8} Materials and methods ===================== Antibodies ---------- Commercial antibodies used were as follows: rabbit anti-GST, anti-p85, anti-IRS-1, and mouse anti-phosphotyrosine (clone 4G10) were from Upstate Biotechnology. Anti-PKB, IGF-1R, pS6 (Ser240/244), PKB Ser473, and total GSK3α/β and GSK3α/β Ser21/9 were from Cell Signaling. Antibodies to ERK1/2 and S6K1 were from Santa Cruz Biotechnology, Inc., and Transduction Laboratories, respectively. An anti-InR mAb CT3 was from K. Siddle (University of Cambridge, Cambridge, UK), and an antibody to S6K2 was from D. Alessi (University of Dundee, Dundee, UK). Antibodies to IRS-2 and IRS-1 phosphorylated at Ser302 were gifts from M. White (Joslin Diabetes Center, Boston, MA). Cell culture, treatments with growth factors, and siRNA transfections --------------------------------------------------------------------- Starved MEFs ([@bib18]) were stimulated with 1 μg/ml insulin, 50 ng/ml IGF-I, or 20 ng/ml EGF for 10 min. CHO-IR cells were maintained in Ham\'s F12 medium with 10% FCS and were starved in medium lacking serum for 24 h. To activate insulin receptors, cells were then stimulated for 10 min with 1 μM insulin. siRNAs (Dharmacon) for S6K were: S6K1, 5′-GGACATGGCAGGAGTGTTT-3′; and S6K2, 5′-GAACCAAGAAGTCCAAGAA-3′. For IRS-1 and IRS-1/IRS-2 double transfections, the sequences used were as described previously ([@bib32]). For IRS-2 single transfection, the following sequence was used: IRS-2, 5′-CCAAGCACAAGTACCTGAT-3′. SiRNAs were transfected using LipofectAMINE™ 2000 and cells were harvested after 24 h (for IRS-1 and IRS-2) or 5 d (S6K1 and S6K2). PI3K assay and PIP3 determination --------------------------------- Assays were performed as described previously ([@bib15]) and were imaged using a PhosphorImager (Fuji); bands were quantified using AIDA analysis software. Results were expressed as histograms in Microsoft Excel. Estimation of PIP3 was by a TRFRET displacement assay ([@bib12]). The estimates of PIP3 were normalized to total lipid extracted as described previously ([@bib37]). RNA analysis ------------ Murine gene oligo microarray slides (∼7.5k genes/slide) were obtained from the Human Mapping Project (Cambridge, UK). Fluorescently labeled cDNA probes were prepared using the Atlas™ Glass Fluorescent Labeling Kit (CLONTECH Laboratories, Inc.) and Cy3 and Cy5 reactive dyes (Amersham Biosciences), and were processed according to the manufacturer\'s instructions. For Northern blotting, RNA was run on agarose-formaldehyde gels, blotted onto Hybond™-N, and hybridized and washed using standard procedures. Two-step quantitative RT-PCR was performed using cDNA synthesized using the Omniscript™ RT Kit (QIAGEN) using total RNA purified from appropriately treated MEFs using the RNeasy™ Mini Kit (QIAGEN). For the actinomycin D experiment, TSC2 ^−/−^ cells were starved for 24 h in the absence or presence of 20 nM rapamycin or for 24 h with rapamycin with addition of 10 μg/ml actinomycin D for the last 10 h. Quantitative PCR was performed using the JOE-labeled mouse β-actin LUX™ Primer set (Invitrogen) and an IRS-1--specific primer pair with a 6-FAM--labeled probe synthesized by QIAGEN. Reactions were performed using the PCR Master Mix for probe assays (Eurogentech) with β-actin LUX™ primers at a final concentration of 200 nM, the IRS-1 primers at a final concentration of 300 nM, and the probe at 100 nM. Reactions were performed in triplicate using a sequence detector (ABI Prism™ 7700; Applied Biosystems). Results were analyzed using Sequence Detector v1.7 software. Immunoprecipitations -------------------- Cells were lysed in buffer (50 mM Tris-HCl, pH 7.5, 120 mM NaCl, 1% NP-40, 1 mM EDTA, 50 mM NaF, 40 mM β-glycerolphosphate, 5 mM Na~3~VO~4~, 1 μg/ml leupeptin, 1 μg/ml aprotinin, and 1 mM benzamidine). 300 μg protein was added to 2 μg anti-IRS-1 antibody and immunoprecipitations were performed for 12 h at 4°C, followed by a further 2-h rotation after addition of 10 μl protein G--agarose and washing. For λ-phosphatase experiments, washed immunoprecipitates were washed with λ-phosphatase reaction buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 2 mM MnCl~2~, 0.1 mM EDTA, and 5 mM DTT) and resuspended in 15 μl of this buffer with or without 400 U purified λ-phosphatase, and reactions were incubated at 30°C for 1 h with regular agitation. Protein methods --------------- GST-IRS-1 (aa 21--400, 108--516, 516--895, and 895--1235) were eluted from glutathione-agarose beads in 50 mM Tris-HCl, pH 8.0, and 10 mM glutathione, dialyzed against 50 mM Tris-HCl, pH 8.5, 150 mM NaCl, 10% glycerol, 1 mM PMSF, 1 mM benzamidine, and 1 mM DTT, and were concentrated. Recombinant EE-S6K1 and EE-S6K2 were purified from insect cells infected with generated viruses using mouse EE mAb immobilized to protein A--Sepharose CL-4B (Amersham Biosciences). In vitro kinase assays were performed in kinase assay buffer (50 mM Tris-HCl, pH 7.5, 10 mM MgCl~2~, 50 μM cold ATP, 5 μCi γ\[^32^P\]-labeled ATP) using either 1 μg GST-IRS-1 fragments or 0.4 μl 40S ribosomal preparation as a substrate ([@bib11]). Reactions were at 30°C for 20 min. For the InR-binding assay, phosphorylation of GST-IRS-1 was performed for 30 min at 37°C in 15 μl kinase reaction buffer with 200 μM cold ATP and 0.6 μg S6K2. Proteins were bound to glutathione-agarose and washed twice with kinase buffer and once with lysis buffer A (50 mM Tris-Cl, pH 7.4, 150 mM NaCl, 50 mM NaF, 1 mM benzamidine, 1 mM EDTA, 1% NP-40, 40 mM β-glycerophosphate, 5 mM sodium orthovanadate, 2 mM PMSF, 1 μg/ml leupeptin, 1 μg/ml aprotinin, and 10% glycerol). CHO cells overexpressing IR were lysed in buffer A, and 0.5 mg protein was used for the binding assay performed at 4°C for 1 h, followed by three washes with A buffer, addition of SDS-PAGE sample buffer, and SDS-PAGE. Mutants of GST-IRS-1 (aa 108--516) were produced using the QuikChange^®^ Site-Directed Mutagenesis Kit (Stratagene). For the quantitation and statistical analysis of InR pull-down, autoradiographs were scanned and the pixel intensity of bands was determined using Adobe Photoshop^®^ and corrected for background pixel intensity. Insulin receptor associated with GST-IRS-1 wild-type and GST-IRS-1 S302A in each control experiment (i.e., without kinase) was assigned a value of 100%. Insulin receptor associated with GST-IRS-1 wild type and GST-IRS-1 S302A after phosphorylation by S6K was normalized relative to the control value of 100% in each experiment. Values from three independent experiments were analyzed, and the average value was plotted on the graph. Cell chemotaxis assay --------------------- MEFs were starved for 24 h in the presence or absence of 20 nM rapamycin and were labeled 1 h further with 2 μg/ml CellTracker™ Green (Molecular Probes, Inc.) before trypsinization. 20,000 cells were plated in duplicate on Fluoro-block Transwell filters (Becton Dickinson) in DME containing 0.5% FCS, and were placed in wells containing the same media or media containing 50 ng/ml recombinant IGF-1 or 20 ng/ml recombinant EGF (Sigma-Aldrich). Chemotaxis was for 6 h, after which the wells were fixed in PBS/4% PFA. Fluorescence was visualized in 10× fields using FITC excitation/emission on an upright microscope (DM-IRB; Leica) equipped with a digital camera (CoolSnap) and Darkroom image acquisition software (Improvision). For quantitation, three random fields were imaged from each duplicate assay and the number of spread fluorescent cells that had crossed the filter was counted manually. Cell numbers were expressed as a percentage of that of TSC2 ^+/+^ in the presence of IGF-1, and a histogram was generated in Microsoft Excel. Cell survival assay ------------------- 20,000 cells were seeded in duplicate onto coverslips in the absence or presence of 20 nM rapamycin. After 36 h, coverslips were washed twice in PBS and placed in wells containing serum-free DME in the presence or absence of 200 ng/ml IGF-1 for 8 h. Cells were fixed in 4% PFA, permeabilized, and subjected to FITC-TUNEL assay using a commercial kit (Apoptosis Detection System; Promega) with the addition of a 30-min labeling stage with 1 μg/ml Hoechst bisbenzamide to label cell nuclei. In each duplicate assay, two 10× fields containing 300--600 nuclei were imaged with DAPI and FITC excitation/emission on a microscope (Axioplan 2; Carl Zeiss MicroImaging, Inc.) with an Axioplan camera and software. In each field, the number of TUNEL-positive nuclei and nuclei for each condition was counted manually and expressed as a percentage and a histogram generated in Microsoft Excel. We wish to thank Alan Ashworth for help with microarray experiments, Tony Ford for advice on quantitative RT-PCR, and Paula Muir for data analysis and DNA sequencing. We are indebted to Stuart Frank for GST-IRS-1 constructs, Morris White for antibodies, Derek LeRoith for expression vectors, and to Chris Marshall for discussion, critical reading of the manuscript, and support. L.S. Harrington is supported by the Tuberous Sclerosis Association (UK), C.P. Downes by a program grant from the Medical Research Council (UK) and by the Division of Signal Transduction Therapy, and J. Barnett by the Biotechnology and Biological Sciences Research Council via a CASE studentship supported by GlaxoSmithKline. T. Tolkacheva, S. Wigfield, and R.F. Lamb are supported by grants from Cancer Research UK, and G.M. Findlay by a studentship from the Institute of Cancer Research. We gratefully acknowledge the help and support of the Tuberous Sclerosis Association (UK) and LAM Foundation (US). [^1]: Address correspondence to Richard F. Lamb, Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, England, UK. Tel.: (44) 207-970-6096. Fax: (44) 207-352-5630. email: <Richard.Lamb@icr.ac.uk>

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