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Summarize: VALLEY, Ala. – You’ve likely heard of students bringing canned food to school for food drives, but have you ever heard of bringing a canned food item to school for safety? A letter sent to parents of students at one school in Chambers County requested just that — students were asked to arm themselves with an eight ounce canned food item. Though it sounds odd, administrators believe the practice could catch potential intruders off guard, possibly even knocking him or her out until police arrive. In the letter to parents, W.F. Burns Middle School Principal Priscilla Holley said, “As a result of school shootings throughout the United States and discussing with law enforcement on the best procedure to follow to keep our students safe, we are enhancing our procedure for intruders.” The idea to arm students with something like a can or a book comes from ALICE training. The ALICE acronym stands for: Alert, Lockdown, Inform, Counter, Evacuate. “I can honestly say that the major point of the the training… is to be able to get kids evacuated and not be sitting ducks hiding under desks,” Superintendent of Chambers County Schools Dr. Kelli Hodge said. Hodge said school systems in 30 states teach the principles of ALICE to students. Auburn University also uses ALICE on its campus. The ALICE program falls in line with new guidelines for school safety issued by the Department of Education in 2013. “Understandably, this is a sensitive topic. There is no single answer for what to do, but a survival mindset can increase the odds of surviving,” the Department of Education said. “There are three basic options: run, hide, or fight. You can run away from the shooter, seek a secure place where you can hide and/or deny the shooter access, or incapacitate the shooter to survive and protect others from harm.” Feedback on the Chambers County Schools program has been somewhat mixed since the letter went home to parents. Hodge said the majority of negative responses have come via Facebook, and often times by people who don’t have children in Chambers County Schools. When WHNT News 19 contacted Hodge, she said her office had received two phone calls and one email about the ALICE program. In the letter, Principal Holley said students who are armed with a canned food item will have a sense of empowerment to protect themselves in the event an intruder enters their classroom. For more information about the ALICE program, click here. Read the letter sent home to W.F. Burns Middle School parents here: Story highlights Alabama students were asked to bring canned goods for school security Cans or other heavy items could be used to fight school shooters It's part of a larger school district plan to empower students (CNN) When is a can of beans more than just a can of beans? When it's a weapon of self-defense for students to throw at an armed intruder who has just entered their school. That's one scenario Valley, Alabama, officials are considering as part of their training to respond to school shootings. Though it may strike some as an insignificant and perhaps even silly response to a deadly problem, it's no joke at W.F. Burns Middle School. It's part of active shooter response training offered by the ALICE Training Institute, a company founded by a former police officer and former elementary school principal. Read More You pretty much can’t ignore a New York Times headline that says “Alabama: School May Arm Students With Canned Peas.” And it’s exactly what it sounds like: A middle school principal wants to stockpile cans of corn and peas in classrooms for students to hurl at possible intruders as a last defense. Thank Principal Priscella Holley of W. F. Burns Middle School in Chambers County, Alabama, for this brainstorm. She sent a letter home to parents asking them to have their kids bring eight-ounce canned items to school so they can fling ’em at the bad guys. How’s this for persuasive? The can “could stun the intruder or even knock him out until the police arrive,” Ms. Holley wrote. “The canned food item will give the students a sense of empowerment to protect themselves and will make them feel secure.” It’s not an entirely insane idea. Al Franken said that after 9/11, he always carried three baseballs in his carry-on because he’s got a deadly accurate fastball and wanted to have something to take down a terrorist. Then again, he was, at the time, a professional satirist; as a senator, he has not introduced any Hurl Things For School Safety legislation. It’s not clear where Holley came up with the idea to bean intruders with actual beans, but it’s no more insane than some other brilliant ideas for keeping kids safe while ensuring that Americans have access to high-powered weaponry everywhere. Within a week of the Sandy Hook massacre, libertarian wackaloon Megan McArdle said that, short of limiting firearms, the best solution would be to “encourage people to gang rush shooters” instead of hiding, and to teach school children the value of a suicidal banzai charge. And then there were the Oklahoma entrepreneurs who want to sell schools semi-bulletproof nap mats — only $1000 each — that will provide a genuine sense of false security while sheltering in place. And they could maybe protect kids from tornados, too! Also, too, there are the more long-term societal changes that could prevent school shootings, like not letting schools be such feminized places where there are no men to protect women and children. Also, teaching morals, like “No, you should not shoot up a school,” could help. A Tennessee preacher figured that school shootings happen because teaching evolution has caused people to act like animals (also, abortion). And a Tea Party activist explained that getting rid of teachers’ unions would probably stop school shootings, though not as much as giving up on schools altogether and just homeschooling your kids. In other words, chucking cans of creamed corn at an intruder is starting to sound pretty damned reasonable. [NYT] W-F Burns Middle School in Alabama Students told to throw cans at a shooter Posted: Tuesday, January 13, 2015 10:42 PM EST Updated: Tuesday, January 13, 2015 10:54 PM EST Posted:Updated: Columbia County parents say their kids have been hours late for school The "Alice" emergency plan is used by over 15-hundred school districts across the country, and is meant to be used in active shooter situations. Auburn University released this video showing the five aspects of the plan. Alice is an acronym for alert, lockdown, inform, counter and evacuate. In the video, the counter strategy involves throwing textbooks at the intruder to stop the attack. For W-F Burns Middle School, they've asked students to bring in canned goods for the same purpose. Dr. Kelli Moore Hodge, Chambers County Schools Superintendent, "their safety and security is the number one thing we are looking at here, and we're trying to give them options, rather than make them sitting ducks." The letter sent home to parents has been shared nationwide and has raised some concern about the school's plan for an emergency situation. Dr. Kelli Moore Hodge, Chambers County Schools Superintendent, "the negativity that we have seen has been put out there on facebook." Chambers County Superintendent Kelli Hodge says the part about canned goods is such a small part of the emergency plan, but she apologizes for sending the letter without educating parents beforehand. Dr. Kelli Moore Hodge, Chambers County Schools Superintendent, "this one very tiny piece got taken out of context of the whole picture." Hodge says the number one goal during an active shooter situation would be evacuation. Throwing cans or textbooks would be considered a last possible option. Dr. Moore Hodge, "what alice promotes is that you have objects around the classroom that are available to you that you can throw, and kids can run out of the room, you know, if that's... but that is the very, very last resort and the very, very smallest part of this entire training." | Summary: With school threats, shootings, and lockdowns in the news at a dizzying pace, educators are naturally looking at ways to keep kids safe. But while those measures typically include security guards or metal detectors, one Alabama middle school is raising more than a few eyebrows by asking parents to arm their children-with canned goods. As WHNT tells it, WF Burns Middle School Principal Priscella Holley recently sent home a letter that began, "We realize at first this may seem odd," and went on to contend that a well-chucked can "could stun the intruder or even knock him out until the police arrive. The canned food item will give the students a sense of empowerment to protect themselves and will make them feel secure." Parents are asked to give their child an 8-ounce can ( "corn, beans, peas, etc.") to bring to school. An administrator tells CNN that the canned-peas defense is part of ALICE (Alert, Lockdown, Inform, Counter, and Evacuate) training it implements "to get kids evacuated and not be sitting ducks hiding under desks." She tells WJBF that the school has seen some "negativity" in response "out there on Facebook," and that it's "the very, very last resort and the very, very smallest part of this entire training." Wonkette runs through a list of ideas it deems much worse, before concluding, "In other words, chucking cans of creamed corn at an intruder is starting to sound pretty damned reasonable." | 1,829 | 339 | multi_news | en |
Summarize: FIELD OF THE INVENTION [0001] The present invention relates to a method for stimulating walls of bodily hollow systems, and also for measuring sensational or physical reactions towards such stimulation by introducing from an exteriorly accessible opening of a bodily hollow system a catheter into the hollow system, said catheter being provided with an inflatable balloon situated between a proximal end and a distal end of the catheter, and inflating the balloon until the balloon abuts an inner wall of the hollow system in order for the balloon and the catheter to be fixed in relation to the hollow system. The method also relates to apparatuses for performing such stimulation and for performing such measurements. BACKGROUND OF THE INVENTION [0002] Visceral pain is among the most common form of pain experienced in medical practice. Despite its greater clinical importance, visceral pain is less well understood and treated than pain from the skin and other somatic tissues. This is mainly due to the difficulties of characterizing the pain, typically described in terms of unpleasant and diffuse sensations with autonomic reactions such as nausea and sweating. In the clinic fear, anxiety and cognitive reactions may also blur the observation of pain as part of an illness. Finally, visceral pain is often part of a multi-organ syndrome with systemic reactions such as fever and malaise. [0003] To overrcome such problems, experimental pain assessment models have been developed to explore pain mechanisms. Most experimental studies in the gut have been performed in anesthetized animals, with the nociceptive response based on neurophysiological or behavioral reactions. As human pain is a multi-modal experience composed of sensory, psychological and physiological aspects, results from animal experiments can, however, only partly be extrapolated to man. Hence, several human models have been developed to stimulate somatic structures. In such models the investigator can control the stimulus with respect to localization, intensity and duration. The response can be asse ssed quantitatively and qualitatively. However, only few models for visceral experimental pain stimuli exist, mainly due to the difficulties for complicated testing equipment to come into contact with the internal organs. The major limitation of the existing human models is that they may not mimic clinical pain, as they are based on single, short-lasting stimuli only partly involving the many mechanisms typically activated during diseases. Thus, the needs for experimental visceral models mimicking more closely the clinical situation are needed. Such a model should be based on multi-modal testing regimes where different receptors and central nervous system mechanisms are activated. [0004] U.S. Pat. No. 4,809,710 describes a catheter for making pressure measurements in a sphincter canal. The catheter is provided with an inflation tube and water-perfusion tubes. A balloon or bag is inflatable through the inflation tube. The water-perfusion tubes have side openings communicating with the sphincter canal. The catheter is capable of providing a three-dimensional pressure profile in a sphincter canal by sensing and measuring canal pressures simultaneously at a plurality of sensing points located in one or more straight lines parallel to an axis and at predetermined levels. The apparatus is only capable of sensing and measuring pressures, and is neither not capable of providing any kind of stimulation to the sphincter canal. The advantage of the catheter described in this piece of prior art is that it provides the possibility of measuring pressures simultaneously at different levels, however, the pressure being provided by the sphincter muscles. Thus, the catheter is only sensing the pressure along an extension of catheter above the balloon, and the balloon is only intended for fixing the catheter in relation to the sphincter canal. [0005] U.S. Pat. No. 5,513,639 describes another type of catheter, also comprising an inflatable balloon member attached to and free of a tubular support member. An array of elongated piezo-electric elements is arranged inside the balloon member. Space is provided between the elements and the balloon for ensuring a space in which the array of piezo-electric elements can rotate irrespective of the shape of the balloon member. The balloon member can be inflated by introducing a liquid therein. The balloon member is inflated subsequent to the introduction of the catheter into the esophagus. The array of piezo-electric elements are used for ultrasonic scanning of in body cavities and is capable of scanning the pain inflicted on the patient during insertion of the probe into a body cavity. Thus, it is the introduction of the probe, which is measured, and not a certain stimulation being subjected subsequent to the insertion of the probe. Once the probe is inserted into the body cavity and while the diagnosis is carried out, the patient does not feel pain, thus no stimulation is taking place after the insertion of the probe. Furthermore, only ultrasonic scanning is capable of being performed by the catheter. Also, the balloon is only intended for fixing the catheter in relation to the esophagus. SUMMARY OF THE INVENTION [0006] The object of the present invention, according to a first aspect, is to provide a method and an apparatus capable of applying chosen stimuli to the bodily hollow system. A further object of the invention, according to second aspect, is to provide a method and an apparatus for subsequently to the method of stimulation, or in stead of the method of stimulating, for measuring any reaction from a patient after of during any stimulation. [0007] The object according to the first aspect of the invention is obtained by a method comprising the steps of: introducing from an exteriorly accessible opening of a bodily hollow system a catheter into the hollow system, said catheter being provided with an inflatable balloon situated between a proximal end and a distal end of the catheter, inflating the balloon until the balloon abuts an inner wall of the hollow system in order for the balloon and the catheter to be fixed in relation to the hollow system, introducing a number of the following stimuli into the hollow system: mechanical stimulus, thermal stimulus, chemical stimulus and electric stimulus, and said number of stimuli being introduced between the exteriorly accessible opening of the hollow system and the distal end of the catheter through canals inside the catheter. [0012] It is important to notice that by the denomination “balloon” is meant only a bag capable of being inflated. The inflation need not result in a dilation of the material of the balloon. Thus, perhaps the balloon is made of a material, which subsequent to inflation is not subjected to any dilation, but merely has an increased volume due to the inflation. Accordingly, in the remainder of application, apart from in the test results in the last part of the specification, the denomination “balloon” will be used, because this is the commonly used denomination, although the balloon may be as a bag, i.e. no dilation of the bag. [0013] An apparatus for performing the method according to the first aspect comprises a catheter being provided with an inflatable balloon situated between a proximal end and a distal end of the catheter, and the apparatus comprising means for passing an inflating fluid, preferably a liquid, from the proximal end to the balloon, and furthermore comprises means for introducing a number of the following stimuli into the hollow system: mechanical stimulus, thermal stimulus, chemical stimulus and electric stimulus, and said means for introducing said number of stimuli being positioned between the proximal end and the distal end of the catheter. [0014] The object according to the second aspect of the invention is obtained by a method comprising the steps of: introducing from an exteriorly accessible opening of a bodily hollow system a catheter into the hollow system, said catheter being provided with an inflatable balloon situated between a proximal end and a distal end of the catheter, inflating the balloon until the balloon abuts the inner wall of the hollow system in order for the balloon and the catheter to be fixed longitudinally in relation to the hollow system, attaching to the surface of the balloon a number of the following measuring means: strain gauges, pressure gauges, temperature gauges, piezo-electrical gauges, electrodes, pH-recording means, and electromyographic (EMG) recording means, and measuring a number of artificially applied stimuli, said stimuli being any of the stimuli: mechanical stimulus, thermal stimulus, chemical stimulus and electric stimulus, when a bodily hollow system of the person or the animal is being subjected to a number of artificially applied stimuli of the above-mentioned kind. [0019] An apparatus for performing the method according to the second aspect a catheter being provided with an inflatable balloon situated between a proximal end and a distal end of the catheter, and the apparatus comprising means for passing an inflating fluid, preferably a liquid, from the proximal end to the balloon, and where the apparatus is provided with means for measuring at least one of the following physical properties of the balloon: the volume of the balloon, the cross-sectional area of the balloon seen in a direction parallel to the a longitudinal extension of the bodily hollow system, when the apparatus is introduced into the body, the diameter of the balloon in a plane perpendicular to a longitudinal extension of the bodily hollow system, when the apparatus is introduced into the body, the tension of the balloon, the strain of the balloon, the pressure of a fluid inside the balloon, and the temperature of a fluid inside the balloon, the apparatus intended for measuring a physical reaction of a person or an animal, when a bodily hollow system of the person or the animal is being subjected to a number of artificially applied stimuli. [0020] A specific method according to the first aspect of the invention comprises the steps of: introducing from an exteriorly accessible opening of a bodily hollow system a catheter into the hollow system, said catheter being provided with an inflatable balloon situated between a proximal end and a distal end of the catheter, inflating the balloon by a fluid, preferably a liquid, until the balloon abuts the an inner wall of the hollow system in order for the balloon and the catheter to be fixed longitudinally in relation to the hollow system, introducing a thermal stimulus to the hollow system, between the exteriorly accessible opening of the hollow system and the distal end of the catheter, by means of the fluid being passed through canals inside the catheter, and maintaining a range of temperatures of the fluid in the balloon by adjusting the temperature of the fluid and passing the fluid to the balloon through one canal inside the catheter and passing the fluid from the balloon through another canal inside the catheter, and by continuously passing the fluid to and from the balloon through the canals. [0025] A specific embodiment of an apparatus according to the second aspect of the invention comprises a catheter being provided with an inflatable balloon situated between a proximal end and a distal end of the catheter, and the apparatus comprising means for passing an inflating fluid, preferably a liquid, from the proximal end to the balloon, and where the apparatus is provided with means for measuring, said apparatus having a number of strain gauges attached to the part of the catheter not being provided with the balloon, said strain gauges intended for measuring a longitudinal extension of the hollow system, and said strain gauges being applied to the catheter at a position between the proximal end and the balloon, and said apparatus intended for measuring a physical reaction of a person or an animal, when a bodily hollow system of the person or the animal is being subjected to a number of artificially applied stimuli, said apparatus. [0026] The invention further relates to the use of an apparatus for performing the method according to the first aspect for stimulating a part of the digestive system including the stomach, or for stimulating a part of the urogenital system including the urinary bladder, or for stimulating part of the cardiovascular system including the heart by any of the following stimuli: mechanical stimulus, thermal stimulus, chemical stimulus and electric stimulus. [0027] In use, the apparatus for performing the method according to the first aspect may, inside the balloon, be provided with a number of the following measuring means: pressure gauges, temperature gauges, visualizational recording means, means for recording flow of fluid. [0028] In use, the apparatus for performing the method according to the first aspect may be intended for being applied with means for establishing a flow of fluid, and said apparatus being capable of passing the flowing fluid from an inlet at a proximal end of the apparatus, being exteriorly accessible when the apparatus is introduced into the body, through a number of canals in the apparatus to the balloon, and said apparatus also being capable of passing the pressurised fluid from the balloon back to an outlet at the proximal end through a number of other canals. The apparatus may be intended for being applied with means for introducing a chemical substance into the apparatus, and said apparatus having a number of canals for passing the chemical substance from the proximal end to a number of outlets, and the outlets intended for passing the chemical substance into the bodily hollow system, said outlets being provided in the vicinity of the balloon. The apparatus may even further be intended for being applied with means for passing an electrical current through the apparatus, and said apparatus having a number canals inside the catheter for passing electrical wires from the proximal end to positions on an outer surface of the balloon, and the positions on the surface of the balloon intended for abutting en inner wall of the hollow system, when the balloon is inflated. The wires may be passed from the proximal end to a position of the catheter between the proximal end and the balloon, where the wires at said position are passed from the canals inside the catheter though wire outlets to the exterior of the catheter, and where the wires are passed from the outlets to an outer surface of the balloon. [0029] The invention even further relates to the use of an apparatus for performing the method according to the second aspect for performing measurements in part of the digestive system including the stomach, or for performing measurements in a part of the urogenital system including the urinary bladder, or for performing measurements in a part of the cardiovascular system including the heart based on a prior stimulation of any of the following kinds: mechanical stimulus, thermal stimulus, chemical stimulus and electric stimulus. [0030] In use, the apparatus for performing the method according to the second aspect may have a number of measuring means attached to the balloon, said measuring means preferably being chosen among means such as strain gauges, pressure gauges, temperature gauges, plezo-electrical gauges, electrodes, pH-recording means, and electromyographic (EMG) recording means. The apparatus may further have a number of measuring means inserted into the balloon, said measuring means preferably being chosen among means such as pressure gauges, temperature gauges, ultrasonic measuring means, visualizatlonal recording means, means for recording flow of fluid. The apparatus may also have a number of measuring means assigned to the catheter outside the balloon, said measuring means preferably being chosen among means such as ultrasonic measuring means, visualizational recording means, scanning means, means for recording a flow of fluid. [0031] The invention further relates to the use of an apparatus for measuring a physical reaction of a person or an animal, when a bodily hollow system of the person or the animal is being subjected to a number of artificially applied stimuli, said apparatus comprising a catheter being provided with an inflatable balloon situated between a proximal end and a distal end of the catheter, and the apparatus comprising means for passing an inflating fluid, preferably a liquid, from the proximal end to the balloon, and where the apparatus is provided with means for measuring, said apparatus having a number of strain gauges attached to the part of the catheter not being provided with the balloon, said strain gauges intended for measuring a longitudinal extension of the hollow system, and said strain gauges being applied to the catheter at a position between the proximal end and the balloon. BRIEF DESCRIPTION OF THE DRAWINGS [0032] The invention will now be described in detail with reference to the drawing, where [0033] FIG. 1 is a sketch showing an apparatus according to the invention being introduced into the esophagus of a patient for physical stimulation and/or measuring properties, [0034] FIG. 2 is a sketch of the apparatus itself being provided with a number of means for stimulating and a number of means for measuring in a bodily hollow system. DETAILED DESCRIPTION OF THE INVENTION [0035] FIG. 1. shows how an apparatus for providing stimuli and/or for measuring certain properties in a bodily hollow system may be utilised in the esophagus of a patient. The apparatus consists of a catheter, alternatively denoted a probe, having a proximal end 2 and a distal end 3. The distal end 3 is introduced into a readily accessible opening from the outside of the esophagus, i.e. the mouth or, as shown, the nose and further down into the esophagus towards the stomach. Nearby the distal end 3, the catheter is provided with a balloon 4, also called a bag, which is inflated so that an outer surface of the balloon is abutting the inner surface of the wall of the hollow system, i.e. of the esophagus. The inflation takes place only after the catheter has been introduced into the esophagus. By inflating the balloon, the balloon and thus the catheter is fixed in relation to the esophagus so that the catheter, in the situation shown, cannot be displaced longitudinally along the length of the esophagus. [0036] Preferably, but not necessarily, the catheter is fixed at the proximal end as well, i.e. is fixed to the nose or any other outer surface or organ. In the situation shown, where the catheter is introduced through the nose, fixation of the proximal end may take place in any suitable manner, perhaps by a clamp being clamped to the wing of the nose, to the nasal bone or to the bridge of the nose. Once introduced into the bodily hollow system, the apparatus may be used for stimulation the hollow system of a person or an animal by one or more of the stimuli: mechanical stimulus, thermal stimulus, chemical stimulus and electric stimulus. Alternatively, or in addition, the apparatus may be used for measuring a physical reaction of a person or an animal, when the bodily hollow system of the person or the animal is being subjected to a number of artificially applied stimuli of the above-mentioned type. [0037] The balloon of the catheter is preferably made from polyestherurethane being a material readily extendable, being non-harmful to the human or animal body and having distinct physical properties such as elasticity, modus of strain etc. The thickness of the material, which the balloon is made of, is perhaps between 30 μm and 50 μm. However, any other well-suited material may be used as long as it fulfils the need for expandability, non-permeability of the fluid inflating of the balloon, and security towards not being harmful to the body. Thus, polypropylene (PP) or polyethylene (PE) may alternatively be used. Even other materials may be used referring to the fact that the denomination “balloon” need not imply that the material, which the balloon is made of, is dilated, when the balloon, or the bag which it may also be called, is inflated. Thus, materials having much less elasticity than the above-mentioned materials may be used, perhaps materials which, when inflated, does not show any noticeably elastic deformation. Also the thickness of the material, which the balloon is made of, may be thicker than the dimensions mentioned above, thus perhaps also resulting in that the material, when inflated, does not show any noticeably elastic deformation. [0038] The size of the balloon, when inflated, differs depending on which bodily hollow system the apparatus is used in and depending on which part of the system in question, that the apparatus is used in. As example, for use in the esophagus, the balloon normally has a size when being inflated of up to 40 mm in diameter seen in a plane perpendicular to the longitudinal direction of the esophagus. However, abnormalities of the esophagus such as outpouchings may necessitate a balloon having an increased diameter when inflated. Also, other hollow systems have either smaller or larger cross-sectional areas than the esophagus. Thus, the cardiovascular system have much smaller cross-sectional areas, whereas the small intestine and even the large intestine and the rectum normally have larger diameters than the esophagus, perhaps necessitating a balloon having up to 80 mm in diameter when inflated. [0039] In the situation shown, the apparatus shown is a longitudinal catheter being introduced into the esophagus of a human being. However, the apparatus may be used on animals as well. Furthermore, the apparatus may be used in any hollow system of the body of the person or the animal, non-limiting examples of such being: the digestive system including the stomach, preferably the gastrointestinal tract, a part of the urogenital system including the urinary bladder, or part of the cardiovascular system including the heart. [0040] FIG. 2 shows part of the apparatus as the one shown in FIG. 1. The part shown is the balloon 4 and the part of the catheter 1 nearby the balloon. Different means for stimulating and for measuring are shown. Firstly, as shown with arrows, the balloon is inflated by means of a fluid, preferably a liquid, and more preferred salt water introduced to the balloon through a canal (see FIG. 3 ) provided in the catheter. The fluid is pumped to the balloon from an exterior reservoir (not shown) such a sterile bag containing the fluid, the pumping being provided by, as example, a pump with rollers exerting a pumping action on a hose, and the fluid is pumped from the reservoir to the proximal end 3 of the catheter. The pressure of the fluid is monitored, possibly by a pressure gauge inside the balloon. Alternatively to measuring the pressure, the volume of the fluid being pumped to the volume may be monitored, either when being pumped to the balloon or after having been pumped to the balloon. The inflation of the balloon constitutes a mechanical stimulus of the hollow system. [0041] For stimulating the hollow system thermally, the fluid may be heated or cooled to a chosen temperature before being pumped to the balloon. By monitoring the temperature of the fluid being pumped to the balloon, either before entering the balloon, or preferably after having entered the balloon, the thermal stimulus to the wall of the hollow system is known. For obtaining an even more precise measurement of the temperature, which the wall of the hollow system is subjected to, it will also be possible in stead or additionally, to monitor the temperature of the outer surface of the balloon, said outer surface being the part of the catheter being in physical contact with the inner side of the wall of the hollow system. [0042] In a preferred embodiment of the apparatus, the catheter is provided with at least two canals (see FIG. 3 ) for establishing a flow of fluid to and a corresponding flow of fluid from the balloon, By continuously flowing the fluid to and from the balloon, and by constantly monitoring the temperature of the fluid, it is assured that the temperature of the fluid in the balloon is constant and do not change, even under influence of any heating or cooling effected by the hollow system, the wall of which the balloon is abutting. [0043] For stimulating the hollow system electrically, different kinds of electrical stimulation may take place such as electrodes 5 being attached to the outer surface of the balloon. In the situation shown in FIG. 1, the electrical stimulus may have an amperage of up to 80 mA and a voltage of between 50 V and 100 V. In the situation shown, the apparatus is inserted in a hollow system being near the heart of the patient. Therefore, care must be taken when applying the electrical current. The electrical current is passed from an external source (not shown) for generating the current, through wires inside canals (sse FIG. 3 ) in the catheter and to one or more small holes 6 provided just above the balloon 4. From there, the wires 7 are passed externally to the outside surface of the balloon, the surface abutting the wall of the hollow system. In the embodiment shown, a couple of electrodes 5 are attached to the outer surface of the balloon in order to pass the electrical current from the balloon to the wall of the hollow system. [0044] For stimulating the hollow system chemically, a number of holes 8 may be provided in the catheter 1. In the embodiment shown, only one hole 8 is provided. The hole is provided between the proximal end 2 (see FIG. 1 ) of the catheter 1 and the balloon 4. Alternatively, or additionally, one or more holes may be provided between the balloon 4 and the distal end 3 of the catheter 1. Any kind of chemical substance, either a chemical substance being foreign to the hollow system or a chemical substance being familiar to the hollow system, may be passed trough canals in the catheter and into the hollow system through the hole leading from the canal to the hollows system. A familiar chemical substance may be a substance commonly present in the bodily hollow system being stimulated, such as an acid like HCl in the esophagus, or such as bile salts in the small intestine. A foreign chemical substance may be a pharmaceutical intended for diagnostics or treatment of diseases in the bodily system being measured, such as smooth muscles relaxants. [0045] For performing measurements of a force applied by the wall of the bodily hollow system strain gauges 9 are attached to the catheter 1 at a position between the proximal end 2 (see FIG. 1 ) and the balloon 4. After the catheter is inserted into the hollow system, and subsequent to the inflation of the balloon, the catheter and the balloon is fixed longitudinally in relation to the hollow system. At the proximal end of the catheter, as mentioned with reference to FIG. 1, the catheter is fixed to the nose, to the cheek or to any other suitable location at the proximal end of the catheter. During stimulation, the hollow system such as esophagus may perform longitudinal movements as a result of the stimulation subjected to the patient. These longitudinal movements are indicative of the motor function of the hollow system and result in a corresponding longitudinal extension or relaxation of the balloon and of the catheter. The longitudinal extension or relaxation of the catheter may thus be measured by the strain gauges. [0046] Inside the balloon, holes 10 are provided for passing fluid to an from the balloon. The holes 10 may also be used for passing measuring means such as temperature gauges and/or pressure gauges to the inside of the balloon for measuring the temperature and the pressure of the fluid inside the balloon. Also other measuring means such as piezo-electrical elements and the such to be used in connection with equipment of the apparatus only being assigned to, but not being attached to the catheter. [0047] The catheter is provided with a number of canals running inside the catheter. Some of the canals are intended for passing stimulating means or measuring means from the proximal end of the catheter to a more distant end of the catheter, either at a position before the balloon, or at a position inside the balloon or a position after the balloon toward the distal end of the catheter. [0048] Thus, canals may be provided for passing electrical wires for performing electrical stimuli, canals may be provided for passing a chemical substance for performing chemical stimuli, and canals may be provided for passing electrical wires for gauges and other recording means attached to the balloon, provided inside the balloon, or attached or provided elsewhere along the extension of the catheter. It will be possible to use one canal for several purposes, thus perhaps one canal for passing more or all of the electrical wires provided in connection with means for electrical stimuli and means for recording temperature, pressure or any other physical property in relation to using the apparatus for measuring. [0049] In the embodiment shown, preferably especially two canals are provided, one canal for passing a fluid from the proximal end of the catheter to the balloon and another canal for passing the fluid from the balloon to the proximal end. The one canal lead to one of the holes 10 inside the balloon, and the other canal lead form the other holes 10 inside the balloon. By providing those two canals it is possible to continuously pass a fluid to and from the balloon. Thereby, it is possible to maintain a chosen temperature of the fluid, substantially independent of any heating or cooling of the fluid in the balloon from the wall of the hollow system, which the balloon is abutting. As mentioned, these two holes 10 may also be used to pass wires for any measuring measn situated inside the balloon [0050] With reference to the figures, it is important to notice that the catheter and the balloon only form part of the apparatus according to the invention, i.e. the apparatus does not consist of the catheter and the balloon, but the apparatus comprises the catheter and the balloon. Other parts of the apparatus may comprise any exterior equipment for generating any of the stimuli and any additional equipment for recording data, possibly provided by the gauges or other recording means attached to, connected to or in any other way assigned to the catheter and the balloon. EXAMPLE OF AN APPARATUS [heading-0051] Subjects [0052] Eleven healthy subjects, 7 males and 4 females, mean age 40±10.4 years were included. None had any previous or current visceral diseases. Specifically they denied any chest pain, heartburn, dyspepsia or irritable bowel syndrome-like symptoms. They received no medication and had no somatic pain complains. The local Ethics Committee approved the protocol. The experiment was carried out at the Gastrointestinal Research Laboratory at Aalborg Hospital a short distance from the Intensive Care Unit, where personnel and equipment for rescue operations were available. [heading-0053] Intubation of Stimulation Device [0054] A probe designed for multimodal stimulation (TensioMed, Hornslet, Denmark) with modifications performed at the Technical Department at Aalborg University included a bag for impedance planimetry (IP), temperature stimuli and electrodes for electrical stimuli. The subjects fasted for at least four hours before the experiment. After applying a small amount of local anaesthetic spray (Xylocaine, AstraZenica, Sweden) in the nose, the participants were intubated. The bag was carefully folded, lubricated and the probe was inserted through the nostrils. The bag was first inserted into the stomach and then retracted to identify the location of the lower esophageal sphincter as a zone of high resting pressure that decreased with swallowing. Then the bag was placed 8 cm proximal to the sphincter and the probe was taped to the nose. After intubation the subjects were asked to lie down with the head tilted by 30 degrees. After 30 min of rest, the experiment was performed in that position. [heading-0055] Sensory Assessment [0056] The assessment parameters were 1) quantitative sensation intensity, 2) qualitative sensation and 3) referred pain size. [0057] The sensory intensity was assessed cont inuously using an electronic visual analogue scale (VAS) (Gatehouse A/S, Aalborg, Denmark). Sensory assessment on a VAS can be complex, as visceral pain is diffuse and difficult to characterize. Therefore, the patients were trained in assessment of sensation to deep pressure at the muscles on the right forearm several times before the visceral stimuli were given. Although still debated, most sensory afferents in the gut are probably polymodal and encode both non-painful and painful sensations. We therefore decided to use the scale for both non-painful and painful sensations. The intensities of the non-painful sensations were scored on the VAS up to 5, where the following descriptors were used to characterize the sensations: 1=vague perception of mild sensation; 2=definite perception of mild sensation; 3=vague perception of moderate sensation and 4=definite perception of moderate perception. Five was the discomfort/pain threshold. A qualitative scale was added to the non-painful intensity scores, as the subjects were asked to assign the feeling to one of the following seven sensations: pressure, burning/warm, stinging, colicky/cramping, fullness/nausea, cold, and others. The method and descriptors were chosen according to earlier studies using bag distension in the gut. For the painful sensations the patients used the scale from 5-10 anchored at 5=discomfort/slight pain to 10=unbearable pain, with anchor words selected from the intensity scale in the Danish version of the McGill Pain Questionnaire (MPQ) 7. Accordingly, when the subject reported that the stimuli resulted in pain and/or severe discomfort (above 5 on the non-painful scale) they were asked to score the intensity from 5-10 on the VAS. The VAS has previously been demonstrated to be useful to assess painful stimuli to electrical current and distension in the stomach, small and large intestine. After the experiment the McGill Pain Questionnaire was used to assess the painful sensations qualitatively. [heading-0058] Referred Pain [0059] After the stimulation the patients were asked about referred pain and if present, the area was marked with a pen and transferred to a transparent paper. Later the area was digitized (ACECAD D900+Digitizer, Taiwan) and the size calculated (Sigma-Scan, Jandel Scientific, Canada). [heading-0060] Stimulation Device and Protocol [0061] The stimulation protocol was composed of electrical stimuli followed by mechanical, cold and warm stimuli. During all stimuli autonomic reactions were monitored and the result was displayed on-screen using a Biopac MP100 system (Biopac Systems inc., Santa Barbara, Calif.) including sensors and recording system. Electrocardiogram was recorded using a multi-lead electrocardiography (ECG) cable record with the following leads: I, II, III, aVR, aVL and AVF. A pulsoxymeter was connected to one finger of the right hand, allowing oxygen saturation monitoring along with changes in pulse rate. Respiration was monitored using a chest belt, adjusted for in- and expiration movements. 1. Electrical stimuli: Two flexible silver-chloride stimulation electrodes (2×4 mm) were glued to the bag ( FIG. 1 ). The electrodes were connected to a computer-controlled constant-current stimulator (NoxiTest A/S, Aalborg, Denmark). The maximum intensity of the current was limited to 80 mA. Previous systems were capable of inducing atrial capturing when parts of the esophagus near the heart were stimulated. Hence, to increase the distance between the electrodes and the heart, the electrodes were placed on the dorsal side of the bag, which was inflated with 10 ml of water corresponding to a diameter of 15 mm. This inflation was not felt by any of the subjects. The construction of the probe made twisting impossible and a mark on the catheter secured that the electrodes were placed at the dorsal site. Thus, the bipolar stimuli secured a maximal electrical field opposite to the heart with a distance of at least approximately 20 mm from the heart. Two other safety procedures were included in the protocol: 1) To give electrical stimuli a special computer should be activated first (and it was disconnected after the stimulation was completed) and 2) the wires connecting the patient to the electrical stimulator were removed after the electrical stimulation. Electrical stimuli were given as single or repeated bursts. “Single burst” stimuli were defined as five rectangular constant-current pulses with duration of 1 Ms at 200 Hz. “Repeated burst” stimuli were defined as five “single burst” stimuli delivered at 2 Hz. These stimulus sequences have previously been shown to be suitable for evoking pain in the esophagus stomach, duodenum and colon. The stimulus intensity was blinded for the subjects. The current intensity was gradually increased in steps of 0.5 mA with an interval of 15 s until the pain detection threshold was found We used a protocol with pseudo-random sequences including lower intensity stimuli interspersed with the ascending stimulus intensities. Such series have proven to be valuable in our previous studies using both electrical and mechanical stimuli. Thus, intermittent sham stimuli with either no current or the same current as in the previous step were given to secure that the subject did not automatically increase the sensory rating. The sensory and pain detection thresholds, corresponding to 1 and 5 on the VAS, were found for the single and repeated stimuli. The subject rated the most intense of the train of the five repeated stimuli. For the repealed stimuli a stimulus-response function was made at baseline, where the current intensities corresponding with 1,3,5,6 and 7 on the VAS scale were found. 2. Mechanical stimuli: The bag contained a four-electrode impedance planimetry system as described previously. The electrodes were located inside a cylindrical bag on a 70-cm long probe with a diameter of 4.5 mm ( FIG. 1 ). Two outer ring electrodes for excitation were placed on the probe with an inter-electrode distance of 38 mm. A constant alternating current of 100 μA at 5 kHz was delivered to the electrodes from a current generator (Gatehouse Medical A/S, Nørresundby, Denmark). Two ring electrodes for detection of potential differences were placed 2 mm apart and midway between the excitation electrodes. The detection electrodes were connected to an impedance-measuring system. The cylindrical bag was 40 mm in length and was made of 35 μm, non-conducting polyurethane. It completely enclosed the electrodes and a side-hole used for measurement of pressure within the bag. The bag could be inflated with electrically conducting fluid (0.09% saline) through a pair of infusion channels each with a diameter of 2 mm. It could be inflated to a cross-sectional area (CSA) of approximately 2000 mm 2 (diameter equal to 50 mm) without stretching the wall of the bag. The infusion channels were connected to an infusion pump (Type III, Ole Dich instrument Makers Aps, Hvidovre, Denmark), that was able to fill or empty the bag continuously at varying flow rates. A safety valve was connected with the pump allowing the subjects to stop the infusion at any time. The system was calibrated before the probe was inserted in the esophagus. The CSA of the bag was measured from the impedance of the fluid inside the bag. Hence, when a current is induced in a uniform cylinder by two excitation electrodes, the voltage difference between the detection electrodes is related to the impedance of the fluid and thus the CSA of the bag. Details of the calculations have been described previously. All data were digitized and stored electronically for later display and processing on the computer system (Gatehouse Medical A/S, Nørresundby, Denmark). A few test stimuli were done for preconditioning the tissue and to teach the subjects to score the sensation intensity. These were followed by three baseline distensions with a constant infusion rate of 25 ml/min until the subject reported pain (5 on the VAS). After these stimuli a stimulus-response function was made, where the volume, pressure and CSA was recorded at intensities corresponding with 1,3,5,6 and 7 on the VAS scale. 3. Temperature stimuli: Recirculating water was infused into the same bag as used for the mechanical stimuli ( FIG. 1 ). The infusion channels in the catheter were attached to a manual pump system where 50 ml of water was infused into one channel and simultaneously sucked out in the other channel with a speed of approximately 300 ml/min. A temperature probe (PR electronics, Roende, Denmark) monitored the water temperature inside the bag. The time elapsing from one temperature level to the next was 60 sec. First, the system was filled with 10 ml of water with the desired temperature. In the range of 25-40° C., this could not be felt by any of the subjects, excluding the possibility for the distension to contribute to the sensation. Immediately after filling of the bag, 50 ml of water with the desired temperature was re-circulated without changing the volume or pressure in the bag. In pilot experiments it was found that during perfusion of the esophagus, temperatures inside the bag of approximately 5, 10, 15, 20, 25, 30, 35, 40, 45 and 50° C. corresponded with water temperatures of 0, 5, 10, 16, 22, 30, 35, 44, 52 and 60° C. in the pump system. Similar to the electrical stimuli, we used a pseudo-random, blinded sequence with lower intensity stimuli interspersed with the ascending stimulus intensities. In each series the stimuli were given with expected intrabag temperatures of 10, 5, 15, 20, 30, 35, 40, 25 (sham) 45 and 50° C., with 2-3 additional sham stimuli having the same temperature as the previous stimulus interposed randomly. | Summary: The invention relates to a method and an apparatus for stimulating and/or measuring visceral pain in a bodily hollow system of a human being or an animal. The method and apparatus is especially well suited for multi-modal stimulation and measuring, where different stimulus modalities are integrated into one stimulus device. The stimuli may be any one or more of the stimuli: mechanical stimulus, thermal stimulus, chemical stimulus and electric stimulus. The stimuli may activate superficial and deeper layers of the hollow system. Distinct responses to the individual stimuli and robust stimulus-response relations are obtained and result in the possibility of comparative studies of different visceral sensations. | 9,501 | 142 | big_patent | en |
Write a title and summarize: Buruli ulcer (BU), one of 17 neglected tropical diseases, is a debilitating skin and soft tissue infection caused by Mycobacterium ulcerans. In tropical Africa, changes in land use and proximity to water have been associated with the disease. This study presents the first analysis of BU at the village level in southwestern Ghana, where prevalence rates are among the highest globally, and explores fine and medium-scale associations with land cover by comparing patterns both within BU clusters and surrounding landscapes. We obtained 339 hospital-confirmed BU cases in southwestern Ghana between 2007 and 2010. The clusters of BU were identified using spatial scan statistics and the percentages of six land cover classes were calculated based on Landsat and Rapid Eye imagery for each of 154 villages/towns. The association between BU prevalence and each land cover class was calculated using negative binomial regression models. We found that older people had a significantly higher risk for BU after considering population age structure. BU cases were positively associated with the higher percentage of water and grassland surrounding each village, but negatively associated with the percent of urban. The results also showed that BU was clustered in areas with high percentage of mining activity, suggesting that water and mining play an important and potentially interactive role in BU occurrence. Our study highlights the importance of multiple land use changes along the Offin River, particularly mining and agriculture, which might be associated with BU disease in southwestern Ghana. Our study is the first to use both medium- and high-resolution imagery to assess these changes. We also show that older populations (≥ 60 y) appear to be at higher risk of BU disease than children, once BU data were weighted by population age structures. Buruli ulcer (BU), a neglected emerging infectious disease, is a skin and soft tissue infection caused by Mycobacterium ulcerans (MU). The infection is characterized by painless nodules with necrotizing toxins that produce lesions in the skin, and which may lead to scarring, contractual deformities, amputations, and disabilities if untreated [1–3]. BU has been reported in over 30 countries in West Africa, Southeast Asia, Central and South America and the Western Pacific, as well as Australia [1,4, 5]. Though the exact transmission mode of BU disease is still unclear, evidence indicates that the outbreak of BU is associated with climate factors (rainfall and flooding), proximity to slow-flowing or stagnant water, and human-linked environmental disturbance, such as alluvial, pit and sand mining operations, deforestation, and agriculture [2,6–8]. Since different types of land cover classes have different influences on the distribution of human population, the habitat of vectors, and the presence of causative pathogens, examining the association between land cover and BU provides valuable information to prioritize and target specific areas for intervention and control of the disease [8]. The association between land cover and BU has been reported in some countries. In Benin, higher BU disease prevalence rates were found to be associated with rural villages surrounded by forest and at low elevation areas with variable wetness patterns [9]. Similarly, in Australia, the highest BU risk areas were also located at low elevation areas covered by forest [10]. In Côte d' Ivoire, high-risk zones for BU were located in irrigated rice fields, as well as in banana fields and areas in the vicinity of dams used for irrigation and aquaculture [11]. In Cameroon, the Nyong River and associated cultivated wetlands were identified as the major driver of BU incidence [12]. Ghana, located in West Africa, with a population of 24. 2 million and a total area of 238,535 km2, is one of the most endemic countries of BU disease, second only to Cote d’Ivoire [13]. The first possible BU case in Ghana was reported about 40 years ago [4]. Since then, more BU cases were reported in the country, especially in southern Ghana [14]. In 1993,1, 200 cases were recorded in four regions by a passive surveillance system. A comprehensive national case search in 1999 identified 5,619 BU patients. Based on this data, the national prevalence rate was estimated as 20. 7 per 100,000, but up to 150. 8 per 100,000 in Amansie West, the most disease-endemic district in Ghana [15]. Since 1999, new BU cases ranged from 326 to 1202 per year, though cases may have been underreported [16]. Based on satellite data, land cover in Ghana has changed dramatically in recent decades [17,18]. Yet, examination of the impacts of land cover and its effect on BU disease has mostly been attempted at district or regional scales [7,19,20], inevitably neglecting local variation in land cover. For example, by analyzing the relationship between land cover and BU disease at the district level using Landsat imagery, Ruckthongsook [20] found that closed-forest areas were positively correlated with BU incidence in southwestern Ghana. In another study, Duker et al. [7] showed that mean BU prevalence was higher in settlements along arsenic-enriched drainages and arsenic-enriched farmlands based on ASTER images. That study examined relationships between the prevalence of BU and several spatial environmental factors in a smaller scale (61 settlements in the Amansie West District), however, it did not examine the association between BU prevalence and land cover. To date, neither the characteristics of recent BU cases nor the association between BU prevalence and land cover at different scales is well understood in southwestern Ghana. In the present study, we aim to 1) characterize the age and sex patterns of recent BU cases (2007–2010) in southwestern Ghana, 2) illustrate spatial distribution and spatial clusters of BU disease surrounding individual villages, and 3) examine the association between BU prevalence and major types of land cover classes at different spatial extents. Approval for this study was obtained from the Institutional Review Board (IRB) at the Pennsylvania State University (PSU), which specified oral informed consent for participation for adults and heads/chiefs of communities as well as implied informed consent for parents on behalf of their children. Assent forms for children <18yrs was also approved by PSU’s IRB. No single individual declined the invitation to participate. In addition, the BU case data were analyzed anonymously and no private information was disclosed in this study. Our study area is in southwestern Ghana, including a large part of Central Region and Western Region, and a small part of Ashanti Region and Eastern Region. For land cover analysis, the whole study area is covered by two Landsat-7 scenes, ranging from 1. 00° W to 2. 875° W, 5. 141° N to 6. 515° N (Fig 1). The focus of the study was the Upper Denkyira District, Central Region, where the prevalence of BU is higher. According to the Ghana national census in 2010, the population in Western Region and Central Region is 2,376,021 and 2,201,863, respectively. The sex ratio of male to female is 50: 50 and 48: 52, respectively. BU case data were collected by district hospitals and clinics mainly located in the Upper Denkyira District, Central Region. This area accounts for the majority of BU cases (>85%) in Central Region and Western Region that was reported by the 2004–2009 Ghana national BU dataset. These hospitals and clinics have good facilities for BU diagnosis and treatment and accept patients mainly from Central Region and Western Region. When patients visit a clinic or hospital, they are diagnosed by experienced doctors to examine whether they have BU based on symptoms. Therefore, these cases were clinically confirmed, rather than laboratory-confirmed. If a case is determined, detailed information about the patients (e. g. age, gender, residence) was recorded. The location of lesions, including the upper limbs, the lower limbs, the head and neck, and other parts were also recorded. According to the date of BU diagnosis, the number of BU cases in each month in the study area was calculated, then its seasonal pattern and annual trend were explored with a seasonal-trend decomposition analysis using the STL function in R package, which decomposed the monthly BU case data into three components: trend, seasonal, and remainder [21]. Based on the residence of these patients, we calculated the number of BU cases in 91 villages [22]. The prevalence of BU disease in these villages was calculated using the observed total numbers of BU cases in a village during 2007–2010 divided by the population of that village. The prevalence of BU disease in the entire study area was calculated using the total number of observed BU cases divided by the total population in the study area (the total population in Central Region and Western Region was used as a proxy). The prevalence of BU in each age and sex group was calculated using the number of BU cases in that age and sex group divided by the total population in that group and expressed as cases per 100,000 people. Spatial Scan statistics [23] were used to determine whether there were spatial clusters of BU among the villages in the study area. For this analysis, 6 of the 91 villages with BU case information were excluded because they fell slightly outside the study area where land cover was analyzed. The scan statistics approach creates a window (a circle or an ellipse) of point data across space and time, then calculates the observed value and expected value in and outside of the window. The null hypothesis is that the observed value in the window should be equal to that outside of the window. A likelihood ratio test is used to examine whether the cluster is a real cluster or due to a chance [24,25]. The likelihood function is maximized across windows in different locations and sizes, and the window with the maximum likelihood is determined as the most likely cluster. The p value is obtained through a Monte Carlo simulation, which is the rank of the maximum likelihood of the observed value divided by the total number of the maximum likelihood values. For example, if the rank is 10, the simulation number is 999, and the total number of the maximum likelihood values is 1000, then p = 10/1000 = 0. 01. SaTScan v9. 1 package was used to detect spatial clusters of BU disease [24,25]. A spatial retrospective analysis with a Poisson probability model was implemented to scan areas with high rates of BU prevalence in 999 Monte Carlo simulations. The total number of BU cases during 2007–2010 in each of the 85 villages was used as the case file, the population in each village in 2010 was used as the population file, and the latitude and longitude of each village was used in the coordinates file. Landsat imagery was used to classify land cover in the study area at a medium spatial resolution (30 m). Two scenes (path 194 and 195, row 56) in 2008 without the coverage of cloud were acquired from the U. S. Geological Survey (USGS) (https: //glovis. usgs. gov). The Landsat scenes were radiometrically corrected by transforming digital number (DN) values to reflectance. Bands 1,2, 3,4, 5 and 7 of each image were selected and stacked into a new image. Then the images were transformed into brightness, greenness and wetness by the Tasseled cap method [26] and followed by land cover classification. To quantify land cover at a finer spatial scale, we used Rapid Eye imagery (BlackBridge Ltd., Germany) with a resolution of 5 m. Rapid Eye images acquired on January 8,2012 were first preprocessed by geometric and radiometric correction, then bands 1,2, 3 were selected for classification. We based our initial land cover classification scheme on the USGS classification system [27] for both Landsat and Rapid Eye images. This system classifies land use and land cover into nine level 1 classes that could be discerned at both scales. According to the land cover characteristics in southwestern Ghana, we are able to classify urban land, agriculture land, grassland, water and forest. Mining area is commonly classified as a level 2 class under urban land or barren land. Here, we classified mining area separately because it is prevalent and a typical type of land cover class in southwestern Ghana [28]. For example, in the Wassa West District, southwestern Ghana, surface mining expanded from 0. 2% of the mining concession areas in 1996 to 49. 6% of the concession area in 2002, leading to a substantial loss of forest (58%) and farmland (45%) within mining concessions [28]. In total, we generated six classes and provide detailed information about each class in Table 1. In the Landsat images, the regularly distributed black strips due to the shutdown of the scan-line corrector (SLC-off) were treated as a separate class, termed unclassified. We used supervised classification with the maximum likelihood algorithm to create classified maps. The training and testing sites in the classification approach were selected randomly in areas where the land covers were seen to be relatively homogeneous, which was determined using multiple sources of information including a ground truth survey in 2012 as well as Google Earth in 2010, community participatory maps in 2011 and 2012, and high resolution images (e. g. Quickbird images in 2010 with 0. 5 m resolution). Land cover classes were initially selected based on participatory mapping activities in each community. Through these mapping activities, community members illustrated their village terrain at the time, including land use and land cover types such as various crop fields, forests, mining areas, and stagnant and flowing water bodies as well as important community infrastructure (e. g. school, wells). During discussions while creating the map, community members also identified areas labeled as “BU risk areas”, indicating polluted or contaminated areas that they considered as possible reservoirs for the MU bacteria and BU transmission (e. g., refuse dumps, areas of stagnant and dirty water in between neighborhoods). In a subsequent mapping activity, community members were encouraged to illustrate changes in land use and land cover over three to four decades, indicating changes in crop lands, areas of deforestation, expanding mining activity, and shifts in areas exposed to flooding. In addition, a ground truth survey included preliminary identification of candidate land covers from an unsupervised classification and field verification of detailed land use/land covers and the associated geographic coordinates. After the supervised classification, isolated classified pixels were removed through the sieving procedure and similar adjacent classified pixels were clumped together through the clumping procedure to smooth these images. The overall accuracy and the Kappa coefficient were used as indices of the classification accuracy, which are derived from the error matrix, a cross-table of the mapped class versus expected class. The image processing was carried out with ENVI 4. 8 package (Exelis, Inc., VA, USA). After classification, we imported the classified images into ArcGIS 10. 1 (ESRI, Redlands, CA, USA) for further analysis. First, we converted raster layers into shapefiles. Where Rapid Eye and Landsat images overlapped, land cover classes from the Rapid Eye image were used; if Rapid Eye image was not present, land cover classes from the Landsat image were used. We created a buffer around each village with the radius as 1 km, 2. 5 km, 5 km, 10 km, 20 km and 30 km and 40 km, respectively. We calculated the area of each land cover class in each buffer by intersecting each buffer with the classified image [22]. The percentage of each land cover was calculated by dividing its area by the total area of the buffer (unclassified land cover areas were included in the total area). In the same way, the percentage of each land cover class for 154 villages/towns, including 85 villages where BU cases were reported and 69 villages randomly selected as the control, where BU cases were not reported. To examine the effect of unclassified areas on the quantification of the land cover classes, mainly caused by the scan line off (SLC-off) problem, we used a modified nearest neighbor approach [29]. Specifically, we replaced the value of unclassified pixels with the average value of the left neighbors and right neighbors, respectively, and then averaged the results to obtain a new land cover class, essentially filling the gaps caused by the SLC-off problem. To compare the number of BU cases by different gender and age groups, the Friedman test, a non-parametric equivalent of two-way ANOVA, was used considering the BU data could not be assumed to follow a normal distribution. In this analysis, the dependent variable was the BU cases, the two influential factors were gender and age group. Gender has two levels: male and female; and age group has three levels: 0–19 yrs, 20–59 yrs, and > 60 yrs. To examine the difference of the percentages of land cover types in the BU clustered area and the whole study area, Wilcoxon signed-rank test, a nonparametric equivalent of Paired t-test was used because the percentages of land cover types around villages were not assumed to follow a normal distribution. These tests were conducted with SAS 9. 3 (SAS Institute, Inc, Cary, NC, USA). To examine the association between BU prevalence and each land cover class, a set of regression models, including Poisson and negative binomial regression models, were developed [8]. In these models, we used the number of BU cases in each village as the dependent variable, the natural logarithm of the population of each village as the offset term, and the percentage of each land cover class as independent variables. Since we had six categories of land cover, we had six independent variables in the model. Initially, we assumed the count data (BU cases, expressed as Y) followed a Poisson distribution, of which the mean, E (Y), and the variance, Var (Y), are assumed equal (E (Y) = Var (Y) = μ). Goodness of fit test using the deviance showed that Poisson distribution was not a good fit (deviance/ degree of freedom >3. 00). Therefore, we selected a negative binomial distribution, which allows the variance is higher than the mean (E (Y) = μ, Var (Y) = μ +kμ2, k is an overdispersion coefficient). The general equation of the negative binomial regression model is written as below: log (μi) =log (Ni) +β0+β1x1i+β2x2i+…+βnxni (1) Where μ is the expected number of BU, i is the index of an individual village, N is the number of population of a village, x1, x2, … xn are the covariates of the model, denoting the percentages of land cover classes, respectively. The summary statistics of these covariates were listed in S1 Table. Considering the interactive effects between water and mining as well as water and agriculture, we put two interaction terms into the model, namely, the percentage of water area multiplied by the percentage of mining area, and the percentage of water area multiplied by the percentage of agriculture area. Before running the model, we examined multicollinearity with correlation matrix generated by Pearson correlation analysis and variance inflation factors (VIF) calculated by SAS reg procedure. If mulitcollinearity was found among covariates (e. g. r >0. 6 or VIF>5), only one of these highly correlated covariates was put into the model. Akaike’s Information (AIC) as the criterion was used to select the best fitted models. A smaller AIC value indicates a better fitted model. If the regression coefficient (β) for a land cover class was significantly larger than zero (β>0, p<0. 05), we assumed the prevalence of BU had a positive association with that land cover class. If β was significantly less than zero (β<0, p<0. 05), a negative association was assumed. To evaluate model performance, we ran residual diagnostics of the top-rank model. We calculated the predicted value, the raw residual, the deviance residual, the standardized Pearson residuals, standardized deviance residual and likelihood residual for each observation and mapped the standardized Pearson residuals and the standardized deviance residual to illustrate the model performance. The raw residual, deviance residual, the standardized Pearson residuals and the standardized deviance residual were also assessed for spatial dependence with global Morans’ I, an index of spatial autocorrelation. The model fitting and residual diagnostics were carried out using the SAS genmod procedure with SAS 9. 3 (SAS Institute, Inc., Cary, NC, USA) and spatial autocorrelation was measured with ArcGIS 10. 1 (ERSI, Redlands, CA, USA) To consider spatial dependence in residuals, a spatial lag model was developed to examine the association between BU cases and the percentages of land cover classes. For the spatial lag model, the dependent variable at village i is assumed to be affected by the neighbors of village i. A general equation for the spatial lag model was shown below [30]: log (yi) =ρW*log (yi) +β0+β1x1i+β2x2i+…+βnxni (2) Where, the dependent variable (log (yi) ) is the natural logarithm transformed BU prevalence in the unit of case per 100,000 people, i is the index of the villages, W is the spatial weight matrix, ρ is the spatial autoregressive coefficient, β1… βn are the regression coefficients of covariates, and x1…xn are the percentages of land cover classes. The covariates in the spatial lag model are same as that in the top-ranked negative binomial models. The spatial weight matrix W was created based on the Euclidean distance among villages. After fitting the model, the normality and spatial autocorrelation of model residuals were assessed using Jarque-Bera test and Morans’ I, respectively. The model fitting and residual diagnostics were carried out with GeoDa 1. 6. 6 package [31]. Of the 339 BU cases reported in the study area during 2007–2010,172 cases were male and 167 cases were female. BU cases were found in all age groups (Fig 2). The cases among children < 5 years account for 8. 6%, age 5–14 account for 19. 8%, age 15–34 account for 26. 3%, while BU cases among the older population (age ≥ 60 y) account for 22. 1%. The Friedman test on this raw data showed that the number of BU cases among older groups was significantly lower than that among the other groups under 60 (p < 0. 01) and there was no difference between the numbers of male cases and female cases (p > 0. 05). However, when the number of BU cases was adjusted by population age structure (the number of the observed BU cases in a specific age or gender group divided by the population in that group) (Fig 2), the prevalence of BU disease was significantly higher for the older population (age ≥ 60) when compared with population under 60 (p < 0. 01). BU cases were reported in each month, making it possible to detect temporal trends (Fig 3). The number of BU cases was slightly higher in July. It also varied across years and was nearly 3. 7 times higher in 2008 than that in 2009. The season-trend decomposition analysis also showed that the number of BU cases had a seasonal pattern, which was higher in summer season (June-August, peak at July), and lower in other seasons, and there was a decreasing trend by year (S1 Fig). In terms of the location of the disease on the human body, 74% of lesions were found in lower limbs and 21. 5% were found in upper limbs. Of the 85 villages in which BU cases were used for spatial analysis, most were located in Central Region and Western Region. The Upper Denkyira District in Central Region and Wasa Amenfi East District in the Western Region have the most BU cases, which accounted for 62. 2% and 15. 3% of the total cases, respectively. Some individual villages/towns such as Dunkwa, Dominase, Ayanfuri, Jameso Nikwanta, and Maudaso had a high number of BU cases (>10 cases). The spatial scan analysis identified two significant BU clusters (the number of BU cases > 10; p < 0. 01) in southwestern Ghana, one primary cluster and one secondary cluster. The primary cluster was located at 5. 930°N and 1. 861°W with a radius of 22. 94 km. It included 33 villages and 174 BU cases (Fig 4). The secondary cluster was located at 6. 135° N and 2. 118° W with a radius of 10. 75 km, which includes 9 villages and 45 BU cases (Fig 4). The overall accuracy of the land cover classification for the high resolution (Rapid Eye) and medium resolution (Landsat) was 93. 4% and 82. 2%, respectively. Based on the Rapid Eye image, the major type of land cover class is agriculture (70. 2%), followed by forest (12. 4%) and grassland (11. 7%). Water and mining areas are relatively small, only accounting for 1. 0–1. 5% (Figs 5 and 6). The classified Rapid Eye image showed that many small scale mining patches were distributed along the river edge or near adjacent water areas (Fig 5). The types of land cover classes in the entire study area covered by the Landsat images (as shown in Fig 1) are similar as those in the area covered by the Rapid Eye image in the BU clustered area. However, the percentages of water, mining and agriculture areas in the entire study area were smaller than these in the BU clustered area, especially for water and mining areas (Fig 6). Wilcoxon signed-rank test showed that land cover components were not significantly different between the two spatial extents (the entire study area vs. the BU clustered area, p>0. 05). In the entire study area, there is nearly 16% of land cover in the unclassified category, largely due to the dysfunction of the satellite detector. The results of the final negative binomial regression model based on AIC values are presented in Table 2, showing that associations between BU prevalence and the percentages of land cover classes at the village level varied as a function of buffer distances (around a village/town). Overall, the percentage of urban area had a significantly negative association (p<0. 01) with BU prevalence in all distances from 1 km to 40 km with the mean regression coefficient ranging from-2. 109 to -0. 035, indicating that more urbanized villages might have a low risk of BU prevalence. The percentage of water area had a positive association with BU prevalence in the distances from 1 km to 20 km and associations were significant except that at 1 km, of which p value was slightly above 0. 05. The mean regression coefficient for the water variable ranged from 0. 224 to 2. 950 and was larger than these of other covariates, which suggested that the increase in water area in a buffer in 2. 5–20 km might lead to a large increase in BU prevalence. However, when the distance was 30 km and 40 km, the positive association between water and BU was not held. Instead, the percentage of mining area showed a strong positive association with BU (p<0. 01, β = 3. 266–4. 195). The percentages of grassland and agriculture also had positive associations with BU prevalence. The association for grassland area was significant at all distances, and the association for agriculture was significant at 30 km to 40 km. The increases in grassland and agriculture areas might slightly increase BU prevalence in some spatial extents, as indicated by the regression coefficients of both covariates, which ranged from 0. 014 to 0. 136 and 0. 091 to 0. 111, respectively. The association between the percentage of forest and BU prevalence varied as the change of the buffer distances, which was positive at the distances of 1,2. 5 and 5km, and was negative at the distances of 20,30 and 40km, respectively. The association was significant only at 2. 5 km and 5 km. Two interaction terms, water with mining and water with agriculture, were not selected in the final model based on AIC, likely because the term was strongly correlated with individual land covers (S2 Table). The evaluation of model performance for the final model with the smallest AIC value (distance = 30 km) showed that the model fitted the data very well, indicated by very small standardized Pearson residuals and standardized deviance residuals (S2 Fig). The examination of Moran’s I showed that both standardized residuals had no significant spatial autocorrelation, while the raw residuals were spatially correlated. The dependent variable and covariates in two top-ranked negative binomial regression models based on the AIC values were re-examined by spatial lag models. In the 30 km buffer radius, the percentages of mining, grassland and agriculture areas had positive associations with BU prevalence, and urban and forest areas had a negative association. In the 40 km buffer radius, the percentages of mining, grassland and agriculture areas also had significantly positive associations with BU prevalence, and the percentage of urban area was negatively associated with BU prevalence, however, the association between forest and BU prevalence was not significant. (Table 3). In this study, we characterized recent cases of BU in southwestern Ghana, identified BU clusters, quantified land cover at two different spatial resolutions (Rapid Eye and Landsat), and evaluated the association between BU prevalence and six types of land cover classes at different spatial extents at the village level. We found that the older population (age ≥ 60) has a higher prevalence than other age groups, indicating higher vulnerability to BU disease. We illustrated that mining and water areas were prevalent in the BU clustered area with high resolution satellite imagery. Moreover, we revealed that urban, water, grassland and mining areas were strongly associated with BU prevalence in the area. While the importance of mining has been independently proposed as key factors, no previous study has quantified their effects at the village level. To our knowledge, these findings have not been reported in Ghana before and might provide new insight in BU disease intervention and control. It is known that BU disease affects people of all age groups. However, the age group most associated with BU is still debated. Several studies on BU in African countries showed that children less than 15 years of age had a higher risk for BU [6,32,33], while in southeastern Australia, people >60 years of age were associated with a higher rate of BU [34]. There are also some studies showing that both young children and old adults could have a higher risk for BU [35–37]. Our results showed that young children (< 20 y) had a higher number of BU cases in contrast to older people. However, after adjusting disease rates by population age structure, we revealed that older people (≥ 60 y) had a higher risk of contracting BU. Our results suggested that a higher number of BU among children in Africa reported in previous studies did not support that young children were a high-risk group for BU disease, because younger children account for a higher percentage of total population than other age groups while older people account for a lower percentage (Fig 2). Our results from Ghana thus indicate that older males had the highest risk for BU disease, which is consistent with the conclusion by Debackert et al. [36] after adjusting for age distribution. Using spatial scan statistics, we identified two BU disease clusters, one primary cluster with 174 BU cases and one secondary cluster with 45 cases. The prevalence rates in both clusters are greater than average prevalence rates. The primary cluster covered the main part of upper Denkyira East District, east part of Wasa Amenfi West District, and south part of Obuasi Municipal, Amansie Central and Amansie West District, where a higher prevalence of BU has been observed [15]. The identification of disease clusters helps us target the specific area with higher prevalence and form hypotheses on the relationships between land cover and BU disease. With the high resolution satellite images, many alluvial gold mining patches distributed along the Offin River were evident throughout the BU clustered area. After classifying satellite images, we also found that the percentages of water and mining areas in the BU clustered area were much higher than those in the whole study area. These particular characteristics of land cover in the BU clustered area gave a strong indication that water and mining areas are related to BU disease. Our results affirm the association between and human modification of aquatic ecosystems [1–3,12,38]. Specifically, the regression coefficients for water as a land cover type were statistically significant at the scales from 1 km to 20 km buffers, while at the 30 km and 40 km buffer scales, the association of BU with mining was significant. In addition, there was a strong correlation between the percentages of water and mining areas, and the interaction term of BU and mining was significant in several competitive models (S3 Table), though not in the final model. These results indicate that water and mining play an important and potentially interactive role in BU occurrence, a finding that should be explored further. Importantly, the high resolution satellite images show evidence of alluvial gold mining along the Offin River. Alluvial mining may promote the formation of stagnant waters that might provide favorable environments for the disease [39]. Other studies have provided evidence for strong associations of BU with main rivers systems and disturbed water bodies [1,2, 6,7, 12]. For example, Landier et al. [12] showed recently that the Nyong River was the major driver of BU incidence in Cameroon, which they attributed to wetland presence, cultivation, and forest clearing. In the case of our study, mining was the primary cause of human modification of the alluvial environment. Ours is the first study to explore the fine-scale relationship between alluvial mining and BU statistically and the results suggest that water and human activity may both contribute to increased BU disease risk. Agriculture and grassland were positively associated with BU prevalence, indicating that mining may not be the only factor contributing to the disease patterns. Marston et al. [25] showed that participating in farming activities near rivers was a risk factor for BU infection in the Daloa region of Côte d' Ivoire [40]. In Benin, farmers accounted for a larger percentage of case-patients compared to controls and female farmers were associated with increased risk for BU [37]. Generally, as with mining, agriculture might increase nutrient and lower dissolved oxygen in water, the environmental condition facilitating the growth of M. ulcerans [1]. The grassland land cover category likely includes mixed agricultural systems that could not be binned into agricultural or other land use classes. Our preliminary water quality tests in the study area [41] did not find significant correlations between BU and nutrient or oxygen conditions in water, but did show significant increase in the concentration of heavy metals in water bodies associated with mining activities. Further studies are needed to explore the specific environmental conditions associated with specific types of land use and land cover changes. Negative correlations between forest area and BU prevalence were expected because other studies have showed that deforestation was associated with BU [2,39]. In general, deforestation can reduce riparian cover and increase water temperature, thus facilitating pathogen growth [42]. It is also thought that through deforestation, M. ulcerans might be washed into the aquatic environment, which could facilitate its growth and proliferation [39]. However, it was also reported that forest might have a positive association with BU prevalence, e. g., the relationship between BU prevalence and forest in Benin [8]. In our study, the negative association between the percentage of forest area and BU prevalence was not significant and there were positive associations, suggesting the relationship between forest and BU might be complicated. Finally, urban land cover was negatively correlated with BU prevalence, which is consistent with some studies in Benin [8,9]. As explained in these studies, villages with a larger percent of urban land cover may have better resources to prevent BU disease and better employment opportunities outside of agriculture and/or mining to lower contact rates with high risk habitats [8,9]. Our study has a few limitations. First, similar to many other studies [2,6, 8,12,37,43,44], it is likely that the number of BU cases analyzed here is underestimated because if BU patients did not visit hospitals or clinics, we would not have those records. Second, due to the coarse resolution (30 m) of Landsat images, we used a conserved land use classification across both sets of imagery. We do not exclude the possibility that some subclasses of land cover, e. g. cocoa farms, rubber and palm plantations, which are common in the area, might have significant associations with BU prevalence. Similarly, we cannot capture small water patches with the Landsat images, which may underestimate the percentage of water area in the whole study area. For the Landsat image, nearly 16% of the land cover was not classified, mainly caused by the scan line issue. However, the results from the simple gap-filling method showed the land cover assignments before and after the assignment of unclassified area were very similar, suggesting a limited influence on final results (S3 Fig). However, another potential issue is that we used satellite imagery at two different spatial resolutions to quantify land cover surrounding villages. For a few villages, quantification of land cover classes in a buffer might contain satellite data from either the high resolution image or medium resolution image, or both. However, we expect this effect to be minor because the area of the land cover classified with Rapid Eye image only accounted for 1. 8% of the total study area. Therefore, in 98. 2% of the study area, we used Landsat. Use of high spatial resolution images across the whole study might be better to illustrate the relationship between BU disease and land cover but these images were not available for the entire study area. The significant association between BU prevalence and land cover does not suggest that land cover change and BU disease have a cause-effect relationship. The land cover change may pose an important but indirect role on BU disease through its impacts on human activities, vector habitat and pathogen distribution. Future studies should investigate how land cover change affects the occurrence of BU disease through landscape pattern analysis and participatory community-based surveys, and examine other risk factors in the area of inquiry, such as socioeconomic status, and environmental and climatic factors. Based on our results, we also suggest that the environmental characteristics of alternative land uses (e. g., mining, agriculture, and their interaction) on water quality in alluvial environments in BU endemic areas is important for understanding spatial patterns of the disease. | Title: Buruli Ulcer Disease and Its Association with Land Cover in Southwestern Ghana Summary: We studied the relationship between a neglected tropical disease, Buruli Ulcer (BU), and landscape disturbance. We hypothesized that the increased presence of BU was related to landscape disturbance, especially alluvial mining, in endemic areas of the disease. We characterized recent cases of BU in southwestern Ghana and characterized six types of land cover classes at different spatial extents at the village level. We illustrated that mining and water areas were prevalent in BU clustered areas and may potentially play an interactive role in BU occurrence, a finding that should be explored further. No previous study has quantified the relationship between mining and BU at the village level. In addition, we found that people ≥ 60 years old had a higher prevalence than other age groups, when data was weighted by the population age structure. To our knowledge, these findings have not been reported in Ghana before and might provide new insight in BU disease intervention and control. While it is unclear how people come in contact with the bacterial source, our study shows that the importance of where people live (specifically, what land activities are occurring in the area) seems to play a large role in determining disease risk. | 9,012 | 264 | lay_plos | en |
Summarize: Amanda Knox Talks for First Time about Agony of Jail, Joys of Freedom She's been free since 2011, but Amanda Knox – who spent four years in Italian prison for murder – still faces moments of crippling anxiety, she tells PEOPLE Magazine exclusively.During an emotional, candid and wide-ranging interview, which took place in her mother's Seattle home over several days, Knox, 25, details her odyssey from carefree American college student in Perugia, Italy, to convicted murderer confined to a cell for four years for allegedly killing her roommate, British student Meredith Kercher."When Meredith was murdered and I was arrested, it was so shocking. It was paralyzing. Everything toppled," says Knox, who also shares the overwhelming joy of being set free after an appeals court overturned the charges in 2011.Although these days she is back at college, dating her hometown boyfriend and relishing every minute she spends with her large and loving family, she is still haunted by the ordeal."Things creep up on me and all of a sudden I'm overwhelmed by the feeling of helplessness and that desperation and fear to even hope," she says. "Just that can make my heart race and makes me paralyzed until I can breathe it away."Knox, who could face a re-trial after an Italian supreme court recently ordered a review of the case, has a new memoir, Waiting to Be Heard, published by HarperCollins, that will be out April 30.For the exclusive interview and photos with Knox and her family, pick up the issue of PEOPLE Magazine on newsstands April 26. During her four years in an Italian prison, Amanda Knox had to fend off unwanted sexual advances three times -- twice from male prison employees and once by a female inmate, according to The New York Times. The Times obtained a copy of Knox's memoir, "Waiting to Be Heard," which is scheduled for release on April 30. Knox spent years in Capanne prison awaiting trial for the 2007 murder of her British roommate, Meredith Kercher, and then while serving a 26-year prison term following her conviction. She was acquitted on appeal. Her nearly 500-page memoir does not cover her life after prison and her most recent nightmare, the ruling in March by Italy's Supreme Court that she must be tried yet again for Kercher's murder. Those details and more will be discussed in her exclusive television interview with ABC News anchor Diane Sawyer. Watch Diane Sawyer's Exclusive Interview With Amanda Knox, April 30, 10 p.m. ET According to the Times, Knox was in such a deep state of despair behind bars in Italy that she considered committing suicide by suffocating herself with a garbage bag. Knox wrote in an author's note at the end of her book, "Until now I have personally never contributed to any public discussion of the case or of what happened to me, while I was incarcerated, my attention was focused on the trial and the day-to-day challenges of life in prison. Now that I am free, I've finally found myself in a position to respond to everyone's questions. This memoir is about setting the record straight." Complete Coverage of the Amanda Knox Story Knox, according to the Times, wrote about having her every move analyzed from afar -- including the video of her kissing her then-boyfriend, Raffaele Sollecito, outside the crime scene. "First I showed not enough emotion; then I showed too much," she wrote. "It's as if any good will others had toward me was seeping out like a slow leak from a tire, without my even realizing it." The Times described how Knox laid out her defense in detail -- writing that on the night of the murder she was at Sollecito's apartment smoking marijuana, reading a Harry Potter book out loud in German and watching the film "Amelie." During her interrogation, she said, police sporadically slapped her on the back of her head. Panicked and confused, when she asked to make a phone call. "The guard looked at me like I'd asked for caviar and prosecco," she wrote. She described her first moments of freedom after her acquittal -- writing that she was handed a touch screen Blackberry to make a call. "I hadn't picked up a cell phone in years, and never a touch-screen," she wrote. "This device was as good as sci-fi to me." Amanda Knox's memoir, "Waiting to be Heard," can be pre-ordered HERE and HERE This story has been updated from an earlier version. | Summary: Amanda Knox continues to raise her profile ahead of the April 30 release of her memoir Waiting to Be Heard. As a teaser to her interview with Diane Sawyer to air that night, ABC News reports that Knox reveals in the book that she considered suicide while in prison in Italy. "I started to understand how you could feel so locked inside your own life that you could be so desperate to escape, even if it meant that you would no longer exist," she writes. People also got an interview with Knox, conducted over several days at her mother's house in Seattle. A few snippets released ahead of the April 26 edition: "When Meredith (Kercher) was murdered and I was arrested, it was so shocking," she recalls. "It was paralyzing. Everything toppled." She's mostly happy now, she says, but "things creep up on me and all of a sudden I'm overwhelmed by the feeling of helplessness and that desperation and fear to even hope. Just that can make my heart race and makes me paralyzed until I can breathe it away." The 25-year-old still isn't in the clear legally, of couse. An Italian court has ordered that the murder case be retried. | 1,065 | 283 | multi_news | en |
Summarize: Lille's Europa League game with Everton on Thursday night proved to be rather uneventful as the Blues secured a well-earned 0-0 draw in France to keep them top of Group H ahead of Wolfsburg. However, unfortunately scenes off the pitch marred the Toffees' trip, with trouble first erupting on Wednesday in Lille's main square as up to 100 hooded hooligans attacked visiting supporters, before there was more unprovoked violence on Thursday. Here Sportsmail's Ashley Clements talks you through his version of events as the shocking violence erupted near him in the main square. I was standing to the side of Lille’s main square with Everton fans. We were enjoying each other’s company and a football was being kicked around the centre. The first sign of trouble came when several bottles started to be thrown and a blue flare was released by the visiting fans. People started to realise something was happening towards a corner of the square and a group of fans started to run towards where the trouble seemed to be brewing. French riot police run towards a group of fans in the Grand Place, Lille's main square. The city's riot place charge through the square while hundreds of supporters watch on. Flares were set off in Lille's main square as Everton fans gathered ahead of Thursday's Europa League game. Unconfirmed reports claim tear gas was used by police on Everton fans in Lille's main square. Thousands of people gathered in Lille's main square on Thursday as they prepared for the Europa League. A large bang echoed through the area before riot police, shields raised, marched towards the area of chaos. One Everton fan, seemingly minding his own business, was knocked to the ground as the police marched through. Fans began to run away from the area (left), some sneezing and rubbing their eyes. One fan shouted that the police were using rubber bullets. Standing slightly behind the riot police, I then saw a number of bottles being thrown their way as they retreated before the area calmed. Everton's official Twitter account sent out a message warning fans not to go near Lille's main square. Unconfirmed reports indicate that French police used tear gas on Everton fans. Everton fan Steve Wakenshaw (left), and his brother Si were attacked ahead of the Europa League match. The Australian (left) and the Queen's Head were both damaged after attacks on Everton fans in Lille. Everton's players train at the Stade Pierre-Mauroy, hours before an attack on their fans in Lille. Everton boss Roberto Martinez spoke to the media ahead of his side's third Europa League group game. VIDEO A hard fought point - Martinez. 'The club has been made aware of an isolated incident in a bar in Lille on Wednesday evening in which a number of Evertonians were attacked by a group of around 50 local men. 'The club understands that two Everton fans suffered minor facial injuries and were taken to the local hospital, and that this was the only incident in what was otherwise a good-natured evening in the city centre. 'The club are in continual contact with Merseyside police officers, who are in Lille today (Thursday), and the city's police representatives. Supporters travelling to tonight's match are advised to utilise the travel information provided on the official website where updates on any safety matters will also be provided.' | Summary: Flares set off in Lille's main square on Thursday as Everton fans gathered. French police used tear gas on visiting Everton fans. Around 7,000 Everton fans travelled to France to see their side play Lille. Trouble first erupted on Wednesday night at a bar in the city centre. Reports claim up to 100 hooded hooligans attacked Toffees supporters. Some fans were left with cuts after the unprovoked assault. Sportsmail's Ashley Clements tells his account of the violence. | 748 | 114 | cnn_dailymail | en |
Write a title and summarize: SECTION 1. SHORT TITLE; TABLE OF CONTENTS. (a) Short Title.--This Act may be cited as the ``Veterans Health Programs Extension Act of 1994''. (b) Table of Contents.--The table of contents of this Act is as follows: Sec. 1. Short title; table of contents. Sec. 2. References to title 38, United States Code. TITLE I--GENERAL MEDICAL AUTHORITIES Sec. 101. Sexual trauma counseling and services. Sec. 102. Research relating to women veterans. Sec. 103. Extension of expiring authorities. Sec. 104. Facilities in Republic of the Philippines. Sec. 105. Savings provision. TITLE II--CONSTRUCTION AUTHORIZATION Sec. 201. Authorization of major medical facility projects and major medical facility leases. Sec. 202. Authorization of appropriations. SEC. 2. REFERENCES TO TITLE 38, UNITED STATES CODE. Except as otherwise expressly provided, whenever in this Act an amendment or repeal is expressed in terms of an amendment to, or repeal of, a section or other provision, the reference shall be considered to be made to a section or other provision of title 38, United States Code. TITLE I--GENERAL MEDICAL AUTHORITIES SEC. 101. SEXUAL TRAUMA COUNSELING AND SERVICES. (a) Authority To Provide Treatment Services for Sexual Trauma; Repeal of Limitation on Time To Seek Services.--Subsection (a) of section 1720D is amended-- (1) by striking out paragraph (2); and (2) by inserting after paragraph (1) the following new paragraph (2): ``(2) During the period referred to in paragraph (1), the Secretary may provide appropriate care and services to a veteran for an injury, illness, or other psychological condition that the Secretary determines to be the result of a physical assault, battery, or harassment referred to in that paragraph.''. (b) Extension of Period of Authority To Provide Sexual Trauma Services.--Such subsection is further amended-- (1) in paragraph (1), by striking out ``December 31, 1995,'' and inserting in lieu thereof ``December 31, 1998,''; and (2) in paragraph (3), by striking out ``December 31, 1994,'' and inserting in lieu thereof ``December 31, 1998,''. (c) Repeal of Limitation on Period of Receipt of Services.--Such section is further amended-- (1) by striking out subsection (b); and (2) by redesignating subsections (c), (d), and (e) as subsections (b), (c), and (d), respectively. (d) Coordination of Care.--Paragraph (1) of subsection (b) of such section, as redesignated by subsection (c)(2), is amended to read as follows: ``(1) The Secretary shall give priority to the establishment and operation of the program to provide counseling and care and services under subsection (a). In the case of a veteran eligible for counseling and care and services under subsection (a), the Secretary shall ensure that the veteran is furnished counseling and care and services under this section in a way that is coordinated with the furnishing of such care and services under this chapter.''. (e) Increased Priority of Care.--Section 1712(i) is amended-- (1) in paragraph (1)-- (A) by inserting ``(A)'' after ``To a veteran''; and (B) by inserting ``, or (B) who is eligible for counseling and care and services under section 1720D of this title, for the purposes of such counseling and care and services'' before the period at the end; and (2) in paragraph (2)-- (A) by striking out ``, (B)'' and inserting in lieu thereof ``or (B)''; and (B) by striking out ``, or (C)'' and all that follows through ``such counseling''. (f) Program Revision.--(1) Section 1720D is further amended-- (A) by striking out ``woman'' in subsection (a)(1); (B) by striking out ``women'' in subsection (b)(2)(C) and in the first sentence of subsection (c), as redesignated by subsection (c); and (C) by striking out ``women'' in subsection (c)(2), as so redesignated, and inserting in lieu thereof ``individuals''. (2)(A) The heading of such section is amended to read as follows: ``Sec. 1720D. Counseling and treatment for sexual trauma''. (B) The item relating to such section in the table of sections at the beginning of chapter 17 is amended to read as follows: ``1720D. Counseling and treatment for sexual trauma.''. (g) Information by Telephone.--(1) Paragraph (1) of section 1720D(c), as redesignated by subsection (c) of this section, is amended to read as follows: ``(1) shall include availability of a toll-free telephone number (commonly referred to as an 800 number); and''. (2) In providing information on counseling available to veterans as required under section 1720D(c)(1) of title 38, United States Code (as amended by paragraph (1)), the Secretary of Veterans Affairs shall ensure that the Department of Veterans Affairs personnel who provide assistance under such section are trained in the provision to persons who have experienced sexual trauma of information about the care and services relating to sexual trauma that are available to veterans in the communities in which such veterans reside, including care and services available under programs of the Department (including the care and services available under section 1720D of such title) and from non- Department agencies or organizations. (3) The telephone assistance service shall be operated in a manner that protects the confidentiality of persons who place calls to the system. (4) The Secretary shall ensure that information about the availability of the telephone assistance service is visibly posted in Department medical facilities and is advertised through public service announcements, pamphlets, and other means. (5) Not later than 18 months after the date of the enactment of this Act, the Secretary shall submit to Congress a report on the operation of the telephone assistance service required under section 1720D(c)(1) of title 38, United States Code (as amended by paragraph (1)). The report shall set forth the following: (A) The number of persons who sought information during the period covered by the report through a toll-free telephone number regarding services available to veterans relating to sexual trauma, with a separate display of the number of such persons arrayed by State (as such term is defined in section 101(20) of title 38, United States Code). (B) A description of the training provided to the personnel who provide such assistance. (C) The recommendations and plans of the Secretary for the improvement of the service. (h) Conforming Repeal.--Section 102(b) of the Veterans Health Care Act of 1992 (Public Law 102-585; 106 Stat. 4946; 38 U.S.C. 1720D note) is repealed. SEC. 102. RESEARCH RELATING TO WOMEN VETERANS. (a) Inclusion of Women and Minorities in Clinical Research Projects.--Section 7303 is amended-- (1) by transferring the text of subsection (c) to the end of subsection (a)(1); and (2) by striking out ``(c)'' and inserting in lieu thereof the following: ``(c)(1) In conducting or supporting clinical research, the Secretary shall ensure that, whenever possible and appropriate-- ``(A) women who are veterans are included as subjects in each project of such research; and ``(B) members of minority groups who are veterans are included as subjects of such research. ``(2) In the case of a project of clinical research in which women or members of minority groups will under paragraph (1) be included as subjects of the research, the Secretary shall ensure that the project is designed and carried out so as to provide for a valid analysis of whether the variables being tested in the research affect women or members of minority groups, as the case may be, differently than other persons who are subjects of the research.''. (b) Health Research.--(1) Such section is further amended by adding after subsection (c), as added by subsection (a), the following new subsection: ``(d)(1) The Secretary, in carrying out the Secretary's responsibilities under this section, shall foster and encourage the initiation and expansion of research relating to the health of veterans who are women. ``(2) In carrying out this subsection, the Secretary shall consult with the following to assist the Secretary in setting research priorities: ``(A) Officials of the Department assigned responsibility for women's health programs and sexual trauma services. ``(B) The members of the Advisory Committee on Women Veterans. ``(C) Members of appropriate task forces and working groups within the Department (including the Women Veterans Working Group and the Task Force on Treatment of Women Who Suffer Sexual Abuse).''. (2) Section 109 of the Veterans Health Care Act of 1992 (Public Law 102-585; 38 U.S.C. 7303 note) is repealed. (c) Population Study.--Section 110(a) of the Veterans Health Care Act of 1992 (Public Law 102-585; 106 Stat. 4948) is amended by adding at the end of paragraph (3) the following: ``If it is feasible to do so within the amounts available for the conduct of the study, the Secretary shall ensure that the sample referred to in paragraph (1) constitutes a representative sampling (as determined by the Secretary) of the ages, the ethnic, social and economic backgrounds, the enlisted and officer grades, and the branches of service of all veterans who are women.''. SEC. 103. EXTENSION OF EXPIRING AUTHORITIES. (a) Authority To Provide Priority Health Care for Veterans Exposed to Toxic Substances.--Chapter 17 is amended-- (1) in section 1710(e)(3)-- (A) by striking out ``June 30, 1994'' and inserting in lieu thereof ``June 30, 1995''; and (B) by striking out ``December 31, 1994'' and inserting in lieu thereof ``December 31, 1995''; and (2) in section 1712(a)(1)(D), by striking out ``December 31, 1994'' and inserting in lieu thereof ``December 31, 1995''. (b) Drug and Alcohol Abuse and Dependence.--Section 1720A(e) is amended by striking out ``December 31, 1994'' and inserting in lieu thereof ``December 31, 1995''. (c) Pilot Program for Noninstitutional Alternatives to Nursing Home Care.--(1) Effective as of October 1, 1994, subsection (a) of section 1720C is amended by striking out ``During the four-year period beginning on October 1, 1990,'' and inserting in lieu thereof ``During the period through September 30, 1995,''. (2) Such subsection is further amended by striking out ``care and who--'' and inserting in lieu thereof ``care. The Secretary shall give priority for participation in such program to veterans Pwho--''. (d) Enhanced-Use Leases of Real Property.--Section 8169 is amended by striking out ``December 31, 1994'' and inserting in lieu thereof ``December 31, 1995''. (e) Authority for Community-based Residential Care for Homeless Chronically Mentally Ill Veterans and Other Veterans.--Section 115(d) of the Veterans' Benefits and Services Act of 1988 (38 U.S.C. 1712 note) is amended by striking out ``September 30, 1994'' and inserting in lieu thereof ``September 30, 1995''. (f) Demonstration Program of Compensated Work Therapy.--Section 7(a) of Public Law 102-54 (105 Stat. 269; 38 U.S.C. 1718 note) is amended by striking out ``1994'' and inserting in lieu thereof ``1995''. (g) Report Deadlines.--Section 201(b) of the Department of Veterans Affairs Nurse Pay Act of 1990 (Public Law 101-366; 38 U.S.C. 1720C note) is amended by striking out ``February 1, 1994,'' and inserting in lieu thereof ``February 1, 1995,''. SEC. 104. FACILITIES IN REPUBLIC OF THE PHILIPPINES. Notwithstanding section 1724 of title 38, United States Code, the Secretary of Veterans Affairs may contract with facilities in the Republic of the Philippines other than the Veterans Memorial Medical Center to furnish, during the period from February 28, 1994, through June 1, 1994, hospital care and medical services to veterans for nonservice-connected disabilities if such veterans are unable to defray the expenses of necessary hospital care. When the Secretary determines it to be most feasible, the Secretary may provide medical services under the preceding sentence to such veterans at the Department of Veterans Affairs Outpatient Clinic at Manila, Republic of the Philippines. SEC. 105. RATIFICATION OF ACTIONS DURING PERIOD OF LAPSED AUTHORITY. Any action of the Secretary of Veterans Affairs under section 1710(e) of title 38, United States Code, during the period beginning on July 1, 1994, and ending on the date of the enactment of this Act is hereby ratified. TITLE II--CONSTRUCTION AUTHORIZATION SEC. 201. AUTHORIZATION OF MAJOR MEDICAL FACILITY PROJECTS AND MAJOR MEDICAL FACILITY LEASES. (a) Projects Authorized.--The Secretary of Veterans Affairs may carry out the major medical facility projects for the Department of Veterans Affairs, and may carry out the major medical facility leases for that Department, for which funds are requested in the budget of the President for fiscal year 1995. The authorization in the preceding sentence applies to projects and leases which have not been authorized, or for which funds have not been appropriated, in any fiscal year before fiscal year 1995 and to projects and leases which have been authorized, or for which funds were appropriated, in fiscal years before fiscal year 1995. (b) Additional Projects.--(1) In addition to the projects authorized in subsection (a), the Secretary may carry out the following major medical facility projects in the amounts specified for such projects: (A) The projects that are proposed in the documents submitted to Congress by the Secretary of Veterans Affairs in conjunction with the budget of the President for fiscal year 1995 to be financed with funds from the proposed Health Care Investment Fund. (B) Construction of a nursing home facility at the Department of Veterans Affairs Medical Center in Charleston, South Carolina, in the amount of $7,300,000. (C) Construction of an outpatient care addition at the Department of Veterans Affairs medical center in Phoenix, Arizona, in the amount of $50,000,000. (D) A lease/purchase of a nursing home facility near Fort Myers, Florida, in the amount of $12,800,000. (2) The authorizations in paragraph (1) apply to projects which have not been authorized, or for which funds have not been appropriated, in any fiscal year before fiscal year 1995 and to projects which have been authorized, or for which funds were appropriated, in fiscal years before fiscal year 1995. (c) Projects for Which Funds Appropriated.--In addition to the projects authorized in subsections (a) and (b), the Secretary may carry out the following major medical facility projects for which funds were appropriated in chapter 7 of the Emergency Supplemental Appropriations Act of 1994 (title I of Public Law 103-211; 108 Stat. 10) in the amounts specified: (1) Construction of an ambulatory care/support services facility at the Department of Veterans Affairs Medical Center in Sepulveda, California, $53,700,000. (2) Other major medical facility projects required to repair, restore, or replace earthquake-damaged facilities at the Department of Veterans Affairs Medical Center in Sepulveda, California, $50,000,000. SEC. 202. AUTHORIZATION OF APPROPRIATIONS. (a) In General.--There are authorized to be appropriated to the Secretary of Veterans Affairs for fiscal year 1995-- (1) $379,370,000 for the major medical facility projects authorized in subsections (a), (b), and (c) of section 201; and (2) $15,800,000 for the major medical facility leases authorized in section 201(a). (b) Limitation.--The projects authorized in subsections (a) and (b) of section 201 may only be carried out using-- (1) funds appropriated for fiscal year 1995 pursuant to the authorization of appropriations in subsection (a); (2) funds appropriated for Construction, Major Projects for a fiscal year before fiscal year 1995 that remain available for obligation; and (3) funds appropriated for Construction, Major Projects for fiscal year 1995 for a category of activity not specific to a project. (c) Limitation on Certain Projects.--The projects authorized in subsection (c) of section 201 may only be carried out using-- (1) funds appropriated to the Construction, Major Projects account under chapter 7 of the Emergency Supplemental Appropriations Act of 1994 (title I of Public Law 103-211; 108 Stat. 10) and funds transferred by the President to the Construction, Major Projects account pursuant to chapter 8 of that Act (108 Stat. 14); (2) funds appropriated to the Medical Care account by chapter 7 of the Emergency Supplemental Appropriations Act of 1994 that are transferred to the Construction, Major Projects account; (3) funds appropriated to the Construction, Major Projects account for a fiscal year before fiscal year 1995 that remain available for obligation; and (4) funds appropriated to the Construction, Major Projects account for fiscal year 1995 for a category of activity not specific to a project. Speaker of the House of Representatives. Vice President of the United States and President of the Senate. | Title: Veterans Health Programs Extension Act of 1994 Summary: TABLE OF CONTENTS: Title I: General Medical Authorization Title II: Construction Authorities Veterans Health Programs Extension Act of 1994 - Title I: General Medical Authorities - Repeals a Federal provision requiring a veteran, in order to be eligible for counseling for sexual trauma from the Department 111Veterans Affairs, to seek such counseling within two years after release from active military service. Extends through December 31, 1998, the authority of the Department to provide such counseling services. Repeals a provision limiting to one year the authorized length of such counseling. Provides a priority for such care in furnishing medical services with funds appropriated for the medical care of veterans. Allows any veteran (currently, only women) to receive such counseling. Requires with respect to such counseling: (1) the availability of a toll-free telephone number; (2) appropriate training to Department personnel who provide counseling assistance; and (3) a report to the Congress on the operation of the telephone assistance service. (Sec. 102) Requires the Secretary of Veterans Affairs, in conducting or supporting clinical research, to ensure that women and minority veterans are included as subjects in such research. Directs the Secretary to foster and encourage the initiation and expansion of research relating to the health of women veterans, requiring specified consultation during such research. Amends the Veterans Health Care Act of 1992 to: (1) repeal a provision requiring the expansion of research relating to women veterans; and (2) require an appropriate test sample of age, background, rank, and service branch under a provision requiring a population study concerning women veterans. (Sec. 103) Extends for an additional year the authority: (1) to provide priority health care to veterans exposed to toxic substances during their military service; (2) for a pilot program for noninstitutional alternatives to nursing home care; (3) of the Secretary to enter into enhanced-use leases of real property; (4) for community-based residential care for homeless chronically mentally ill veterans and other veterans under the Veterans' Benefits and Services Act of 1988; and (5) for a demonstration program of compensated work therapy and therapeutic transitional housing for certain veterans. Amends the Department of Veterans Affairs Nurse Pay Act of 1990 to extend until February 1, 1995, the deadline of a required report on the findings of a study concerning noninstitutional alternatives to nursing home care. (Sec. 104) Authorizes the Secretary, from February 28, 1994, through June 1, 1994, to contract with facilities in the Republic of the Philippines other than the Veterans Memorial Medical Center to furnish hospital care and medical services to veterans for nonservice-connected connected disabilities if such veterans are unable to defray the cost of such care. (Sec. 105) Ratifies certain action taken by the Secretary during the period between July 1, 1994, and the date of enactment of this Act with respect to the furnishing of hospital and nursing home care to eligible veterans. Title II: Construction Authorization - Authorizes the Secretary to carry out the major medical facility projects and leases for the Department for which funds are requested in the FY 1995 budget, as well as certain prior year projects and leases. Authorizes the Secretary to carry out certain additional major medical facility construction projects, each with a cost limitation. Authorizes appropriations for such projects and leases, with limitations. | 4,629 | 797 | billsum | en |
Summarize: Captain Wentworth was come to Kellynch as to a home, to stay as long as he liked, being as thoroughly the object of the Admiral's fraternal kindness as of his wife's. He had intended, on first arriving, to proceed very soon into Shropshire, and visit the brother settled in that country, but the attractions of Uppercross induced him to put this off. There was so much of friendliness, and of flattery, and of everything most bewitching in his reception there; the old were so hospitable, the young so agreeable, that he could not but resolve to remain where he was, and take all the charms and perfections of Edward's wife upon credit a little longer. It was soon Uppercross with him almost every day. The Musgroves could hardly be more ready to invite than he to come, particularly in the morning, when he had no companion at home, for the Admiral and Mrs Croft were generally out of doors together, interesting themselves in their new possessions, their grass, and their sheep, and dawdling about in a way not endurable to a third person, or driving out in a gig, lately added to their establishment. Hitherto there had been but one opinion of Captain Wentworth among the Musgroves and their dependencies. It was unvarying, warm admiration everywhere; but this intimate footing was not more than established, when a certain Charles Hayter returned among them, to be a good deal disturbed by it, and to think Captain Wentworth very much in the way. Charles Hayter was the eldest of all the cousins, and a very amiable, pleasing young man, between whom and Henrietta there had been a considerable appearance of attachment previous to Captain Wentworth's introduction. He was in orders; and having a curacy in the neighbourhood, where residence was not required, lived at his father's house, only two miles from Uppercross. A short absence from home had left his fair one unguarded by his attentions at this critical period, and when he came back he had the pain of finding very altered manners, and of seeing Captain Wentworth. Mrs Musgrove and Mrs Hayter were sisters. They had each had money, but their marriages had made a material difference in their degree of consequence. Mr Hayter had some property of his own, but it was insignificant compared with Mr Musgrove's; and while the Musgroves were in the first class of society in the country, the young Hayters would, from their parents' inferior, retired, and unpolished way of living, and their own defective education, have been hardly in any class at all, but for their connexion with Uppercross, this eldest son of course excepted, who had chosen to be a scholar and a gentleman, and who was very superior in cultivation and manners to all the rest. The two families had always been on excellent terms, there being no pride on one side, and no envy on the other, and only such a consciousness of superiority in the Miss Musgroves, as made them pleased to improve their cousins. Charles's attentions to Henrietta had been observed by her father and mother without any disapprobation. "It would not be a great match for her; but if Henrietta liked him,"-- and Henrietta did seem to like him. Henrietta fully thought so herself, before Captain Wentworth came; but from that time Cousin Charles had been very much forgotten. Which of the two sisters was preferred by Captain Wentworth was as yet quite doubtful, as far as Anne's observation reached. Henrietta was perhaps the prettiest, Louisa had the higher spirits; and she knew not now, whether the more gentle or the more lively character were most likely to attract him. Mr and Mrs Musgrove, either from seeing little, or from an entire confidence in the discretion of both their daughters, and of all the young men who came near them, seemed to leave everything to take its chance. There was not the smallest appearance of solicitude or remark about them in the Mansion-house; but it was different at the Cottage: the young couple there were more disposed to speculate and wonder; and Captain Wentworth had not been above four or five times in the Miss Musgroves' company, and Charles Hayter had but just reappeared, when Anne had to listen to the opinions of her brother and sister, as to which was the one liked best. Charles gave it for Louisa, Mary for Henrietta, but quite agreeing that to have him marry either could be extremely delightful. Charles "had never seen a pleasanter man in his life; and from what he had once heard Captain Wentworth himself say, was very sure that he had not made less than twenty thousand pounds by the war. Here was a fortune at once; besides which, there would be the chance of what might be done in any future war; and he was sure Captain Wentworth was as likely a man to distinguish himself as any officer in the navy. Oh! it would be a capital match for either of his sisters." "Upon my word it would," replied Mary. "Dear me! If he should rise to any very great honours! If he should ever be made a baronet! 'Lady Wentworth' sounds very well. That would be a noble thing, indeed, for Henrietta! She would take place of me then, and Henrietta would not dislike that. Sir Frederick and Lady Wentworth! It would be but a new creation, however, and I never think much of your new creations." It suited Mary best to think Henrietta the one preferred on the very account of Charles Hayter, whose pretensions she wished to see put an end to. She looked down very decidedly upon the Hayters, and thought it would be quite a misfortune to have the existing connection between the families renewed--very sad for herself and her children. "You know," said she, "I cannot think him at all a fit match for Henrietta; and considering the alliances which the Musgroves have made, she has no right to throw herself away. I do not think any young woman has a right to make a choice that may be disagreeable and inconvenient to the principal part of her family, and be giving bad connections to those who have not been used to them. And, pray, who is Charles Hayter? Nothing but a country curate. A most improper match for Miss Musgrove of Uppercross." Her husband, however, would not agree with her here; for besides having a regard for his cousin, Charles Hayter was an eldest son, and he saw things as an eldest son himself. "Now you are talking nonsense, Mary," was therefore his answer. "It would not be a great match for Henrietta, but Charles has a very fair chance, through the Spicers, of getting something from the Bishop in the course of a year or two; and you will please to remember, that he is the eldest son; whenever my uncle dies, he steps into very pretty property. The estate at Winthrop is not less than two hundred and fifty acres, besides the farm near Taunton, which is some of the best land in the country. I grant you, that any of them but Charles would be a very shocking match for Henrietta, and indeed it could not be; he is the only one that could be possible; but he is a very good-natured, good sort of a fellow; and whenever Winthrop comes into his hands, he will make a different sort of place of it, and live in a very different sort of way; and with that property, he will never be a contemptible man--good, freehold property. No, no; Henrietta might do worse than marry Charles Hayter; and if she has him, and Louisa can get Captain Wentworth, I shall be very well satisfied." "Charles may say what he pleases," cried Mary to Anne, as soon as he was out of the room, "but it would be shocking to have Henrietta marry Charles Hayter; a very bad thing for her, and still worse for me; and therefore it is very much to be wished that Captain Wentworth may soon put him quite out of her head, and I have very little doubt that he has. She took hardly any notice of Charles Hayter yesterday. I wish you had been there to see her behaviour. And as to Captain Wentworth's liking Louisa as well as Henrietta, it is nonsense to say so; for he certainly does like Henrietta a great deal the best. But Charles is so positive! I wish you had been with us yesterday, for then you might have decided between us; and I am sure you would have thought as I did, unless you had been determined to give it against me." A dinner at Mr Musgrove's had been the occasion when all these things should have been seen by Anne; but she had staid at home, under the mixed plea of a headache of her own, and some return of indisposition in little Charles. She had thought only of avoiding Captain Wentworth; but an escape from being appealed to as umpire was now added to the advantages of a quiet evening. As to Captain Wentworth's views, she deemed it of more consequence that he should know his own mind early enough not to be endangering the happiness of either sister, or impeaching his own honour, than that he should prefer Henrietta to Louisa, or Louisa to Henrietta. Either of them would, in all probability, make him an affectionate, good-humoured wife. With regard to Charles Hayter, she had delicacy which must be pained by any lightness of conduct in a well-meaning young woman, and a heart to sympathize in any of the sufferings it occasioned; but if Henrietta found herself mistaken in the nature of her feelings, the alteration could not be understood too soon. Charles Hayter had met with much to disquiet and mortify him in his cousin's behaviour. She had too old a regard for him to be so wholly estranged as might in two meetings extinguish every past hope, and leave him nothing to do but to keep away from Uppercross: but there was such a change as became very alarming, when such a man as Captain Wentworth was to be regarded as the probable cause. He had been absent only two Sundays, and when they parted, had left her interested, even to the height of his wishes, in his prospect of soon quitting his present curacy, and obtaining that of Uppercross instead. It had then seemed the object nearest her heart, that Dr Shirley, the rector, who for more than forty years had been zealously discharging all the duties of his office, but was now growing too infirm for many of them, should be quite fixed on engaging a curate; should make his curacy quite as good as he could afford, and should give Charles Hayter the promise of it. The advantage of his having to come only to Uppercross, instead of going six miles another way; of his having, in every respect, a better curacy; of his belonging to their dear Dr Shirley, and of dear, good Dr Shirley's being relieved from the duty which he could no longer get through without most injurious fatigue, had been a great deal, even to Louisa, but had been almost everything to Henrietta. When he came back, alas! the zeal of the business was gone by. Louisa could not listen at all to his account of a conversation which he had just held with Dr Shirley: she was at a window, looking out for Captain Wentworth; and even Henrietta had at best only a divided attention to give, and seemed to have forgotten all the former doubt and solicitude of the negotiation. "Well, I am very glad indeed: but I always thought you would have it; I always thought you sure. It did not appear to me that--in short, you know, Dr Shirley must have a curate, and you had secured his promise. Is he coming, Louisa?" One morning, very soon after the dinner at the Musgroves, at which Anne had not been present, Captain Wentworth walked into the drawing-room at the Cottage, where were only herself and the little invalid Charles, who was lying on the sofa. The surprise of finding himself almost alone with Anne Elliot, deprived his manners of their usual composure: he started, and could only say, "I thought the Miss Musgroves had been here: Mrs Musgrove told me I should find them here," before he walked to the window to recollect himself, and feel how he ought to behave. "They are up stairs with my sister: they will be down in a few moments, I dare say," had been Anne's reply, in all the confusion that was natural; and if the child had not called her to come and do something for him, she would have been out of the room the next moment, and released Captain Wentworth as well as herself. He continued at the window; and after calmly and politely saying, "I hope the little boy is better," was silent. She was obliged to kneel down by the sofa, and remain there to satisfy her patient; and thus they continued a few minutes, when, to her very great satisfaction, she heard some other person crossing the little vestibule. She hoped, on turning her head, to see the master of the house; but it proved to be one much less calculated for making matters easy--Charles Hayter, probably not at all better pleased by the sight of Captain Wentworth than Captain Wentworth had been by the sight of Anne. She only attempted to say, "How do you do? Will you not sit down? The others will be here presently." Captain Wentworth, however, came from his window, apparently not ill-disposed for conversation; but Charles Hayter soon put an end to his attempts by seating himself near the table, and taking up the newspaper; and Captain Wentworth returned to his window. Another minute brought another addition. The younger boy, a remarkable stout, forward child, of two years old, having got the door opened for him by some one without, made his determined appearance among them, and went straight to the sofa to see what was going on, and put in his claim to anything good that might be giving away. There being nothing to eat, he could only have some play; and as his aunt would not let him tease his sick brother, he began to fasten himself upon her, as she knelt, in such a way that, busy as she was about Charles, she could not shake him off. She spoke to him, ordered, entreated, and insisted in vain. Once she did contrive to push him away, but the boy had the greater pleasure in getting upon her back again directly. "Walter," said she, "get down this moment. You are extremely troublesome. I am very angry with you." "Walter," cried Charles Hayter, "why do you not do as you are bid? Do not you hear your aunt speak? Come to me, Walter, come to cousin Charles." But not a bit did Walter stir. In another moment, however, she found herself in the state of being released from him; some one was taking him from her, though he had bent down her head so much, that his little sturdy hands were unfastened from around her neck, and he was resolutely borne away, before she knew that Captain Wentworth had done it. Her sensations on the discovery made her perfectly speechless. She could not even thank him. She could only hang over little Charles, with most disordered feelings. His kindness in stepping forward to her relief, the manner, the silence in which it had passed, the little particulars of the circumstance, with the conviction soon forced on her by the noise he was studiously making with the child, that he meant to avoid hearing her thanks, and rather sought to testify that her conversation was the last of his wants, produced such a confusion of varying, but very painful agitation, as she could not recover from, till enabled by the entrance of Mary and the Miss Musgroves to make over her little patient to their cares, and leave the room. She could not stay. It might have been an opportunity of watching the loves and jealousies of the four--they were now altogether; but she could stay for none of it. It was evident that Charles Hayter was not well inclined towards Captain Wentworth. She had a strong impression of his having said, in a vext tone of voice, after Captain Wentworth's interference, "You ought to have minded me, Walter; I told you not to teaze your aunt;" and could comprehend his regretting that Captain Wentworth should do what he ought to have done himself. But neither Charles Hayter's feelings, nor anybody's feelings, could interest her, till she had a little better arranged her own. She was ashamed of herself, quite ashamed of being so nervous, so overcome by such a trifle; but so it was, and it required a long application of solitude and reflection to recover her. | Summary: Captain Wentworth decides to stick around Kellynch, since looking for his own potential wife is more interesting than meeting his brother's new bride. He frequently visits Uppercross - not surprisingly, since the Musgroves treat him like a rock star, while the Crofts have their own couple-y things to do. Wentworth's universal popularity takes a hit, though, when Charles Hayter returns to town. Hayter is cousin to Henrietta and Louisa, and in fact had a thing going with Henrietta before Wentworth came on the scene. He isn't too pleased that Henrietta is giving him the cold shoulder while falling over Wentworth. Still, Henrietta may be counting her chickens early, as she and Louisa are running neck and neck for the Wentworth prize. Charles thinks Louisa is ahead, but Mary backs Henrietta; she has ulterior motives, though, as she doesn't want the low-class Hayters as her in-laws. Anne's opinion is that it doesn't make much difference whether Louisa or Henrietta is the chosen one, so long as Wentworth makes up his mind soon enough that the other one isn't too heartbroken to be passed over for her sister. One morning Anne is alone in a room with the still-invalid injured boy, when Captain Wentworth walks in on her. It's a mistake, of course, as he's really looking for the Musgrove girls. Awkward silence ensues. Someone approaches...perhaps this will help ease the situation? Nope, it's Charles Hayter. The awkwardness increases. Another new arrival, but still no help: this one's two years old and not the world's most brilliant conversationalist. In fact, the kid is downright annoying, literally hanging around Anne's neck as she's trying to tend to his older brother. Charles H. limits himself to ineffectual scolding from across the room, but suddenly Anne finds herself free of the nuisance. It is Captain Wentworth who has come to her rescue, and Anne finds herself once more all a-flutter and ashamed that her emotions still manage to run away with themselves whenever the Captain is around. | 3,750 | 486 | booksum | en |
Summarize: CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application claims priority to U.S. Provisional Patent Application Ser. No. 61/226,556, filed Jul. 17, 2009, the entire contents of which is hereby incorporated by reference. This application is also related to U.S. patent application Ser. No. 12/605,624, filed Oct. 26, 2009, U.S. Provisional Patent Application Ser. No. 61/108,552, filed Oct. 27, 2008, and U.S. Provisional Patent Application Ser. No. 61/226,533, filed Jul. 17, 2009, the entire contents of which are hereby incorporated by reference. BACKGROUND [0002] The present invention relates to x-ray imaging, including dental x-ray imaging. More particularly, embodiments of the invention relate to a data transfer cable for an intraoral sensor with improved mechanical strength and heat transfer properties [0003] X-rays have been used in dentistry to image teeth and parts of the mouth for many years. In general, the process involves generating x-rays and directing the x-rays at the patient's mouth. The x-rays are attenuated differently by different parts of the mouth (e.g., bone versus tissue) and this difference in attenuation is used to create an image, such as on film or by using electronic image sensor. SUMMARY [0004] One challenge associated with electronic intraoral x-ray systems relates to the mechanical stress on a cable coupling the sensor capturing images and an output device, such as a computer. To capture dental x-ray images, the intraoral sensor is positioned within the oral cavity of each patient, which often includes twisting and tugging forces being exerted on the cable. The repeated and continuous positioning of the intraoral sensor for each patient results in increased mechanical stress, which wears the cable. With increased use and wear, the cable can malfunction and become unusable. [0005] An additional challenge relates to the environment in which the intraoral sensor operates: the oral cavity of a patient. The electronics within the intraoral sensor generate heat and, if left unchecked, can result in injury to the patient. Certain governmental regulations or other standards apply to devices, such as intraoral sensors, that limit the maximum operating temperature. For instance, safety standard 60601-1 2 nd edition from the International Electrotechnical Commission (IEC) limits the outside temperature of such intraoral sensors to 41 degrees Celsius. [0006] Embodiments of the invention provide, among other things, an intraoral sensor including a sensor housing having a top portion and a bottom portion. The sensor further includes a twisted-quad universal serial bus (USB) cable coupled to the top portion. The twisted-quad USB cable includes an outer sheath and, within the outer sheath, a first data line, a second data line, a ground line, a power line, and four fillers that are twisted together to form a single bundle. The sensor also includes circuitry within the sensor housing. The circuitry converts x-rays received through the bottom portion into x-ray data and outputs the x-ray data along the twisted-quad USB cable. [0007] In some embodiments, the first data line, the second data line, the ground line, the power line, and the four fillers are symmetrically organized about a centerline of the twisted-quad USB cable. Additionally, in some embodiments, the four fillers includes a first filler, a second filler, a third filler, and a fourth filler. The first filler abuts the ground line and the first data line; the second filler abuts the ground line and the second data line; the third filler abuts the power line and the first data line; and the fourth filler abuts the power line and the second data line. In some embodiments, the four fillers are made of a plastic, electrically insulating material. [0008] In some embodiments, the outer sheath includes a braided shield and is coupled via a heat-conducting wire to a metallic layer substantially covering an inner surface of the top portion. In some embodiments, the outer sheath further comprises a jacket layer outside of the braided shield and a tape layer inside of the braided shield. Additionally, in some embodiments, the sensor includes an isolation layer within the sensor housing. The isolation layer is between the circuitry and the top portion and wherein the isolation layer is electrically insulating and heat conducting. In some embodiments, the isolation layer is coupled to one of the metallic layer and the braided shield via one of a second heat-conducting wire and direct contact to provide heat transfer from within the sensor housing to the twisted-quad USB cable. [0009] Additionally, embodiments of the invention provide an intraoral x-ray sensor including a housing and circuitry within the housing. The housing includes a top portion and a bottom portion. The top portion has a first inner surface and a first thermal resistance. The first inner surface is substantially covered by a metallic layer with a second thermal resistance that is lower than the first thermal resistance. The circuitry converts x-rays received through the bottom portion into x-ray data and outputs the x-ray data along a data cable. The data cable includes wires within a metallic shield. The metallic shield is coupled to the metallic layer by a thermally conductive path that has a thermal resistance that is less than the thermal resistance of air. [0010] In some embodiments, the bottom portion includes a second inner surface substantially covered by a second metallic layer that is coupled to the metallic layer either directly or via another thermally conductive path. The circuitry is contained on a printed circuit board (PCB) that is isolated from the metallic layer by an isolation layer. The isolation layer is thermally conductive and electrically insulating, and includes (in some implementations) an opening through which the circuitry and the wires are connected. Additionally, in some embodiments, the circuitry includes an array of pixels on a first side of the PCB and, on a second side of the PCB, a processor and an input/output module. The sensor includes x-ray attenuation components between the second side and a surface of the bottom portion through which x-rays are received. The x-ray attenuation components may include: a lead layer, a fiber optic covered by a scintillating layer, and copper planes. The top portion includes a dome (with the shape of a partial, elliptical paraboloid) having a face with a circular opening. The circular opening receives the data cable. [0011] Other aspects of the invention will become apparent by consideration of the detailed description and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS [0012] FIG. 1 is a schematic illustration of a dental x-ray system including an x-ray source, an intraoral sensor located in a patient's mouth, and a computer connected to the intraoral sensor. [0013] FIG. 1 a is a schematic illustration of the intraoral sensor shown in FIG. 1 showing internal components of the sensor. [0014] FIG. 2 depicts an exploded view of the intraoral sensor shown in FIG. 1. [0015] FIG. 3 depicts a cross section along line A of FIG. 4. [0016] FIG. 4 depicts a top view of the intraoral sensor shown in FIG. 1 and a cable connector. [0017] FIG. 5 a depicts a cross section of a prior-art universal serial bus (USB) cable. [0018] FIG. 5 b depicts a wiring diagram of a prior-art universal serial bus (USB) cable. [0019] FIG. 6 a depicts a cross section of a cable according to embodiments of the invention. [0020] FIG. 6 b depicts a wiring diagram of a cable according to embodiments of the invention. [0021] FIG. 7 depicts the underside of the top cover of the intraoral sensor of FIG. 1. DETAILED DESCRIPTION [0022] Before any embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. [0023] FIG. 1 illustrates a dental x-ray system 10. The system includes an x-ray source 12. In the embodiment shown, the source is located on an end 13 of a mechanical arm 15. When activated, the x-ray source 12 generates an x-ray stream 16 that has a generally circular cross-section. (Of course, x-rays are generally invisible, but a representation of a stream is illustrated to facilitate understanding of the invention.) In many applications, a collimator is used to reduce the size of the stream and generate a smaller x-ray stream having a rectangular cross-section. A collimator may be used with a mechanical positioning device to help align the x-ray stream with an x-ray sensor. As shown in FIG. 1, x-ray source 12 is positioned (e.g., by an operator) so that the x-ray stream 16 is directed to an intraoral sensor 20. The intraoral sensor 20 is shown located in the mouth of a patient 21. In some embodiments, the intraoral sensor 20 includes a scintillator that coverts x-ray radiation to visible light. In other embodiments, the sensor 20 is configured to convert x-rays into electric charge without a scintillator. Unless otherwise specified, the term pixel refers both to a pixel in the array of pixels that converts x-rays to electrons without a scintillator and a pixel in the array of pixels and its associated scintillator or portion of a scintillator. [0024] As best seen by reference to FIG. 1 a, the sensor 20 also includes an array of pixels 22. The components of FIG. 1 a, including the array of pixels 22, are not drawn to scale relative to the outline of the sensor 20. Each pixel produces an electric signal in response to light (from the scintillator) or x-ray radiation impinged upon it. In one embodiment, the sensor 20 includes one or more “on-board” analog-to-digital converters to covert analog signals generated by the pixels to digital signals. These signals are provided to a processor 23 (such as a programmable, electronic microprocessor, field programmable gate array, erasable programmable logic device(s), or similar device(s)). In the embodiment shown, the processor 23 is connected to memory 24 (ROM and RAM) and an input-output interface 25. The sensor 20 also includes one or more electronic circuits for power supply, driving the array of pixels, and driving the output (e.g., circuits located in the I/O interface 25 ). In some embodiments, the I/O interface 25 is a universal serial bus (“USB”) interface. [0025] In some embodiments, the processor 23 controls image capture or triggering of the sensor 20. In other embodiments, the x-ray source 12 is coupled to the sensor 20, e.g., via computer 30, such that when the x-ray source 12 is activated, a command is sent (simultaneously or nearly simultaneously) to the sensor 20 to perform an image capture. Thus, it is possible to generate a burst of x-ray radiation and be assured that an image will be captured by the sensor 20 during the relatively short period of x-ray exposure either through automatic triggering or via a specific capture command sent to the intraoral sensor 20. [0026] Referring back to FIG. 1, a wire, cable, or similar connector 27 of the sensor 20 connects the sensor 20 to a computer 30. The computer 30 includes various components, including a processor or similar electronic device 32, an input/output interface 34, and memory 36 (e.g., RAM and ROM). In some embodiments, the input/output interface 34 is a USB connection and the cable 27 is a USB cable. FIG. 1 illustrates that image data captured by the sensor 20 and processed by the computer 30 is sent to a display 38 and viewed as image 40. (Image 40 is drawn more distinctly than an x-ray image would typically appear.) [0027] The location of the intraoral sensor 20 in the patient's mouth determines what part of the patient's anatomy can be imaged (e.g., the upper jaw versus the lower jaw or the incisors versus the molars.) An x-ray operator places (or assists the patient in placing) the intraoral sensor 20 at a desired location with the patient's mouth. Various sensor holders (including those that are used with or that include a collimator) may be used to keep the sensor 20 in the desired location until an image is created or captured. For example, some holders are designed so that the patient bites the holder with his or her teeth and maintain the position of the sensor 20 by maintaining a bite on the holder. After the sensor 20 is positioned behind the desired anatomical structure, and the x-ray field to be generated by the x-ray source 12 is aligned with the sensor 20, it is possible that the source 12 and sensor 20 will, nevertheless, become misaligned. Misalignment can be caused by the patient moving his or her head, moving the intraoral sensor 20 (by re-biting the holder, moving his or her tongue, etc.), and other causes. [0028] FIG. 2 depicts an exploded view of the intraoral sensor 20. The sensor 20 includes a housing 45. The housing 45 has a top portion 50 and a bottom portion 55. Within the housing 45 is an insulator 60, a printed circuit board (“PCB”) 65, a silicon detecting layer 67, an x-ray converter 70, and a cushioning layer 71, which protects against mechanical shocks. Some embodiments of the sensor 20 do not include the cushioning layer 71. [0029] The top portion 50 includes a dome 75 that receives cable 27. The dome 75 has a shape that approximates an elliptical paraboloid divided in half by the surface 76 of the top portion 50 (a partial, elliptical paraboloid shape). Other dome shapes are contemplated for use in embodiments of the invention. The dome 75 includes a face with an approximately circular opening through which the cable 27 passes. The cable 27 includes connectors (e.g., wires), a portion of which pass through an opening 79 of the insulator 60 to connect to the PCB 65. In some embodiments, a ribbon or other connector passes through the opening 79 to couple the wires of cable 27 to the PCB 65. The insulator 60 provide electrical isolation between the PCB 65 and the housing 45 of the sensor 20. In some embodiments, the insulator 60 also secures the PCB 65 and x-ray converter 70 in position and protects each against mechanical shocks. Although the insulator 60 resists conducting electricity it is a conductor of heat, which assists in transferring heat away from the PCB 65. [0030] The PCB 65, silicon detecting layer 67, and converter 70 include the components of the sensor 20 illustrated in FIG. 1 a, namely the array of pixels 22, the processor 23, the memory 24, and I/O interface 25. In the embodiment depicted in FIG. 2, the array of pixels 22 includes a plurality of pixels, each pixel including a converting portion (i.e., a portion of converter 70 ) and a detecting portion (i.e., a portion of silicon detecting layer 67 ). The PCB 65 supports the silicon detecting layer 67 (e.g., a CMOS die) and converter 70, with the silicon detecting layer 67 being secured, e.g., using a glue or epoxy, to the PCB 65. The converter 70 converts x-rays received through the bottom portion 55 into light. The light travels to the silicon detecting layer 67, which converts the received light into charge. The charge is integrated at each pixel and the quantity of charge integrated represents the amount of x-rays received (although some of the integrated charge is attributable to noise and dark current). During a read-out of the array of pixels 22, the processor 23 determines the quantity of charge integrated at each pixel in the array of pixels 22. In some embodiments, the converter 70 and silicon detecting layer 67 include a fiber optic with scintillator. In some embodiments, the array of pixels 22 converts x-rays directly to charge without an intermediate step of converting x-ray to light. In such embodiments, among other possible alterations, an additional insulator (similar to insulator 60 ) is positioned in place of converter 70, and is used to provide electrical isolation between the housing 45 and the PCB 65 and help transfer heat away from the PCB 65. [0031] FIG. 3 depicts a cross section of the sensor 20 along line A as shown in FIG. 4. The top portion 50 is secured to the bottom portion 55 for instance, using ultrasonic welding and machining. The welding bonds the top portion 50 to the bottom portion 55, and machining smoothes the surface. Additionally, the top portion 50 and bottom portion 55 include interlocking portions 56. The converter 70, PCB 65, silicon detecting layer 67, and insulator 60 are shown within the housing 45. Also depicted is the cable 27 including stress relief portion 77. The stress relief portion 77 is secured to the cable 27, for instance, using an adhesive. Additionally, the stress relief portion 77 includes a circumferential notch 80 that matches up with ridge 85 on the dome 75. The stress relief portion 77 is secured to the dome 75 using the interlocking notch 80 and ridge 85. An adhesive may also be used to secure stress relief portion 77 to the dome 75. The stress relief portion 77 alleviates mechanical stress on the cable-to-housing coupling 81 created from twisting, pulling, and other forces on cable 27 and housing 45. Thus, the stress relief portion 77 extends the life of the cable-to-housing coupling 81, preventing or delaying malfunction of the sensor 20 caused by breaking the connection between the cable 27 and the housing 45. FIG. 4 depicts a top view of the sensor 20 and a USB connector 82 at the end of cable 27. [0032] FIG. 5 a depicts a cross section of a standard universal serial bus (USB) cable 100 capable of high speed USB version 2.0 communication. The standard USB cable 100 includes four main wires: data line 105 (D+), data line 110 (D−), power line 115, and ground line 120. Additionally, surrounding the four main wires is an isolating jacket 125, an outer shield 130 made of 65% interwoven tinned copper braid, and an inner shield 135 made of aluminum metallized polyester. The isolating jacket 125 is made of polyvinyl chloride (PVC) in some embodiments. Running lengthwise along with wire between the inner shield 135 and the outer shield 130 is a copper drain wire 140. The standard USB cable 100 is not symmetrical. Rather, the standard USB cable 100 has an internal, non-circular, oval structure, although fillers and plastic (not shown) may be used to create an external, circular shape of the cable. The external, circular shape can be approximately 4 mm in diameter. [0033] FIG. 5 b depicts a wiring diagram of the standard USB cable 100. As illustrated, the standard USB cable 100 has one twisted signaling pair including the data line 105 (D+) and data line 110 (D−). In some implementations, the power line 115 and ground line 120 are twisted (possibly to a lesser extent) or, as shown in FIG. 5 b, not twisted at all. [0034] FIG. 6 a depicts a cross section of a cable 150 according to embodiments of the invention. The cable 150 includes four main wires 210 and four fillers 175 a - d. The four main wires 210 include data line 155 (D+), data line 160 (D−), power line 165, and ground line 170, which provide data transmission, power transmission, and grounding, respectively. The data line 155 (D+), data line 160 (D−), power line 165, and ground line 170 each include a metal conductor encapsulated by a co-axial insulator. The four fillers 175 a - d are made of plastic and are twisted along with the four main wires 210 to form a twisted quad cable. The four mains wires 210 and four fillers 175 a - d are surrounded by three layers that run the length of the cable 150. The three layers include polytetrafluoroethylene (“PTFE”) tape 180, a braided shield 185, and a polyurethane jacket 190. In some embodiments, other materials are used for the jacket 190 and the tape 180 (e.g., another material similar to PTFE with a low surface roughness). The braided shield 185 is made up of, for instance, tinned copper wires with 0.08 mm diameter (40 AWG). As will be discussed further below, in some embodiments, the braided shield 185 is a heat conductor. In some embodiments, the polyurethane jacket 190 is approximately 0.432 mm thick. The total diameter of the cable 150 is less than 3.0 mm. In some embodiments, additional or fewer layers surround the four main wires 210 and fillers 175 a - d used within cable 27. [0035] The wiring diagram of FIG. 6 b illustrates the main wires 210 and fillers 175 a - d twisted together to form a single bundle 195. Although not shown in FIG. 6 b, the (“PTFE”) tape 180, a braided shield 185, and a polyurethane jacket 190 encapsulate the single bundle 195 as shown in FIG. 6 a. The twisted quad cable is symmetrical about center line 197, as shown in FIG. 6 a. The symmetrical characteristic of the cable 150 provides increased strength and resistance to mechanical stress with a lower outside diameter, relative to the standard USB cable. That is, the cable 150 is less susceptible to damage from twisting, pulling, and other forces on the cable 150, despite the reduced diameter of the cable 150. In particular, the cable 150 is less susceptible to damage due to rotational mechanical stress, which is often present during use of an intraoral sensor cable. [0036] FIG. 7 depicts the inside 200 of the top portion 50. The inside 200 includes a metallization layer 205. The cable 27 is shown inserted into the dome 75. The four main wires 210 (i.e., the data line 155 (D+), data line 160 (D−), power line 165, and ground line 170 ) are attached to a PCB connector 215, which is connected to the PCB 65. In some embodiments, the four main wires 210 are coupled or soldered directly to the PCB 65. The braided shield 185 is coupled to the metallization layer 205 via a heat conducting wire 220. The heat conducting wire 220 is coupled to the braided shield 185 and metallization layer 205 by, for instance, soldering. [0037] As the PCB 65 generates heat while in operation, a substantial portion of the generated heat is transferred through the insulator 60 to the metallization layer 205. The portion of generated heat is then transferred to the braided shield 185 via the heat conducting wire 220. The level of thermal resistance may vary by application. For instance, the more heat the PCB 65 generates in a particular embodiment, the lower the thermal resistances are of the materials chosen for the metallization layer 205, heat conducting wire 220, and insulator 60. In general, however, the insulator 60 and heat conducting wire 220 have a thermal resistance that is lower than the thermal resistance of air (which is approximately 1/0.025 W/(mK) at 20 degrees Celsius). Additionally, the metallization layer 205 has a thermal resistance that is less than the thermal resistance of the top portion 50 of the housing 45 and less than the thermal resistance of air. Thus, the sensor 20 provides improved heat transfer away from the sensor 20 along the cable 27. [0038] Although not shown, in some embodiments the inside of the bottom portion 55 also includes a metallization layer, which is similar to the metallization layer 205 in form and function. The bottom metallization layer is coupled to the braided shield 185 as well. In some embodiments, the coupling is provided by an additional heat conductor connection between the bottom metallization layer and either the braided shield 185 or the metallization layer 205. In other embodiments, the coupling is provided by direct contact between the bottom metallization layer and the metallization layer 205. [0039] Thus, the invention provides, among other things, an intraoral sensor with a cable providing greater resistance to mechanical stress. Additionally, the invention provides an intraoral sensor with improved heat transfer. Various features and advantages of the invention are set forth in the following claims. | Summary: An intraoral x-ray sensor with embedded standard computer interface. The sensor includes a data transfer cable with improved mechanical strength and heat transferring properties. The cable is quad-twisted USB cable and includes two data lines, a ground line, and fillers twisted within a metallic sheath, e.g., a metal braided shield. The cable is symmetrically organized about a centerline. The symmetric cable has an improved life due to the ability to withstand mechanical stress (e.g., rotational stress). The sensor includes a processor and a housing with an inner metallization layer. The sheath is coupled to the inner metallization layer to transfer heat generated by the processor from the inner metallization layer to the sheath. | 6,388 | 159 | big_patent | en |
Summarize: Government and Politics Introduction and Situation before October 2009 Elections The Greek city-state of Athens is believed to have developed the first known democracy around 500 B.C. Modern Greece has been a democracy since the toppling of a military junta in 1974. Since then, two large parties have alternated leadership of the government: the New Democracy (ND) party and the PanHellenic Socialist Movement (PASOK). ND was in power from March 2004 until October 2009.In the September 2007 national elections, held after the government was criticized for poor performance in fighting widespread fires and some officials were implicated in corruption scandals, ND was able to eke out only a slim majority of 152 seats in the unicameral 300-seat parliament. At the time, PASOK also suffered losses, while three small parties on the left and right registered significant gains and won seats. One of these, the ultra-nationalist, anti-immigrant Popular Reforming and Orthodox Rally (LAOS) party, entered parliament for the first time. After the 2007 election, ND lost one seat in parliament and its position declined due partly to additional corruption scandals, a crisis of law and order, and the economic situation. An ongoing scandal over the Siemens Group's alleged bribery of politicians and officials sullied both major parties. Then, in September 2008, Merchant Marine Minister George Voulgarakis resigned amid allegations that government ministers had helped a monastery trade inexpensive land for prime real estate, at a cost of an estimated $130 million to the government. In October, the same scandal led to the resignation of State Minister and government spokesman Theodoros Roussopoulos, a close associate of then Prime Minister Constantine (Costas) Karamanlis. Perhaps more significantly, the government's ability to ensure public security came into question. In December 2008, police fatally shot a teenage boy, provoking days of violent protests by anarchists, students, and labor groups in Athens and elsewhere. It was the worst rioting in years, and its duration generally was attributed to socioeconomic causes (i.e., the youths' joblessness and lack of hope), although a culture of impunity also was blamed. Critics castigated the government for its passive response and slowness in reestablishing law and order. In June 2009, the murder of a police officer who was a member of the counterterrorism squad protecting a witness in a trial involving a terrorist group again highlighted the government's deficiencies in this area. PASOK polled ahead of ND in public opinion surveys throughout 2008 and 2009, and PASOK leader George Papandreou repeatedly called for early elections. PASOK came in first, and the LAOS registered striking gains in the European Parliament elections of June 2009. In August, Greece again experienced terrible fires and, while they were not as severe as in 2007, some criticized the government for its alleged failure in the intervening years to improve fire protection or to establish better coordination of fire-fighting efforts. The government blamed extremely strong winds for the destruction. Other observers said that the government had mobilized assistance from the European Union (EU) and from individual European governments. October 4, 2009, Elections The president is head of state, but the prime minister is head of government and exercises most powers. In February 2005, former Foreign Minister Karolos Papoulias, the ND consensus candidate and a founding member of the opposition PASOK, won the presidency with 279 out of 296 votes cast in parliament. His term expires in March 2010. On September 3, 2009, Prime Minister Karamanlis called for early national elections because, he said, he wanted to avoid a protracted pre-election period. Parliamentary elections had been scheduled for September 2011 and now would take place on October 4, 2009. Karamanlis claimed that PASOK had "forced" the early election when it announced that it would not support President Papoulias for reelection. Without PASOK, Karamanlis's ND party would not have sufficient votes in parliament to reelect the president and a national election would have been required in order to reconstitute parliament so that a new president could be elected. Thus, the election campaign would have lasted for at least six months. ND's election prospects were bleak from the outset of the campaign as the economy was experiencing a recession. At the same time, the European Commission estimated that Greece's 2009 budget deficit would be 8% of gross domestic product (GDP), well above the 3% ceiling that the EU mandates for members, and the national debt would be 110% of GDP. (These estimates have since risen.) By October 24, Greece was supposed to present to the EU a package of measures aimed at restructuring its public finances and cutting its fiscal deficit to 3.7% by the end of 2009, which few considered feasible. In addition, commentators and opposition politicians had criticized the government for what they claimed was its poor performance in fighting fires again in August. (However, others thought that the government had mobilized rapidly, but that extreme winds had affected the effectiveness of fire-fighting.) Critics also assailed the government for its failure to improve law and order in the face of domestic terrorism and anarchism. To help Greece overcome its financial crisis, Prime Minister Karamanlis presented an economic plan on September 5. It called for cuts in public spending, freezing public-sector wages and pensions, combating tax evasion, and structural changes. Critics wondered why the party had not done all that in its six years in office, although its one-seat majority in parliament probably constrained boldness. The plan could not have appealed to voting public-sector workers and pensioners. On September 12, PASOK leader Papandreou presented a program for his first 100 days in office, calling for boosting demand with pay increases above the rate of inflation, extra pay for lower incomes, protection of borrowers and households in debt, combating price increases in the market, freezing utility rates for one year, and passing tax reforms to promote redistribution of income. He also proposed increases in public investments, supporting employment by subsidizing social security contributions for new hires of unemployed persons, and increasing unemployment benefits. The PASOK stimulus plan had a price tag €3 billion or U.S.$4.38 billion. Papandreou said that he would fund it with better tax collection, with the EU's National Strategic Reference Framework (ESPA) cohesion policy funds, and public-sector real estate. The smaller parties also presented their views. LAOS leader George Karatzaferis sounded nationalist and populist themes, calling for EU help in guarding Greece's borders against illegal immigrants, the establishment of a quota for immigrants, and stronger policies to combat "the Turkish threat." He attributed a large percentage of what he asserted was a rising crime rate to illegal immigrants. Meanwhile, at the outset of the campaign, the Coalition of the Radical Left (SYRIZA) survived a leadership dispute with the main party in its alliance, the Coalition of the Left Movements and Ecology's (Sinapismos/SYN). SYN President Alexis Tsipras demanded to lead both SYRIZA and SYN, but other parties in SYRIZA resisted, and some wanted the head of SYRIZA's parliamentary group and former head of SYN, Alekos Alavanos, to head the list. SYRIZA entered the elections without a leader at the head of its list and Alvanos did not run for parliament. In the end, it was widely believed that Greeks voted against the ND government more than for PASOK. Voter turnout was 70.92%, down slightly from 74.14% in 2007. Karamanlis resigned as ND leader and assumed a seat as a Member of Parliament from Thessaloniki. His successor is former Culture Minister Antonis Samaras. New Government Prime Minister Papandreou proposed a smaller cabinet, created the new post of Vice President, and reconfigured several ministries. The Ministry of Economy, Competitiveness, and Shipping has been created from some elements of the former Merchant Marine, Aegean, and Island Policy Ministry and others from the former Economy and Finance Ministry. The Ministry of Citizens' Protection took over responsibility for public order from the Interior Ministry along with parts of Merchant Marine Ministry's marine safety and other components. Economy Greece has a mixed capitalist economy, with the public sector accounting for about 40% of the gross domestic product (GDP). In its first term, the ND government cut the budget deficit and taxes on corporations, and was able to raise tax revenues due to an average annual growth rate of 4% and a crackdown on tax evasion. Unemployment decreased at first, but 20% of the population remained below the poverty level. ND also passed some social security reforms, despite political opposition and labor protests. The European Commission wants even more action in this area. Greece sustained its growth due to booms in tourism and shipping. (Greece has the largest merchant marine in the world.) It also plans to ensure its own energy security as well as become a major "energy corridor" with the Turkish-Greece-Italy (TGI) natural gas pipeline, the Burgas (Bulgaria)-Alexandroupolis oil pipeline, the South Stream natural gas pipeline from Russia to Europe, and a gas pipeline between Greece and Bulgaria. However, during the brief second ND term, Greece began experiencing the effects of the global financial crisis and recession, which hurt shipping and tourism among other key sectors. GDP has contracted for three consecutive quarters in 2009. Almost all industrial sectors have seen declines. Unemployment hit 9.6% in July and is expected to grow. Moreover, Greece is facing a crippling projected budget deficit of more than 12% of GDP and a debt in excess of 125% of GDP for 2010. As of December 2009, the Finance Ministry stated that the debt was a record €300 billion (U.S.$442 billion). Credit rating agencies have downgraded the debt, meaning that it will be more difficult for Greece to find lenders and cost it more to borrow. The Papandreou government expects to submit a revised Stability and Growth Program to the EU in January 2010, with measures to reduce spending, increase revenues, and resume growth. Its 2010 budget reduces operational expenditures by 10%, suspends public sector hiring except in "sensitive" sectors, and proposes economic reforms. The economy benefits from Greece's membership in the EU and the euro zone. Greece received an estimated $8 billion annually from the EU between 2000 and 2006 and will receive another $24 billion for 2007-2013. Participation in the euro zone is believed responsible for controlling inflation. Terrorism Greek authorities have worked to dismantle two main domestic terrorist groups, the Revolutionary Organization 17 November (17N) and Revolutionary Popular Struggle (ELA). The U.S. State Department lists 17N, which was responsible for the murders of five U.S. embassy employees in Athens, beginning with CIA station chief Richard Welch in 1975, as a Foreign Terrorist Organization (FTO). Although arrests and convictions of 17N leaders and members have been made since 2002, retrials and acquittals have led to the release of some of those convicted. Neither 17N nor ELA has been active for several years. Possible copycats, successor groups, or renamed cells of the older groups such as Revolutionary Struggle (EA) and Popular Revolutionary Action (LED) are active, as are small anarchist and anti-globalization groups, which operate mainly in the Athens area. A January 12, 2007, rocket-propelled grenade attack on the U.S. Embassy in Athens caused no casualties and did little material damage. EA claimed responsibility. In 2009, attacks by Revolutionary Struggle have become more frequent. In September, it claimed responsibility for a car bomb attack at the Athens Stock Exchange that caused widespread damage and injured a security guard. In June 2004, parliament passed a law to implement the common EU counterterrorism policy. In January 2006, Greece began using new, more secure passports with biometrics to comply with EU regulations and executing EU-wide arrest warrants. It also ratified the extradition agreement between the United States and EU. The Greek navy participates in Operation Active Endeavor, NATO's antiterrorism ship monitoring effort in the Mediterranean Sea. Foreign Policy Greece is a member of the EU and NATO. In addition to participating in NATO's Operation Active Endeavor and the International Security Assistance Force in Afghanistan, Greece also is engaged in EU missions such as the EU Military Force in Bosnia and Herzegovina (EUFOR—Operation ALTHEA) and the EU Rule of Law Mission in Kosovo (EULEX). It also has military observers as part of an Organization for Security and Cooperation in Europe (OSCE) force in Georgia and, in January 2009, Greece assumed the rotating presidency of that organization. Cyprus The Republic of Cyprus has been partitioned between the Greek Cypriot south and the Turkish Cypriot north since Turkish forces invaded in 1974 in response to a coup on the island backed by the Greek junta, which favored uniting Cyprus and Greece. Greece strongly supports its Greek Cypriot ethnic kin in their efforts to reunify the island. In November 2002, U.N. Secretary General Kofi Annan offered a draft settlement plan to unite Greek Cypriots and Turkish Cypriots in a loosely federated United Republic of Cyprus. Prime Minister Karamanlis cautiously stated on April 15, 2004, that the plan's "positive points can prove to be superior to the negative ones," adding that it was up to the Cypriots to decide and that Greece would support their decision. On April 24, 2004, 76% of Greek Cypriots rejected the "Annan Plan," while 65% of Turkish Cypriots accepted it. The settlement process then stalemated. In July 2005, Turkey extended its customs union with the EU to all new members, including Cyprus, but did not recognize the Republic of Cyprus or open its ports to Greek Cypriot ships. Greece has seconded the Greek Cypriots' demand that Turkey recognize Cyprus de jure and fully implement the customs union. It welcomed the renewal of the settlement process in March 2008, and has supported Republic of Cyprus President Dimitris Christofias in his direct talks with Turkish Cypriot leader Mehmet Ali Talat, which have been conducted under U.N. auspices since September 2008. Turkey Greece secured its independence from the Ottoman Empire, the precursor of modern-day Turkey, in 1832. The two neighbors historically have had strained relations, but began a period of rapprochement in 1999. In order for Turkey to become a more stable and peaceful democracy, Athens supports Turkey's full membership in the EU if it meets EU standards. Greece and Turkey share interests in regional peace, growing bilateral trade ($2.8 billion in 2008), a natural gas pipeline, and combating terrorism and illegal immigration. Greece is now the fourth-largest investor in Turkey. In 2006, the National Bank of Greece purchased Turkey's fifth-largest bank for $2 billion. Prime Minister Karamanlis visited Turkey in January 2008, becoming the first Greek prime minister to visit in almost 49 years. However, a number of issues remain impediments to greater progress in normalizing bilateral relations. They include the unresolved Cyprus dispute, the failure of Ankara to authorize the reopening of the Greek Orthodox Theological Seminary on the Turkish island of Halki and its refusal to recognize the ecumenical (worldwide) status of the Greek Orthodox Patriarch whose seat is in Istanbul, and what some Greeks consider Turkey's suspicious advocacy and political support for Muslims of Turkish origin in Greek Thrace. Sharp differences over Aegean Sea sovereignty issues produced major crises in 1987 and 1996 that appeared to bring the two neighbors to the brink of military conflict. In order to avoid similar developments in the future, Greece and Turkey have held more than 40 rounds of exploratory talks concerning disputes over air space, territorial seas, continental shelf, and related issues over several years. Both sides appear satisfied with continuing talks, which have produced neither resolution nor conflict. Greece did not take its disagreements with Turkey to the International Court of Justice (ICJ) in December 2004, as proposed at the 1999 EU summit in Helsinki which reaffirmed Turkey's candidacy for EU membership. Greece accepts the Court's jurisdiction, but Turkey does not. Greece officially recognizes only a dispute over the continental shelf and, in July 2009, its Foreign Ministry reiterated readiness to refer that one issue to the Court. Athens also wants Ankara to rescind a 1995 casus belli parliamentary authorization of any steps, including military ones, if Greece exercises a right to a 12-mile territorial sea as allowed under the Law of the Sea Treaty. Greece is a signatory of the Treaty; Turkey is not. In addition, Greece objects to Turkey's repeated infringements of Greece's claimed 10-mile air space over the Aegean and to Turkish commanders' references to (Greek) Aegean islands/islets not named in treaties as "gray zones" that must be demilitarized. Territorial disputes appear to be surfacing more frequently and serve to highlight the continuing lack of a solution. Some emanate from each country's desire to explore for oil. On October 10, 2009, Prime Minister Papandreou, who had been one of the fathers of the Greek-Turkish rapprochement in 1999 when he was foreign minister along with the late Turkish Foreign Minister Ismail Cem, made a lightning visit to Istanbul for a meeting with fellow ministers from southeastern Europe. It was his first trip abroad taken in his capacity as foreign minister. Macedonia The former Yugoslav republic of Macedonia declared its independence in 1991. Its territory covers 39% of the historic region of Macedonia; the remaining 51% is in Greece and 9% is in Bulgaria. Macedonia asserts its right to use and be recognized by its constitutional name, the Republic of Macedonia. Greece objects, claiming that the name usurps Greece's heritage and conveys irredentist ambitions against Greece's largest province, also called "Macedonia," which borders the former Yugoslav republic. Due to Greek objections, Macedonia joined the U.N. in 1992 under the provisional name of The Former Yugoslav Republic of Macedonia (FYROM), which is how Greece refers to it. In 1995, Athens and Skopje signed an interim agreement to normalize relations and settle all outstanding disputes except for the name, and Greece ended an 18-month long trade blockade of FYROM. Since then, officials of both governments have met with the U.N. Secretary General's personal envoy, U.S. lawyer Matthew Nimetz, to discuss the name, but have not reached a mutually acceptable solution. Greek officials call for a compromise composite name with a clear geographic qualifier (e.g., Republic of Northern Macedonia) to be used internationally. They reject the suggestion that one name be used solely in Greek-Macedonian bilateral relations and another internationally. In April 2008, Greece, whose position is "no solution means no invitation" for Macedonia to join NATO and the EU, prevented NATO from reaching a consensus on extending an invitation to Macedonia to join the alliance because no solution to the name dispute had been found. Athens argued that, because of that situation, Macedonia had failed to meet what Greece said was the criterion of "good neighborliness" required of new NATO members. The international trend in name usage favors Macedonia, with 125 governments recognizing it as the Republic of Macedonia. The government of Macedonia has said that it would never renounce the achievement of this recognition. Despite the name problem, Greece is the top investor in the FYROM and bilateral trade is strong. At the same time, however, Macedonian Prime Minister Nikola Gruevski appeared to exacerbate bilateral relations with a spate of actions. In July 2008, he sent a letter to Prime Minister Karamanlis calling on him to recognize a "Macedonian minority" in Greece, with a basic right to be educated in its mother tongue (Macedonian). Greece recognizes only a Muslim minority as called for in the 1923 Treaty of Lausanne and described the letter as "provocative." Foreign Minister Bakoyannis charged that Gruevski was "trying to deliberately undermine" the name negotiations by inserting onto the agenda an "alleged Macedonian minority," whose existence Greece does not recognize. In his reply, Karamanlis declared, "There is no 'Macedonian' minority," and called on Gruevski to leave behind "nationalist formulas of a bygone era." A month later, Gruevski wrote to the U.N. Secretary General and to Nimetz, requesting that recognition of the Macedonian Orthodox Church be included in the name discussions. Nimetz said, "We are dealing with the name of the country and (not)... with the national or with other personal identities of people." Finally, in November, Macedonia filed a complaint with the International Court of Justice (ICJ) charging that Greece had violated the 1995 Interim Accord because Article 11 obliged it not to object to Macedonia's application to international organizations of which Greece is a member (e.g., NATO). Greece said that it would respond with evidence that Skopje has failed to adhere to the 1995 agreement. Prime Minister Papandreou agrees with Karamanlis's position regarding the negotiations with the FYROM. Officials in the new government have said that the FYROM's entry into the EU is conditional on a solution to the name issue and, due to Greece's insistence, the EU has postponed a decision on Macedonia's candidacy. However, Papandreou does have sufficient political capital at this stage in his tenure to compromise on the issue should he wish to do so. Other Regional Issues Greeks and Serbs have particularly close ties based on their common Orthodox Christianity, their alliance during the 20 th -century Balkan wars, and Greek empathy during the division of Yugoslavia. Greece hopes that Serbia and all of its Balkan neighbors eventually will become EU members in order to strengthen regional stability. Greece sought a U.N. Security Council-legitimized, mutually acceptable agreement on Kosovo to reassure Serbia and protect Kosovar Serbs. Therefore, it opposed Kosovo's unilateral declaration of independence—perhaps also wary that it might set a precedent for northern Cyprus. Athens has a liaison office and not an embassy in Pristina, as it still does not recognize Kosovo's independence. Greece sent a 20-member military team to join an OSCE observer force in Georgia in August 2008, in the aftermath of the Georgia-Russia conflict. Athens does not recognize the Russian-backed independence of the secessionist Georgian regions of South Ossetia and Abhazia. Greece's policies towards Kosovo, South Ossetia, and Abhazia, and to a great extent Cyprus, are consistent with its support for the inviolability of international borders. Afghanistan In response to domestic critics, the Papandreou government has defended Greece's participation in NATO's Afghan mission in terms of its own national interests: providing diplomatic prestige, proving Greece's reliability, and adding to Greece's effectiveness in managing its own national issues. Yet, the government may find its ability to support even limited commitments for Afghanistan severely constrained due to the ongoing economic crisis. Greece's participation in the NATO mission is limited. The European Council on Foreign Relations lists Greece among the countries that have "underperformed" in Afghanistan. According to the IISS Military Balance, 2009, Greece has an engineering company of 137 soldiers and one C-130 Hercules transport aircraft in Afghanistan. Former Defense Minister Evangelos Meimarakis argued that Greece is unable to send more troops or equipment to Afghanistan because of its own defense commitments, which usually refers to confronting a perceived threat from fellow NATO member Turkey. In particular, Greece believes that it cannot redeploy aircraft and helicopters from the Aegean Sea, where it accuses Turkey of violating Greek airspace and territorial waters. Perhaps as a gesture to President Obama at the beginning of his administration, on April 4, 2009, former Greek Prime Minister Costas Karamanlis restated plans that had already been in motion. A Greek mechanized company would assume command of Kabul International Airport in 2010, with a reinforced strength of 30-40 officers. Until then, seven Greek soldiers were to be sent to assist other international forces already at the airport. If and when the airport is transferred to the Afghans, the mechanized company would move to the western province of Herat under Italian command. Officials suggested that these forces then would be closer to combat because more armed clashes occur in Herat. A battalion specialized in bridge construction already had deployed. In addition, Greece would return a medical unit to the field and a special unit would deploy to Kabul to train Afghan police officers. Former Defense Minister Meimarakis also said that Greece was willing to train Afghan soldiers in Greece. Soon after it took power, the Papandreou government modified these plans. In particular, it declared that forces based in Kabul would not relocate to an area of higher risk (e.g., Herat) as had been anticipated by its predecessor. However, two medical units probably would deploy. On March 31, 2009, former Foreign Minister Dora Bakoyannis called for a more prominent civilian presence in Afghanistan to assist with education, culture, economic development, and agriculture. Greek non-governmental organizations are involved in such programs. On September 22, the Greek Ambassador to NATO presented €300,000 (approximately U.S.$438,000) to his Hungarian counterpart to support development projects being implemented by the Hungarian PRT in Baghlan province, including building an outpatient clinic and rebuilding and equipping a school. In 2007, Greece had donated €500,000 (approximately U.S.$700,000) to Hungary for similar purposes. Despite the financial constraints noted above, the Papandreou government may opt to continue to contribute some funds for Afghan reconstruction in order to ease pressure from NATO allies. Relations with the United States U.S.-Greek bilateral relations are good and are based on historical, political, cultural, military, economic, and personal ties. The active, well-organized Greek-American community advocates pro-Greek positions and seeks close U.S.-Greek ties. The State Department refers to Greece as a "strategic partner," and Greece and the United States share interests in stability in southeastern Europe. Since the 1960's, the United States has operated a Naval Support Activity for the United States and NATO at Souda Bay on the Greek island of Crete under the terms of a mutual defense cooperation agreement (MDCA). The activity is a tenant of the Hellenic Air Force and supports U.S. Sixth Fleet Aircraft, U.S. Navy Air Detachments deployed at Souda, and transient U.S. military aircraft. In addition, an estimated 430 U.S. ships to visit the base annually for servicing. A NATO Missile Firing Installation, used for testing, is located nearby. The Greek government responded to the September 11, 2001, terrorist attacks on the United States with strong political support, unimpeded U.S. and coalition use of Greek airspace, and military assets for counterterrorism. Like some other EU countries, Greece does not view the war in Iraq as part of the war against terror and is not part of the coalition there. It refused to participate in training the Iraqi army in either Iraq or Greece and, along with five other EU member countries, refused to allow its military personnel assigned to NATO's international command staff to join a senior officer training mission in Iraq. It did, however, send military personnel to train Iraqis at a camp in Bulgaria and 100 BMP-1 armored personnel carriers to Iraq to help equip the Iraqi armed forces. It also contributed financially to the cost of training Iraqi police and provided Greek commercial ships to transport NATO military equipment to Iraq. In addition, Greece provided some humanitarian and development assistance to Iraq. U.S. aid for Greece has not been a major element in the bilateral relationship since the 1990's. In response to the 2007 wildfires, the U.S. Agency for International Development Office of Foreign Disaster Assistance (OFDA) provided more than $600,000 in emergency aid and $1.35 million through agreements with the U.S. Forest Service to implement a technical assistance program through the remainder of 2007 and throughout 2008. In FY2008, Greece also received $443,000 in International Military Education and Training (IMET) funds. In FY2009, it is receiving an estimated $100,000 for IMET, and the Administration has requested $100,000 in IMET funds for Greece for FY2010. The United States has encouraged the rapprochement between Greece and Turkey, believing that direct bilateral talks are the best route to normalized relations. Both Greece and Turkey participate in the U.S.-initiated Southeast Europe Brigade (SEEBRIG), a rapid-reaction force consisting of contingents from seven regional countries. At the same time, there have been some tensions in U.S.-Greek relations. In November 2004, Greece responded with a demarche when the United States formally recognized the FYROM as the Republic of Macedonia. The State Department said that the decision was not directed against Greece but intended to bolster Macedonia's stability and ensure its path toward a multiethnic, democratic state within its existing borders. President Bush added that the United States still would embrace any name that emerges from negotiations between Athens and Skopje. The Bush Administration supported the U.N.-assisted negotiations. Because the United States strongly supports Macedonia's integration in the Euro-Atlantic community, it regretted Greece's lack of agreement to a NATO invitation to Macedonia because the name issue was unresolved. Then Assistant Secretary of State for European and Eurasian Affairs Daniel Fried stated that the Administration would even have accepted a NATO invitation to Macedonia as the FYROM. Greece is one of only a few remaining EU member states not part of the U.S. Visa Waiver Program (VWP), which allows short-term visitors to enter the United States without a visa. Greece had failed to meet the eligibility criteria by the time the program was frozen after 9/11. After the Greek government began issuing the more secure passports in 2006, it made joining the VWP a high priority. The Department of Homeland Security is conducting a process to include Greece in the VWP. H.R. 2261, introduced on May 5, 2009, would designate Greece a program country for the purpose of the VWP. On June 16, 2009, Assistant Secretary of State for European and Eurasian Affairs Philip Gordon told the House Foreign Affairs Committee that he thought that the process was near an end. Greece values its role as an international energy hub in order to guarantee its own energy security and to collect transit fees. Yet, the Bush Administration was concerned about planned Greek energy links to Russia (i.e., the Burgos-Alexandroupolis oil pipeline from Russia via Bulgaria to Greece and the South Stream natural gas pipeline from Russia, Bulgaria, and Greece to Italy and Austria). This was because the Administration thought that the pipelines would increase Greek dependence on Russia, which already supplies 80% of its natural gas, and undermine efforts to ensure Europe's energy security by diversifying sources from excess dependence on Russia. In line with this view, the Bush Administration welcomed plans for the Turkey-Greece-Italy (TGI) pipeline that will bypass Russia to supply Azerbaijani natural gas to Europe. The Obama Administration's Special Envoy for Eurasian Energy Richard Morningstar has said that the Administration is neither "for" nor "against" South Stream. Although official U.S.-Greek relations are generally cordial, there is a strong strain of anti-Americanism in Greece, stemming from U.S. support for the Greek military junta that ruled from 1967-1974 and perceptions of U.S. failure to prevent the Turkish invasion of/intervention in Cyprus in 1974, among other issues. Unsupported allegations of U.S. interference in domestic Greek political affairs surface regularly. Anti-American sentiment is manifest in periodic mass demonstrations mobilized by Communists, anarchists, unions, antiwar activists, and anti-globalization forces, whose influence is disproportionate to their numbers in society. | Summary: The Greek city-state of Athens is believed to have developed the first known democracy around 500 B.C. Modern Greece has been a democracy since the toppling of a military junta in 1974. Since then, the New Democracy (ND) party and the PanHellenic Socialist Movement (PASOK) have alternated leadership of the government. ND ruled from March 2004 until October 4, 2009, when PASOK won national elections and a clear majority of the seats in parliament. PASOK's victory has been attributed to anti-ND public sentiment caused by the economic recession, corruption scandals, and law-and-order issues. On taking power, PASOK inherited a severe financial crisis: economic growth has contracted for three consecutive quarters in 2009, and the budget deficit is projected to be 12.7.% of gross domestic product (GDP) and debt to be 125% of GDP in 2010. Therefore, the economy is the dominating issue on the government's agenda. The Greek government's foreign policy focuses on the European Union (EU), sometimes-strained relations with Turkey, reunifying Cyprus, resolving a dispute with Macedonia over its name, other Balkan issues, and sustaining good relations with the United States. Greece has assisted with the war on terrorism, but is not a member of the U.S.-led coalition in Iraq and has a limited presence with NATO in Afghanistan. See also CRS Report RL33497, Cyprus: Status of U.N. Negotiations and Related Issues, by [author name scrubbed]. | 7,536 | 366 | gov_report | en |
Summarize: Last night, during a talk at Stanford University, former Speaker of the House John Boehner was extremely blunt when asked for his opinion on Ted Cruz: “Lucifer in the flesh,” the former speaker said. “I have Democrat friends and Republican friends. I get along with almost everyone, but I have never worked with a more miserable son of a bitch in my life.” I like this Boehner! Something about “the enemy of my enemy” comes to mind… In any case, is Ted Cruz really the Devil incarnate? I asked The Satanic Temple to weigh in — after all, they have a vested interest in this matter — and spokesperson Lucien Greaves told me this: Cruz’s failures of reason, compassion, decency, and humanity are products of his Christian pandering, if not an actual Christian faith. It grows tedious when pedophile priests and loathsome politicians are conveniently dismissed as Satanic, even as they spew biblical verse and prostrate themselves before the cross, recruiting the Christian faithful. Satanists will have nothing to do with any of them. You know things are bad in the Republican Party when even Satanists are saying you’re too extreme for us. But that’s exactly the problem, isn’t it? People assume the worst about them, when the truth is Satanists are far more inclusive and tolerant than modern day Christians. (Image via Medill DC on Flickr) Rep. Peter King is no fan of Sen. Ted Cruz. AP Photo Rep. Peter King: Cruz gives Lucifer a bad name Peter King really hates Ted Cruz, so much so that he suggested John Boehner gave the devil a bad name by comparing him to the Texas senator. In an interview with CNN, the New York Republican congressman told Wolf Blitzer he agreed with the former House speaker, who called Cruz “Lucifer in the flesh” on Wednesday night. “Maybe he gives Lucifer a bad name by comparing him to Ted Cruz,” King said. “Listen, what John Boehner was most concerned about was Ted Cruz perpetrated a fraud and a hoax when he brought about the shutdown of the government on some kind of a vague promise that he was gonna be able to take Obamacare out of the budget or to end Obamacare.” King argued that Cruz knew his strategy would never work, but he did it anyway. He “shut down the government, cost the government money” and “served no purpose whatsoever other than to boost his name identification.” Ahead of New York's primary earlier this month, King, who voted for John Kasich to send a message to Donald Trump, said he hates Cruz and would take cyanide if he ever won the GOP nomination. Trump often ridicules Cruz on the trail for his lack of support among his congressional colleagues, proudly boasting that Alabama Sen. Jeff Sessions endorsed his campaign over Cruz, who often cited him in his stump speeches. While a handful of former Republican presidential candidates have supported his candidacy in an effort to stop Trump from being the party’s standard-bearer, members of Congress have been slow to voice their support for the senator, even if they’ve voted for him in the Republican primary. Sens. Ben Sasse of Nebraska and Pat Toomey of Pennsylvania, for example, have voted for Cruz, but they haven’t formally endorsed him, like Sens. Lindsey Graham of South Carolina, Mike Lee of Utah and Cory Gardner of Colorado. If Satanists were angry at Ted Cruz before, they certainly won't be happy with him now. Hours after former House Speaker John Boehner told a crowd at Stanford University that one of the most unpopular men in the Senate was "Lucifer in the flesh," it appears the Prince of Darkness has had his identity hijacked even further. The URL Lucifer2016.com reroutes directly to CruzCarly.com, the campaign site set up by the Cruz campaign following his announcing rival Carly Fiorina as his running mate. Looks like somebody really took Boehner's words and ran with them. There is, of course, no love lost between the man who was once third in line for the presidency and Cruz, who's widely credited as being responsible for the 16-day government shutdown in 2013. "I have Democrat friends and Republican friends," Boehner said in an appearance reported by the Stanford Daily. "I get along with almost everyone, but I have never worked with a more miserable son of a b**** in my life." Boehner even went so far as to say that he would vote for Donald Trump come November, but that he would never vote for Cruz. The Texas senator fired back later that day, saying, "What Boehner is angry at is me standing with the American people." As of Thursday afternoon, Satan2016.com was still available on GoDaddy. (As was Jesus2016.com.) --Eder Campuzano 503.221.4344 @edercampuzano [email protected] | Summary: Likening Ted Cruz to "Lucifer in the flesh" is deeply unfair to the Dark One, according to annoyed Satanists. After John Boehner made the comparison, adding that he had "never worked with a more miserable son of a bitch," the Satanic Temple was quick to distance itself from Cruz, Raw Story reports. "Cruz's failures of reason, compassion, decency, and humanity are products of his Christian pandering, if not an actual Christian faith," a temple spokesman tells the Friendly Atheist blog. "It grows tedious when pedophile priests and loathsome politicians are conveniently dismissed as Satanic, even as they spew biblical verse and prostrate themselves before the cross, recruiting the Christian faithful. Satanists will have nothing to do with any of them." Cruz is notoriously unpopular among his fellow Republicans, some of whom agreed that Boehner was doing Satan a disservice, Politico reports. "Maybe he gives Lucifer a bad name by comparing him to Ted Cruz," New York Rep. Peter King said. "Listen, what John Boehner was most concerned about was Ted Cruz perpetrated a fraud and a hoax when he brought about the shutdown of the government on some kind of a vague promise that he was gonna be able to take ObamaCare out of the budget or to end ObamaCare." The Oregonian reports that in a development that may anger Satanists further, the domain Lucifer2016.com now redirects to Cruz's new CruzCarly.com website. | 1,109 | 338 | multi_news | en |
Summarize: By. Daily Mail Reporter. PUBLISHED:. 17:16 EST, 3 January 2014. |. UPDATED:. 18:13 EST, 3 January 2014. An Orthodox Jewish real estate developer was allegedly kidnapped, taped up and thrown into a van outside his Brooklyn office in the midst of the blizzard late on Thursday night. The family of Menachem Stark, 40, offered a $100,000 'no questions asked' reward for his safe return on Friday, as police combed through surveillance video that appears to show his abduction. Officers say the incident happened at around 11.20pm, when Stark was grabbed by two men on Rutledge Street in South Williamsburg. Some reports suggest he was carrying $4,000 in cash. Missing: Police are looking for Jewish Orthodox real estate developer Menachem Stark, who was allegedly kidnapped from outside his office in Willliamsburg on Thursday night. Hunt: Police and the Willliamsburg community are looking for clues on the light-colored Dodge minivan (circled) which Stark appears to have been bundled into. DNA Info reported that Stark was approached and manhandled into a light-colored van by two men as he left his office at Southside Associates at 331 Rutledge Street. His wife Bashie apparently became concerned when Stark did not return after midnight and contacted Shomrim, a neighborhood patrol group for the Orthodox community. Surveillance footage was then discovered in Stark's office that shows a struggle with one man, before the van pulls up and he is wrestled by two men into the vehicle. Stark's brothers Yitzy and Yoely told the New York Post: 'We saw two people fighting with him, and they put him into a big white van, a Dodge Caravan,' Yitzy, 30, said. Investigations: The incident is being looked into by the police and the Shomrim, a neighborhood patrol group for the Orthodox community, who produced this report. The brothers described Menachem's alleged attackers to the Post as 'big' and 'black.' The New York Daily News reported that Stark was carrying $4,000 in cash, but Yitzy Stark denied this when he offered the six-figure reward for his brother's return. 'We're waiting for a phone call with demands. [We're] just hoping that he is still alive,' Yitzy told DNA Info. 'We'll do anything they ask.' Shomrim reportedly informed the NYPD of the incident at around 2.30 a.m. on Friday. Both the police and the community are now looking for clues on the white Dodge minivan. Officials spent the day in the local area conducting interviews and reviewing surveillance footage from local businesses. The Real Deal claimed that Stark, and associate Israel Perlmutter, were being sued more than $51 million in 2011, over loans for development projects in Williamsburg and Greenpoint. Scene: Stark was reportedly grabbed from outside his office on Rutledge Street in South Williamsburg, seen in this file photo. And a number of tenants who claimed to live in properties owned by Southside Associates have left a number of angry complaints on sites such as Yelp about the condition and maintenance of the apartments, also describing Stark as a'slumlord.' One user wrote: 'These people are absolutely terrible. It's as though they have no hearts and no compassion for anyone else. All they seem to care about is their bank account.' Yitzy Stark described his brother to the Daily News as 'a good man, a great man.' 'Nobody around here would say anything bad about him,' he added | Summary: Menachem Stark, 40, allegedly kidnapped from outside his New York office during the blizzard on Thursday. Two men reportedly forced Stark into a white Dodge minivan. His family has put up a $100,00 reward for his safe return. Brother Yitzy describes Menachem as a 'good man, a great man' But former tenants have complained online about properties owned by Stark's company and called him a'slumlord' | 843 | 104 | cnn_dailymail | en |
Summarize: Former CBS CEO Les Moonves will not receive his $120 million severance package following a sexual misconduct probe, the company's board of directors announced Monday evening. "With regard to Mr. Moonves, we have determined that there are grounds to terminate for cause, including his willful and material misfeasance, violation of Company policies and breach of his employment contract, as well as his willful failure to cooperate fully with the Company's investigation," the board said in a statement. The media executive resigned from his role at the company in September after a dozen women came forward alleging sexual misconduct. Moonves has denied the accusations of nonconsensual sexual relations. CBS shares were up slightly in extended trade. The stock has fallen sharply this year, declining nearly 20 percent since the start of 2018. A version of the report prepared for the CBS board said that Moonves destroyed evidence and misled investigators, The New York Times reported earlier this month. The lawyers wrote that they found Moonves to be "evasive and untruthful at times and to have deliberately lied about and minimized the extent of his sexual misconduct." Andrew Levander, Moonves's attorney, told the Times that Moonves "cooperated extensively and fully with investigators." Activist groups immediately praised the board's decision. "CBS has heard our call! No golden parachute for Moonves," the National Organization for Women's New York chapter wrote on Twitter. The group protested against Moonves's severance package last week at CBS's annual shareholders meeting. The company said that its inquiry into Moonves, CBS News and "cultural issues at CBS" did not turn up evidence of pervasive problems related to harassment and retaliation. But it noted investigators did uncover incidents of "improper and unprofessional conduct." Given the size of CBS's business, investigators concluded that the company was not providing adequate resources to its human resources department, to training and development, or for diversity and inclusion initiatives. The statement said that the company's "historical policies, practices and structures have not reflected a high institutional priority on preventing harassment and retaliation." The company said that it had already begun to take "robust steps" to improve its workplace. "Among other things, the Company appointed a new Chief People Officer, is actively engaged in ways to enhance and reimagine the Human Resources function, and has retained outside expert advisors to develop other initiatives for promoting a workplace culture of dignity, transparency, respect and inclusion," the statement said. The CBS board of directors has denied former chairman-CEO Leslie Moonves any of the $120 million severance he was due under his employment contract after conducting a five-month internal probe of his conduct and the corporate culture at CBS Corp. “We have determined that there are grounds to terminate for cause, including his willful and material misfeasance, violation of Company policies, and breach of his employment contract, as well as his willful failure to cooperate fully with the Company’s investigation. Mr. Moonves will not receive any severance payment from the Company,” the board said in a statement on Monday. CBS’ longtime leader was forced out on Sept. 9 amid a cascade of sexual assault and misconduct allegations. The probe reportedly found damning allegations of Moonves abusing his power as CEO and engaging in shocking instances of sexual misconduct with employees at CBS. The move sets the stage for a long legal battle, starting in arbitration, between CBS and Moonves. Moonves has denied many of the allegations against him and maintained that his sexual encounters were consensual. Moonves’ attorney Andrew Levander, of Dechert LLP, blasted the probe and its conclusions, and he denied the assertion that Moonves tried to mislead or lie to investigators. “The conclusions of the CBS board were foreordained and are without merit. Consistent with the pattern of leaks that have permeated this ‘process,’ the press was informed of these baseless conclusions before Mr. Moonves, further damaging his name, reputation, career, and legacy,” Levander said. “Mr. Moonves vehemently denies any non-consensual sexual relations, and cooperated extensively and fully with investigators.” After the torrent of accusations, the CBS board was under pressure from women’s advocacy groups, shareholder rights activists, and others to deny Moonves his nine-figure golden parachute. The pressure stepped up after a preliminary draft of the probe, full of shocking details, was obtained by the New York Times. It’s understood, as reported by the Wall Street Journal, that the final report in the investigation led by lawyers at Covington & Burling and Debevoise & Plimpton was delivered Monday in a long verbal presentation to CBS board members rather than in written form. “While CBS still has a long way to go to fully rid itself of the toxic culture of abuse that Moonves perpetuated, this is a strong step in the right direction,” said Shaunna Thomas, executive director of advocacy group UltraViolet, which has been vocal amid the #MeToo outpouring of the past 18 months. As for the company as a whole, the board asserted that the investigators “concluded that harassment and retaliation are not pervasive at CBS.” But it faulted the company for protecting high-profile and successful employees in the past and not devoting enough resources to preventing harassment. “The investigators learned of past incidents of improper and unprofessional conduct, and concluded that the Company’s historical policies, practices, and structures have not reflected a high institutional priority on preventing harassment and retaliation,” the board stated. “The investigation determined that the resources devoted to the Company’s Human Resources function, to training and development, and to diversity and inclusion initiatives have been inadequate, given the size and complexity of CBS’ businesses. Employees also cited past incidents in which HR and the Company did not hold high performers accountable for their conduct and protect employees from retaliation.” The board’s determination that Moonves was fired for cause amid numerous violations of CBS policy for employees comes after the CBS board of directors has been overhauled following his ouster. Six new members joined the 11-member panel and five longtime directors were forced out by controlling shareholder Shari Redstone, whose National Amusements controls nearly 80% of the voting power in CBS and its corporate sibling Viacom. The sexual misconduct storm around Moonves came up as the then-revered CBS boss engaged in a bold legal battle with Shari Redstone for control of the company that her father, Viacom mogul Sumner Redstone, acquired in 2000. Moonves was previously celebrated for his stewardship of CBS as a programmer and as a business strategist in bucking some of the digital turbulence that traditional media companies have faced. His objection to Shari Redstone’s push for CBS and Viacom to reunite at a time of major consolidation in media was the spark for the lawsuit against Redstone’s National Amusement holding company. Now Moonves’ legacy has been all but destroyed by the drumbeat of sexual assault allegations. The lawsuit, which was a longshot at best, was settled as part of Moonves’ exit agreement, set the day the New Yorker published the second of two damning stories on Moonves’ long history in Hollywood. Moonves is said to be resolute in pursuing the severance through arbitration in order to seek a measure of vindication. Inside CBS, there is deep resentment toward Moonves for deeply tarnishing the network’s legacy as America’s most-watched network with allegations of egregious sexual misconduct too numerous to ignore. As such, the denial of severance and finding that he was fired for cause marks the latest step in the extraordinary downfall of one of the most powerful figures in the entertainment industry during the past 25 years. Moonves’ hasty departure from CBS Corp. has jolted the company, spurring a management overhaul under acting CEO Joe Ianniello amid expectations that merger discussions will begin once again for CBS Corp. and Viacom after the new year. Internally, CBS is roiling from the Times’ continued revelations from the report about settlements and disturbing allegations about the behavior of some insiders. Last week, the Times reported that CBS paid nearly $10 million in a settlement to actor Eliza Dushku after she raised complaints about alleged verbal harassment from Michael Weatherly, star of the CBS drama “Bull.” The investigation began in August in the wake of allegations of assault and misconduct made against Moonves in Farrow’s New Yorker exposes. Moonves has maintained all sexual encounters were consensual and denied other allegations, including being violent with women. In response, the CBS board hired two top-flight legal firms, although the choice of Covington and Debevoise was criticized as both firms have done corporate work for CBS in recent years, raising the question of whether they would go easy on the company to protect future business. An investigation into the culture of CBS News, which had started earlier in the year of #MeToo after former “CBS This Morning” co-anchor Charlie Rose left in the wake of harassment allegations, was rolled up into the larger probe. Moonves is facing allegations that he was evasive and at times misled investigators during the probe. He was reported by the Times to have turned over his son’s iPad instead of his own. The allegations against Moonves included the assertion that he kept a woman on the payroll for the purpose of providing oral sex on call, according to the Times. Moreover, a picture of desperation around Moonves was painted by another report in the Times last month. In the months before the first damning New Yorker expose hit in July, Moonves according to the Times, courted down-and-out talent manager Marv Dauer for the purpose of keeping him and his actor client Bobbie Phillips quiet about a March 1995 incident during a meeting at Moonves’ office at Warner Bros. Television. He reportedly pushed CBS executives to offer Phillips a role on a network series to persuade her from talking about the decades-old encounter in which she alleges he exposed himself, grabbed her by the neck, and forced his erect penis into her mouth. Moonves told the Times that he “strongly believe(s)” the encounter was consensual. The board statement pointed to CBS’ appointment of Laurie Rosenfield as chief people officer, with a mandate to improve the company’s focus and training for employees on matters of sexual harassment and workplace retaliation issues, as well as diversity and inclusion. The statement also acknowledged the internal unrest stirred by Moonves’ downfall and the lengthy probe. “We would like to thank everyone who cooperated with the investigation and applaud CBS’ employees for remaining focused on their jobs during this very difficult time. We look forward to the people of CBS returning their full attention to the outstanding work that they do every single day.” Ianniello sought to emphasize the company’s effort to address the shortcomings exposed by the months-long Moonves scandal in a memo sent to CBS employees. The memo included the board’s statement and cited internal avenues for employees to flag problems or raise concerns, including direct lines to HR executive at each of the company’s major divisions. Here is part of Ianniello’s memo: I’m sure we all agree that it’s good to have the investigation behind us. At the same time, this does not mean that our work is done, or that we don’t have significant improvements that will continue to be made. Our commitment to a safe, collaborative and inclusive workplace is ongoing, and remains a top priority for us. In order to honor that commitment, I want to outline and refresh the many avenues our employees have to report complaints or other incidents that you feel are contrary to CBS policies. Additionally, as noted in the Board’s statement, we need to add resources and enhance our existing HR function. I look forward to communicating more about this soon. I hope you are as proud as I am to be a part of this great Company. More than anything else, our success will continue to be tied to the quality of the people we retain and attract, and we must aspire to have the very best. So thank you for your continued commitment to CBS, and here’s to a great 2019. Joe FILE - In this July 29, 2013, file photo, Les Moonves arrives at the CBS, CW and Showtime TCA party at The Beverly Hilton in Beverly Hills, Calif. CBS is pledging $20 million in grants to 18 organizations... (Associated Press) FILE - In this July 29, 2013, file photo, Les Moonves arrives at the CBS, CW and Showtime TCA party at The Beverly Hilton in Beverly Hills, Calif. CBS is pledging $20 million in grants to 18 organizations... (Associated Press) NEW YORK (AP) — CBS on Friday pledged to give $20 million to 18 organizations dedicated to eliminating sexual harassment in the workplace as the network tries to recover from a scandal that led to the ouster of its top executive, Les Moonves. The announcement comes as the network's crisis deepens, with details emerging from an ongoing investigation into Moonves' conduct and news surfacing of other instances of sexual misconduct at CBS. In the latest revelation, CBS acknowledged that it reached a $9.5 million confidential settlement last year with actress Eliza Dushku, who said she was written off the show "Bull" in March 2017 after complaining about on-set sexual comments from its star, Michael Weatherly. Some women's rights activists called on CBS to fire Weatherly. The funds for the grants to the 18 organizations are being deducted from severance owed to Moonves under his contract, and the company had previously said the former CEO would have a say in which groups would receive the money. But whether Moonves, who was one of the television industry's most powerful executives, receives the remaining $120 million of his severance hinges on the investigation, which is being conducted by two outside law firms. The company has said Moonves would not be entitled to the severance if its board of directors determines he was fired for cause. CBS said its donation to the 18 groups will go toward helping expand their work and "ties into the company's ongoing commitment to strengthening its own workplace culture." Among the recipients are Catalyst, a 56-year-old organization dedicated to empowering women in the workplace, and several groups that have emerged as prominent voices since the downfall last year of Hollywood producer Harvey Weinstein, which triggered an avalanche of sexual misconduct allegations against powerful men across several industries. The 18 organizations issued a joint statement praising the donations as a first step while calling on CBS to disclose the results of the Moonves investigation and the company's efforts to rectify practices that may have enabled misconduct. "We thank CBS for these donations. We also recognize these funds are not a panacea, nor do they erase or absolve decades of bad behavior," the groups said. Moonves was ousted in September after the New Yorker published allegations from 12 women who said he subjected them to mistreatment that included forced oral sex, groping and retaliation if they resisted. Moonves has denied having any non-consensual sexual relationships. Two other major figures at CBS have lost their jobs in the past year over misconduct allegations: "60 Minutes" top executive Jeff Fager, and news anchor Charlie Rose. The New York Women's Foundation said it is receiving $2.25 million from CBS to support its "Fund for the Me Too Movement and Allies," which is co-led by #MeToo founder Tarana Burke. The fund invests in community organizations nationwide dedicated to fighting sexual violence and harassment. Ana Oliveira, the foundation's president and CEO, said the donation will help give survivors of sexual misconduct a voice in developing solutions. But she urged CBS to do the same within its own organization. "Those who have lived through the issues have some of the best solutions. This is not a conversation about the perpetrators. CBS needs to do its own work there," Oliveira said. Other grant recipients include Time's Up, a Hollywood-based group promoting gender equity in the workplace, and Press Forward, an organization of women dedicated to fighting sexual harassment in the news industry. Time's Up Entertainment said it will use its $500,000 from CBS to launch an initiative to increase the presence of people of color and of different social backgrounds in the entertainment industry's producing and executive ranks. Carolyn McGourty Supple, co-founder of Press Forward, said the new funding would accelerate her group's programs, which include a partnership with the Poynter Institute to develop innovative sexual-harassment training and a study on the state of women in America's newsrooms. She said Press Forward has been "very encouraged" by the willingness of CBS News' leadership "to engage with us." "We have faith that we will work side by side to make sure our newsrooms are places where journalists do their best work," McGourty Supple said. The entertainment business of CBS, however, is facing new outcry over the revelations about "Bull" star Weatherly, which were first reported by The New York Times. Shaunna Thomas, executive director of the women's rights organization UltraViolet, said CBS tried to sweep "his abuse under the rug" and "must immediately move to fire Michael Weatherly." Melissa Silverstein, founder of the "Women and Hollywood" initiative, tweeted that she was "still wondering why" Weatherly has a job. Neither UltraViolet nor Silverstein's group received funds from CBS. Weatherly, who appeared on the CBS series "NCIS" for 13 years before "Bull" began in 2016, said in an email to the Times that he had apologized to Dushku after she confronted him. Weatherly's manager, Doug Wald, has not responded to Associated Press requests for additional comment. In a September interview with the AP, Weatherly said his long history with CBS made it difficult to comment on the Moonves scandal. "Not to get into any of the ifs, ands or buts about what is right or wrong and where it comes from," Weatherly said then. "Professionally I owe a great part of my career to the decision-making of the higher-ups at the company. It's a complicated place to be." For more than twenty years, Leslie Moonves has been one of the most powerful media executives in America. As the chairman and C.E.O. of CBS Corporation, he oversees shows ranging from “60 Minutes” to “The Big Bang Theory.” His portfolio includes the premium cable channel Showtime, the publishing house Simon & Schuster, and a streaming service, CBS All Access. Moonves, who is sixty-eight, has a reputation for canny hiring and project selection. The Wall Street Journal recently called him a “TV programming wizard”; the Hollywood Reporter dubbed him a “Wall Street Hero.” In the tumultuous field of network television, he has enjoyed rare longevity as a leader. Last year, according to filings with the Securities and Exchange Commission, he earned nearly seventy million dollars, making him one of the highest-paid corporate executives in the world. In recent months, Moonves has become a prominent voice in Hollywood’s #MeToo movement. In December, he helped found the Commission on Eliminating Sexual Harassment and Advancing Equality in the Workplace, which is chaired by Anita Hill. “It’s a watershed moment,” Moonves said at a conference in November. “I think it’s important that a company’s culture will not allow for this. And that’s the thing that’s far-reaching. There’s a lot we’re learning. There’s a lot we didn’t know.” But Moonves’s private actions belie his public statements. Six women who had professional dealings with him told me that, between the nineteen-eighties and the late aughts, Moonves sexually harassed them. Four described forcible touching or kissing during business meetings, in what they said appeared to be a practiced routine. Two told me that Moonves physically intimidated them or threatened to derail their careers. All said that he became cold or hostile after they rejected his advances, and that they believed their careers suffered as a result. “What happened to me was a sexual assault, and then I was fired for not participating,” the actress and writer Illeana Douglas told me. All the women said they still feared that speaking out would lead to retaliation from Moonves, who is known in the industry for his ability to make or break careers. “He has gotten away with it for decades,” the writer Janet Jones, who alleges that she had to shove Moonves off her after he forcibly kissed her at a work meeting, told me. “And it’s just not O.K.” Thirty current and former employees of CBS told me that such behavior extended from Moonves to important parts of the corporation, including CBS News and “60 Minutes,” one of the network’s most esteemed programs. During Moonves’s tenure, men at CBS News who were accused of sexual misconduct were promoted, even as the company paid settlements to women with complaints. It isn’t clear whether Moonves himself knew of the allegations, but he has a reputation for being closely involved in management decisions across the network. Some of the allegations, such as those against the former anchor Charlie Rose, as reported by the Washington Post, have already become public. Other claims are being reported here for the first time. Nineteen current and former employees told me that Jeff Fager, the former chairman of CBS News and the current executive producer of “60 Minutes,” allowed harassment in the division. “It’s top down, this culture of older men who have all this power and you are nothing,” one veteran producer told me. “The company is shielding lots of bad behavior.” In a statement, Moonves said, “Throughout my time at CBS, we have promoted a culture of respect and opportunity for all employees, and have consistently found success elevating women to top executive positions across our company. I recognize that there were times decades ago when I may have made some women uncomfortable by making advances. Those were mistakes, and I regret them immensely. But I always understood and respected—and abided by the principle—that ‘no’ means ‘no,’ and I have never misused my position to harm or hinder anyone’s career. This is a time when we all are appropriately focused on how we help improve our society, and we at CBS are committed to being part of the solution.” According to CBS, there have been no misconduct claims and no settlements against Moonves during his twenty-four years at the network. A statement from the company said, “CBS is very mindful of all workplace issues and takes each report of misconduct very seriously. We do not believe, however, that the picture of our company created in The New Yorker represents a larger organization that does its best to treat its tens of thousands of employees with dignity and respect. We are seeing vigorous discourse in our country about equality, inclusion, and safety in the workplace, and CBS is committed to being part of the solution to those important issues.” The allegations are surfacing at a time when CBS is engaged in an increasingly acrimonious fight with its former parent company, Viacom, which acquired CBS in 1999 and spun it off as a separate entity seven years later. A holding company founded by the mogul Sumner Redstone still owns a majority stake in both Viacom and CBS, and Redstone’s daughter and heir, Shari Redstone, has sought to reunite the businesses. Moonves has resisted the move, and in May Redstone’s holding company and CBS filed lawsuits against each other. All of the women making allegations against Moonves began speaking to me before the current lawsuits, in independent interviews carried out during the past eight months. All said that they were not motivated by any allegiance in the corporate battle. But several felt that this was an opportunity to examine a workplace culture that many of the women in this story described as toxic. Illeana Douglas, who later received an Emmy nomination for her role in HBO’s “Six Feet Under,” was introduced to Moonves in 1996. At the time, she was meeting with networks, looking for a deal to write and perform for television. Moonves, who was then the president of CBS Entertainment, seemed to take a personal interest in her. He told Douglas that he was a fan of her performances in the Martin Scorsese films “Cape Fear” and “Goodfellas,” and urged her to work with CBS. “There was the big sell—he was telling me, ‘You’re gonna get a house with a pool, you’re gonna love it, it’s a great life,’ ” Douglas recalled. She agreed to sign a holding deal with CBS, which promised to pay her three hundred thousand dollars to appear exclusively in the network’s programs. CBS ultimately didn’t proceed with a pilot that Douglas wrote, but the network cast her in a comedy called “Queens,” as an eccentric native of the New York borough. In March, 1997, shortly before production of the pilot episode began, Moonves called Douglas’s manager, Melissa Prophet, and told her that he was concerned about Douglas’s attitude during a reading with her co-star, Penelope Ann Miller. Prophet relayed the concern to Douglas, who was surprised and confused: the reading, in front of a group of CBS executives, had elicited uproarious laughter. Moonves, she said, had taken her by the shoulders and congratulated her. Moonves had told Prophet that he wanted to meet with Douglas, alone, to insure that they were creatively aligned. (Prophet told me that she did not recall the conversation or setting up the meeting.) By then, Douglas had worked closely with Moonves for months. “He seemed more than just my boss,” she told me. “He was very much like a father figure.” When Douglas met with Moonves at his office, she began to raise concerns about the “Queens” script, but Moonves, she recalled, cut her off. “He interrupts me to ask me am I single,” she said. Douglas, whose nearly decade-long relationship with Scorsese was coming to an end, was caught off guard. “I didn’t know what to say at that point,” she told me. “I was, like, ‘I’m single, yes, no, maybe.’ ” She began talking about the script, but Moonves interjected, asking to kiss her. According to Douglas, he said that they didn’t have to tell her manager: “It’ll just be between you and me. Come on, you’re not some nubile virgin.” As Douglas attempted to turn the focus back to work, Moonves, she said, grabbed her. “In a millisecond, he’s got one arm over me, pinning me,” she said. Moonves was “violently kissing” her, holding her down on the couch with her arms above her head. “What it feels like to have someone hold you down—you can’t breathe, you can’t move,” she said. “The physicality of it was horrendous.” She recalled lying limp and unresponsive beneath him. “You sort of black out,” she told me. “You think, How long is this going to go on? I was just looking at this nice picture of his family and his kids. I couldn’t get him off me.” She said it was only when Moonves, aroused, pulled up her skirt and began to thrust against her that her fear overcame her paralysis. She told herself that she had to do something to stop him. “At that point, you’re a trapped animal,” she told me. “Your life is flashing before your eyes.” Moonves, in what Douglas assumed was an effort to be seductive, paused and asked, “So, what do you think?” Douglas told me, “My decision was to get out of it by joking my way out, so he feels flattered.” Thinking that reminding Moonves that he was her boss might discourage him, she told him, “Yes, for the head of a network you’re some good kisser.” Moonves frowned and got up. She scrambled to find her briefcase. “Well, this has been great. Thanks,” she recalled saying, moving toward the door. “I’ve got to go now.” Moonves, she said, followed her to the door and blocked her path. He backed her up to the wall, pressing against her, with his face close to hers. “It was physically scary,” Douglas told me. “He says, ‘We’re going to keep this between you and me, right?’ ” Attempting to put him off with a joke, she replied, “No, sir, we won’t tell anyone that you’re a good kisser.” Moonves released her and, without looking at her, walked away. “It was so invasive,” she said of the threatening encounter. “It has stayed with me the rest of my life, that terror.” Outside Moonves’s office, she began to cry. “My skirt is all twisted,” she recalled. “I’m standing in the hall and I thought of his family.” Moonves’s assistant, sitting nearby, asked whether her parking needed to be validated. Douglas told me, “I remember thinking, Does she know? Does this happen all the time?” In her car, Douglas said, “I lost it. I felt sick.” Prophet, her manager, called and, as Douglas worked up the nerve to tell her what had happened, Prophet said that she had just got off the phone with Moonves. He’d said that he and Douglas had a great meeting and “had a lot of fun.” Douglas told me, “I thought, Oh, my God, he’s covered his tracks.” In that moment, she said, “I decided, just bury it.” Later that day, Douglas returned to the house she was renting and told a friend who was staying with her, the actor Craig Chester, about the incident. “She was trying not to cry, but her voice was shaking. I’ve never seen her that emotional before,” Chester recalled. “She said that he got on top of her and held her down and she couldn’t get away. If it was any other situation outside business, I would have said, ‘Let’s go to the cops.’ ” But, Chester said, “there was no talk about going to the police or anything like that, because it was obvious that it would be career suicide.” The following week, Moonves showed up at the first day of rehearsals for “Queens.” “As soon as I saw him, I thought I was going to collapse. Everything came back to me. I was shaking,” Douglas told me. She felt that Moonves’s demeanor was intended to intimidate her. “He was eying me warily,” she said. Her distress was evident to her co-stars. “There was obviously something going on with her emotionally,” Penelope Ann Miller told me. “When she came in to test, everything was on. And then, after, on set, it was like she wasn’t there.” Last year, before the rise of #MeToo, Douglas told Miller what had happened. “Hearing her story, it all made sense,” Miller recalled. After the second rehearsal, Moonves took Douglas aside. “ ‘What the fuck do you think you’re doing out there? You’re not even trying,’ ” Douglas recalled Moonves saying. She took it as a reference to her failure to comply with his advances and to maintain her composure afterward. Douglas told me that she had “played by all the rules, I didn’t say anything, and now he was berating me.” On set, she struggled to keep her comedic timing, and cried in front of other cast members. Several days into rehearsals, Moonves called Douglas at home. “It was, you know, ‘You make me fucking sick. You are not funny,’ ” she recalled. Moonves told her that she wouldn’t “get a fucking dime” of the money she was owed, and that she would “never work at this network again.” (In a statement, CBS said that Moonves acknowledges trying to kiss Douglas, but that “he denies any characterization of ‘sexual assault,’ intimidation, or retaliatory action,” including berating her on set and personally firing her from “Queens.”) Prophet told me that Moonves and CBS Business Affairs called her to say that Douglas would be replaced on the show and that her deal would be cancelled. According to Douglas, Prophet called her and “said I’d burned all my bridges at CBS, that she was firing me.” (Prophet recalled firing Douglas and said that the two had a heated exchange. She said that she didn’t know about Douglas’s allegation, and denied the comment about burning bridges. “There are no bridges at CBS,” she said. “There is just Les Moonves.”) Douglas said that her agent, Patrick Whitesell, who was then at Creative Artists Agency, later called to say that the agency wished her well in future endeavors of her own. “I love the way C.A.A. fired me,” Douglas said. “They never told me I was fired. They just kept wishing me the best of luck.” (Whitesell told me that he had not been aware of Douglas’s allegation and did not recall that her departure from C.A.A. was related to the dissolution of her CBS deal.) Distraught, Douglas called Scorsese and told him the story, saying that she wanted to hire a lawyer and sue Moonves. Scorsese said that he remembers Douglas calling him about the allegation and being shocked by it. Scorsese urged her to be cautious about taking legal action against such a powerful person, but agreed to refer her to his law firm; there, Douglas began working with an attorney named Bill Sobel. Sobel confirmed that Douglas had described the encounter with Moonves at the time, and his contemporaneous notes back up her account. “I believed Illeana,” he told me. “What happened to her was reprehensible.” Douglas told me that Sobel warned her that it was a matter of her word against Moonves’s. Sobel, who said that he had a frank conversation with Douglas about the risks of suing, ultimately called CBS to attempt to recoup some of her lost wages. (She had received a fifty-thousand-dollar advance payment for her appearance in the “Queens” pilot, but felt that she was owed the remaining two hundred and fifty thousand.) After a junior staff member at CBS Business Affairs told Sobel that Douglas had been fired because of her poor performance in rehearsals, and that the network intended to withhold her pay, Sobel suggested that he ask Moonves about the meeting he had had alone with Douglas. “My conversation was simply ‘Hey, ask Les what happened in the room, and he’ll probably want you to do the right thing here,’ ” Sobel told me. “I felt he knew what I was saying.” According to communications and contracts reviewed by The New Yorker, the head of CBS Business Affairs, rather than the junior staffer, replied to Sobel with a new proposition. “When the head of the whole thing called me back,” Sobel said, “it was very clear to me that they took my comments about what happened in the room very seriously.” CBS proposed that the agreement be “settled out” for a hundred and twenty-five thousand dollars, and then agreed to pay Douglas an additional two hundred and fifty thousand to appear in a new miniseries. Douglas and Sobel both saw the miniseries as cover for a settlement; she didn’t even know what the show was about. “I go from being sexually assaulted, fired for not having sex with Les Moonves, fired by everyone, to ‘We are going to pay you in full and we also want you to be on this miniseries,’ ” Douglas recalled. “My understanding is, this is what they were going to do in exchange for not suing.” Shortly after the offer came, Douglas received a call from Moonves. “ ‘So, you’re gonna do the mini?’ ” she remembered him asking. Although she wanted accountability, she was still frightened, and said that she would do it. She recalled Moonves, sounding upbeat, remarking, “ ‘Tits and guns, baby. Tits and guns.’ ” (Douglas later learned that the miniseries, called “Bella Mafia,” focussed on the women of an Italian crime family and emphasized sex and violence.) Moonves asked Douglas if they were “O.K.,” and Douglas replied, “Yes, sir.” In its statement, CBS said that the agreement with Douglas about “Bella Mafia” was intended to fulfill her over-all deal with the network, and was unrelated to her meeting with Moonves. “There were no funds added for settlement purposes,” CBS said. “The amount paid was half of what she was owed, which is not what one might do if concerned about a claim such as this.” Jo An Kincaid, an executive producer on the “Queens” pilot and Penelope Ann Miller’s manager at the time, said that she was not consulted about Douglas’s dismissal. “One day she was just not there. Gone and replaced,” Kincaid said. “It was very unusual. I was an executive producer. There should have been an explanation.” In an e-mail, Judge Reinhold, one of Douglas’s co-stars, wrote, “Illeana was hilariously unique in her comedy and fun to work with.” He added, “We were all surprised and disappointed that she left.” Douglas told numerous people about the incident over the years, and even published a lightly fictionalized version of it in a 2006 compilation, “Fired!” She also performed the story before audiences. “I didn’t exactly keep it a secret,” Douglas said. “People used to come up to me afterward and go, ‘I know who it is,’ and just laugh about it.” Douglas appeared in “Bella Mafia,” and, afterward, C.A.A. resumed representing her. But she believes that the incident “derailed any future career I would have had at CBS.” In two instances, years later, personal connections helped her secure acting roles on shows that aired on the network, and a Web series of hers appeared on a CBS streaming service. But otherwise, in a career that has included extensive work with every other major network, she said, “I never auditioned or ever had any kind of television-show deal at CBS.” Like the other women I spoke to, she said that people around her discouraged her from publicly naming Moonves in this story. She told me that she was doing so because she wanted to protect other women, and that she wished she had been warned before her meeting. “In retrospect, of course, you say, ‘Oh, it’s all a crazy setup,’ ” she told me. “I was, I hate to say it, the perfect victim.” More than a decade earlier, in the spring of 1985, Janet Jones was attempting to break into the industry as a writer. The producer Mike Marvin liked an idea that Jones had for a screenplay, and helped broker a meeting between her and Moonves, who at the time was a vice-president at Twentieth Century Fox. It was Jones’s first pitch meeting in Hollywood. Moonves’s assistant scheduled a late-afternoon appointment at his office. When Jones arrived, many employees were leaving for the day, but Moonves’s assistant was there. “I had my briefcase and my pants suit,” Jones recalled. “I was really prepared.” Moonves surprised her by asking if she wanted a glass of wine. She declined, sat down on the couch, and began pitching her screenplay. Suddenly, Jones told me, “he came around the corner of the table and threw himself on top of me. It was very fast.” Moonves, she said, began trying to kiss her. Jones said that she struggled, and then shoved Moonves away hard, yelling, “What do you think you’re doing?” Moonves, appearing startled, got up. “ ‘Well, I was hitting on you. I wanted a kiss,’ ” she recalled him saying. Jones began to leave. “He said, ‘Oh, come on, it’s nothing,’ ” she said. “ ‘Calm down, don’t be so excited.’ ” When Jones got to the door, it was locked. She was terrified. “If you don’t open this door,” she told him, “I am going to scream so loud and so long that everyone on the lot is going to come over.” She remembered Moonves walking to his desk or to a nearby bureau to unlock the door, rather than doing so directly. She fled, noticing on her way out that the assistant had left. “That’s when I got really upset,” she told me. “I just thought, Oh, my God. This wasn’t like a little momentary boo-boo. It was this well-thought-out thing.” Jones drove to the house of a friend, the artist Linda Salzman Sagan. There, Jones told me, “I just completely melted down, just crying and shaking.” Sagan told me that she remembers the visit clearly, and that Jones described the incident in detail at the time. “She was very, very upset,” Sagan recalled. “I had never seen her like that. I was really astounded by what she told me. I knew how powerful he was in terms of a career.” Jones also told her boyfriend at the time, Larry Jackson, who said, “She came home one day scared and in tears because she said Les had jumped her at a business meeting.” Mike Marvin told me that he remembers introducing Jones to Moonves, and that she was troubled by the meeting. He said that he confronted Moonves about it at a gathering, saying, “Whatever happened, that girl was upset.” Moonves, Marvin said, became furious. “We definitely had a screaming match over this,” Marvin told me. Not long afterward, Jones received a call from Moonves’s assistant, who said that she had Moonves on the line. “My heart went into my feet,” Jones recalled. Moonves began shouting at her. “ ‘People’s reputations are important. Do you understand?’ ” she remembered him saying. “ ‘I’m warning you. I will ruin your career. You will never get a writing job. No one will hire you. Do you understand what I’m saying to you?’ ” Jones hung up the phone, then threw up. “I was just absolutely mortified. Does this mean he’ll be putting me on a list somewhere and I’ll never get a job?” she recalled thinking. “This person could stop me from doing this passion, this career I had spent my whole life putting together. It’s kind of hard to fathom that one person could do that, but he could.” (CBS said that Moonves has no recollection of the interactions with Jones.) Jones told me that she found the threats more scarring than the original incident. She said, “The revenge behavior, the ‘I’ll get you for not kissing me, I’ll get you for not doing what the hell I want you to do’—it never quite leaves you.” Years later, she saw him at an industry event and, she said, “I almost fainted. I was still terrified.” Two other women described Moonves forcibly touching or kissing them during business meetings. The producer Christine Peters was an industry veteran when she first encountered Moonves, in the early aughts. She had worked as a story analyst for the company behind “Rain Man” and “Gorillas in the Mist” before becoming a production head for Robert Evans, who had produced “The Godfather” and “Chinatown.” She became a close friend and confidante of Sumner Redstone, the owner of Viacom, to whom she was at times romantically linked in the press. (Peters, like the other women in this story, said that she had no interest in the battle over the future of Redstone’s empire.) After Viacom acquired CBS, Redstone enlisted Peters to help build a rapport with Moonves, who was the president and C.E.O. of CBS Television at the time. They had a series of dinners with Moonves and his wife in 2003 and 2004. Peters produced the 2003 romantic comedy “How to Lose a Guy in Ten Days,” which was based on a book she had acquired, and which ultimately grossed more than a hundred and seventy-seven million dollars. “I was proud to be bringing females into the seats and really addressing them,” she told me. In 2006, Moonves, who had become the chairman of CBS, had dinner with Peters and Redstone to discuss his plans to launch a film studio, CBS Films, which was founded the next year. Moonves was considering executives to oversee the endeavor, and Redstone suggested Peters. Moonves seemed excited about the idea. When Moonves and Peters met at his office to discuss the prospect, Peters told me, she came with a detailed presentation on her business model, which focussed on female audiences. “It was: this is the demographic, here are the underutilized release dates, here’s why female buyers predominate,” she said. “I remember him being very enthusiastic, saying it made a lot of sense.” She was sitting on a couch and, as she continued her pitch, he sat down uncomfortably close. “He said, ‘This is really great,’ ” she recalled. “Then he just put a hand up my skirt.” Moonves, she said, slid his hand up her thigh and touched her underwear. “I was in a state of shock,” Peters recalled. Immediately, she worried about how Moonves would react to a rejection. She tried to get out of the situation by gathering her documents and saying, “Oh, wow, oh, my God, it’s late, I have to be at another meeting. Can we finish this tomorrow? I’m so excited! So excited!” Moonves, she recalled, suggested that he walk her to her car. Fearing further advances, Peters said that she had a driver outside. She had come to the meeting with a colleague, who was waiting in the lobby. The colleague told me that Peters emerged earlier than anticipated, appearing shaken, and said that they had to leave quickly. An acquaintance of Peters’s told me that she recounted the story to him several years ago, describing an advance from a top executive and a job that she didn’t get afterward, without naming Moonves. Last year, Peters told him that the executive was Moonves. (CBS said that Moonves categorically denies any alleged touching or inappropriate conduct during the meeting.) Peters told me, “I remember sitting in the car and just crying. I worked my whole life to be here and I just lost my opportunity.” Because of her long tenure in the industry, Peters said, “I expected to be taken seriously. I never in a million years saw that coming.” She said that she was surprised in part because she thought her relationship with Redstone would have put Moonves on guard. “I couldn’t understand why he would do that in light of the situation with Sumner,” she told me. In the end, she decided not to tell Redstone, because she worried about what the fallout might be. Like Jones, Peters told me that Moonves “was smart enough to not have anyone there. It was a setup.” (Twice in later years, Peters participated in group meetings that involved Moonves.) A prominent actress who played a police officer on a long-running CBS program, who was too frightened of reprisals to use her name, said that she also attended a business meeting with Moonves that ended in unwanted advances. The actress had known Moonves for years. In the late eighties, at the height of her show’s popularity, Moonves, who was then at a production company called Lorimar, requested a lunch meeting at a restaurant. There, Moonves told the actress that he had long had a crush on her but had not said anything to her because she had been in a relationship with a mutual friend. She declined his advance but thanked him for lunch. “It wasn’t offensive,” she recalled. In 1995, when Moonves became president of CBS Entertainment, the actress called to congratulate him. “He said, ‘You should have fucked me when I asked you to,’ and I said, ‘No shit!’ ” the actress told me. They laughed. Soon afterward, CBS Business Affairs informed the actress that her series deal with CBS was being terminated. She called Moonves and expressed shock. He requested a lunch meeting in his private dining room at the office. She told me, “I went in, I thought, to make a deal.” At the lunch, Moonves told her that he intended to focus on younger talent, and that she was too old. “Then he again said, ‘I’ve always been so attracted to you,’ ” she told me. “I was so upset. I said, ‘Jesus, Leslie, I’m gonna go.’ ” Moonves asked her to sit down. She did so, pushing food around her plate until she had to leave. Then, she told me, “I walked over and leaned to give him a kiss on the cheek.” Moonves, she said, grabbed her and forcibly kissed her: “He shoved his tongue down my throat. I mean shoved.” Appalled, she pushed him away. “He had approached me to go to bed with him twice, but he did it politely,” she said. “But this time he just stuck his tongue down my throat.” As she left, she began to cry. “No one had ever done that to me before,” she said. “I found it sickening.” Like Douglas, the actress said that she never worked for CBS again. Almost two decades later, an executive at CBS contacted her about coming back to the network. It turned out that the executive wanted her to sign a book deal with Simon & Schuster, which is owned by CBS. (CBS said that Moonves has no recollection of making unwelcome advances toward the actress, and that he made no efforts to block future business between her and CBS.) The actress thought that the consequences would be too great if she told CBS about the incident. “I never reported it,” she told me. “I just thought, Gee, there goes my career.” At an event not long afterward, she encountered a showrunner who has overseen multiple programs at CBS, and told her the story. The showrunner, who had also worked with Moonves, recalled that the actress was still hurt by the incident and told me that she was “not surprised” by the story. “I had already had to deal with misogynist bullying from him myself,” she told me. “Our research has proved that the chicken came not just before the egg but before anything else in the known universe.” Two women told me that they rebuffed unwanted advances from Moonves in professional settings, and that they believed career opportunities disappeared as a result. Dinah Kirgo, who won an Emmy as a writer for “The Tracey Ullman Show,” first encountered Moonves in the early eighties, when he was the vice-president of development at Saul Ilson Productions, a partnership with Columbia Pictures Television. She and her sister and producing partner, Julie Kirgo, met with Moonves and others about a television deal. “We left the meeting very confident we had an over-all deal with Leslie,” Kirgo told me. The sisters told their agent to expect an offer from Moonves. Instead, shortly after Kirgo got home, Moonves called her directly. “He said, ‘That was a great meeting, now we have to go out to dinner,’ ” she recalled. Kirgo replied that she and Julie would be happy to have dinner with him. “He said, ‘No, just you and me.’ He said, ‘You’re very expensive, and I need to know you’re worth it,’ ” Kirgo told me. “I was sort of in shock and I said, ‘Well, Leslie, I don’t think your wife would appreciate us having that kind of dinner.’ ” Moonves coldly ended the conversation. (CBS said that Moonves has no recollection of the meeting or the phone call.) Kirgo and her sister never heard from Moonves again. Afterward, Kirgo’s agents told her they had received reports that she had a reputation for being difficult to work with. Kirgo told me that she had never heard complaints before, and that she believed saying no to Moonves had hurt her career. “It’s very insidious, what he did,” she said. Julie Kirgo confirmed the details of her sister’s story and said that Dinah had told her about the call at the time. “It’s just kind of awful to feel that you have energy and talent and that’s being appreciated, and then suddenly to find out that that’s not where somebody’s interests lie at all. You feel betrayed,” she said. “It pisses me off to this day.” In 1992, a former child star who asked to be identified only by her first name, Kimberly, was introduced to Moonves by a friend, who was a member of Moonves’s staff and told her that Moonves could help her get back into television. At a dinner meeting that the three attended, Moonves began by asking questions about Kimberly’s acting career. But when the friend went to the bathroom Moonves turned to Kimberly and said, in a perfunctory way, “Let’s go. Let’s just get a hotel room. Let’s just do this.” She was shocked. “I said, ‘What are you talking about?’ ” When she explained that she had a husband and a child, Moonves became angry and left. (The friend recalled making the introduction to Moonves, and said that her only motivation in doing so was to help Kimberly’s career. CBS said that Moonves has no memory or record of the meeting.) “The power differential was so great,” Kimberly told me. “I was really scared, because I thought I was burning some sort of a bridge that was going to be great for me.” As a child star, she said, “I’d been taught that powerful people can hurt you, they can ruin you, they can ruin your career.” She said that the turn from business meeting to sexual overture seemed to be well practiced. “It was set up to be that way,” she said. “I thought, Wow, is this the way the world works and I just don’t get it?” CBS is a multibillion-dollar corporation, with dozens of divisions, and Moonves is only indirectly involved with many of them. However, experts on sexual harassment told me that misconduct by a chief executive can reverberate across aspects of even the largest companies. “If you have a company with an abuser on the top, they typically surround themselves with people like them, who engage in similar behavior,” Debra Katz, a lawyer specializing in sexual harassment, told me. “It can put a set of enablers in place, who protect powerful people when they get challenged for misconduct, and who work to discredit and manage out women who come forward with allegations.” Thirty current and former CBS employees described harassment, gender discrimination, or retaliation at the network. Many said that men accused of misconduct were promoted, even after the company was made aware of those allegations. Their stories match several that have already emerged in public reports. Earlier this year, Leslie Isaacs, a vice-president at Pop, the cable channel jointly operated by CBS and the film studio Lionsgate, filed a lawsuit alleging that CBS was aware of a hostile workplace at the channel. Her complaint described harassment and discrimination by male colleagues, including a vice-president who allegedly instructed female employees to “show your clients your tits.” Isaacs told me, “It wouldn’t be happening at Pop if it wasn’t covered up at CBS, and if CBS wasn’t complicit. They know, and it’s been tolerated.” (Isaacs has entered into a private mediation process with CBS. A Pop spokesperson said, “Pop engaged an independent investigator who conducted a complete investigation and found nothing to corroborate this alleged statement.” CBS said that it flatly denies any efforts to cover this up.) In December, CBS confirmed that Brad Kern, the showrunner and executive producer of “NCIS: New Orleans,” had been the subject of sexual-harassment and gender-discrimination allegations. He had retained his position for more than a year after the company was made aware of the claims. (This season, Kern stepped down from his position as showrunner, but he remains a consulting producer. Last month, the company said that it was launching a new investigation—its third—into Kern’s behavior. CBS said that the allegations were investigated and resulted in disciplinary action but that the matter “merits further inquiry.”) Other allegations have centered on CBS News. Last summer, Erin Gee, who worked at CBS for more than fifteen years, filed a lawsuit alleging that an executive director at “CBS Evening News” urged her to have sex with a co-worker with whom she was having difficulties in order to “break the ice,” and that she was demoted after complaining about gender discrimination. In May, a magistrate judge in New York criticized CBS for failing to save e-mails from the time of Gee’s allegation. “I find the conduct of CBS here to be shocking,” the judge, Sarah Netburn, reportedly said during a hearing. “It is hard to draw any other conclusion than that they were trying to avoid producing and saving those e-mails.” (The network has since reached a settlement with Gee, and her attorney declined to comment. CBS said that “the matter has been resolved.”) In 2015, a CBS reporter, Kenneth Lombardi, alleged in a lawsuit that a CBS News supervisor texted him links to pornography, and that a senior producer had grabbed his crotch. Lombardi claimed that when he complained to a manager she replied, “Never bring up gender discrimination again!” (An attorney for Lombardi said that he was not at liberty to discuss the suit. CBS said that the matter has been resolved.) In November, Charlie Rose was suspended after the Washington Post reported that eight women had accused him of sexual harassment, including groping. According to the Post, Rose has now been accused of sexual harassment by at least thirty-five women, and managers at the network were made aware of the allegations on at least three occasions. (Rose apologized in response to the initial allegations, but called the paper’s subsequent reporting on additional complaints “unfair and inaccurate.”) “60 Minutes,” the news division’s flagship program, for which Rose was a contributing correspondent, has been a focal point of allegations. Some of those allegations involve Jeff Fager, who is currently the executive producer of “60 Minutes,” and whom Moonves appointed chairman of CBS News in 2011, a position he held until 2015. Six former employees told me that Fager, while inebriated at company parties, would touch employees in ways that made them uncomfortable. One former “60 Minutes” producer told me, “It was always ‘Let’s go say hello to Jeff, ’cause you have to pay homage to him, but let’s do it early in the evening, before he starts getting really handsy.’ ” In one incident, at which several employees were present, Fager allegedly made drunken advances to an associate producer, commenting on her breasts and becoming belligerent when she rebuffed him. (Fager denied the allegations, saying that “they never happened.”) Others said that Fager protected men accused of misconduct, including men who reported to him. According to several people who were told about the incident at the time, a senior producer named Vicki Gordon alleged that another senior producer, Michael Radutzky, threatened to throw furniture at her and twisted her arm behind her back, causing her to scream. (Radutzky categorically denied the allegations, saying that they were fabricated.) The sources told me that Fager said he would address the matter with Radutzky directly, and instructed Gordon not to inform the CBS office of human resources. Later, Fager asked her to apologize to Radutzky, to mitigate conflict in the office. (Fager said, “I have never discouraged anyone from going to H.R.”) Radutzky, who left the network earlier this year, remained in his job for several years after the alleged incident. “It was common knowledge at ‘60 Minutes’ that Michael Radutzky was an out-of-control guy, especially but not exclusively toward women. We all saw it, almost on a daily basis,” David Gelber, a former producer, told me. “And yet Fager not only tolerated him—he elevated him to a position of leadership, even after Fager knew perfectly well how abusive he was.” (Radutzky strongly denied Gelber’s characterization of his behavior.) Sophie Gayter, a “60 Minutes” employee who alleged to the Post that Charlie Rose had groped her, told me that Fager “enabled the other men on the floor to do whatever the heck they wanted.” Fager, one network executive said, “would let people know he communicated with Les directly,” adding that “people took that to mean Les supported him completely.” CBS, one former associate producer said, “is an old network. Everything in there feels old: the people, the furniture, the culture, the mores.” Many of the women described the atmosphere at CBS News specifically as a “frat house.” One former employee said, “I had several producers and editors over the age of sixty who would greet me by kissing me on the mouth. I had people touch my butt a couple times.” She added, “Fager seemed to encourage that climate. It wasn’t even that he turned a blind eye toward it.” Katie Couric, who was an anchor at the network and a contributing correspondent for “60 Minutes” from 2006 to 2011, when Fager helped force her out, told me that it “felt like a boys’ club, where a number of talented women seemed to be marginalized and undervalued.” In a statement, Fager said, “It is wrong that our culture can be falsely defined by a few people with an axe to grind who are using an important movement as a weapon to get even, and not by the hundreds of women and men that have thrived, both personally and professionally, at ‘60 Minutes.’ ” He added, “A majority of our senior staff are women. All of them worked their way up the ranks and are now managers of our broadcast. Half of our producers and a majority of our associate producers are women. It is a challenging place to do well and promotions are earned on merit and are not based on gender.” Lesley Stahl, who has been a “60 Minutes” correspondent since 1991, told me, “This notion that ‘60 Minutes’ is an unpleasant, unwelcoming place for women isn’t true.” She said, “In my own experience, Jeff is supportive of women and decent to women.” Anderson Cooper, who has been a correspondent for the show since 2006, told me, “I work there part time, but in all the years I’ve been there I’ve never seen Jeff engage in any inappropriate behavior.” Gayter and another junior female employee told me that their bosses asked them to complete the company’s mandatory online sexual-harassment training programs for them. “Many assistants did it for their bosses,” Gayter said. “We’d book their travel, do their expenses, and then do their sexual-harassment training.” Former employees told me that there were few avenues for them to register confidential complaints about discrimination and misconduct. “People say, ‘You could call H.R.’ Honestly, I’ve never met a single person from H.R.,” one producer said. “There’s no oversight.” Some said that they had witnessed retaliation against those who did attempt to speak out. At CBS News, “there was no one to turn to,” one former producer told me, saying that she had reported Charlie Rose’s behavior, and that the complaint resulted in no repercussions for Rose. “If it’s just behavior from the top, tolerated at the top, and there’s no one to talk to, what do you do?” she said. A former journalist at “60 Minutes” named Habiba Nosheen told me that she had complained to management that Ira Rosen, a producer on the program, had subjected her to numerous sexual comments and suggested that she flirt with sources. Two other women told me that they had experienced similar conduct from Rosen. (In a statement, Rosen said that “CBS extensively investigated these complaints and found them to be false, misleading, and unsubstantiated.” He said, “I have always and continue to deny these allegations.”) “But seriously, folks, the way you raised me it’s no wonder I can’t get a gig in a real night club.” When Nosheen filed a written complaint and met with Fager about the allegations against Rosen, she said, he told her not to worry about the possibility that other women might be harassed by Rosen. She told me that Fager is “an enabler of this ‘Mad Men’ culture at ‘60 Minutes.’ ” Afterward, there appeared to be no repercussions for Rosen, and she was frozen out of assignments. Days after she made her complaint to Fager, he and two of his deputies called Nosheen into a meeting to go over criticisms of her work performance which she found specious. One involved a tense exchange with a co-worker that had happened a year earlier. The format of the meeting, she said, was highly unusual. “It was so obvious to me that they began to implement a strategy of retaliation,” she told me. In June, 2016, Nosheen filed a complaint with the Equal Employment Opportunity Commission. She resigned a month later. “As an investigative journalist, every day I try to hold people in power accountable. I look people in the eye and ask them why they turned their backs when they witnessed something unethical happening,” she told me. “I knew I couldn’t look myself in the mirror and hold others accountable if I wasn’t brave enough to do the same in my own place of work.” An e-mail from a CBS lawyer shows that, after Nosheen left the network, CBS threatened to enforce a non-compete clause in her contract, which would prevent her from seeking employment elsewhere, unless she withdrew her E.E.O.C. complaint and signed a nondisclosure agreement. The E.E.O.C. ultimately issued a Notice of Dismissal and Right to Sue letter, saying that it was unable to conclude whether or not a violation of federal law had occurred and that it would be up to Nosheen to pursue the matter in civil court. Another woman told me that she had spoken to CBS’s legal department about Rosen’s and Fager’s behavior. “I was shocked by the lack of seriousness and regard that CBS legal showed my story,” she told me. (In a statement, CBS’s chief compliance officer said, “It is the policy and practice of CBS to investigate all complaints and to promptly remediate any problems that are identified,” adding that “the policies against discrimination and harassment include anti-retaliation provisions, and anyone raising a complaint is assured that he or she will be protected from retaliation.”) The woman told me that she eventually left the network because of the atmosphere. “A lot of my memories of ‘60 Minutes’ are of other women coming into my office, closing the door, and just breaking down because of working as a woman at CBS,” she said. “Toward the end of my time there, I thought, God, I love the stories, I love the work, but this has to be easier somewhere else.” The producer who talked about Fager’s behavior at parties told me that she, too, left the show because of “a very toxic culture toward women.” She said, “What makes me really upset was this was something I really loved doing, and I was good at, and won a lot of awards for. And I basically had to leave the business, because where else am I going to go? There were other places, but nothing of that stature.” The New Yorker reviewed three six-figure settlements with “60 Minutes” employees who have filed complaints of sexual harassment or discrimination. The women who received those payments were required to sign nondisclosure agreements that prevented them from speaking about their experiences, with penalties for any breach. Several other women who have made allegations against CBS News declined to speak with me on the record, citing nondisclosure agreements. (The CBS chief compliance officer said, “On occasion, the resolution of allegations in the workplace has involved financial settlements,” adding that “settlements do not amount to admissions of guilt.”) “The N.D.A.s are a silencer and a bully tactic,” Mo Cashin, who worked in several roles for CBS News, including as a broadcast manager, told me. “It’s unfortunate and hypocritical, particularly in the media, where it appears executives have more interest in protecting and oftentimes rewarding fellow senior employees who have a documented history of bad behavior than protecting their victims.” Fager has tried to keep the allegations about the treatment of women at “60 Minutes” from surfacing publicly. According to the Times, in 2015 Fager took over the writing of a book about “60 Minutes” after the original author, Richard Zoglin, began asking people about the subject. In April, as two Washington Post reporters, Irin Carmon and Amy Brittain, were reporting an article about the allegations of harassment at CBS News, including complaints about Fager and Rosen, lawyers retained by Fager threatened to sue the Post, and presented testimonials about Fager’s good character. “There was this ham-handed effort to make women at the show say Jeff was a wonderful person,” one producer said. “It was so obvious we were doing it with a gun to our heads.” Fager’s lawyers also attacked the professionalism of the two reporters. In the end, the paper published a story that included complaints of harassment against Charlie Rose from dozens of women, but not allegations about Fager or Rosen. In a statement, the Post said, “The reporting throughout was vigorous and sustained and fully supported by Post editors. Nothing that met our longstanding standards for publication was left out. Nor did outside pressures, legal or otherwise, determine what was published.” CBS employees told me that they were alarmed by the attempts to kill the reporting. “The hypocrisy of an investigative news program shutting down an investigative print story is incredible,” one told me. Fager said, “There’s a reason these awful allegations have not been published before—despite the efforts of a few former employees who did not succeed at ‘60 Minutes.’ It is because they are false, anonymous, and do not hold up to editorial scrutiny.” The CBS chief compliance officer said, “CBS previously retained attorney Betsy Plevan of Proskauer Rose to conduct an independent investigation of alleged misconduct at CBS News. Ms. Plevan’s work is ongoing, and includes investigating allegations in this story. CBS has taken the allegations reported in the press seriously, and respects the role of the press in pursuing the truth, which is a role that is central to the mission of CBS News.” In June, Carmon, in a speech accepting a Mirror Award for the Post’s reporting on Charlie Rose, warned that stories of abuse by powerful men in the news industry were still being suppressed. “The stories that we have been doing are actually about a system. The system has lawyers and a good reputation. It has publicists,” she said. “Indeed, the system is sitting in this room. Some more than others. The system is still powerful men getting stories killed that I believe will someday see the light of day.” Fager was seated in the audience, and later in the ceremony accepted an award on behalf of “60 Minutes.” | Summary: That $120 million? Don't bank on it, Les. CBS says an internal sexual-misconduct probe has tanked any hope of ex-CEO Les Moonves getting his ginormous severance, CNBC reports. "We have determined that there are grounds to terminate for cause, including his willful and material misfeasance... as well as his willful failure to cooperate fully with the Company's investigation," per the company board. CBS says its investigation into the news division, Moonves, and company culture didn't reveal widespread harassment but did uncover some "improper and unprofessional conduct." It also found a lack of support for the human resources department and "dignity, transparency, respect and inclusion" in the workplace-which CBS vows to improve. The investigation, conducted by two law firms, follows a shakeup of the CBS board that saw five veteran directors pushed out and six new faces placed on the 11-member panel, per Variety. The AP notes that CBS has also promised $20 million to 18 women's rights groups. Moonves resigned in September after a bombshell New Yorker report uncovered misconduct allegations from six women and a corporate culture that ignored sexual harassment and worse. A later report accused Moonves of keeping a female employee "on call to perform oral sex." He has denied most of the accusations. | 16,315 | 310 | multi_news | en |
Summarize: By this time, some months had passed since our interview on the bank of the river with Martha. I had never seen her since, but she had communicated with Mr. Peggotty on several occasions. Nothing had come of her zealous intervention; nor could I infer, from what he told me, that any clue had been obtained, for a moment, to Emily's fate. I confess that I began to despair of her recovery, and gradually to sink deeper and deeper into the belief that she was dead. His conviction remained unchanged. So far as I know--and I believe his honest heart was transparent to me--he never wavered again, in his solemn certainty of finding her. His patience never tired. And, although I trembled for the agony it might one day be to him to have his strong assurance shivered at a blow, there was something so religious in it, so affectingly expressive of its anchor being in the purest depths of his fine nature, that the respect and honour in which I held him were exalted every day. His was not a lazy trustfulness that hoped, and did no more. He had been a man of sturdy action all his life, and he knew that in all things wherein he wanted help he must do his own part faithfully, and help himself. I have known him set out in the night, on a misgiving that the light might not be, by some accident, in the window of the old boat, and walk to Yarmouth. I have known him, on reading something in the newspaper that might apply to her, take up his stick, and go forth on a journey of three--or four-score miles. He made his way by sea to Naples, and back, after hearing the narrative to which Miss Dartle had assisted me. All his journeys were ruggedly performed; for he was always steadfast in a purpose of saving money for Emily's sake, when she should be found. In all this long pursuit, I never heard him repine; I never heard him say he was fatigued, or out of heart. Dora had often seen him since our marriage, and was quite fond of him. I fancy his figure before me now, standing near her sofa, with his rough cap in his hand, and the blue eyes of my child-wife raised, with a timid wonder, to his face. Sometimes of an evening, about twilight, when he came to talk with me, I would induce him to smoke his pipe in the garden, as we slowly paced to and fro together; and then, the picture of his deserted home, and the comfortable air it used to have in my childish eyes of an evening when the fire was burning, and the wind moaning round it, came most vividly into my mind. One evening, at this hour, he told me that he had found Martha waiting near his lodging on the preceding night when he came out, and that she had asked him not to leave London on any account, until he should have seen her again. 'Did she tell you why?' I inquired. 'I asked her, Mas'r Davy,' he replied, 'but it is but few words as she ever says, and she on'y got my promise and so went away.' 'Did she say when you might expect to see her again?' I demanded. 'No, Mas'r Davy,' he returned, drawing his hand thoughtfully down his face. 'I asked that too; but it was more (she said) than she could tell.' As I had long forborne to encourage him with hopes that hung on threads, I made no other comment on this information than that I supposed he would see her soon. Such speculations as it engendered within me I kept to myself, and those were faint enough. I was walking alone in the garden, one evening, about a fortnight afterwards. I remember that evening well. It was the second in Mr. Micawber's week of suspense. There had been rain all day, and there was a damp feeling in the air. The leaves were thick upon the trees, and heavy with wet; but the rain had ceased, though the sky was still dark; and the hopeful birds were singing cheerfully. As I walked to and fro in the garden, and the twilight began to close around me, their little voices were hushed; and that peculiar silence which belongs to such an evening in the country when the lightest trees are quite still, save for the occasional droppings from their boughs, prevailed. There was a little green perspective of trellis-work and ivy at the side of our cottage, through which I could see, from the garden where I was walking, into the road before the house. I happened to turn my eyes towards this place, as I was thinking of many things; and I saw a figure beyond, dressed in a plain cloak. It was bending eagerly towards me, and beckoning. 'Martha!' said I, going to it. 'Can you come with me?' she inquired, in an agitated whisper. 'I have been to him, and he is not at home. I wrote down where he was to come, and left it on his table with my own hand. They said he would not be out long. I have tidings for him. Can you come directly?' My answer was, to pass out at the gate immediately. She made a hasty gesture with her hand, as if to entreat my patience and my silence, and turned towards London, whence, as her dress betokened, she had come expeditiously on foot. I asked her if that were not our destination? On her motioning Yes, with the same hasty gesture as before, I stopped an empty coach that was coming by, and we got into it. When I asked her where the coachman was to drive, she answered, 'Anywhere near Golden Square! And quick!'--then shrunk into a corner, with one trembling hand before her face, and the other making the former gesture, as if she could not bear a voice. Now much disturbed, and dazzled with conflicting gleams of hope and dread, I looked at her for some explanation. But seeing how strongly she desired to remain quiet, and feeling that it was my own natural inclination too, at such a time, I did not attempt to break the silence. We proceeded without a word being spoken. Sometimes she glanced out of the window, as though she thought we were going slowly, though indeed we were going fast; but otherwise remained exactly as at first. We alighted at one of the entrances to the Square she had mentioned, where I directed the coach to wait, not knowing but that we might have some occasion for it. She laid her hand on my arm, and hurried me on to one of the sombre streets, of which there are several in that part, where the houses were once fair dwellings in the occupation of single families, but have, and had, long degenerated into poor lodgings let off in rooms. Entering at the open door of one of these, and releasing my arm, she beckoned me to follow her up the common staircase, which was like a tributary channel to the street. The house swarmed with inmates. As we went up, doors of rooms were opened and people's heads put out; and we passed other people on the stairs, who were coming down. In glancing up from the outside, before we entered, I had seen women and children lolling at the windows over flower-pots; and we seemed to have attracted their curiosity, for these were principally the observers who looked out of their doors. It was a broad panelled staircase, with massive balustrades of some dark wood; cornices above the doors, ornamented with carved fruit and flowers; and broad seats in the windows. But all these tokens of past grandeur were miserably decayed and dirty; rot, damp, and age, had weakened the flooring, which in many places was unsound and even unsafe. Some attempts had been made, I noticed, to infuse new blood into this dwindling frame, by repairing the costly old wood-work here and there with common deal; but it was like the marriage of a reduced old noble to a plebeian pauper, and each party to the ill-assorted union shrunk away from the other. Several of the back windows on the staircase had been darkened or wholly blocked up. In those that remained, there was scarcely any glass; and, through the crumbling frames by which the bad air seemed always to come in, and never to go out, I saw, through other glassless windows, into other houses in a similar condition, and looked giddily down into a wretched yard, which was the common dust-heap of the mansion. We proceeded to the top-storey of the house. Two or three times, by the way, I thought I observed in the indistinct light the skirts of a female figure going up before us. As we turned to ascend the last flight of stairs between us and the roof, we caught a full view of this figure pausing for a moment, at a door. Then it turned the handle, and went in. 'What's this!' said Martha, in a whisper. 'She has gone into my room. I don't know her!' I knew her. I had recognized her with amazement, for Miss Dartle. I said something to the effect that it was a lady whom I had seen before, in a few words, to my conductress; and had scarcely done so, when we heard her voice in the room, though not, from where we stood, what she was saying. Martha, with an astonished look, repeated her former action, and softly led me up the stairs; and then, by a little back-door which seemed to have no lock, and which she pushed open with a touch, into a small empty garret with a low sloping roof, little better than a cupboard. Between this, and the room she had called hers, there was a small door of communication, standing partly open. Here we stopped, breathless with our ascent, and she placed her hand lightly on my lips. I could only see, of the room beyond, that it was pretty large; that there was a bed in it; and that there were some common pictures of ships upon the walls. I could not see Miss Dartle, or the person whom we had heard her address. Certainly, my companion could not, for my position was the best. A dead silence prevailed for some moments. Martha kept one hand on my lips, and raised the other in a listening attitude. 'It matters little to me her not being at home,' said Rosa Dartle haughtily, 'I know nothing of her. It is you I come to see.' 'Me?' replied a soft voice. At the sound of it, a thrill went through my frame. For it was Emily's! 'Yes,' returned Miss Dartle, 'I have come to look at you. What? You are not ashamed of the face that has done so much?' The resolute and unrelenting hatred of her tone, its cold stern sharpness, and its mastered rage, presented her before me, as if I had seen her standing in the light. I saw the flashing black eyes, and the passion-wasted figure; and I saw the scar, with its white track cutting through her lips, quivering and throbbing as she spoke. 'I have come to see,' she said, 'James Steerforth's fancy; the girl who ran away with him, and is the town-talk of the commonest people of her native place; the bold, flaunting, practised companion of persons like James Steerforth. I want to know what such a thing is like.' There was a rustle, as if the unhappy girl, on whom she heaped these taunts, ran towards the door, and the speaker swiftly interposed herself before it. It was succeeded by a moment's pause. When Miss Dartle spoke again, it was through her set teeth, and with a stamp upon the ground. 'Stay there!' she said, 'or I'll proclaim you to the house, and the whole street! If you try to evade me, I'll stop you, if it's by the hair, and raise the very stones against you!' A frightened murmur was the only reply that reached my ears. A silence succeeded. I did not know what to do. Much as I desired to put an end to the interview, I felt that I had no right to present myself; that it was for Mr. Peggotty alone to see her and recover her. Would he never come? I thought impatiently. 'So!' said Rosa Dartle, with a contemptuous laugh, 'I see her at last! Why, he was a poor creature to be taken by that delicate mock-modesty, and that hanging head!' 'Oh, for Heaven's sake, spare me!' exclaimed Emily. 'Whoever you are, you know my pitiable story, and for Heaven's sake spare me, if you would be spared yourself!' 'If I would be spared!' returned the other fiercely; 'what is there in common between US, do you think!' 'Nothing but our sex,' said Emily, with a burst of tears. 'And that,' said Rosa Dartle, 'is so strong a claim, preferred by one so infamous, that if I had any feeling in my breast but scorn and abhorrence of you, it would freeze it up. Our sex! You are an honour to our sex!' 'I have deserved this,' said Emily, 'but it's dreadful! Dear, dear lady, think what I have suffered, and how I am fallen! Oh, Martha, come back! Oh, home, home!' Miss Dartle placed herself in a chair, within view of the door, and looked downward, as if Emily were crouching on the floor before her. Being now between me and the light, I could see her curled lip, and her cruel eyes intently fixed on one place, with a greedy triumph. 'Listen to what I say!' she said; 'and reserve your false arts for your dupes. Do you hope to move me by your tears? No more than you could charm me by your smiles, you purchased slave.' 'Oh, have some mercy on me!' cried Emily. 'Show me some compassion, or I shall die mad!' 'It would be no great penance,' said Rosa Dartle, 'for your crimes. Do you know what you have done? Do you ever think of the home you have laid waste?' 'Oh, is there ever night or day, when I don't think of it!' cried Emily; and now I could just see her, on her knees, with her head thrown back, her pale face looking upward, her hands wildly clasped and held out, and her hair streaming about her. 'Has there ever been a single minute, waking or sleeping, when it hasn't been before me, just as it used to be in the lost days when I turned my back upon it for ever and for ever! Oh, home, home! Oh dear, dear uncle, if you ever could have known the agony your love would cause me when I fell away from good, you never would have shown it to me so constant, much as you felt it; but would have been angry to me, at least once in my life, that I might have had some comfort! I have none, none, no comfort upon earth, for all of them were always fond of me!' She dropped on her face, before the imperious figure in the chair, with an imploring effort to clasp the skirt of her dress. Rosa Dartle sat looking down upon her, as inflexible as a figure of brass. Her lips were tightly compressed, as if she knew that she must keep a strong constraint upon herself--I write what I sincerely believe--or she would be tempted to strike the beautiful form with her foot. I saw her, distinctly, and the whole power of her face and character seemed forced into that expression.---Would he never come? 'The miserable vanity of these earth-worms!' she said, when she had so far controlled the angry heavings of her breast, that she could trust herself to speak. 'YOUR home! Do you imagine that I bestow a thought on it, or suppose you could do any harm to that low place, which money would not pay for, and handsomely? YOUR home! You were a part of the trade of your home, and were bought and sold like any other vendible thing your people dealt in.' 'Oh, not that!' cried Emily. 'Say anything of me; but don't visit my disgrace and shame, more than I have done, on folks who are as honourable as you! Have some respect for them, as you are a lady, if you have no mercy for me.' 'I speak,' she said, not deigning to take any heed of this appeal, and drawing away her dress from the contamination of Emily's touch, 'I speak of HIS home--where I live. Here,' she said, stretching out her hand with her contemptuous laugh, and looking down upon the prostrate girl, 'is a worthy cause of division between lady-mother and gentleman-son; of grief in a house where she wouldn't have been admitted as a kitchen-girl; of anger, and repining, and reproach. This piece of pollution, picked up from the water-side, to be made much of for an hour, and then tossed back to her original place!' 'No! no!' cried Emily, clasping her hands together. 'When he first came into my way--that the day had never dawned upon me, and he had met me being carried to my grave!--I had been brought up as virtuous as you or any lady, and was going to be the wife of as good a man as you or any lady in the world can ever marry. If you live in his home and know him, you know, perhaps, what his power with a weak, vain girl might be. I don't defend myself, but I know well, and he knows well, or he will know when he comes to die, and his mind is troubled with it, that he used all his power to deceive me, and that I believed him, trusted him, and loved him!' Rosa Dartle sprang up from her seat; recoiled; and in recoiling struck at her, with a face of such malignity, so darkened and disfigured by passion, that I had almost thrown myself between them. The blow, which had no aim, fell upon the air. As she now stood panting, looking at her with the utmost detestation that she was capable of expressing, and trembling from head to foot with rage and scorn, I thought I had never seen such a sight, and never could see such another. 'YOU love him? You?' she cried, with her clenched hand, quivering as if it only wanted a weapon to stab the object of her wrath. Emily had shrunk out of my view. There was no reply. 'And tell that to ME,' she added, 'with your shameful lips? Why don't they whip these creatures? If I could order it to be done, I would have this girl whipped to death.' And so she would, I have no doubt. I would not have trusted her with the rack itself, while that furious look lasted. She slowly, very slowly, broke into a laugh, and pointed at Emily with her hand, as if she were a sight of shame for gods and men. 'SHE love!' she said. 'THAT carrion! And he ever cared for her, she'd tell me. Ha, ha! The liars that these traders are!' Her mockery was worse than her undisguised rage. Of the two, I would have much preferred to be the object of the latter. But, when she suffered it to break loose, it was only for a moment. She had chained it up again, and however it might tear her within, she subdued it to herself. 'I came here, you pure fountain of love,' she said, 'to see--as I began by telling you--what such a thing as you was like. I was curious. I am satisfied. Also to tell you, that you had best seek that home of yours, with all speed, and hide your head among those excellent people who are expecting you, and whom your money will console. When it's all gone, you can believe, and trust, and love again, you know! I thought you a broken toy that had lasted its time; a worthless spangle that was tarnished, and thrown away. But, finding you true gold, a very lady, and an ill-used innocent, with a fresh heart full of love and trustfulness--which you look like, and is quite consistent with your story!--I have something more to say. Attend to it; for what I say I'll do. Do you hear me, you fairy spirit? What I say, I mean to do!' Her rage got the better of her again, for a moment; but it passed over her face like a spasm, and left her smiling. 'Hide yourself,' she pursued, 'if not at home, somewhere. Let it be somewhere beyond reach; in some obscure life--or, better still, in some obscure death. I wonder, if your loving heart will not break, you have found no way of helping it to be still! I have heard of such means sometimes. I believe they may be easily found.' A low crying, on the part of Emily, interrupted her here. She stopped, and listened to it as if it were music. 'I am of a strange nature, perhaps,' Rosa Dartle went on; 'but I can't breathe freely in the air you breathe. I find it sickly. Therefore, I will have it cleared; I will have it purified of you. If you live here tomorrow, I'll have your story and your character proclaimed on the common stair. There are decent women in the house, I am told; and it is a pity such a light as you should be among them, and concealed. If, leaving here, you seek any refuge in this town in any character but your true one (which you are welcome to bear, without molestation from me), the same service shall be done you, if I hear of your retreat. Being assisted by a gentleman who not long ago aspired to the favour of your hand, I am sanguine as to that.' Would he never, never come? How long was I to bear this? How long could I bear it? 'Oh me, oh me!' exclaimed the wretched Emily, in a tone that might have touched the hardest heart, I should have thought; but there was no relenting in Rosa Dartle's smile. 'What, what, shall I do!' 'Do?' returned the other. 'Live happy in your own reflections! Consecrate your existence to the recollection of James Steerforth's tenderness--he would have made you his serving-man's wife, would he not?---or to feeling grateful to the upright and deserving creature who would have taken you as his gift. Or, if those proud remembrances, and the consciousness of your own virtues, and the honourable position to which they have raised you in the eyes of everything that wears the human shape, will not sustain you, marry that good man, and be happy in his condescension. If this will not do either, die! There are doorways and dust-heaps for such deaths, and such despair--find one, and take your flight to Heaven!' I heard a distant foot upon the stairs. I knew it, I was certain. It was his, thank God! She moved slowly from before the door when she said this, and passed out of my sight. 'But mark!' she added, slowly and sternly, opening the other door to go away, 'I am resolved, for reasons that I have and hatreds that I entertain, to cast you out, unless you withdraw from my reach altogether, or drop your pretty mask. This is what I had to say; and what I say, I mean to do!' The foot upon the stairs came nearer--nearer--passed her as she went down--rushed into the room! 'Uncle!' A fearful cry followed the word. I paused a moment, and looking in, saw him supporting her insensible figure in his arms. He gazed for a few seconds in the face; then stooped to kiss it--oh, how tenderly!--and drew a handkerchief before it. 'Mas'r Davy,' he said, in a low tremulous voice, when it was covered, 'I thank my Heav'nly Father as my dream's come true! I thank Him hearty for having guided of me, in His own ways, to my darling!' With those words he took her up in his arms; and, with the veiled face lying on his bosom, and addressed towards his own, carried her, motionless and unconscious, down the stairs. | Summary: Mr. Peggotty's dream comes true. Mr. Peggotty continues his search for Little Em'ly, never losing hope. Martha seeks out David and says that she has news for Mr. Peggotty; she has been to his house, but he is not at home, so she left a note for him to meet her. Martha takes David to the slum dwelling where she lives. Inside the house, they see a woman enter Martha's room. David sees that it is Rosa Dartle. Martha and David listen at the door, and overhear Rosa pouring contempt onto Little Em'ly and blaming her for laying waste to the Steerforth family. Little Em'ly points out that Steerforth deceived her, and that her mistake was to love and trust him. Rosa tells Little Em'ly to leave the house or Rosa will proclaim her story to the world. Mr. Peggotty arrives. Little Em'ly faints, and Mr. Peggotty takes her tenderly in his arms. | 5,678 | 223 | booksum | en |
Write a title and summarize: Recent analyses of human-associated bacterial diversity have categorized individuals into ‘enterotypes’ or clusters based on the abundances of key bacterial genera in the gut microbiota. There is a lack of consensus, however, on the analytical basis for enterotypes and on the interpretation of these results. We tested how the following factors influenced the detection of enterotypes: clustering methodology, distance metrics, OTU-picking approaches, sequencing depth, data type (whole genome shotgun (WGS) vs. 16S rRNA gene sequence data), and 16S rRNA region. We included 16S rRNA gene sequences from the Human Microbiome Project (HMP) and from 16 additional studies and WGS sequences from the HMP and MetaHIT. In most body sites, we observed smooth abundance gradients of key genera without discrete clustering of samples. Some body habitats displayed bimodal (e. g., gut) or multimodal (e. g., vagina) distributions of sample abundances, but not all clustering methods and workflows accurately highlight such clusters. Because identifying enterotypes in datasets depends not only on the structure of the data but is also sensitive to the methods applied to identifying clustering strength, we recommend that multiple approaches be used and compared when testing for enterotypes. Together with the MetaHIT consortium [1], the Human Microbiome Project (HMP) represents one of the first major attempts to define the microbial diversity comprising the “normal healthy” human microbiome [2]. The HMP dataset includes 16S rRNA gene sequence data of roughly twice the size of all similarly derived data in previously published studies, effectively tripling the size of combined data available for comparative studies (Table S1). In addition, the HMP generated whole-genome shotgun (WGS) metagenomic data for a subset of individuals. These data allowed for the characterization of patterns of microbial diversity across body sites and between individuals [2]. The HMP data also provides an opportunity to test the generality of the concept of enterotypes in the human microbiome. Arumugam et al. first articulated the concept of enterotypes as robust clustering of human gut samples based on microbial community composition, and largely driven by the abundances of key bacterial genera [3]. Although the term ‘enterotype’ refers to microbiota types within the gut, the concept can be applied generally, and here, for convenience, we use the term ‘enterotype’ to refer to microbiota types across different body sites. The HMP data are ideally suited to test the robustness of the enterotype concept in multiple body sites, and together with recently published community-generated datasets, across multiple populations. In this report, we combined 16S rRNA gene sequence data generated using next-generation sequencing by the scientific community (hereafter, ‘community data’) together with the MetaHIT WGS data [3] and the recently released HMP 16S rRNA gene sequence data and WGS data [2]. Because there is currently no community standard for testing for enterotypes, we explore how the detection of enterotypes is affected by the following: clustering methodology, distance metrics, OTU-picking approaches, sequencing depth (i. e., rarefaction), data type (16S rRNA vs. WGS), and the specific region of the 16S rRNA gene sequenced. We find that the emergence of enterotypes is sensitive to the community structure of communities within each body site, and importantly also to the analysis methods employed. Our comparative analysis of various approaches across datasets informs the discussion on the technical basis for enterotyping and on how to interpret enterotype results. We constructed a database containing the recently released HMP 16S rRNA gene sequence data [4] and publically available (published) human microbiome datasets (community data). For inclusion, community datasets were required to contain a minimum of 25 samples per study and sequences generated using the Roche 454 platform (Table S1). The majority of samples were from healthy controls; however, a small subset of samples was derived from subjects that differed from adult healthy subjects due to age (i. e., infants and the elderly), use of antibiotics, or possible presence of disease (Fig. S1). We acquired raw SFF files and metadata files containing the unique identifiers for each sample within a study (barcodes) from the authors and re-processed the data using the default settings in the Quantitative Insights Into Microbial Ecology (QIIME) analysis pipeline [5]. For the majority of samples, quality filtering consisted of rejecting reads <200 nt and >1000 nt, excluding homopolymer runs >6 nt, accepting 0 barcode corrections and 0 primer mismatches; two datasets were processed with slightly different screening parameters, as described in their respective publications [6], [7]. When picking operational taxonomic units (OTUs) we used the OTU tables generated by the HMP, which were created de novo. Because the regions of the 16S rRNA gene differed between studies (and within: the HMP sequenced both V1–V3 and V3–V5 regions), we used a reference-based approach (hence, we did not denoise the data) to pick OTUs at 97% pairwise identity using as a reference the latest release of the GreenGenes (GG) taxonomy [8]. We also used the phylogenetic tree from GG to calculate weighted (abundance based) and unweighted (presence/absence based) UniFrac distances between communities [9], after applying two rarefactions (1,000 and 2,000 sequences/sample) to standardize sequence counts. Principal coordinates analysis (PCoA) was applied to the distance matrices for visualization. The HMP and MetaHIT shotgun metagenomic datasets were taxonomically profiled using MetaPhlAn [10] (version 1. 1, default parameter settings), which infers relative abundances for all taxonomic levels (from phyla to species) for Bacteria and Archaea. We performed standard quality control on the HMP and MetaHIT samples as reported in the original studies [2], [3] - other metagenomic pre-processing steps (e. g., error detection, assembly, or gene annotation) are not required by MetaPhlAn. The taxonomic profiles of HMP metagenomes are available at http: //www. hmpdacc. org/HMSMCP/, and the MetaHIT profiles can be downloaded from http: //huttenhower. sph. harvard. edu/metaphlan/. The 690 HMP metagenomic samples from 7 different body sites can be accessed at http: //hmpdacc. org/HMASM/, from which we used the ‘WGS’ reads (i. e., we did not use the ‘PGA’ assemblies), collapsing multiple visits from the same individual into one sample. The 124 fecal samples from MetaHIT were downloaded from the European Nucleotide Archive (http: //www. ebi. ac. uk/ena/, study accession number ERP000108). To evaluate the clustering results in the context of previously published results reporting enterotypes, we merged publicly available data (genus relative abundance tables) from MetaHIT [3] with data for the 16S rRNA-based HMP and non-HMP samples, based on genus-level taxonomy assignments. We performed enterotype testing using the relative abundances of OTUs (rarified at 1,000 sequences/sample for the majority of analyses, except where effect of rarefaction was tested specifically), to which we applied five distance metrics: Jensen-Shannon divergence (JSD), Root Jensen-Shannon divergence (rJSD), Bray-Curtis (BC), and weighted/unweighted UniFrac distances. For the calculation of JSD and BC distances, we first binned the counts of OTUs at the desired level (95% and 97% ID for genus and species level OTUs, respectively). We used the R “vegan” package [11] for calculating the Bray-Curtis distance according to this formula for the distance between samples j and k, with taxa/OTUs indexed by i: Clustering was performed via partitioning around medoids in the R package “cluster” [12]. We chose the number of clusters and quality of the resulting clusters by maximizing the prediction strength (PS) [13] and silhouette index (SI) [14]. We applied a criterion of ≥0. 90 for PS to signify strong clustering (this implies that 90% of the data points fall within the cluster and 10% are outliers). For SI, we used a score of 0. 5 for moderate clustering as described by Wu et al. [15], and ≥0. 75 for strong clustering (note this is close to the value of 0. 71 originally reported for strong clustering [16]). We performed kernel density estimation of the global distribution of gut microbial communities using the R package “ks” [17]. This included automatic inference of unconstrained (non-diagonal) bandwidth parameters using the function “Hscv”. We also calculated the Caliński-Harabasz (CH) statistic for comparison to PS and SI, using the R ‘fpc’ package [18]. This package uses the following formula for the CH statistic [19]: whereandIn this formula, n is the number of data points w, k is the number of clusters, and Ch represents the set of data points in cluster h. We chose to use PS and SI to assess the support for clustering (and to choose the number of clusters if supported), as they are both absolute measures of the clustering quality, while CH is only a relative assessment of the quality of the clustering. We generated a synthetic dataset of 100 communities each containing 3,000 “sequences” belonging to 500 mock OTUs. For each synthetic community, 90% (2,700 sequences, or OTU observations) was drawn from the same randomly generated lognormal abundance distribution (shared across all communities) and the remaining 10% (300 sequences) drawn from one of four unique lognormal distributions, forcing the data into four clusters. We then applied the enterotyping methods as described above. Beta-diversity measures provide a view of how diversity differs between sets of samples and quantifies those differences. We used the unweighted UniFrac measure of β-diversity to contrast the range of bacterial phylogenetic diversity captured by the HMP data to existing community data (Fig. 1). This analysis showed that the overall pattern of diversity is similar for HMP and community data, with clear separation between body sites (Figs. 1A, B, S1) as has been described previously [2], [20]. Similarly, Fig. S2 shows the locations of the MetaHIT samples relative to the HMP and other community fecal samples. The HMP and MetaHIT data map onto the community data well (Fig. 1C; Fig. S2), lending support for the approach of combining these sets in a meta-analysis of body habitats. The gut microbiota are the most extensively studied of the human-associated microbiota. Combining community and HMP fecal microbial 16S rRNA gene sequence data effectively extended the subject age range from early infancy to old age (3 days to 85 years old), with the HMP supplying the majority of the middle years of the human life span. Interestingly, infant samples (younger than 2. 5 years) were outliers in the range of diversity represented by the healthy adult and elder (older than 70 years) gut (Fig. 1D) and were more similar to vaginal and skin communities. Adult HMP samples cluster together with those from the community studies, excluding samples from infants (<2. 5 yrs) and elders (Table S1). This combined analysis corroborates the previously described vast difference between bacterial diversity of infants and adults [21], [22]. We first tested the effects of different cluster scoring methods using a lognormally distributed synthetic community data containing 4 clusters that served as a positive control for enterotypes. We applied the JSD, rJSD and BC distance measures to the synthetic dataset and compared cluster scores using prediction strength (PS, Fig. 2A), silhouette index (SI, Fig. 2B) and Calińksi-Harabasz (CH, Fig. 2C) scores. This analysis revealed strong support for 4 clusters using PS for the BC, JSD and rJSD distance metrics, but SI provided no support for clustering using BC and rJSD, and only weak support for 3–5 clusters using the JSD distance metric. The CH index supported 4 clusters using only the JSD distance metric. Wu et al. also reported a discrepancy in cluster scoring strengths between clustering methods [15]: CH indicated that 3 enterotypes were present, but SI provided weak support using rJSD. Wu et al. also compared clustering with CH and SI together with weighted/normalized unweighted UniFrac, BC and Euclidean distances, and reported concordant numbers of clusters with weighted UniFrac only. Together these results indicate that these different clustering methodologies can yield inconsistent results, although SI and CH have been reported to be stable and comparable [23], [24]. Arumugan et al. used CH as the basis for choosing the number of enterotypes, even when SI values were very low (all published values were less than or equal to 0. 25), indicating weak or no support for clustering [3]. It is important to note that the CH score is a relative measure that alone cannot be used to determine statistical significance of clustering in the data, and that furthermore, CH is intended to indicate the optimal number of clusters based on the assumption that clusters exist. PS and SI, on the other hand, are absolute measures of how likely cluster structure is to emerge from a dataset. Based on our results, we recommend using at least one absolute measure (specifically, we recommend PS), and if possible confirming those results with an additional absolute measure (such as SI), when searching for enterotypes. Depending on the signal-to-noise distribution within individual datasets and data types, PS may have difficulty identifying clusters represented by few samples, as we discuss below (e. g., posterior fornix WGS data). In such cases SI may be relied on, but we recommend using a high threshold (e. g., ≥0. 75) in identifying potentially reproducible clusters. We prefer PS over SI for large sample sizes because (1) it has a clear quantitative and intuitive interpretation, (2) it allows estimation of the clustering stability of individual samples, and (3) it performs better than SI in recovering known enterotypes in synthetic datasets. Note however that there is currently no consensus in the field on the specific thresholds that should be used with these methods for assessing clustering strength, making it all the more important for researchers to clearly state the criteria they apply when reporting enterotypes. We searched for fecal enterotypes in the HMP and community 16S rRNA gene sequence data using the relative abundances of OTUs across samples, and applying five different distance metrics: JSD, rJSD, BC, and weighted/unweighted UniFrac distances, and three cluster evaluation methods (PS, CH and SI; Fig. 3). Using PS, we observed at best moderate support for 2 fecal enterotypes in the HMP data using weighted UniFrac, but little or no support using other distance metrics (Fig. 3A). We obtained similar results using community data alone and when combined together (Fig. 3A). Weighted UniFrac scoring for enterotypes was weak with SI (Fig. 3). Figs. S3, S4, S5, S6, S7 show similar analyses for 3 different vaginal sites, and 9 oral and 3 skin sites. Moderate to strong clustering is evident in only 3 out of these 15 body sites. In the mid vagina there is strong support for 2 clusters (discussed below) using BC, JSD and rJSD (Fig. S3; weighted UniFrac provided moderate support; unweighted UniFrac provided no support). In the posterior fornix (Fig. S3) and the attached keratinized gingiva (Fig. S4), we observed moderate support for 2 clusters using 5 and 4 distance metrics, respectively (unweighted UniFrac resulted in little or no support in the gingiva). These results indicate that the detection of enterotypes is sensitive to the distance metric used, a result also recently reported by Claesson et al. [25]. Note that this sensitivity is not dependent on body site. However, because enterotyping is driven by the relative abundances of specific genera within samples, unweighted UniFrac, which takes into account presence/absence of tree branches but not abundances of sequences mapping to those branches, may not be an ideal distance measure to use for enterotyping. We include it here because it is widely used in microbiome studies. In contrast, the weighted UniFrac, BC, JSD and rJSD distance metrics are based on OTU abundances and should in principle be more appropriate. The lack of concordance between results based on different abundance-based distance metrics raises the following questions: if enterotypes are to be considered robust, must they be observed using more than one distance metric? Or does the lack of concordance between results using different distance metrics indicate that (here at least) weighted UniFrac is the best choice for enterotyping? Because the interpretation of the findings is currently subjective, and in the absence of any community-wide best practices, we recommend using at least 2 or 3 distance metrics and clearly stating the criteria used for calling enterotypes within the context of any particular study. Particularly, if different metrics yield different results, authors should attempt to understand the discrepancies and justify their choice of distance metric. The effects of OTU taxonomic levels (for instance, clustering sequences at genus or species level) on the recovery of enterotypes are best illustrated with 16S rRNA gene sequence data from vaginal sites (Figs. 4 and S3). Ravel et al. [26] reported enterotypes in the vagina based on the abundances of bacterial species (as opposed to genera used in gut studies). We used the abundances of both species and genus-level OTUs from the Ravel et al. dataset to test for enterotypes. Our analysis shows strong support for two genus-level enterotypes using 4 of 5 distance metrics (i. e., unweighted UniFrac had moderate support) for the Ravel et al. dataset when using the PS to test the strength of the clustering (Fig. 4). We also observed strong support for genus-level mid-vaginal enterotypes using 3 of 5 distance metrics (BC, JSD and rJSD) for the HMP dataset (Fig. 4). Additionally, using a species-level analysis, we obtained moderate support for five enterotypes using BC and JSD in the Ravel et al. data (we also scored strong support for 2 enterotypes with weighted UniFrac), and moderate to strong support for 2 clusters (i. e., little or no support for five clusters) in the HMP data (Fig. 4). We also tested for clustering of vaginal samples using SI and CH. When using SI (Fig. S8) at the genus level we found strong support for 2 clusters in the HMP and Ravel et al. datasets using 3 and 1 distance metrics respectively. But when using CH (Fig. S9) on the HMP data at the genus level, the highest scores were obtained for 2–3 and 9–10 clusters, and in the Ravel data the strongest support was for 2 clusters. At species level, we observed strong support with SI for 2 enterotypes in the HMP data using weighted UniFrac, and for 5 enterotypes using JSD (Fig. S8). No strong support was observed for the Ravel data for any number of clusters at the species level using SI. With CH, at the species level, the highest score was for 10 clusters in the HMP data, while for the Ravel data the highest score was for 2 clusters. The differences in number of enterotypes found at the genus and species levels underscore the sensitivity of enterotyping to the taxonomic depths used in constructing OTUs. To test for the influence of the specific variable region of the 16S rRNA gene on the detection of fecal enterotypes, we compared fecal samples from the HMP for which sequence data for both the V1–V3 and V3–V5 regions were available. Data from the V3–V5 region yielded moderate support for two fecal enterotypes, but no enterotypes were detected using data from the V1–V3 region. When using SI, we observed moderate support for 2 clusters when using JSD on the V1–V3 data and weak support for the V3–V5 data. The highest scores using CH were three clusters using BC for V1–V3 data and two clusters using weighted UniFrac for V3–V5 data (Fig. S10). Different primers amplifying different regions of the 16S rRNA gene sequence are known to impact the diversity described for a microbial community. For example, primers for the V1–V3 region (e. g., 27F-338R) are not efficient for amplifying 16S rRNA gene sequences from members of the Bifidobacteria genus, which can dominate the infant microbiota [22], [27]. Our analysis demonstrates that the specific region of the 16S rRNA gene that is amplified during PCR is another factor that can affect the outcome when searching for enterotypes. We compared enterotype clustering using two methods for OTU picking: (1) de novo sequence clustering into OTUs, in which sequences are clustered based on similarity to one another, and (2) a reference based approach, in which sequences are clustered based on similarity to sequences in a reference database [27]. We found that for the HMP dataset, the two OTU picking approaches yielded consistent results for the majority of body sites (Fig. 5). However, for the attached keratinized gingiva, posterior fornix and tongue dorsum, the reference-based approach provided moderate support for enterotypes, whereas the de novo approach did not support clustering. One important difference between the two OTU-picking approaches is that the reference-based method can yield fewer OTUs, particularly at fine taxonomic resolution, because any sequence that fails to find a match in the database is discarded. In contrast, the de novo approach retains all sequences and has the potential to yield higher OTU counts. Fewer OTUs would have the effect of increasing the relative abundances of the dominant genera, and may therefore strengthen the gradient effect frequently observed (see below). Thus, the reference-based OTU picking approach may result in over-confidence in enterotype discovery. Rarefaction is the commonly used normalization practice of randomly subsampling the data so that an equal number of sequences are drawn for each sample. We rarefied the sequences from the HMP fecal samples at 2,000 sequences per sample and compared the results to those obtained after rarefying at 1,000 sequences per sample (Fig. S11). Rarefaction depth did not seem to strongly affect the results of the clustering. We also implemented our methodology in the smaller set of HMP samples for which WGS data were available, in addition to the MetaHIT WGS data [3]. While the HMP WGS data included fewer samples and body sites than the 16S rRNA gene sequence data (approximately 700 spanning the gut, nares, three oral habitats, and posterior fornix), they provided consistent species-level resolution. We found a strong gradient effect in the fecal samples (see discussion on gradients below) for almost all genera and species, and between species within the genus Bacteroides and members of the Firmicutes. We also found that the presence of Prevotella (specifically, P. copri) was clearly associated with the first principal coordinate in the PCoA using three distance measures. This feature in turn drove moderate support for two clusters in the HMP data (using JSD and rJSD) and strong support for 2 clusters in the MetaHIT data (Figs. 6 and S12), that appeared to separate roughly according to presence/absence of Prevotella. Prevotella is similarly influential in driving variation along the first principal coordinate axis when using Jensen-Shannon divergence for the 16S-based samples, albeit not with weighted UniFrac (Figs. S13-S14). Although the importance of Prevotella in clustering analysis clearly depends on the choice of distance metric, the genus does exhibit enterotype-like behavior in that it follows a bimodal distribution: high relative abundance in a small fraction of samples, but low or zero relative abundance in many other samples. Note that the HMP 16S rRNA gene sequence surveys include a smaller fraction of samples containing high relative abundance of Prevotella compared to WGS data (12. 3% and 10. 9% of samples contained >10% Prevotella in the HMP V1–V3 and HMP V3–V5 data sets, respectively, compared to 13. 9% and 24. 2% in the HMP and MetaHIT shotgun metagenomics). Although a bias of certain primers against Prevotella in 16S surveys has been reported previously [28], this is not likely to have affected the HMP data. The difference in Prevotella abundance between MetaHIT and HMP samples remains to be explained. In all other body sites, we again found general agreement between metagenomics clustering results and the 16S rRNA gene sequence-based clustering results regarding cluster quality (Figs. S15-S16), with the exception of the moderate support for two enterotypes in the buccal mucosa WGS data (Fig. S15), and lack of consistent support for enterotypes in the posterior fornix (Fig. S16). As we described above, we found moderate support for enterotypes in the posterior fornix in 16S data (Fig. S3). The discrepancy might be due to the fact that the WGS data included too few samples from the smaller “clusters” to permit detection by the prediction strength approach; SI was highest for two enterotypes at the genus level corresponding to Lactobacillus (either dominant or absent; JSD jackknifed SI: 0. 89±0. 012), and statistically tied as highest for five (four Lactobacillus species or Lactobacillus absent, JSD jackknifed SI: 0. 79±0. 005) and eight (JSD jackknifed SI: 0. 79±0. 008) enterotypes at the species level (Fig. S17). Our results underscore the importance of methodology in assessing whether populations can be categorized by enterotypes. Table 1 summarizes the factors that might have an effect on enterotyping: the two with the largest effect are the distance metric and the clustering score method. We recommend using at least one absolute scoring method (i. e., PS or SI) combined with at least 2–3 distance metrics to verify the presence of enterotypes. When using the different scoring methods, authors should indicate and justify the choice of thresholds for indicating levels of support for enterotypes. Other factors that should be kept in mind are the data type (and if using 16S rRNA gene sequence data, the variable region sequenced) and the OTU picking method. At the present time, there is no community consensus on how to define an enterotype, and two researchers with the same data can easily come to opposite conclusions regarding the presence of enterotypes if they apply different criteria. Microbial ecologists and clinicians interested in the enterotype concept need to standardize enterotyping methods for the concept to gain utility. The large size of the HMP dataset, augmented with the community and MetaHIT data, brought to light the extent of bacterial abundance gradients within body habitats. The presence of these gradients underscores that discrete enterotypes (i. e., enterotypes with distinct boundaries) are lacking. Instead, for continuous OTU and genus gradients are the norm for most body sites, although a few body sites had multimodal distributions of samples with modes near the extremes of the gradients, and very few cases (e. g., the vagina) had consistent discrete community types. The biological drivers of these patterns, and their robustness over time, may be manifestations of host-microbial interactions, especially if they correlate with host factors such as diet, lifestyle, or genetics. | Title: A Guide to Enterotypes across the Human Body: Meta-Analysis of Microbial Community Structures in Human Microbiome Datasets Summary: Recent work has suggested that individuals can be classified into 'enterotypes' based on the abundance of key bacterial taxa in gut microbial communities. However, the generality of enterotypes across populations, and the existence of similar cluster types for other body sites, remains to be evaluated. We combined the Human Microbiome Project 16S rRNA gene sequence data and metagenomes with similar published data to assess the existence of enterotypes across body sites. We found that rather than forming enterotypes (note we use this term for clusters in all body sites), most samples fell into gradients based on taxonomic abundances of bacteria such as Bacteroides, although in some body sites there is a bi/multi modal distribution of samples across gradients. Furthermore, many of the methods used in the analysis (e. g., distance metrics and clustering approaches) affected the likelihood of identifying enterotypes in particular body habitats. We recommend that multiple approaches be used and compared when testing for enterotypes. | 6,592 | 245 | lay_plos | en |
Summarize: GLENDIVE, Mont. (AP) — Truckloads of drinking water were being shipped to the eastern Montana city of Glendive on Monday after traces of a major oil spill along the Yellowstone River were detected in public water supplies, raising concerns about a potential health risk. Paul Peronard, left, with the U.S. Environmental Protection Agency, describes a pipeline spill along the Yellowstone River near Glendive, Mont. as Gov. Steve Bullock listens, Monday, Jan. 19, 2015. Up... (Associated Press) Bob Habeck, left, with the Montana Department of Environmental Quality, speaks at a meeting in Glendive, Mont., discussing concerns about drinking water supplies after a pipeline spill along the Yellowstone... (Associated Press) A warning sign shows the location of a 12-inch oil pipeline owned by Bridger Pipeline Co. that spilled up to 50,000 gallons of crude along the Yellowstone River near Glendive, Mont., Monday, Jan. 19,... (Associated Press) Cleanup workers cut holes into the ice on the Yellowstone River near Crane, Mont. on Monday, Jan. 19, 2015 as part of efforts to recover oil from an upstream pipeline spill that released up to 50,000... (Associated Press) Montana Gov. Steve Bullock, left, talks with Glendive Mayor Jerry Jimison on Monday, Jan. 19, 2015 about an oil spill along the Yellowstone River upriver of the city that released up to 50,000 gallons... (Associated Press) A warning sign shows the location of a 12-inch oil pipeline owned by Bridger Pipeline Co. that spilled up to 50,000 gallons of crude along the Yellowstone River near Glendive, Mont., Monday, Jan. 19,... (Associated Press) Preliminary tests at the city's water treatment plant indicated that at least some oil got into a water supply intake along the river, according to state and federal officials. About 6,000 people are served by the intake, Glendive Mayor Jerry Jimison said. Officials stressed that they were bringing in the shipments of drinking water as a precaution and did not know yet whether there was any health threat. Results of further tests to determine the scope of the danger were expected in coming days. Up to 50,000 gallons of oil spilled in the pipeline accident Saturday. Cleanup crews trying to recover the spilled crude were hampered by ice that covered most of the river, making it hard to find the oil. Initial tests of water supplies Saturday and Sunday revealed no evidence of oil. But by late Sunday, residents began complaining that the water coming from their taps had an unusual odor, officials said. An advisory against ingesting water from the city's treatment plant was issued late Monday. After hearing about it, Glendive resident Ed Miller, 67, picked up an extra gallon of water from the fast-dwindling supplies at a convenience store. Miller hadn't noticed any odors from his own tap water. But his neighbors had, and Miller said he wouldn't be drinking any city water until the advisory was lifted. Glendive City Councilman Gerald Reichert said he first noticed an odor in the water at his house Sunday night. He said it smelled like diesel fuel. Officials with Bridger Pipeline LLC of Casper, Wyoming, have said the break in the 12-inch steel pipe happened in an area about 5 miles upstream from Glendive, an agricultural community in east-central Montana near the North Dakota border. Bridger spokesman Bill Salvin said Monday that the company is confident that no more than 1,200 barrels — or roughly 50,000 gallons — of oil spilled during the hour-long breach. An oil sheen was seen near Sidney, almost 60 river miles downstream from Glendive, said Paul Peronard, the on-scene coordinator for the U.S. Environmental Protection Agency. Booms were being placed in areas of open water to try and trap oil. Near Crane, which is about 30 miles downstream from the spill, crews were chopping holes into the ice in hopes that they will be able to vacuum up crude as it comes down the river in coming days. "These are horrible working conditions to try to recover oil," Peronard said Monday. "Normally you at least see it, but you can't see it, you can't smell it.... We're going to have to hunt and peck through ice to get it out," Peronard said. Bridger Pipeline crews were still working Monday to determine exactly where the breach occurred. If it happened on the bank, some of the oil may be trapped in the soil near the river. If it was beneath the river, "then it's all in the river," Peronard said. Montana Gov. Steve Bullock toured the spill site Monday afternoon. He said he expected Bridger to continue its cleanup efforts "until it's cleaned up to our standards." "The water's a concern," Bullock said. "I expect Bridger to continue and provide all the resources needed." The Poplar Pipeline system runs from Canada to Baker, Montana, and carries crude oil from the Bakken oil producing region in Montana and North Dakota. It remained shut down Monday while crews planned to pump out any remaining oil from the section of the pipeline where the breach occurred. The pipeline receives oil at the Poplar Station in Roosevelt County, Fisher and Richey stations in Richland County, and at Glendive in Dawson County, all in Montana. It was last inspected in 2012, Salvin said, and is at least 8 feet below the Yellowstone River bed where it crosses the river near Glendive. Bridger Pipeline, a subsidiary of True Cos., also owns and operates the Four Bears Pipeline System in North Dakota along with the Parshall Gathering System and the Powder River System in Wyoming, according to the company's website. Bridge Pipeline Vice President Tad True said the company apologizes for the spill and has taken responsibility for the cleanup. The company will not be able to restart the pipeline until it receives approval from the U.S. Department of Transportation's Pipeline and Hazardous Materials Safety Administration. Inspectors from the federal agency were at the spill and also planned to inspect Bridger Pipeline's control room in Casper, Wyoming, to gather more information, PHMSA spokeswoman Susan Lagana said. Crews work to contain an oil spill from Bridger Pipeline’s broken pipeline near Glendive, Mont., in this aerial view on Monday. (Photo by Larry Mayer / The Billings (Mont.) Gazette) Fresh water being trucked into Glendive, Mont., after almost 50,000 gallons of Bakken crude oil spills into Yellowstone River Fresh water being trucked into Glendive, Mont., after almost 50,000 gallons of Bakken crude oil spills into Yellowstone River Fresh water being trucked into Glendive, Mont., after almost 50,000 gallons of Bakken crude oil spills into Yellowstone River GLENDIVE, Mont. -- Truckloads of water are being brought into Glendive after a spill of close to 1,200 barrels of oil, roughly 50,000 gallons, has officials concerned about the town’s water supply. Montana officials have notified Sidney, Mont., and Williston, N.D., both downstream from the leak, and municipal water systems there are being tested for contamination, too, according to the Montana Department of Environmental Quality. The Environmental Protection Agency said in a statement Monday evening that elevated levels of hydrocarbons have been found in Glendive’s water supply. “This is a significant spill, and the coordination of various response activities at the spill site, the city of Glendive, and downstream locations will be a priority over the next several days,” the EPA said in its statement. Bridger Pipeline’s Poplar line, leaked oil Saturday near where it crosses the Yellowstone River, Glendive’s water supply. The leak occurred roughly 9 miles south -- upstream -- from the town of about 5,000 along Interstate 94 in eastern Montana. As crews worked to find the cause of the leak, officials closed water intakes in the river and brought semi-loads of fresh water here Monday evening after 20 to 30 residents reported a smell or taste to their drinking water. “We don’t know 100 percent yet that there’s contamination on the system but we are going to put out warnings to the residents of Glendive that they probably shouldn’t be drinking the water until we get definite results back,” Mayor Jerry Jimison said earlier Monday. As of about 5 p.m. MDT Monday, as the EPA reported elevated hydrocarbons in initial test results, responders were placing containment structures across the Yellowstone River at Sidney, Mont., about 30 miles downstream from the leak, according to the EPA. More specific test results are expected in the next couple days. After passing Sidney, the river enters North Dakota and shortly thereafter joins the Missouri River, near Williston. The state of North Dakota has dispatched an official to watch for signs of the oil on its side of the border, according to the Montana Department of Environmental Quality. Governor declares emergency When Gerald Reichert first heard reports of smelly drinking water Sunday, he thought it could all be psychological, residents nervous after hearing about an oil spill. Then he smelled it himself in his Glendive home. “Suddenly at our house there was a definite smell. It was a diesel smell,” Reichert, a member of the Glendive City Council, said Monday afternoon. Reichert was one city official getting calls Sunday from residents who smelled something funny in the water. Bridger Pipeline planned to continue bringing in a semi-load of water each day until the system is clear, Jimison said. Officials from EPA, Bridger, the state of Montana and the city of Glendive are developing a plan to flush the water distribution system, according to the EPA. The U.S. Fish and Wildlife Service, the U.S. Department of Transportation and the U.S. Coast Guard are also responding. Officials said earlier Monday that contamination was unlikely because the water intake is 14 feet below the water surface and the oil tends to float. Montana Gov. Steve Bullock visited the site Monday afternoon for a briefing, Jimison said. The governor’s office issued an executive order declaring a state of emergency in Dawson and Richland Counties. The river’s frozen state hinders response efforts, Bullock said in the order. The leak began at 10 a.m. Saturday and Bridger shut down the line by 11 a.m., according to a company statement. The spill has wound up being on the higher end of the company’s initial estimate of 300 to 1,200 barrels. “Our primary concern is to minimize the environmental impact of the release and keep our responders safe as we clean up from this unfortunate incident,” Tad True, vice president of Bridger Pipeline, said in a statement. A spokesman for Bridger didn’t return a call for comment. Bridger Pipeline is under the umbrella of the True Companies, which also owns Belle Fourche Pipeline Co., Black Hills Trucking and other energy businesses. The spill is the second in the river in recent years. In 2011, Exxon Mobil Corp.’s 40,000 barrel-per-day Silvertip pipeline in Montana ruptured underneath the river, releasing more than 1,000 barrels of crude and costing the company about $135 million to clean up. The price of Bakken crude was little changed on the Martin Luther King, Jr. holiday despite the shutdown of the Poplar line, which carries Bakken crude to Baker, Mont. Bakken crude narrowed slightly to $5.40 per barrel below the West Texas Intermediate benchmark, according to Shorcan Energy brokers, compared with a settlement of $5.80 under the benchmark on Friday. One trader in Calgary said he did not expect the outage to have a significant impact on differentials as the pipeline is not a major conduit for crude in the area. Reuters contributed to this report. Ten groundwater wells have also been sampled. The wells were selected due to their shallow depth and vicinity to the break. Results for all ten wells sampled were non-detect for VOCs. Permanent monitoring equipment was installed at the water plant. This equipment detects VOCs and other oil constituents entering the system, providing continuous data to operators, and sounding an alarm that will trigger a shutdown of the treatment plant if benzene levels reach 2 ppb (less then half of the benzene maximum contaminant level - MCL). On March 14, a higher than normal level of VOCs was detected by the equipment during the ice breakup. The situation was planned for and the plant shut down to preserve the clean water in the storage system. A water conservation request was made to the City of Glendive for the weekend of March 14-15. An aeration system was put in place and the plant began treating water again on March 15. The conservation request was lifted on March 16 and there have been no detections since. Water samples have been taken along the river at the site of the release and select points downstream. Sediment and surface water sampling at the irrigation intake located approximately 17 miles downstream of Glendive has been conducted at the request of the Lower Yellowstone Irrigation District. There has been no visual or other evidence of crude oil at the intake's irrigation structures. There was some light oil staining at the I-94 bridge that was cleaned up. Additional sediment sampling will take place. Crews recovered approximately 490 barrels of oil from the pipeline after it was shut down, and about 60 barrels from the river. On April 10, 2015 at 7:00 a.m., the Unified Command dissolved and operations moved into a more traditional response under the authority of the Montana Water Quality Act (WQA) and the Comprehensive Environmental Cleanup and Responsibility Act (CECRA). Bridger and its consultants will coordinate directly with DEQ regarding work plans, reports, additional cleanup, other remediation work confirmation sampling and reclamation work. The pipeline was 12 inches in diameter and one-half-inch thick in the area where it crossed under the Yellowstone River just upstream from Glendive. A breach in the line occurred between two block valves approximately 6,800 feet apart where the line crosses the river. The point of the release was determined to be under the river. The line was carrying Bakken crude oil at the time of the release. The damaged pipeline was pulled from the river and sent to a lab in Oklahoma for metallurgical testing. April 13, 2015 Montana Fish, Wildlife and Parks has lifted its consumption advisory for fish caught on the Yellowstone River near the spill. After the ice left the river in March, FWP fisheries biologists were able to catch 213 fish representing species known to live in the river between the spill site and the North Dakota border. Laboratory tests of those fish showed no detectible levels of petroleum contamination in the edible muscle tissues. *The following updates came from information provided by the Unified Command. April 10, 2015 At 7:00 a.m. today, the Unified Command was dissolved. Work will continue with oversight from DEQ under the authority of the Montana Water Quality Act and the Comprehensive Environmental Cleanup and Responsibility Act. Bridger and its consultants will coordinate with DEQ on work plans, reports, additional cleanup and other work regarding remediation, confirmation sampling and reclamation work. April 8, 2015 The Unified Command has been notified that an eight-foot section of damaged pipeline has been successfully withdrawn from the Yellowstone River. The linked image shows a break along a section weld line. Go to the Poplar Pipeline Response website for more information. April 3, 2015 The Montana Department of Environmental Quality has received Bridger Pipeline's work plan to remove the exposed section of damaged pipeline in the Yellowstone River. The plan calls for dive vessels and support craft to be launched on Monday and Tuesday, April 6 and 7 while divers locate and survey the pipeline. A small, temporary hydro-dam diversion wall will allow for some protection against river flow as survey and withdrawal work is underway. "Pigs" remain in the broken section of the line and were used to purge remaining oil toward the gate valves where it was recovered. These devices may be pushed out of the pipeline after sectioning the line, or withdrawn manually. A 10 to 15-foot section of the line containing the rupture is expected to be removed to the north shore on Wednesday, April 8. Questions about the pipe removal should be addressed to Bridger. March 27, 2015 The Montana Department of Environmental Quality has issued comments on the Poplar Pipeline Response for Sediment and Co-located Water Sampling Work Plan and Schedule. For the Comments document, click here. March 25, 2015 The Unified Command has transitioned from emergency response and oil recovery under the Incident Command System to long-term remediation and monitoring. The EPA will issue its final report and DEQ will assume the role of lead agency. Cleanup, monitoring and data collection will continue. The Montana DNRC and FWP will continue to serve in support roles for the State. The EPA will remain available for consultation and assistance as necessary. The last of the ice in the Yellowstone River melted during the week of March 13. Extensive reconnaissance by boat and air is being conducted from the spill site to the Montana/North Dakota border. Staining and sheen has been noted, but no recoverable oil has been found. For the full press release, click here. March 16, 2015 The City of Glendive has lifted its "conserve water" advisory for residents on the City's water system. The water treatment plant is up and running and the water being produced is clean and safe to drink. March 15, 2015 The Glendive Water Treatment plant is back online and making water. Workers completed the aeration system late this morning and it is working as expected. Readings of Volatile Organic Compounds (VOCs) have been zero throughout the morning. The aeration system will allow the plant to continue operations as the last of the ice melts on the river and releases whatever amount of oil remains from the Poplar Pipeline spill January 17. Officials at the Glendive Water Department are asking residents to continue to conserve water until Monday so that the water plant can refill its reserve tanks. The level in the reserve tanks dropped while the system was shutdown the last 30 hours. Workers from Dawson County provided more than 750 gallons of bottled water the last two days to local residents, the prison and the local hospital. It is important to point out that at no time did any contamination make its way into the Glendive water system. The system was shut down because of higher than normal levels of VOCs at the intake for the system. The new monitoring system installed after the January 17 breach of the Poplar Pipeline worked as designed and allowed workers to keep the city’s water supply safe. The water in the system remains clean and safe to drink. March 14, 2015 - City of Glendive – Water Conservation Advisory The City of Glendive is asking residents on the city water system to conserve water this weekend. On Saturday morning, due to the ice break-up in the river, the city water plant detected a higher than normal level of Volatile Organic Compounds (VOCs) at the intake. This situation was planned for and the plant is currently shut down to preserve the clean water in the system. Currently, all of the water in the city’s water system is clean and safe to drink and water is available for emergency fire response. The main concern is that if current conditions remain and no action is taken, the water plant may need to be shut down for a longer period of time. The Unified Command is taking actions to ensure the residents of the city of Glendive continue to have an uninterrupted supply of clean drinking water: Installing an aeration system at the water plant to remove traces of VOCs from the water. That will be completed as soon as possible, but no later than Sunday and will enable the plant to produce clean water regardless of the conditions on the river. Asking residents to conserve water during the weekend of March 14-15. Providing bottled water assist with water conservation to anyone who needs extra supply of drinking water. Bottled water can be picked up from 1-5pm Saturday at the Dawson County Emergency Operations Center. Testing the water at the intake and distribution point to ensure the city’s water supply is protected efforts. March 13, 2015 Warm weather has made on-ice recovery of oil unsafe. Members of the Unified Command are monitoring conditions and responding to reports of oil on the river. Spill responders will resume assessing the impact of the spill on the river once the ice is clear. In the meantime, local residents can report oil sightings or odor complaints by calling the Poplar Response Hotline at 888-959-8351. A joint press release notes additional resources have been deployed to Glendive in anticipation of the ice break-up. Air monitoring and water sampling equipment will be on-hand for quick response. Specialized monitoring equipment has been installed at the Glendive Water Treatment Plant that will detect crude oil contaminants at the intake. Should Volatile Organic Compounds (VOCs) be detected, the intakes will automatically close to prevent contaminants from entering the system. March 6, 2015 The U.S. Department of Transportation's Pipeline and Hazardous Materials Safety Administration has approved Bridger Pipeline's request to reopen a 49-mile portion of the Poplar System beyond the rupture point that occurred on January 17 under the Yellowstone River. The approved section does not cross any major waterways and will be restarted under reduced operating pressure and enhanced surveillance. March 5, 2015 DEQ continues to have a presence in Glendive as the Poplar Pipeline spill response is in it's interim phase. Weather conditions are still hampering the recovery of oil. Surveillance continues and no new visible impacts downstream have been observed. Information is being developed and disseminated to landowners along the river with instructions on who to contact and what to do if any oil is spotted. Bridger Pipeline, LLC has responded to DEQ's Notice of Potential Liability Letter under the Comprehensive Environmental Cleanup and Responsibility Act and the Water Quality Act, sent February 12. Bridger Pipeline, LLC Response to DEQ Notice of Potential Liability Letter DEQ Notice of Potential Liability Letter to Bridger Pipeline, LLC February 26, 2015 The long-term monitoring equipment, or Total VOC Analyzer, is now online at the Glendive Water Treatment Plant. The daily sampling of water at the intake and output will be discontinued today. The EPA mobile lab will demobilize on February 27. February 23, 2015 On Friday, Montana Fish, Wildlife & Parks updated its fish consumption advisory. Detectable levels of petroleum were found in tests of fish pulled from the Yellowstone River downstream from the Poplar Pipeline break near Glendive. See the full press release here: http://fwp.mt.gov/news/newsReleases/fishing/nr_0887.html February 20, 2015 The results for the ten groundwater wells sampled on February 11 and 12 came back non-detect for volatile organic compounds. These wells were selected due to their shallow depth and vicinity to the pipeline break. February 18, 2015 Daily updates coming from the Unified Command continue to be much of the same. Reconnaissance has been conducted from the incident location to the confluence of the Yellowstone and Missouri Rivers. On February 17, there were no visible impacts observed. A flyover was conducted with notes of some open water and no sheen from Glendive to Savage. Oil recovery continues to be hampered by weather conditions. February 13, 2015 Cold temperatures have drastically slowed oil recovery again. However, 3.5 barrels of oil have been recovered from the river this week. Booms have been deployed on the ice to help capture and collect oil on the surface. February 12, 2015 Five shallow groundwater wells in the vicinity of the break (from the pipeline to Glendive) were sampled yesterday and came back non-detect for crude oil or crude oil constituents. An additional four to five will be sampled today. The long-term monitoring equipment for the water treatment plant has arrived and is being installed today. It should be operational in the coming days. Oil recovery has been limited due to weather and ice conditions. A small amount of oil was recovered Monday and Tuesday. Estimates of how much was recovered are still being calculated. Wildlife agencies are still waiting for the fish tissue sample results to come back. There have been no reports of oiled wildlife. February 9, 2015 Response crews are back out on the ice today recovering oil from the Yellowstone River. Over the weekend, weather conditions became more favorable and crews were able to use oil spill boom to keep oil on the ice from spreading, and cut slots into the ice in some places. Confirmed oil recovered from both the pipeline and the river stands at about 23,000 gallons. Updated recovery numbers will be provided as they are available. Water sampling continues daily at the Glendive Water Treatment Plant. All samples continue to confirm the water in Glendive is safe to drink. Environmental specialists continue their sampling efforts at various locations along the Yellowstone River. February 6, 2015 A spill response crew continues to monitor the river everyday. With warmer weather in the coming days, there is a chance that more oil may be recovered. Unified Command has signed a groundwater sampling plan and sampling will begin next week. We continue to encourage people to call the hotline at 888-959-8351 if they have questions or concerns regarding the spill and response. February 4, 2015 The Unified Command has received comment asking why individual home water sampling is not taking place. The Glendive public water supply is a regulated entity and two samples per day are taken before the water goes through the treatment process and after the treatment process. These are the compliance points and we now have a consistent data set showing no elevated levels of contaminants. (See Water Treatment Plant Sampling Results in the Maps and Documents tab.) The public water supply is in compliance and safe. Residents need to make sure they have flushed their systems properly. Steps Glendive residents should take to flush their systems If anyone still has questions, call the hotline at: 888-959-8351 If anyone detects odors in their water, call the hotline. The hotline is manned from 8:00 a.m. to 8:00 p.m. If you reach the hotline after hours, leave a message and someone will call you back. February 2, 2015 Oil recovery activities were suspended over the weekend due to weather conditions. The current oil recovery estimate is 548 barrels (23,016 gallons) from both the pipeline and the river. Water samples are still being taken at the Glendive Water Treatment Plant and continue to show no detection of contaminants. Response teams are staged in Glendive to quickly recover oil should it be observed or reported. Detailed incident plans for both Phase II (Interim) and Phase II of the spill response can be found here. January 31, 2015 January 30, 2015 The Unified Command is shifting to an interim phase now that all of the oil remaining in the pipeline has been recovered. On-ice recovery of oil from the Yellowstone River will continue as conditions allow. During the interim phase, workers will continue water sampling at the Glendive Water Treatment Plant and environmental specialists will take water samples along the river at the site of the the release and at select points downstream. Additional environmental sampling will also be conducted to determine the extent of the spill's environmental impact and to guide future response plans once the ice breaks up. Bridger Pipeline will have a team of oil spill response specialists stationed in Glendive to support environmental monitoring and to collect any residual, recoverable oil from the January 17 release. Both the U.S. Environmental Protection Agency and the Montana Department of Environmental Quality will have on-scene coordinators to oversee response efforts. To date, response crews have collected 536.6 barrels of oil (about 22,537 gallons) out of more than 1,200 barrels that could have been released. Most of the oil recovery was from within the pipeline after it was shut down. Workers have been collecting about 400 gallons of oil a day from their on-ice recovery efforts. Air monitoring concluded in the city of Glendive on January 28. Seven days of continuous monitoring showed no elevated levels of hydrocarbon components in the air. All drinking water sampling continues to show the water in Glendive is safe to drink. Scientists from the National Oceanographic and Atmospheric Administration (NOAA) Emergency Response Division analyzed sampling data and their consensus was that the levels of contaminants were "well below public health concern thresholds and may in fact be near background levels." At the height of the response, more than 125 workers from Bridger Pipeline, the State of Montana, and the Federal government were responding to the pipeline breach. During the interim operations, approximately 20 people will be working daily on environmental monitoring, oil recovery, and claims processing. January 29, 2015 Crews will continue oil recovery on the Yellowstone River today. Safety is a top priority and river conditions are constantly monitored; however, temperatures have cooled and river conditions have stabilized. January 28, 2015 Oil Recovery Update: 490 barrels (20,580 gallons) recovered from pipeline, 41 barrels (1,722 gallons) recovered from river, 694 barrels (29,148 gallons) un-recovered from river. High resolution sonar did not reveal any new information on the pipeline; however, it did confirm what the lower resolution sonar identified over the last couple of days. The river flow rate and turbidity under the ice is too high for any camera results. The warm weather has created difficult river ice conditions hampering recovery and investigation at the pipeline crossing. Planned Pipeline Activities: The pipeline crew is now working on a camera that can be inserted into the pipe and attempt to capture information on the pipeline breach from inside the pipeline. First attempts will be to insert the camera from the northwest side of the river. January 27, 2015 Oil Recovery Update: Another 10 barrels of oil were recovered from the river today, bringing the total recovered to 518 barrels (21,756 gallons). January 26, 2015 Oil Recovery Update: 490 barrels (20,580 gallons) recovered from pipeline, 28 barrels (1,176 gallons) recovered from river, 707 barrels (29,694 gallons) un-recovered from river. EPA Pollution Report: River conditions are hampering access to the spilled oil. There is extensive ice cover on the Yellowstone River, but the ice is not sound enough in many locations to conduct response efforts. Significant thawing has occurred in the past two days and is increasing the risks associated with oil assessment and recovery efforts. Current reconnaissance indicates that there is not much oil remaining in the operational theater. More than 160 man-hours per day and an extensive array of equipment is being used to recover oil within the first three miles downstream of the pipeline break. Given the unsafe working conditions and the limited oil recovered, as discussed earlier in the pollution report, the response is rapidly approaching the point of diminishing returns. This is especially relevant given evidence of the physical damage caused to the river by activities of the response crews and equipment. Representatives from Montana Department of Natural Resources & Conservation and Fish, Wildlife & Parks have expressed concern that this is likely to be the most significant source of damages to the riverine system. It has been brought to the attention of the Unified Command by the U.S. Fish & Wildlife Service that much of the river corridor hosts nesting sites used by bald eagles; golden eagles; least terns; piping plovers; and great blue herons that are protected, threatened, or endangered. Eagles have already returned to the area and it is expected that they will begin nesting as early as February. Other significant species include the endangered pallid sturgeon and the spiny softshell turtle. The UC is weighing the impacts of the response (airboats, helicopters, and vehicular and foot traffic) along the shoreline versus the limited oil recovery and limited product remaining. Water Sampling Update: Drinking water sampling in the community of Glendive has been conducted daily since Montana environmental officials declared the water safe to drink on January 22. Environmental specialists have sampled water at the intake of the water treatment plant, as well as treated water from the plant, each day. All results have been well within drinking water standards. Additionally, 24 surface water samples have been taken on the river, including at the spill site, and all of them have been within standards. Workers took potable water samples from fire hydrants, residences, and public buildings and all samples have been below Maximum Contaminant Levels. Water is tested for Volatile Organic Compounds, including benzene, and other components of crude oil. Based on these samples, Glendive residents should feel comfortable continuing to use their water as normal. Sampling of water at the intake and treated water at the water treatment plant will continue. Equipment is expected to be put in place to detect and alert water treatment plant operators of anything abnormal entering the system long-term. Unified Command Update: January 24, 2015 Air Monitoring Update: The air in the community of Glendive has been monitored 24 hours a day since Sunday afternoon, January 18. Monitoring has been for benzene, Volatile Organic Compounds, and other compounds associated with crude oil. None of these compounds have been detected in the air anywhere in the community. Based on these results, the residents of Glendive should feel comfortable with their normal activities, including allowing their children to play outside. Any questions about air monitoring can be referred to the Poplar Response Hotline 1-888-959-8351. Pipeline Update: A sonar survey of the Poplar Pipeline where it crosses the Yellowstone River near Glendive shows that the pipeline is exposed on the river bed for approximately 100-110 feet near the site of the breach. At one point, the bottom of the river bed is about one foot (1 ft) below the pipeline. Bridger Pipeline last confirmed the depth of the pipeline under the river in September 2011. At that time, the pipeline was about eight feet (8 ft) below the river bed at its shallowest point. The sonar survey did not identify a cause of the pipeline breach that occurred January 17, but this data will assist investigators in determining the cause of the spill. Current estimates show the pipeline could have leaked up to 925 barrels of oil (38,850 gallons) into the Yellowstone River. Responders recovered a significant amount of oil from the pipeline on January 23 and January 24. A final tally of the total oil recovered is being made and a more precise estimate of the volume lost is being calculated. These numbers will be released in the next few days. On Sunday, workers from Ballard Marine Construction will continue to examine the pipeline to further assess the line. Oil recovery continues on the river. The weather will play a big factor in the coming days. Crews also continue to try to determine the cause of the pipeline breach. The information center has been closed; however, if people still have questions, they may call the hotline. Unified Command Update: January 23, 2015 Bottled Water Distribution Update: Bottled water distribution is being discontinued for residents on the City of Glendive's water system as the city's water has been certified safe to drink by the Montana Department of Environmental Quality. As a precaution, local authorities have stockpiled a two-day supply of bottled water at the Dawson County Disaster and Emergency Services office in Glendive. Residential Water System Update: Some residents have reported a dark brown to black material coming out of taps at or near the end of the flushing process. The EPA has evaluated several of these incidents. Environmental Protection Agency Incident Commander Paul Peronard says the material is not related to the spill but rather is naturally occurring sediment that built up when the water system was not in use. If you encounter sediment during the flushing process, please continue to flush and wash the material down the drain. No further action is needed. If you encounter odor in your water after the flushing process, please report that to the hotline at 888-959-8351. Unified Command Update: Glendive municipal water supply now meeting standards set by the federal Safe Drinking Water Act, according to DEQ. Read More January 22, 2015 Unified Command Update: Steps Glendive residents should take to flush their systems. Public Meeting: A Glendive Water System Public Meeting Update will be held this evening, Thursday, January 22, at 7:00 p.m. at the Glendive High School, 900 North Merrill Avenue. This is an informational meeting for all users of the municipal water system to carry out several steps to flush any remaining contamination from the system. January 21, 2015 Unified Command Update: The Glendive water treatment plant has been decontaminated. Preliminary sampling shows all of the contaminants that were elevated in water samples earlier this week are now below federal clean water standards. Confirmation testing is being done overnight and certified test results available tomorrow. The main water distribution lines have been flushed through the fire hydrants and samples have been taken. If those samples also show levels within safe drinking water limits, workers will begin the process of instructing residents how to flush the water in their homes and businesses. Montana Public Radio offers interviews with EPA on-site coordinator Paul Peronard, Bridger on-site public information officer Bill Salvin, and Glendive Mayor Jerry Jimison. The Montana Department of Fish Wildlife & Parks has issued a press release calling for a fish consumption advisory for the Yellowstone River between the spill site just upstream from Glendive and the North Dakota state line. January 20, 2015 Unified Command Update: Oil spill response workers recovered approximately 240 barrels of crude oil from the Poplar Pipeline Tuesday. Workers recovered the oil from the south side of the Yellowstone River where the pipeline crosses about six miles upstream from Glendive. Responders earlier had calculated the pipeline breach to have a worst-case discharge of up to 1,200 barrels (50,000 gallons) of crude oil. Today’s recovery reduces the total estimated escaped crude into the river to be about 960 barrels (or 40,000 gallons.) Drinking water is still being made available due to concerns about safety of the city’s water supply. Testing Monday showed elevated levels of Volatile Organic Compounds (VOCs), predominantly benzene in the water. Workers continue installing additional treatment capability at the Glendive Water Treatment Plant to clean the system and bring it back online. The Unified Command is sampling water from the plant so that the water system can be restarted. Residents will be able to resume using their water once the water quality is determined safe. In the meantime, 16,500 gallons of drinking water is available for residents to pick up at the Eastern Plains Event Center at 313 South Merrill Avenue in Glendive. A community center has been established at the Dawson County Courthouse at 207 W. Bell in Glendive. Representatives of Bridger Pipeline will be available to answer questions about the response. A representative from the Governor’s office will also be on hand. The center will be open from 9:00 a.m. to 5:00 p.m. daily. 11:00 a.m.: The City of Glendive is advising residents to not drink or cook with water from the city's municipal water system. Drinking water is being distributed at the Eastern Plains Event Center at 313 South Merrill Avenue in Glendive. Water is being delivered daily and will be available. Please monitor the Dawson County website at www.dawsoncountymontana.org for updates on water arrival. Work at the Glendive Water Treatment Plant is underway to remove the contamination and bring the system back on line. Those actions include: Increasing the dose of activated carbon, which removes contaminants. If the activated carbon does not prove adequate, workers will add air stripping equipment at the plant inlet to pretreat water coming into the facility. The increased activated carbon treatment began at 9:00 a.m. Tuesday and testing will be done later today to determine if this treatment is effective. If workers need to install the air stripping equipment a the plant inlet, it will take an additional day to complete that work. Once DEQ certifies the water safe at the plant, the system will be flushed so that residents can resume using their water. Drinking water will continue to be made available until the water system is certified safe to drink. Residents can pick up the water at Eastern Plains Event Center at 313 South Merrill Avenue in Glendive. 7:45 a.m.: A hotline has been established for drinking water concerns: 888-959-8351 7:30 a.m.: Results from the first water sample taken from the Glendive Municipal Water Treatment Plant has come back and the sample showed an elevated level of volatile organic compounds (VOCs), predominantly benzene. The presence of benzene would account for reports of adverse odor in the local water supply. This test result confirms findings from field samples taken Monday at several locations in the city. While the elevated levels are above the level for long-term consumption, the scientists who reviewed the data at the Centers for Disease Control have told the Unified Command that they “do not see that domestic use of this water poses a short term public health hazard.” Because of the public concern over the safety of the Glendive municipal water supply, the Unified Command has made arrangements to provide drinking water to Glendive residents on the city’s municipal water supply. The Unified Command is taking two additional actions to confirm these test results and to remove the contamination from the Glendive Municipal Water System. First, plans are being put in place to fully decontaminate the Glendive Municipal Water system. Also, responders will continue to sample the water from multiple locations for testing in both field sites and laboratories. Those results will be released as they become available. The Unified Command was established in response to a release from the Poplar Pipeline System owned by Bridger Pipeline, LLC. The command is operating out the Dawson County Disaster and Emergency Service Center in Glendive. Officials believe up to 1,200 barrels of crude oil (approximately 50,000 gallons) leaked from the Poplar Pipeline near where the line crosses the Yellowstone River near Glendive. January 19, 2015 Unified Command Update: On January 17th at 3:00 pm, Bridger Pipeline, LLC notified local authorities of a potential release from a pipeline that crosses the Yellowstone River approximately five miles upstream from Glendive. Dawson County has received complaints of odor in drinking water from people who use the municipal water supply. Water samples were taken from the municipal drinking water supply on Monday morning and were expedited to Energy Labs in Billings for analysis. Until more definitive information is made available, the Centers for Disease Control (CDC) recommends that residents do not ingest municipal water and to use bottled water for drinking and cooking. The Incident Management Team has ordered bottled water for public distribution at The EPEC building located at 313 South Merrill Avenue – time to be announced – for individuals seeking assistance. Water conservation is encouraged to preserve water capacity for emergency response. Additional information about testing and drinking water will be posted as soon as it becomes available. For the most current information please visit the DEQ Bridger Pipeline Spill website at http://www.deq.mt.gov/yellowstonespill2015.mcpx. Updates will also be posted on the DEQ Twitter and Facebook. For more information, contact the Dawson County Health Department at (406) 377-5213 An Executive Order has been issued by the Governor's office proclaiming an emergency to exist in the counties of Dawson and Richland along the Yellowstone River. GIS Map of Bridger Pipeline Oil Spill Water samples will be taken in Glendive and tested to determine any potential impact to drinking water supply. DEQ and EPA are responding to concerned citizens to sample their water using portable hand-held devices. January 18, 2015: BILLINGS, Mont. (AP) — Montana officials said Sunday that an oil pipeline breach spilled up to 50,000 gallons of oil into the Yellowstone River near Glendive, Montana, but they said they are unaware of any threats to public safety or health. The Bridger Pipeline Co. said the spill occurred about 10 a.m. Saturday. The initial estimate is that 300 to 1,200 barrels of oil spilled, the company said in a statement Sunday. Some of the oil did get into the water, but the area where it spilled was frozen over and that could help reduce the impact, said Dave Parker, a spokesman for Gov. Steve Bullock. "We think it was caught pretty quick, and it was shut down," Parker said. "The governor is committed to making sure the river is cleaned up." Bridger Pipeline Co. said in the statement that it shut down the 12-inch-wide pipeline shortly before 11 a.m. Saturday. "Our primary concern is to minimize the environmental impact of the release and keep our responders safe as we clean up from this unfortunate incident," said Tad True, vice president of Bridger. The EPA and state Department of Environmental Quality have responded to the area about 9 miles upriver from Glendive, Parker said. An Exxon Mobil Corp. pipeline broke near Laurel during flooding in July 2011, releasing 63,000 gallons of oil that washed up along an 85-mile stretch of riverbank. Montana officials are trying to determine if oil could have been trapped by sediment and debris and settled into the riverbed. Exxon Mobil is facing state and federal fines of up to $3.4 million from the spill. The company has said it spent $135 million on the cleanup and other work. Montana and federal officials notified Exxon that they intend to seek damages for injuries to birds, fish and other natural resources from the 2011 spill. The company also is being asked to pay for long-term environmental studies and for lost opportunities for fishing and recreation during and since the cleanup. These crawls are part of an effort to archive pages as they are created and archive the pages that they refer to. That way, as the pages that are referenced are changed or taken from the web, a link to the version that was live when the page was written will be preserved.Then the Internet Archive hopes that references to these archived pages will be put in place of a link that would be otherwise be broken, or a companion link to allow people to see what was originally intended by a page's authors.The goal is to fix all broken links on the web. Crawls of supported "No More 404" sites. | Summary: Montana Gov. Steve Bullock declared a state of emergency for two counties yesterday after a 12-inch oil pipeline burst Saturday, pouring up to 50,000 gallons of oil into the Yellowstone River near the town of Glendive, the state's Department of Environmental Quality reports. Bridger Pipeline Co. noticed the breach Saturday around 10am and shut the pipeline down by 11am, per a company statement. A spokesman for Bullock initially told the AP that "we think it was caught pretty quick" and noted the frozen river may minimize damage. But cleanup crews are struggling through the ice, the AP notes. And although initial tests revealed no oil in the drinking water, residents started noting Sunday that they "smelled something funny" in the water; the EPA said in a statement last night that elevated hydrocarbon levels were detected in Glendive's water, the Grand Forks Herald reports. Drinking water is now being trucked into Glendive "as a precaution," say officials; an advisory against drinking water from the local treatment plant was also issued last night, the AP notes. Officials had said earlier yesterday that contamination was unlikely because of oil's tendency to float (the water intake is nestled 14 feet below the surface). The DEQ notes a few oil sheens have been seen, with the AP reporting one 60 miles downstream from Glendive. In addition to the EPA and DEQ, the Coast Guard, Fish and Wildlife Service, and DOT are all assessing the mess and assisting with cleanup, notes the Herald. "Our primary concern is to minimize the environmental impact of the release and keep our responders safe as we clean up from this unfortunate incident," Bridger VP Tad True said in the statement. | 10,910 | 392 | multi_news | en |
Summarize: CROSS-REFERENCE TO RELATED APPLICATIONS This application is a division of application Ser. No. 13/725,339, filed Dec. 21, 2012, which in turn claims priority from U.S. Provisional Application No. 61/582,323, filed Dec. 31, 2011, and from U.S. Provisional Application 61/729457, filed Nov. 23, 2012, the entire contents of which applications are hereby incorporated by reference. BACKGROUND The use of displays in a Magnetic Resonance Imaging (MRI) equipment environment was first developed in the late 80's and early 90's, as described in U.S. Pat. No. 5,412,419, 5,432,544, 5,627,902, and 5,877,732. The earliest form of three dimensional (3D) technology first appeared in the movie industry at the end of the 19th century. The principal concept of this technology is to recreate the way humans see depth in real life; through a phenomenon called “binocular fusion”. 3D TVs digitally recreate the perception of binocular fusion to give viewers an immersive viewing experience with pictures that pop off the screen. With the recent release of new 3D TVs to the market, together with readily available 3D movies and other content, it would be advantageous to bring this new technology to patients in the MRI environment. BRIEF DESCRIPTION OF THE DRAWINGS Features and advantages of the disclosure will readily be appreciated by persons skilled in the art from the following detailed description when read in conjunction with the drawing wherein: FIG. 1 is a schematic illustration of a 3D LCD monitor setup in an MRI suite. FIG. 2 is a diagrammatic cross-sectional view of an exemplary embodiment of a system for 3D display delivery in the MRI. FIGS. 3A and 3B are cross-sectional diagrammatic illustrations of an exemplary embodiment of a 3D display. FIG. 3B illustrates features within circle 3 B of FIG. 3. FIG. 4 is a diagrammatic depiction of a patient viewing a 3D display while lying in an MRI bore. DETAILED DESCRIPTION In the following detailed description and in the several figures of the drawing, like elements are identified with like reference numerals. The figures are not to scale, and relative feature sizes may be exaggerated for illustrative purposes. A 3D TV and the human eye have a lot in common. Since our eyes are spaced slightly apart, the left and right eye sees images from a slightly different perspective. The human brain then combines the two images to create a 3D impression. A 3D TV works the same way. Two images—displayed from slightly different angles—are viewed through 3D glasses and then combined by the brain to construct a 3D image The first generation of 3D shutter glasses produced a 3D effect, in part, with technology embedded in the glasses. 3D shutter glasses function just like a camera shutter. A 3D television, in synchronization with the 3D glasses, alternately flashes a 2D image to each eye through a liquid crystal layer embedded within each lens of the glasses. The viewer's brain then combines the images flashed to each eye to create a 3D effect. However, the use of 3D shutter glasses in an MRI magnet room application is useless due to the electronics and battery existing in the active shutter glasses. The next generation FPR (Film Patterned Retarder) 3D relies on technology embedded in the television. FPR 3D glasses use a circular polarized filter to present two images concurrently to each eye. FPR 3D TVs incorporate the FPR technology in which a polarized film is placed on the 3D television screen to effectively split the left and right images into interweaving odd and even lines onscreen, and along with the 3D glasses which use circular polarization filters of opposite sense, separates the left and right images before they are delivered to the brain. This technically halves the original resolution of 3D content to each eye. The images are then combined by the brain to create the 3D impression. The applicant has recognized that this technology is ideal for use in MRI applications. An LCD TV can be shielded to block the emission of electromagnetic interference (EMI) inside of the MRI room, to provide an MRI-compatible display. For example, the front active part of the LCD TV may be shielded with a micro conductive mesh or laser aided conductive mesh which is 30 micrometers thick and will not appear when viewed with the naked eye. The entire LCD monitor will then be housed in a shielded Faraday cage, with inputs for power and the video/audio signals (e.g. carried by fiber optics or by Wi-Fi signals). FIG. 1 illustrates a typical component layout within the MRI suite. In this exemplary layout, the MRI magnet is disposed in the magnet room, with a patient table for positioning the patient in the bore of the MRI magnet 10. An MRI-compatible 3D display such as a large MRI-compatible LCD display 100 is positioned on a wall in the magnet room at a position selected to allow the patient in the MRI bore to observe the display, with the aid of a mirror. In this exemplary embodiment, the MRI-compatible 3D display is a display 100 which employs FPR technology to provide a 3D effect when used with an appropriate set of goggles or glasses, with circular polarization filters of opposite sense through which the image generated by the 3D display is viewed. The control room includes the Technologist Station 20 for controlling the MRI system. An FPR-compatible video source 22 capable of generating signals to produce the 3D image is placed in the control room, and its signal is converted (e.g. through an HDMI-to-Fiber Optic Converter 24 ) to an optical signal carried on an optical fiber 26. The video source may be, for example, a DVD player, HDTV receiver, a PC, etc. The optical fiber is passed from the control room into the equipment room and through a waveguide 28 positioned in a penetration panel 30 to the magnet room and to the large MRI-compatible LCD display 100. Alternatively, in another embodiment, the video source signals may be broadcast using a Wi-Fi broadband network, wherein a Wi-Fi repeater is used to transmit signals (e.g. from an antenna mounted to the magnet room wall). FIG. 2 illustrates the patient setup for the system in further detail. The patient wears the circular polarized passive glasses or goggles 40, with lenses 42 having circular polarization filters of opposite polarization sense for the left and right eye, typically applied by a filter film, and through the use of a reflective mirror 44, can view the 3D MRI-compatible display (e.g. a shielded 3D LCD TV) located on either end of the MRI bore (tunnel). The patient goggles 40 are configured to be MRI-compatible and fabricated without magnetic materials. Alternatively, the circularly polarized filters can be built into the passive goggles or applied to the mirror 44 into which the patient looks to see the display image. The patient goggles are typically fabricated of a very thin layer of optically clear plastic on which the filters are formed, and, because of the thinness, do not affect substantially the 3D image quality. In exemplary embodiments, the display 100 may be a large screen high definition 3D display or TV, utilizing LCD, LED or OLED technology (i.e. a 3D HD TV) and images generated by the display are relayed to the subject via a reflective mirror applied to a rear surface of a substrate formed of optically isotropic material. Alternatively, this could be a front surface mirror. In an exemplary embodiment for use in an MRI magnet room, the 3D TV is housed in a non-magnetic Faraday cage to shield EMI. A clear conductive window overlay is specially made for the MRI 3D application utilizing FR technology, where it is optically clear or transparent and does not affect screen polarization. The process of making the conductive window for the display in one exemplary embodiment uses a very fine conductive mesh laminated between two layers of optically isotropic glass or plastic material in a way that the edge of the mesh at the window edges is exposed. A conductive adhesive such as silver epoxy is applied to the mesh and window edges. By applying the silver epoxy, all the window edges become shorted to the mesh, increasing a surface area of conductive material in electrical contact with the mesh. With the conductive window assembled in the housing, the edge of the conductive window stays in tight contact with the housing of the display. For the 3D system to operate properly, the base material of any adhesive or other structures used to build the window may not cause interference with the polarization of the TV. Optically isotropic materials are used for the rf (radio frequency) conductive window on the display and the reflective mirror (i.e. materials having the same optical properties in all directions). The mesh may be sandwiched between the two layers of the window because the mesh is very fine and to protect it from damage. Another alternative for constructing the fine mesh is to start with a sheet of conductive copper applied to a glass layer, and then etch away most of the copper, leaving only a very fine line in the shape of very fine mesh. The etching may be done by a laser or other etching techniques. FIG. 3A is a diagrammatic cross-sectional view illustrating features of an exemplary embodiment of a 3D flat panel display 100 suitable for use in the magnet room environment of FIGS. 1 and 2. FIG. 3B illustrates features within circle 3 B of FIG. 3A. The display is constructed to provide a Faraday cage 110 defined by non-magnetic, electrically conductive materials. The Faraday cage 110 includes a front bezel or cover structure 112 which circumscribes the display panel area 114, and rear cover 116. The cover structure 112 may be fabricated of a non-magnetic electrically conductive material such as, by way of example only, brass or aluminum. The rear cover 116 attaches to the back of the cover structure 112. The Faraday Cage 110 includes an internal mounting frame structure 120 which is positioned between the inside of the front bezel portion 112 A of the cover structure 112 and the rear cover 116. The rear cover and the internal mounting frame structure are also fabricated of non-magnetic electrically conductive material, such as brass or aluminum. The internal mounting frame structure 120 and the cover structure 112 are configured to support the planar display system components, including the LCD/LED/OLED display panel 130, an LED backlight panel 140 (for an LCD implementation), and a mesh panel assembly 150 to cover the display panel or window area 114. The display panel may be a flat panel display such as an LCD (liquid crystal display) panel, an LED (light emitting diode) panel, an OLED (organic light emitting diode) panel, or even a plasma panel, for example. In the case of an LCD display panel, the backlight panel 140 is provided behind the display panel 130. The backlight panel 140 may be omitted for the implementation in which the display panel is OLED. The mesh panel assembly 150 in this exemplary embodiment includes planar layers 150 A and 1508 of transparent optically isotropic material, such as a glass, which sandwich a non-magnetic, electrically conductive mesh 150 C. The opening size of the mesh is preferably sufficiently small so as to block RF signals from passing through, yet large enough to allow the optical image rays pass through. An exemplary mesh opening size is on the order of 50 mesh openings per square inch. The mesh may be fabricated from copper, tungsten or alloy thereof, for example. The mesh panel assembly 150 is constructed to be optically isotropic, i.e. with a refractive index not dependent on the polarization and propagation direction of light. If the mesh panel assembly 150 were to be anisotropic, and exhibit birefringence, this could affect the polarized light emitted from the panel 130 and destroy the 3D effect. The panel 150 could also be a single layer of optically isotropic material, on which the mesh is applied or etched. However, to protect the mesh from damage, sandwiching the mesh between two layers can be advantageous. High quality isotropic glass, and plastics such as isotropic acrylic and CR39, may be employed to form the window assembly 150. In this exemplary embodiment, the display panel 130 is spaced from the mesh panel assembly 150 by an elastomeric spacer member 122. An EMI (electromagnetic interference) gasket 124 A is positioned between adjacent surfaces of the edge of the mesh panel 150 and the inner surface of flange portion 120 A 1 of the internal mounting frame structure 120. Another EMI gasket 1248 is positioned between adjacent portions of the back edge 1128 of the cover structure 112 and the back flange portion 120 C 1 of the internal mounting frame structure 120. The EMI gaskets can be fabricated of a springy non-magnetic, electrically conductive material, such as a copper/bronze alloy. The edges of the electrically conductive mesh layer 150 C are brought into contact with the adjacent surface of the internal mounting frame structure 120, e.g. at 120 D, so that the mesh is electrically connected to the internal mounting frame structure 120. A grounding connection 180 at the rear cover is connected to system ground within the magnet room so that the Faraday cage 110 is grounded. A support structure 160 is positioned between a back panel portion 1208 of the internal mounting frame structure 120 and the lower portion of the LED backlight 140. The support structure 160 is fabricated of a non-magnetic material such as aluminum. The top edge of the LED backlight is secured by a bracket portion 120 A 2 of the frame structure 120. A circuit board structure 170 is positioned with an upwardly extending board portion 170 A positioned between the display panel 130 and the backlight panel 140. The board portion can include circuit traces for making electrical contact with the circuit of the display panel, for example. The particular technique for fabricating the display panel 130 and driving it to provide the 3D display images may be conventional. An interface module 190 is positioned within the Faraday cage, adjacent the rear cover 116, and provides a power supply for the 3D flat panel display 100, and a connection (e.g. fiber optic, broadband Wi-Fi) for the video source signals to be supplied to the 3D flat panel display 100. The 3D flat panel display 100 in this exemplary embodiment employs FPR technology to provide a 3D effect when used with an appropriate set of goggles or glasses, with circular polarization filters of opposite sense through which the image generated by the 3D display is viewed. Alternatively, the display could use left and right linear polarizations to produce the 3D effects, with corresponding left and right linear polarization on the polarized films applied to the goggles worn by the patient. Other display technologies could produce the 3D effect in conjunction with electronics to create the 3D effect on the display itself, without the need for the patient to wear polarized glasses. For example, parallax barrier, glasses-free displays are known, which work by placing an opaque screen door-like barrier over the screen. Each eye views the barrier from a slightly different angle, and therefore sees different sets of pixels behind it. Some manufactures use an LCD barrier that can be turned off to enable 2D viewing. In the case of the parallax barrier, glasses-free display, the patient might directly view the 3D image reflected from the mirror. In all cases, the optical path between the image panel generating the 3D images and the patient's eyes should not pass through birefringent materials, which may adversely affect the 3D content of the images. FIG. 4 diagrammatically illustrates how, in one exemplary embodiment, a patient in an MRI tunnel could view the 3D images generated by the 3D flat panel display 100. The patient wears the circular polarized passive glasses or goggles, with lenses having circular polarization filters of opposite polarization sense for the left and right eye, typically applied by a filter film, and through the use of a reflective mirror, can view the MRI-compatible display, e.g. a shielded LCD TV, located on either end of the MRI bore (tunnel). The glasses are configured to be MRI-compatible, without magnetic materials. Alternatively, the circularly polarized filters can be built into the passive glasses or applied to the mirror into which the patient looks to see the display image. The patient can see the display while lying down on the MRI bore, using the combination of the polarized films in conjunction with the reflective mirror. The reflective mirror 44 in the MRI bore is optically isotropic, i. e. with a refractive index not dependent on the polarization and propagation direction of light. Typically, the reflective surface is placed on a back side of the mirror substrate, to reduce chances of scratching or damaging the reflective surface (as compared to forming the reflective surface on the front face of the mirror substrate). A suitable exemplary plastic for the mirror substrate is acrylic or CR39. For the case in which the reflective surface is placed on the back surface of the mirror substrate, the light path is through the substrate, which in this case should be formed of an optically isotropic plastic material, to avoid affecting the 3D image content of the viewed image. If the reflective surface is placed on the mirror front face, then the light path does not pass through the mirror substrate, and the substrate material should have little effect on the image quality. Although the foregoing has been a description and illustration of specific embodiments of the subject matter, various modifications and changes thereto can be made by persons skilled in the art without departing from the scope and spirit of the invention. | Summary: A display system compatible with a magnetic resonance imaging (MRI) apparatus disposed in a magnet room for producing video images to a patient in an MRI magnet tunnel, the images having a three-dimensional (3D) effect. An MRI-compatible 3D display includes a display panel configured to generate optical images having 3D content, and RF and electromagnetic interference filtering. A Faraday cage encloses the display panel, and includes an optically transparent window panel having an electrically conductive mesh and a layer of transparent optically isotropic material. | 4,316 | 122 | big_patent | en |
Summarize: CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of U.S. patent application Ser. No. 10/142,559 filed on May 9, 2002 now abandoned. BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a chum delivery container, or chumpot, for delivering chum or bait in a controlled manner below the surface of the water to attract fish, and more specifically to a chum delivery container which is made of a luminescent material to multiply the attraction effects and that is of simple and inexpensive construction which permits rapid and controlled cleaning and restocking of the container under nearly all weather conditions and which includes a rigid weighting arrangement made of an environmentally compatible material. 2. Description of the Related Art Chum delivery containers are well known in the art of sport fishing. Such containers typically are designed to automatically dispense the chum or bait either as the container moves in the water or by the natural water currents near the bottom of the water or when impacted by a fish or actually triggered by the fisherman. One of the more recent examples is U.S. Pat. No. 4,829,705 issued May 16, 1989 to Dorsey which discloses a pair of perforated frusto-conically shaped sections that are joined together at their larger ends and having a weight in the in the lower end to impose a vertical position. A door is provided in the upper section for access. Another recent example is U.S. Pat. No. 5,913,672 issued Jun. 22, 1999 to Nicholson which is a chum delivery assembly that includes a perforated container with a bottom panel. The container can be raised while on the water bottom to permit the chum that is positioned on the bottom panel to be exposed in a concentrated manner so as to attract larger types of gaming fish that would might otherwise be wary of approaching the area of the container. A third recent example is U.S. Pat. No. 5,617,669, issued Apr. 8, 1997 to Levey which is a perforated container comprised of a pair of longitudinally divided cylinder halves molded with a hinge running the entire length of the container. Weight-receiving pockets are molded integrally into the lower half of the cylinder. The problems with the prior art devices are that generally they do not provide for delivering chum or bait in a controlled manner below the surface of the water to attract fish, and are not made of a luminescent material to multiply the attraction effects. Furthermore, the prior art devices generally are not of simple and inexpensive construction that includes a rigid, environmentally compatible weighting arrangement and at the same time are not designed to permit rapid and controlled cleaning and restocking of the container under weather conditions suitable for sport fishing. SUMMARY OF THE INVENTION The present invention is directed to a chum delivery container, or perforated chum pot, which delivers chum or bait in a controlled manner below the surface of the water to attract fish, and which is made of a luminescent material to multiply the attraction effects, and that is of simple and inexpensive construction to permit rapid and controlled cleaning and restocking of the container under weather conditions suitable for sport fishing and includes a rigid weighting arrangement made of an environmentally compatible material. The chum delivery container of the present invention comprises a containment member, the containment member including a base and a surrounding wall surface, the base and the surrounding wall surface therein defining an open interior chamber and an open upper surface. The surrounding wall surface includes a plurality of perforations therein permitting release of the chum from the open interior chamber. Anchoring means are disposed at the base within the open interior chamber. Lowering means are provided for lowering the chum delivery container to an underlying surface at a location, and sealing and unsealing means are provided for sealing and unsealing the open upper surface of the containment member. At least a portion of the sealing and unsealing means can be of a curvilinear shape and can be comprised of a plurality of perforations. The sealing and unsealing means can further comprise at least one locking tab or spacer section which permits outward folding of the tab to seal and unseal the sealing means to and from the open upper surface of the containment member. The lowering means for lowering the chum delivery container is operatively connected to the anchoring means, and the lowering means penetrates through the sealing and unsealing means. The lowering means further comprises a locking means for locking in position the sealing means for sealing the open upper surface of the containment member, the locking means permitting both sealing and unsealing of the containment member. The lowering means further comprises a limiting means for limiting travel of the sealing and unsealing means along the lowering means. The locking means is capable of movement on, or travel along, the lowering means and is capable of being unlocked in a single action. Typically, the containment member further comprises a weighting material disposed at the base, typically a concrete containing Portland cement. The containment member and the sealing and unsealing means are comprised of a plastic material, typically a high-density polyethylene with a luminescent material, such as phosphorescent cadmium-zinc sulfide. Typically, the containment member is substantially cylindrical. In one embodiment, the anchoring means, except for a portion at which the lowering means for lowering the chum delivery container is operatively connected to the anchoring means disposed at the base, is contained within the weighting means. In another embodiment, the anchoring means is at least partially surrounded by the weighting material, and the anchoring means is substantially exposed to the interior region of the containment member. These and other objects, features and advantages of the present invention will become more readily apparent from the drawings and the detailed description of exemplary embodiments, which follows. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an elevation view of the chum pot of the present invention in the closed position. FIG. 2 is an elevation view of the chum pot of the present invention in the open position. FIG. 3 is a plan view of the chum pot of the present invention. FIG. 4 is a cross-sectional view of the present invention along section 4 - 4 ′ of FIG. 3. FIG. 5 is a cross-sectional view of an alternate embodiment of the present invention along section 5 - 5 ′ of FIG. 3. FIG. 6 is an elevation view of another embodiment of the present invention. FIG. 7 is an elevation view of the chum pot of the embodiment of the present invention of FIG. 6 in the open position. FIG. 8 is a plan view of the chum pot of the embodiment of the present invention of FIG. 6. FIG. 9 is a cross-sectional view of the embodiment of the present invention along section 9 - 9 ′ of FIG. 8. DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS The present invention generally comprises a chum delivery container, or chum pot, which is perforated to provide a controlled release of chum or bait below the surface of the water to attract fish. The chum pot is made of a plastic material. The plastic material includes a light-emitting luminescent material, capable of being activated under darkness by a lighting source, to multiply the attraction effects, even during night fishing. The chum pot includes a rope line connected at the base to a rigid weighting arrangement made of an environmentally compatible material. The rope line controls the movement of the lid of the chum pot to facilitate both secure closure while the chum pot is submerged and also to facilitate quick and easy restocking of the chum pot even during difficult weather conditions such as wind, rain or snow. The chum pot is made of simple and inexpensive construction that permits rapid and controlled cleaning and restocking. FIG. 1 illustrates a side elevation view of the present chum dispensing container, or chum pot, which is generally designated by the reference numeral 100. The chum pot 100 comprises a bucket 10 which has a series of perforations 15 which are provided for the release of the chum or bait while the chum pot 100 is submerged under the water. The chum is released in a controlled manner by the underwater currents. Typically the bucket 10 is nearly cylindrical in shape, although other configurations can be used within the scope of the present invention. The bucket 10 typically includes a rim 20 which provides a mating surface for a bucket lid 30, so as to permit sealing and unsealing of the bucket 10. The lid 30 is shown in a sealed (closed) position with respect to the bucket 10. A lowering line 40, typically a rope line, is provided which includes a knot or loop clasp or other fastening device 50 or other limiting means for limiting the travel of the lid 30 for sealing and unsealing the bucket 10. The lowering line 40 is further provided with a locking device, tightener 60, which prevents undesired release of the lid 30 from the bucket rim 20. The tightener 60 is typically a quick release device which is commercially available as Model No. 7097 from the Lehigh Group of Allentown, Pa., USA. The quick release device typically is capable of being unlocked in a single action. The single action is typically, but not limited to, a manual action by the user. The action can be performed by power-operated means if desired. To significantly enhance the effectiveness of the chum pot 100 as a fish lure, at least one of the bucket 10, rim 20, and lid 30, and preferably each, is made of a plastic material such as high-density polyethylene which further includes typically a re-chargeable, re-usable, long-term luminescent (phosphorescent) material such as cadmium-zinc sulfide. Luminescent properties are thus imparted to the bucket 10 or the rim 20 or the lid 30, or any combination thereof, by light to which the former are exposed before the chum pot 100 is submerged under the water. The luminescent properties can be made to last for several hours, as desired based on the intended usage of the chum pot 100 and are renewable every time the chum pot 100 is again exposed to light either above or below the water. Those skilled in the art will recognize that the term luminescent as used herein includes both long-term light emitting properties as exhibited by phosphorescent materials and also short-term light emitting properties as exhibited by fluorescent materials when an external light source is removed. FIG. 2 illustrates a side elevation view of the present chum dispensing container, or chum pot, 100 with the lid 30 in the unsealed (open) position. The travel or movement of the quick release tightener 60 and the lid 30 on the line 40 is limited by the knot or loop clasp or other fastening device 50. In the open position, the lowering line 40 facilitates user control over the lid 30 even during windy or rainy or snowy conditions suitable for sport fishing. The quick release feature of the tightener 60 permits the user to quickly raise the lid 30 and replenish the supply of chum or bait inside the chum pot 100. Once this is accomplished, the user can simply reposition and seal the lid 30 back over the rim 20. FIG. 3 illustrates a plan view of the chum pot 100. Preferably at the center of the lid 30 is positioned a sleeve 65 through which the lowering line 40 passes. The sleeve 65 prevents lateral motion and reduces degradation of the lowering line 40 and also reduces the frictional resistance as the lid 30 is raised and lowered on the lowering line 40. FIG. 4 illustrates a cross-sectional view of the chum pot 100 along section line 4 - 4 ′ of FIG. 3. Anchor bolts 68 are positioned through the lower surface 70 of the bucket 10 into a weighting material 75 which preferably is provided and is positioned at least partially if not entirely over eye-bolt anchor 80. The weighting material 75 holds the eye-bolt anchor 80 in place in a rigid manner. The weighting material 75 is typically an environmentally safe concrete containing Portland cement that is sold commercially under the trade name Top'n Bond® by American Stone-Mix, Inc. of Towson, Md., USA. The line 40 is fastened to the eye of the eye-bolt anchor 80 by a second knot or loop clasp or other fastening device 55 so that the eye-bolt anchor 80 acts as an anchoring point for the line 40. When in use, the chum or bait is placed on the upper surface 78 of the weighting material 75 for dispersal through the perforations 15 in FIG. 1 and FIG. 2. FIG. 5 illustrates a cross-sectional view of an alternate embodiment of the chum pot 100 along section line 5 - 5 ′ of FIG. 3. In this embodiment, the weighting material 75 is preferably provided and is positioned at least partially if not entirely around the U-bolt anchor 85. The line 40 is fixed to the U-bolt of the U-bolt anchor 85 by the second knot or loop clasp or other fastening device 55 so that the U-bolt anchor 85 acts as an anchor point for the line 40. As is the case of FIG. 4, when in use, the chum or bait is placed on the upper surface 78 of the weighting material 75 for dispersal through the perforations 15 in FIG. 1 and FIG. 2. The weighting material 75 surrounds the U-bolt anchor 85 in place to maintain a rigid position for the U-bolt anchor 85. Again, the weighting material 75 is typically an environmentally compatible concrete that is sold commercially as described previously. FIG. 6 is an elevation view of another embodiment of the present invention in the closed position. The chum pot 120 comprises the bucket 10 with perforations 15 which are again provided for the release of chum or bait while the chum pot 120 is submerged under the water. The bucket 10 with rim 20 and perforations 15 are typically the same as for the first embodiment of FIG. 1. In this embodiment, a curvilinear lid 70, typically dome-shaped, mates with the rim 20 of the bucket 10 in the closed position. The lid 72 also contains perforations 15. The lid 72 can be mated to the rim 20 typically in the same manner as illustrated in FIG. 1 to permit sealing and unsealing of the bucket 10. Typically, the lid 72 is configured to provide a single interior compartment volume or chamber when joined to the bucket 10. However, if desired, the lid 72 can be configured to provide two or more interior compartment volumes when joined to the bucket 10. The lowering line 40, as for the embodiment of FIG. 1, penetrates through the top of the lid 72 and permits the lid 72 to move on or travel along the lowering line 40. Similarly, the locking device or tightener 60 is provided to minimize undesired separation of the lid 72 from the bucket 10. The knot or loop clasp or other fastening device 50 can be provided as before on the lowering line 40 to limit travel of the lid 72. In addition, optional locking tabs or spacer sections 82 can be provided to secure the lid 72 to the rim 20. The locking tabs or spacer sections 82 can either be the primary means of sealing the lid 72 to the rim 20 or can supplement the mating of the lid 72 to the rim 20. The locking tabs or spacer sections 82 can be formed by means of a break-away flange portion (not shown) so as to permit outward folding of the tabs 82 to release the lid 72 from the rim 20, as disclosed in U.S. Pat. No. 4,735,337 issued to Von Holdt. An optional ring 90 can be coupled to the lowering line 40 to enhance the capability of moving of the chum pot 120 by a boat or other means, such as by a user manually moving the chum pot 120 up and down to stir up the chum for release through the perforations. Typically, the chum pot is only filled with chum to a level to enable circulation of the water to expel the chum from the perforations. This is typically at the rim level. The curvilinear shape of the lid 72 reduces the frictional drag of the chum pot 120 while being moved, particularly under water. Those skilled in the art recognize that, although not shown in FIGS. 1 through 5, the ring 90 can be provided to the lowering line 40 for the previously described embodiments in the same manner as shown in FIG. 6. As before, the quick release device 60 typically is capable of being unlocked in a single action. The single action is typically, but not limited to, a manual action by the user. The action can be performed by power-operated means if desired. Again to significantly enhance the effectiveness of the chum pot 120 as a fish lure, at least one of the bucket 10, rim 20, and lid 72, and preferably each, is made of a plastic material such as high-density polyethylene which further includes typically a re-chargeable, re-usable, long-term luminescent (phosphorescent) material such as cadmium-zinc sulfide. Luminescent properties are thus imparted to the bucket 10 or the rim 20 or the lid 72, or any combination thereof, by light to which the former are exposed before the chum pot 120 is submerged under the water. The luminescent properties can be made to last for several hours, as desired based on the intended usage of the chum pot 120 and are renewable every time the chum pot 120 is again exposed to light either above or below the water. FIG. 7 illustrates an elevation view the embodiment of the present invention of FIG. 6 in the open (unsealed) position. As before, the travel or movement of the quick release tightener 60 and the lid 72 on the line 40 is limited by the knot or loop clasp or other fastening device 50. In the open position, the lowering line 40 facilitates user control over the lid 72 even during windy or rainy or snowy conditions suitable for sport fishing. Again, the quick release feature of the tightener 60 permits the user to quickly raise the lid 72 and replenish the supply of chum or bait inside the chum pot 120, and once this is accomplished, the user can simply reposition and seal the lid 72 back over the rim 20. FIG. 8 illustrates a plan view of the chum pot 120. Preferably at the upper center of the lid 72 is positioned the sleeve 65 through which the lowering line 40 passes. As before, the sleeve 65 prevents lateral motion and reduces degradation of the lowering line 40 and also reduces the frictional resistance as the lid 72 is raised and lowered on the lowering line 40. FIG. 9 illustrates a cross-sectional view of the chum pot 120 along section line 9 - 9 ′ of FIG. 8. As before, anchor bolts 68 are positioned through the lower surface 70 of the bucket 10 into a weighting material 75 which preferably is provided and is positioned at least partially if not entirely over eye-bolt anchor 80. The weighting material 75 holds the eye-bolt anchor 80 in place in a rigid manner. The line 40 is fastened to the eye of the eye-bolt anchor 80 by a second knot or loop clasp or other fastening device 55 so that the eye-bolt anchor 80 acts as an anchoring point for the line 40. When in use, the chum or bait is placed on the upper surface 78 of the weighting material 75 for dispersal through the perforations 15 in FIG. 6 and FIG. 7. Although not shown separately, those skilled in the art recognize that the curvilinear lid 72 and optional locking tabs 82 can be combined the bucket 10 in the alternate embodiment shown in FIG. 5 to replace the lid 30. The invention has now been explained with reference to specific embodiments. Other embodiments will be apparent to those of ordinary skill in the art in view of the foregoing description. It is not intended that this invention be limited except as indicated by the appended claims and their full scope equivalents. | Summary: A chum delivery container, or chumpot, which includes a base and a surrounding wall surface. The base and the surrounding wall surface define an open interior chamber and an open upper surface. The surrounding wall surface includes a plurality of perforations permitting release of the chum. An anchoring fixture is disposed at the base of the open interior chamber. A rope line for lowering the chum delivery container to an underlying surface is connected to the anchoring fixture. The open upper surface of the containment member can be sealed or unsealed and the rope line penetrates through the seal. A portion of the seal can be of a curvilinear shape and the seal can include locking tabs to facilitate removal of the seal from the container. The container includes a weighting material disposed at the base, and the container can be made of a luminescent material. | 4,976 | 185 | big_patent | en |
Summarize: CROSS-REFERENCE TO RELATED APPLICATIONS U.S. Provisional Application No. 61/220,893 for this invention was filed on Jun. 26, 2009, U.S. Provisional Application No. 61,238,067 was filed on Aug. 28, 2009, and U.S. Provisional Application No. 61/278,522 was filed on Oct. 6, 2009, for which three applications these inventors claim domestic priority. BACKGROUND OF THE INVENTION The present invention generally relates to agricultural equipment, and devices which are utilized with agricultural equipment for controlling dust and other particulates generated from operation of the equipment. In particular, a mobile harvester is disclosed which is used for harvesting crops, such as nuts and/or fruits, where the harvester utilizes high volume air generated by an on-board fan to separate crops from foreign matter. The disclosed harvester addresses problems presented by the deposition of particulate matter into the air through the air exhaust of the harvester. The disclosed harvester comprises means for reducing dust and other particulate matter generated by the operation of the machinery which, by the nature of its operation, would otherwise generate substantial quantities of dust and disperse it into the atmosphere. The general mechanisms employed by the disclosed harvester capture and immobilize dust particles before the particles are dispersed into the atmosphere by the fan exhaust emitted from the machinery. Dust generation by agricultural and construction machinery is a known problem, particularly in arid areas. To name just a few problems caused by the dust generation, dust particles result in air pollution, water pollution, soil loss, human and animal health problems, and potentially hazardous reductions in visibility. In addition, the dust can adversely impact the health of various plants. In an effort to reduce dust production, some air pollution control districts impose various operating limitations on farm machinery or otherwise impose different dust control measures. Dust generation from nut and fruit harvesting equipment can be particularly problematic. These devices typically utilize high volume fans to separate nuts and/or fruit from the debris which may be picked up by the harvesting equipment, including leaves, branches, dirt clods, soil, etc. (collectively, “foreign material”). However, a large portion of the foreign material is typically blown out through the fan discharge, resulting in the dispersion of a large volume of dust into the atmosphere. An example of such a harvester is disclosed in U.S. Pat. No. 4,364,222, which is incorporated herein by this reference. In these devices, a mixture of fruit or nuts (generally referred to as “crops”) and foreign material is picked up and deposited on conveyors enclosed by a housing connected to a fan inducing a vigorous flow of air through the conveyors. Various baffles, walls and guide plates direct the air so as to enhance the separation of the desirable crops from the foreign material. However, a substantial volume of foreign material is typically discharged into the atmosphere with a minimum amount of processing, thus creating a large discharge of dust. SUMMARY OF THE INVENTION The system described herein utilizes a primary separation methodology comprising an “air stream cleaning chain” to remove the larger particles of foreign material from the air stream before these particles are passed through the fan, pulverized, and discharged into the atmosphere. The collected larger particles of foreign material are thereafter deposited on a separate conveyor for discharge through an air lock and collected or disposed of as solid material rather than being entrained in the air stream and discharged through the fan exhaust. Not only does this greatly reduce dust produced by the discharge but it also greatly reduces fan wear by preventing the foreign material from passing through the discharge fan. The system further utilizes a fine particle collection methodology which is applied to the air stream which has passed through the air stream cleaning chain, which air stream contains fine particulate matter. Harvested crops, such as fruit or nuts, and associated foreign material are gathered together at the front end of the harvesting unit by gathering means and then picked off the ground using lifting means such as a pick up belt or conveyor. The crops and foreign matter are eventually transferred onto a primary cleaning chain. As crops and foreign matter are transferred from the primary cleaning chain to an elevator chain, air is pulled through the cleaning chain and the articles conveyed thereon by the high volume fan. The air stream generated by the fan is effective in for removing the foreign material from the crops. It is to be appreciated that through the various stages of the device, a fraction of the crops and foreign material may be dropped from the harvester. Thus, the utilization of the terms “crops” and “foreign matter” are not intended to mean that the volume of these materials remain constant as they are transported through the stages of the invention. The air stream cleaning chain is the key component of the primary separation methodology. The air stream cleaning chain may comprise, but is not limited to, a chain of about 4 feet in width which allows air to pass through the chain but stops larger foreign material such as grass, leaves, dirt clods, etc. Other embodiments of this component could include but are not limited to various widths, lengths, and structure of material that would accomplish the purpose of stopping foreign material while allowing the air to pass through. This allows the air stream cleaning chain to remove much of the foreign material from the air stream and delivering the foreign material to the cross conveyor discharge belt to be discharged from the machine through the air lock rather than being discharged through the fan. Following this primary separation, the air discharge from the fan, which may include fine dust particles, is directed through an air baffle or air stream discharge duct, through which the air stream is discharged from the unit. The air stream discharge duct comprises dust particle suppression means comprising liquid introduction means and particulate collection means. Liquid is introduced into the dust-laden air stream through liquid introduction means, such as spray tips, jets, or other orifices. For example, spray tips comprising a variety in number and tip size may be used for this purpose. As another embodiment, the system may utilize multiple manifolds of spray tips to offer various options of liquid volume to be introduced into the dust infused air stream. As another embodiment, the liquid introduction means may comprise nozzles contained within the walls of the air stream discharge duct. The liquid introduction means causes a pressurized liquid, such as water, to be sprayed into the dust-laden air stream, essentially creating a curtain of mist for the air stream to pass through. The dust particle suppression system further comprises a dust scrubber, such as a wafer brush drum, through which the air stream passes after having passed through the spray of the liquid introduction means. The wafer brush drum consists of multiple wafer brushes mounted on a brush attachment sleeve. The wafer brush drum is typically rotated in a concurrent direction with the discharged air flow so as not to cause undue back pressure on the air system. The moistened air stream flows through the rotating wafer brush drum, which radially extending members collect small pieces of moist dirt from the air stream. The accumulated dust particles are discharged from the wafer brush drum as solids, thus allowing generally clean air to be discharged from the harvesting unit. The disclosed dust suppression system may be adapted for use in any application which presents a high velocity air discharge to minimize the dust pollution from the discharge. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a left hand view of a harvester comprising an embodiment of the disclosed dust suppression system. FIG. 2 is a right hand view of a harvester comprising an embodiment of the disclosed dust suppression system. FIG. 3 is a front view of a harvester comprising an embodiment of the disclosed dust suppression system. FIG. 4 is a rear view of a harvester comprising an embodiment of the disclosed dust suppression system. FIG. 5 is a top view of a harvester comprising an embodiment of the disclosed dust suppression system. FIG. 6 is an isometric view of the left hand side of a harvester comprising an embodiment of the disclosed dust suppression system. FIG. 7 is an isometric view of the right hand side of a harvester comprising an embodiment of the disclosed dust suppression system. FIG. 8 is a sectional view of a harvester along line 8 - 8 of FIG. 6. FIG. 9 is a sectional view of a harvester along line 9 - 9 of FIG. 6, with a portion of the housing removed to show the fan rotor and drum brush. FIG. 10 is a top view of an embodiment of the harvester. FIG. 11 is a sectional view taken along line 11 - 11 of FIG. 10. FIG. 12 is a partial isometric showing a portion of the upper housing for for an embodiment of the disclosed dust suppression system. FIG. 13 shows a partial front view of the housing for an embodiment of the harvester. FIG. 14 is a sectional view taken along line 14 - 14 of FIG. 13. FIG. 15 is a partial top view of the housing for an embodiment of the harvester. FIG. 16 is a partial isometric view of the housing for an embodiment of the harvester. FIG. 17 is a partial sectional view showing, among other things, the relative positions of the air stream cleaning chain and the cross conveyor discharge belt which may be utilized in an embodiment of the disclosed harvester. FIG. 18 shows a partial isometric view of a fan-brush combination which may be utilized in an embodiment of the disclosed harvester, showing the flow direction. FIG. 19 shows a partial side view of the fan-brush combination shown in FIG. 18. FIG. 20 shows a partial top view of the exterior of the housing for the fan-brush combination shown in FIG. 18. FIG. 21 shows a partial front view of the fan-brush combination shown in FIG. 18, showing an option for placement for liquid spray tips. FIG. 22 shows a partial isometric view of a fan brush combination which may be utilized in an embodiment of the disclosed harvester. FIG. 23 shows another view of a fan brush combination which may be utilized in an embodiment of the disclosed harvester. FIG. 24 shows a view of a liquid introduction means which might be utilized in an embodiment of the disclosed harvester. FIG. 25 shows a close up view of another liquid introduction means which might be utilized in an embodiment of the disclosed harvester. DETAILED DESCRIPTION OF THE EMBODIMENTS Now with reference to the figures, FIG. 1 shows an embodiment of a harvesting unit 10 which may comprise the dust suppression system disclosed herein. This type of harvesting unit 10 is mobile, having ground conveyance means such as wheels 12, but it might also comprise tracks, rollers, etc. Harvesting unit 10 gathers harvested crops, such as nuts, fruits and the like, from the ground surface, where the crops will typically have been deposited from the shaking of trees or other harvesting method. The crops are typically deposited in a spread out configuration, forming a carpet on the ground surface. This type of harvesting unit 10 is well suited for the processing of almonds, but could also be utilized in the gathering of a variety of other crops lying on a ground surface after having been removed from a tree. In addition to almonds, the harvested crop may be another variety of nut, such as cashews, chestnuts, hazelnuts, macadamia nuts, pecans, walnuts and tung nuts. Certain fruits, such as figs and oranges, and any fruit, nut or vegetable, as conventionally known to require collection and processing from the ground, may also be gather with this type of harvester, and the present dust suppression system employed. It is to be appreciated that while the Figures herein show a harvester 10 which is equipped to be towed by a tractor or other towing vehicle, the present dust suppression system may equally be utilized with a self-propelled harvesting unit. The various conveyors, chains, drive wheels, etc. of the harvester will be driven by the means known in the art, typically by hydraulic motors. The type of harvesting unit 10 which may comprise the dust suppression system disclosed herein generally comprises a collection means for collecting the agricultural products, such as crops 14, from the ground surface S. Because the crops 14 are blanketed across the ground dispersed among other foreign matter 16, such as leaves, twigs, dirt, gravel, dirt clods, etc., the collection means will gather a combination of all of these materials into the harvesting unit. The foreign matter 16 will typically comprise a mixture of larger and smaller particles, and some foreign matter will comprise dirt or other relatively fine grained particles. The collection means may comprise brushes, conveyors, or a sweeping array as disclosed in U.S. Pat. Nos. 7,131,254 and 7,412,817 which were invented by some of the inventors herein and which are incorporated herein in their entireties by this reference. One embodiment of the collection means may comprise a rotating sweeper 18 and/or pickup belt 20 which gather the agricultural products and foreign matter from the ground S. The collection means directs all of the gathered materials onto a primary chain 22. The primary chain 22 has a receiving end 24 which receives the crops and foreign matter which have been collected by the collection means. At the end opposite the receiving end 24, the primary chain comprises a delivery end 26 to which substantially all of the crops and foreign matter are delivered. However, it is to be appreciated that the primary chain 22, and the other chains of most harvesters, are typically linked chain with openings, such that smaller foreign matter and perhaps smaller crops will fall through back onto the ground surface S. Therefore, while a substantial amount of the crops and foreign matter will reach the receiving end 24, some of the crops and foreign matter may have fallen through the openings in the primary chain 22. The harvesting unit 10 further comprises an elevator chain 28. The elevator chain 28 receives crops and foreign matter from primary chain 22. The crops are carried up elevator chain 28 and discharged through discharge chute 30 to a storage container, the ground, or other repository for the crops. Adjacent to elevator chain 28 is the end 32 of a ductwork or housing 34 which may be oriented along the lengthwise axis of the harvesting unit 10. An opening is defined at the end 32 of the housing by the top 36, side pieces 38, and bottom 40. A fan 42 is disposed within housing 34 within its own fan housing 46. Fan 42 generates an air stream A by pulling air from the opening at the end 32 of the housing 34 and discharging the air into discharge duct 44 on the opposite site of the fan 42. The air stream A flows through housing 34, with the direction of the air stream generally moving from the elevator chain 28 toward the fan 42. The fan 42 may thus be considered to have a suction side which is oriented toward end 32 and at least a portion of elevator chain 28 and a discharge side which begins on the opposite side of the fan, with the generated air stream discharging into air stream discharge duct 44. As suction is pulled by the air stream A through the openings in elevator chain 28, and through the crops and foreign matter being transported on the elevator chain, the lighter foreign matter is carried in the air stream toward fan 42 through housing 34. Disposed between fan 42 and elevator chain 28 is an air stream cleaning chain assembly 48. The air stream cleaning chain assembly 48 comprises the primary separation methodology for removing foreign material from the air stream before much of the foreign material is passed through the fan 42 and discharged into the atmosphere. The air stream cleaning chain assembly 48 may comprise air stream cleaning chain 50, drive roller 52 and idler rollers 54. As air stream cleaning chain 50 is rotated about the idler rollers 54, a portion of the air stream cleaning chain is continually positioned to be normal to the general direction of the air stream A. Air stream cleaning chain 50 allows the air stream to pass through it, but stops the larger particles of foreign material, such as leaves, grass, etc., because the air stream cleaning chain comprises a plurality of closely spaced links, wherein the openings between the links are relatively small. Air stream cleaning chain 50 may have a width of approximately four feet in width. Foreign material which is stopped by the air stream cleaning chain 50 is discharged from the harvesting unit 10 by discharging means which transport the larger particles of the foreign matter collected on the air stream cleaning chain to the exterior of the harvesting unit. The discharging means may comprise a cross conveyor discharge belt 56 which is disposed below the air stream cleaning chain 50. Foreign material accumulated on the air stream cleaning chain is deposited onto the cross conveyor discharge belt 56, which transports the larger particles of the foreign material to a disposal duct through an air lock assembly 58. The finer particles of foreign material will be carried through the openings in air stream cleaning chain 50 and transported through housing 34 by air stream A through fan 42 and into air stream discharge duct 44, which is on the discharge side of the fan. The air stream discharge duct 44 comprises a further mechanism for removing particulates from the air exhaust of the harvester 10, which is utilized to remove smaller particles which passed through the air stream cleaning chain 50. This mechanism employs injecting water or other appropriate liquid into the air stream A as it enters the air stream discharge duct 44. As shown in FIGS. 18 through 25, the air stream discharge duct 44 comprises liquid introduction means such as a plurality of spray tips 60, or other liquid introduction means, such as directional jets 160 shown on FIG. 25. Directional jets 160 may be set within the inside wall of air stream discharge duct 44 and may be installed and directed to provide a curtain of liquid spray through which the air stream A, with its entrained dust particles, passes. Other liquid introduction means may be utilized. For example, spray tips comprising a variety in number and tip size may be used for this purpose. As another embodiment, the system may utilize multiple manifolds of spray tips to offer various options for the introduction of the liquid into the dust infused air stream. The harvester 10 may comprise liquid storage tanks for storing the liquid utilized for the liquid sprayed into the air stream discharge duct 44, and the related pumps and conduits required for the liquid injection process. Alternatively, the storage tanks and pumps may be carried on a separate apparatus. The air stream discharge duct 44 may comprise additional means for suppressing the fine dust particles transported in the air stream A. The air stream discharge duct may further comprise a dust scrubber assembly 62. Dust scrubber assembly 62 may comprise a rotating wafer brush drum 64. The wafer brush drum consists of multiple wafer brushes 66 mounted on a brush attachment sleeve 68, or other collection members which radially extend from the brush attachment sleeve. The wafer brush drum 64 may be rotated in a concurrent direction with the flow of air stream A so as not to cause undue back pressure on the air system. Because of the liquid introduction means discussed above, the air stream A reaching the wafer brush drum is moistened. As the moistened air stream A flows through the wafer brushes, small pieces of moist dirt are scrubbed from the air stream, accumulating on the collection members such that the air being discharged through air exhaust 70 has been substantially cleaned of particulate matter. Aggregated solids may be discharged from the apparatus through solids discharge chute 71. Air stream discharge duct 44 connects to fan housing 46 at flange 72. Portions of air stream discharge duct 44 may be easily removable to gain access to the various components of the dust scrubber assembly 62 and the liquid introduction means contained therein. For example, flange 72 may be held together with a quick-release mechanism 74 and air stream discharge duct 44 may be hinge connected at the flange to allow the air stream discharge duct to pivot outwardly so there is easy access to the internal components. While the above is a description of various embodiments of the present invention, further modifications may be employed without departing from the spirit and scope of the present invention. Thus the scope of the invention should not be limited according to these factors, but according to the following appended claims. | Summary: A mobile harvesting unit which utilizes a high volume fan to separate crops from foreign matter, has a dust suppression system which substantially reduces particulates which are discharged with the fan exhaust. The dust suppression system has two stages. The first stage separates larger particles of foreign matter by deploying an air stream cleaning chain upstream of the fan. The second stage is contained within a air stream discharge duct. Within the air stream discharge duct, a liquid, such as water, is sprayed into the dust entrained air stream. The moistened air stream flows through a plurality of collection members which extend radially from a brush drum, where the moistened dust particles are accumulated on the collection members, such that the volume of dust particles contained within the air discharged from the harvesting unit is substantially reduced. | 4,726 | 175 | big_patent | en |
Write a title and summarize: SECTION 1. SHORT TITLE. This Act may be cited as the ``Child Care Infrastructure Act of 2001''. SEC. 2. ALLOWANCE OF CREDIT FOR EMPLOYER EXPENSES FOR CHILD CARE ASSISTANCE. (a) In General.--Subpart D of part IV of subchapter A of chapter 1 of the Internal Revenue Code of 1986 (relating to business related credits) is amended by adding at the end the following: ``SEC. 45E. EMPLOYER-PROVIDED CHILD CARE CREDIT. ``(a) In General.--For purposes of section 38, the employer- provided child care credit determined under this section for the taxable year is an amount equal to the sum of-- ``(1) 25 percent of the qualified child care expenditures, and ``(2) 10 percent of the qualified child care resource and referral expenditures, of the taxpayer for such taxable year. ``(b) Dollar Limitation.--The credit allowable under subsection (a) for any taxable year shall not exceed $150,000. ``(c) Definitions.--For purposes of this section-- ``(1) Qualified child care expenditure.-- ``(A) In general.--The term `qualified child care expenditure' means any amount paid or incurred-- ``(i) to acquire, construct, rehabilitate, or expand property-- ``(I) which is to be used as part of a qualified child care facility of the taxpayer, ``(II) with respect to which a deduction for depreciation (or amortization in lieu of depreciation) is allowable, and ``(III) which does not constitute part of the principal residence (within the meaning of section 121) of the taxpayer or any employee of the taxpayer, ``(ii) for the operating costs of a qualified child care facility of the taxpayer, including costs related to the training of employees, to scholarship programs, and to the providing of increased compensation to employees with higher levels of child care training, ``(iii) under a contract with a qualified child care facility to provide child care services to employees of the taxpayer, or ``(iv) to reimburse an employee for expenses for child care which enables the employee to be gainfully employed including expenses related to-- ``(I) day care and before and after school care, ``(II) transportation associated with such care, and ``(III) before and after school and holiday programs including educational and recreational programs and camp programs. ``(B) Fair market value.--The term `qualified child care expenditures' shall not include expenses in excess of the fair market value of such care. ``(2) Qualified child care facility.-- ``(A) In general.--The term `qualified child care facility' means a facility-- ``(i) the principal use of which is to provide child care assistance, and ``(ii) which meets the requirements of all applicable laws and regulations of the State or local government in which it is located, including the licensing of the facility as a child care facility. Clause (i) shall not apply to a facility which is the principal residence (within the meaning of section 121) of the operator of the facility. ``(B) Special rules with respect to a taxpayer.--A facility shall not be treated as a qualified child care facility with respect to a taxpayer unless-- ``(i) enrollment in the facility is open to employees of the taxpayer during the taxable year, ``(ii) if the facility is the principal trade or business of the taxpayer, at least 30 percent of the enrollees of such facility are dependents of employees of the taxpayer, and ``(iii) the use of such facility (or the eligibility to use such facility) does not discriminate in favor of employees of the taxpayer who are highly compensated employees (within the meaning of section 414(q)). ``(3) Qualified child care resource and referral expenditure.-- ``(A) In general.--The term `qualified child care resource and referral expenditure' means any amount paid or incurred under a contract to provide child care resource and referral services to an employee of the taxpayer. ``(B) Nondiscrimination.--The services shall not be treated as qualified unless the provision of such services (or the eligibility to use such services) does not discriminate in favor of employees of the taxpayer who are highly compensated employees (within the meaning of section 414(q)). ``(d) Recapture of Acquisition and Construction Credit.-- ``(1) In general.--If, as of the close of any taxable year, there is a recapture event with respect to any qualified child care facility of the taxpayer, then the tax of the taxpayer under this chapter for such taxable year shall be increased by an amount equal to the product of-- ``(A) the applicable recapture percentage, and ``(B) the aggregate decrease in the credits allowed under section 38 for all prior taxable years which would have resulted if the qualified child care expenditures of the taxpayer described in subsection (c)(1)(A) with respect to such facility had been zero. ``(2) Applicable recapture percentage.-- ``(A) In general.--For purposes of this subsection, the applicable recapture percentage shall be determined from the following table: The applicable recapture ``If the recapture event occurs in: percentage is: Years 1-3............................ 100 Year 4............................... 85 Year 5............................... 70 Year 6............................... 55 Year 7............................... 40 Year 8............................... 25 Years 9 and 10....................... 10 Years 11 and thereafter.............. 0. ``(B) Years.--For purposes of subparagraph (A), year 1 shall begin on the first day of the taxable year in which the qualified child care facility is placed in service by the taxpayer. ``(3) Recapture event defined.--For purposes of this subsection, the term `recapture event' means-- ``(A) Cessation of operation.--The cessation of the operation of the facility as a qualified child care facility. ``(B) Change in ownership.-- ``(i) In general.--Except as provided in clause (ii), the disposition of a taxpayer's interest in a qualified child care facility with respect to which the credit described in subsection (a) was allowable. ``(ii) Agreement to assume recapture liability.--Clause (i) shall not apply if the person acquiring such interest in the facility agrees in writing to assume the recapture liability of the person disposing of such interest in effect immediately before such disposition. In the event of such an assumption, the person acquiring the interest in the facility shall be treated as the taxpayer for purposes of assessing any recapture liability (computed as if there had been no change in ownership). ``(4) Special rules.-- ``(A) Tax benefit rule.--The tax for the taxable year shall be increased under paragraph (1) only with respect to credits allowed by reason of this section which were used to reduce tax liability. In the case of credits not so used to reduce tax liability, the carryforwards and carrybacks under section 39 shall be appropriately adjusted. ``(B) No credits against tax.--Any increase in tax under this subsection shall not be treated as a tax imposed by this chapter for purposes of determining the amount of any credit under subpart A, B, or D of this part. ``(C) No recapture by reason of casualty loss.--The increase in tax under this subsection shall not apply to a cessation of operation of the facility as a qualified child care facility by reason of a casualty loss to the extent such loss is restored by reconstruction or replacement within a reasonable period established by the Secretary. ``(e) Special Rules.--For purposes of this section-- ``(1) Aggregation rules.--All persons which are treated as a single employer under subsections (a) and (b) of section 52 shall be treated as a single taxpayer. ``(2) Pass-thru in the case of estates and trusts.--Under regulations prescribed by the Secretary, rules similar to the rules of subsection (d) of section 52 shall apply. ``(3) Allocation in the case of partnerships.--In the case of partnerships, the credit shall be allocated among partners under regulations prescribed by the Secretary. ``(f) No Double Benefit.-- ``(1) Reduction in basis.--For purposes of this subtitle-- ``(A) In general.--If a credit is determined under this section with respect to any property by reason of expenditures described in subsection (c)(1)(A), the basis of such property shall be reduced by the amount of the credit so determined. ``(B) Certain dispositions.--If, during any taxable year, there is a recapture amount determined with respect to any property the basis of which was reduced under subparagraph (A), the basis of such property (immediately before the event resulting in such recapture) shall be increased by an amount equal to such recapture amount. For purposes of the preceding sentence, the term `recapture amount' means any increase in tax (or adjustment in carrybacks or carryovers) determined under subsection (d). ``(2) Other deductions and credits.--No deduction or credit shall be allowed under any other provision of this chapter with respect to the amount of the credit determined under this section.''. (b) Conforming Amendments.-- (1) Section 38(b) of the Internal Revenue Code of 1986 is amended by striking ``plus'' at the end of paragraph (12), by striking the period at the end of paragraph (13) and inserting ``, plus'', and by adding at the end the following: ``(14) the employer-provided child care credit determined under section 45E.''. (2) The table of sections for subpart D of part IV of subchapter A of chapter 1 of such Code is amended by adding at the end the following: ``Sec. 45E. Employer-provided child care credit.'' (3) Section 1016(a) of such Code is amended by striking ``and'' at the end of paragraph (26), by striking the period at the end of paragraph (27) and inserting ``, and'', and by adding at the end the following: ``(28) in the case of a facility with respect to which a credit was allowed under section 45E, to the extent provided in section 45E(f)(1).''. (c) Effective Date.--The amendments made by this section shall apply to taxable years beginning after December 31, 2001. | Title: A bill to amend the Internal Revenue Code of 1986 to provide a credit against tax for employers who provide child care assistance for dependents of their employees, and for other purposes Summary: Child Care Infrastructure Act of 2001 - Amends the Internal Revenue Code to allow an employer-provided child care credit for qualified expenses to: (1) build, rehabilitate, or expand a qualified child care facility; (2) operate a qualified child care facility; (3) contract with a qualified child care facility to provide child care services to employees; or (4) reimburse an employee for expenses for child care which enables the employee to be gainfully employed. | 2,535 | 142 | billsum | en |
Summarize: Breast milk purchased online could contain cow's milk and other contaminants, research shows. A safer bet is milk from non-profit milk banks, such as this milk at the Mother's Milk Bank of Iowa in Coralville, Iowa. But milk from milk banks is available only by prescription. (Photo: Stephen Mally for USA TODAY) Human breast milk has been sold online for years, and health experts have warned about possible dangers. Now they have a new warning: Some of the milk for sale isn't strictly human — it's been topped off with cow's milk. That milk could be dangerous for some babies, says Sarah Keim, a researcher at Nationwide Children's Hospital in Columbus, Ohio. Keim led a study published Monday in Pediatrics that shows 10 out of 102 breast milk samples purchased online contained at least 10% cow's milk. The added milk could have come straight from cartons or from baby formula, Keim says. "It could be very harmful to babies with allergies or intolerance" to cow's milk, she says. In a previous study using the same samples, Keim found 75% were contaminated with viruses or bacteria. The Food and Drug Administration has warned since 2010 that milk sold or shared online could be unsafe. The samples in the study, purchased in 2012, came from several sites, Keim says, including one called Only The Breast that continues to operate and appears to be the leading site for such transactions. Other sites, such as Eats on Feets and Human Milk 4 Human Babies, facilitate the sharing of milk but discourage sales. In ads at Only The Breast, thousands of nursing mothers offer to sell excess breast milk for prices that appear to range from $1 to $6 per ounce. Many feature pictures of mothers and children and boast that the sellers eat organic diets, are free of drugs, alcohol and caffeine, and have other healthy habits. Some say they have been screened for drug use and for diseases such as HIV by milk banks — non-profit and for-profit operations that provide milk to premature and sick babies in hospitals. In an emailed statement, Only The Breast, a corporation based in Reno, said the site's terms of use forbid members from adding any contaminants to milk sold or donated there. The statement says: "We believe most OTB members are honest, abiding by OTB terms and are simply looking to provide safe milk for babies in need." If some sellers are intentionally adding cow's milk to their supplies, the obvious motive would be profit, Keim says: "Sellers might have an incentive to try to increase their production. … It could really add up." Who is buying this milk? Most buyers are families who want breast milk for babies and, for whatever reason, don't have enough milk from the babies' mothers, says a recent editorial in the journal BMJ. The editorial, which called online milk sales and sharing unsafe, said buyers also include "a narrow group of adult consumers (including people with cancer, gym enthusiasts, and fetishists)." The market for breast milk exists largely because health authorities "have done a really good job over the past 20 years of promoting the benefits of breastfeeding," Keim says. "Unfortunately, some women are very focused on feeding their babies breast milk at all costs." Keim's samples did not include milk shared free online. She says such milk is unsafe because it has not been screened for contamination. Sites for sharing and selling milk include instructions for home pasteurization — heating the milk to kill harmful microbes — and say it is necessary. But home methods are unlikely to be as reliable as the procedures used by milk banks, Keim says. The 18 non-profit banks in the Human Milk Banking Association of North America do not get enough donations to provide safe, screened breast milk to the general public, says Kim Updegrove, executive director of the Mothers' Milk Bank in Austin. Their milk is needed for sick and low-weight babies for whom it is "life-saving," she says. It is available only by prescription. Women who have trouble breastfeeding should seek help from lactation counselors and other health professionals rather than turning to the internet for possibly tainted supplies, Updegrove says. "Body fluids are dangerous, and milk is a body fluid," she says. The addition of cow's milk is "alarming," because it could cause symptoms ranging from stomach upset to bloody diarrhea and eczema in some infants, Updegrove says. Women thinking of selling or donating their milk could do more good by donating to the neediest infants through milk banks, she says. "I do believe that most of those women looking to share or sell their milk are compassionate women who want to help other women," Updegrove says. Read or Share this story: http://usat.ly/1FeAFUn A study published today on the safety of human breast milk bought over the Internet found that 10 percent of samples contained added cow's milk. The discovery that purchased samples of human milk may be purposely "topped off" with cow's milk or infant formula confirms a danger for the large number of babies receiving the purchased milk due to medical conditions. These babies are also vulnerable to the risk of infectious disease from bacterial and viral contamination of such milk, which was identified in a prior study by the same research team led by Nationwide Children's Hospital. "We found that one in every 10 samples of breast milk purchased over the Internet had significant amounts of cow's milk added, and this poses a risk to infants with an allergy or intolerance to cow's milk," said Sarah A. Keim, PhD, principal investigator in the Center for Biobehavioral Health in The Research Institute at Nationwide Children's and lead author on the study. "If a baby with cow's milk allergy were to drink this milk, it could be very harmful." The team's previous research found that 21 percent of individuals seeking human milk online did so for a child with a pre-existing medical condition. And 16 percent of these parents specifically sought out the purchased human milk due to their baby's formula intolerance. Also troubling is their prior discovery of bacterial or viral contamination in more than 75 percent of milk samples purchased online, which became the first data to confirm the Food and Drug Administration's 2010 warning of possible contaminants in unpasteurized human milk obtained from sources other than the baby's mother. The study published today in the journal Pediatrics is the first to document that milk purchased online is frequently adulterated with intentionally added ingredients. "We were concerned that, because money is exchanged in these transactions, there might be an incentive to boost milk volumes in order to make more money," Dr. Keim said. "Cow's milk and infant formula resemble human milk and could potentially be added to boost volumes without the recipient knowing. Mothers who consider purchasing breast milk over the Internet should beware -- when you obtain milk from an unfamiliar source, you cannot know for sure that what you are getting is safe for your baby." Dr. Keim's team at Nationwide Children's collaborated with researchers from The Ohio State University and Cincinnati Children's Hospital Medical Center to purchase and test 102 samples of breast milk advertised on milk-sharing websites. The team compared the purchased samples with their own preparations of human milk diluted with cow's milk to approximate the amount of contamination required in order to test positive for bovine DNA. All purchased samples did contain human milk, but 11 also contained bovine DNA, 10 of which had results consistent with more than minor, accidental contamination with cow's milk. The findings suggest that a notable number of sellers intentionally added cow's milk or infant formula to the breast milk. "Pediatricians who care for infants should be aware that milk advertised as human is available via the Internet, and some of it may not be 100 percent human milk," said Dr. Keim, who also is a faculty member at The Ohio State University. "And patients should be counseled against obtaining milk in this way for their infant." In a recent survey Dr. Keim conducted of 499 women, published in Breastfeeding Medicine, 25 percent of women considered milk sharing and almost 4 percent of women shared milk among friends or relatives or had a preterm infant who received donor milk. She suggested that women with extra milk could help a baby in need by donating their milk to a non-profit milk bank instead of selling it over the Internet. "Quality, timely lactation support for moms who want to breastfeed their babies could help avoid the need for many mothers to seek milk online," said Dr. Keim, who is continuing a variety of investigations into the phenomenon of Internet-based human milk donation and purchasing. "Women who have difficulty making enough milk for their child should work with their pediatrician to identify safe, healthy ways to feed their baby. The risk of contamination and added cow's milk makes it unsafe to purchase breast milk over the Internet." ### Abstract BACKGROUND: The US Food and Drug Administration recommends against feeding infants human milk from unscreened donors, but sharing milk via the Internet is growing in popularity. Recipient infants risk the possibility of consuming contaminated or adulterated milk. Our objective was to test milk advertised for sale online as human milk to verify its human origin and to rule out contamination with cow’s milk. METHODS: We anonymously purchased 102 samples advertised as human milk online. DNA was extracted from 200 µL of each sample. The presence of human or bovine mitochondrial DNA was assessed with a species-specific real-time polymerase chain reaction assay targeting the nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 5 gene. Four laboratory-created mixtures representing various dilutions of human milk with fluid cow’s milk or reconstituted infant formula were compared with the Internet samples to semiquantitate the extent of contamination with cow’s milk. RESULTS: All Internet samples amplified human DNA. After 2 rounds of testing, 11 samples also contained bovine DNA. Ten of these samples had a level of bovine DNA consistent with human milk mixed with at least 10% fluid cow’s milk. Post an ad and help babies get Only The Breast. Buy, sell or donate breast milk with our discreet classifieds system. Want to donate breast milk to a fellow mother? Considering selling or donating to a needy baby? Need natural breastmilk for your growing baby? Do you believe breastfeeding is best? Are you over producing and want to list your liquid gold for sale? Looking to make a few extra bucks while clearing out your freezer? The vast majority of OTB members are honest, abiding by OTB terms and are simply looking to provide safe milk for babies in need. However in light of cow’s milk contamination of some breast milk samples purchased via the internet, Only The Breast reiterates our long-term guidance that all OTB sellers should follow best practices using aseptic technique for expressing, handling, and storing human milk which also addresses shipping freezing, and all buyers must follow safety guidelines for peer to peer donor screening. Additionally it is expressly forbidden in our terms of use to add any form of contaminants such as bovine i.e., cow’s milk. Proper DONOR SCREENING is crucial, and must be followed before feeding milk to babies in need. Studies show that unpasteurized milk may have bacteria. IT IS ADVISED THAT ALL MILK MUST BE PASTEURIZED BEFORE USE. Please see our at home pasteurization tips. WARNING DO NOT ACCEPT COURIER SERVICES, these are almost always scams to get you to send them money. Never wire funds like with Western Union. SIGN IN AND CHECK YOUR PAYPAL BALANCE, to be sure that funds have been sent and you haven’t sent a fake email. Listing milk for more than $1/oz is likely to receive only responses from scammers. WARNING DO NOT ACCEPT CHECKS, FAKE CASHIER CHECKS & MONEY ORDERS ARE COMMON, and BANKS WILL CASH THEM AND THEN HOLD YOU RESPONSIBLE when the fake is discovered weeks later. More info on how to recognize and avoid scams Only The Breast is not affiliated with any breast milk banks or human milk processing companies other than those identified on the About Us page of the Only The Breast website. Any other statements of affiliation not made by Only The Breast, Inc. should be reported via the notification procedures. Featured Media | Summary: Women who purchase breast milk online likely have their baby's health in mind, which makes the findings of a study published today in Pediatrics so concerning. Researchers led by Nationwide Children's Hospital bought 102 samples of milk via milk-sharing websites and discovered that 10 of them "had a level of bovine DNA consistent with human milk mixed with at least 10% fluid cow's milk," they write in the study. That's a concentration high enough to indicate the cow milk was intentionally added, either straight from the carton or by way of baby formula. "This poses a risk to infants with an allergy or intolerance to cow's milk," says researcher Sarah Keim, in a press release. One milk bank director tells USA Today infants could experience bloody diarrhea or eczema as a result of ingesting it. The newspaper reports that one of the sites the researchers purchased the milk from is Only The Breast, which bills itself as a "community for moms to buy, sell, and donate natural breast milk" at prices that USA Today noted were typically $1 to $6 per ounce. The site referenced its terms of use in an emailed statement, pointing out that members were barred from adulterating the milk. Why might someone do so? Profit. "Because money is exchanged in these transactions, there might be an incentive to boost milk volumes in order to make more money," says Keim, who advises pediatricians to caution mothers against sourcing any needed breast milk this way. USA Today notes these particular samples were used in a 2013 study by the team, which found that 72% of those samples contained bacteria; the types of bacteria they identified were pretty off-putting. | 2,798 | 373 | multi_news | en |
Summarize: Bringing people together so they can experience the world through other people’s eyes. Live broadcasting Looping videos & unlimited length Multiple photos in a single update Status & Check In Music Articles Premium User: Allows you to enjoy mobli ADS FREE DIRECT MESSAGING with other premium users LIVE PLAYBACK... This vision is expressed through all our products: mobli, EyeIn for Publishers, Slant News Creating technologies that enable people all over the globe to share and discover crowdsourced content. Mobli Media Inc. is a cutting edge technology company that creates unique products leveraging crowd based activities for the benefit of all people through content sharing and social media. Founded in 2011, has raised up to date over $90M. With offices in Tel Aviv and New York, Mobli Media Inc.’s prominent investors are Kenges Rakishev, Carlos Slim with America Movil and Leonardo DiCaprio. Galaxia - Persona-lized Social Networks Everyone of us has more than one Persona (= Public Personality). These Personas are reflected in our behavior, desires, and yes - our social activity as well. Galaxia is a social platform focusing on this aspect of everyday life, that brings it into the social landscape. Now you can explore, consume, interact, create and even set the rules to your own social network, directly linked to different sides of your personality. Galaxia holds a “no real name” policy so you can express yourself freely. We value your privacy. Visit www.galaxia.co You must enable JavaScript to use foursquare.com We use the latest and greatest technology available to provide the best possible web experience. Please enable JavaScript in your browser settings to continue. Download Foursquare for your smart phone and start exploring the world around you! Starting in 1996, Alexa Internet has been donating their crawl data to the Internet Archive. Flowing in every day, these data are added to the Wayback Machine after an embargo period. These days, top celebrities aren't just spending money on Hollywood mansions and private yachts — they're also investing millions of dollars in startup tech companies. From websites that let you show off your best dance moves to ecommerce solutions that help you find the perfect shoes, check out this gallery to see where celebs are putting their money in the startup scene. They say more than a sentence ever could. Snap a pic on the go or share an old one to relive some memories together. Share the sights and sounds of your life as it happens. Take a video right from the app, or upload an old memory to share with your friends. Easily explore all the photos that have been shared to every group you are in. Sometimes a message doesn't need a text response. Tap the heart to show you care. Who knows the address of anything anymore? Send where you are or where you're going to be so no one gets lost. Say more with our expressive emoji. These little guys will make your conversations cuter and much more fun, and we release new ones all the time! Not every message should go to the whole group. Tap a friend's avatar anywhere in the app and take your private conversation aside. Some groups can get pretty chatty. Mute them for a little peace. Or, if you have a meeting, easily mute everything for a while. | Summary: More than just Oscars and Grammys, becoming a big star today requires mastering the world of online and social media. So it's no surprise that many of today's brightest glitterati are also eager to become leading digerati, investing in a wide range of startup tech companies. Mashable presents eight stars making a splash with their online investments: Lady Gaga. Along with Kanye West, Gaga contributed to the $7.5 million financing raised in July by Turntable.fm, a music rating and deejaying site. Leonardo DiCaprio. He contributed to the $4 million first-round funding into Mobli, a social media company that specializes in sharing user videos. Justin Timberlake. He's a co-owner of MySpace and now he's invested in Dekko, a stealthy new startup that apparently is trying to create an "augmented reality" experience, bringing online information to real-world experiences. Ashton Kutcher. The Two and a Half Men has invested in more than 10 companies now, including Foursquare, GroupMe, and TinyChat. (Just don't ask him about Twitter). (Actually, maybe he should be careful about all those startups, too). Check out Mashable for the full list. | 697 | 269 | multi_news | en |
Write a title and summarize: HCV entry into cells is a multi-step and slow process. It is believed that the initial capture of HCV particles by glycosaminoglycans and/or lipoprotein receptors is followed by coordinated interactions with the scavenger receptor class B type I (SR-BI), a major receptor of high-density lipoprotein (HDL), the CD81 tetraspanin, and the tight junction protein Claudin-1, ultimately leading to uptake and cellular penetration of HCV via low-pH endosomes. Several reports have indicated that HDL promotes HCV entry through interaction with SR-BI. This pathway remains largely elusive, although it was shown that HDL neither associates with HCV particles nor modulates HCV binding to SR-BI. In contrast to CD81 and Claudin-1, the importance of SR-BI has only been addressed indirectly because of lack of cells in which functional complementation assays with mutant receptors could be performed. Here we identified for the first time two cell types that supported HCVpp and HCVcc entry upon ectopic SR-BI expression. Remarkably, the undetectable expression of SR-BI in rat hepatoma cells allowed unambiguous investigation of human SR-BI functions during HCV entry. By expressing different SR-BI mutants in either cell line, our results revealed features of SR-BI intracellular domains that influence HCV infectivity without affecting receptor binding and stimulation of HCV entry induced by HDL/SR-BI interaction. Conversely, we identified positions of SR-BI ectodomain that, by altering HCV binding, inhibit entry. Finally, we characterized alternative ectodomain determinants that, by reducing SR-BI cholesterol uptake and efflux functions, abolish HDL-mediated infection-enhancement. Altogether, we demonstrate that SR-BI is an essential HCV entry factor. Moreover, our results highlight specific SR-BI determinants required during HCV entry and physiological lipid transfer functions hijacked by HCV to favor infection. Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease world-wide. With 180 million persistently infected people, chronic hepatitis C infection, which induces end-stage liver disease such as liver cirrhosis and hepatocellular carcinoma (HCC), represents a major public health problem of high socio-economic impact [1]. However, treatment options for chronic hepatitis C are limited, and a vaccine for prevention against HCV infection is not available. HCV is a positive strand RNA enveloped virus from the Flaviviridae family. Viral attachment and entry—representing the first encounter of the virus with the host cell—are major targets of adaptive host cell defenses. Detailed understanding of the HCV entry process should offer interesting opportunities for development of novel therapeutic strategies to prevent or cure HCV infection. HCV entry is thought to be a multi-step process (reviewed in [2], [3], [4]). The interactions between envelope glycoproteins and glycosaminoglycans might contribute to the primary binding of virus particles to host cells. Because of the association of HCV with low-density lipoproteins (LDL) in serum of infected patients [5], the LDL receptor (LDLr) has also been proposed as an alternative capture receptor [6]. Following this initial engagement, the scavenger receptor class B type I (SR-BI) [7], the CD81 tetraspanin [8] and the tight junction protein Claudin-1 (CLDN1) [9] may contribute to uptake and cellular penetration of HCV in a clathrin-dependent manner [10], [11]. Using HCVpp and HCVcc infection assays as well as in vitro membrane fusion assays, HCV entry was shown to occur in a pH-dependent manner [12], [13], [14], [15], [16], through endocytosis of the viral particles [10], [11]. Like other Flaviviridae [17], the low endosomal pH may induce conformational rearrangement of HCV glycoproteins, leading to fusion of the viral membrane with that of the endosome. The exact function of these molecules, and particularly SR-BI, in HCV infection is still enigmatic. SR-BI, also called CLA-1, was originally defined as a class B scavenger receptor [18] in a family that includes CD36, LIMPII and SR-BII, an SR-BI isoform with an alternate cytoplasmic tail [19]. SR-BI mediates binding and lipid transfer from different classes of lipoproteins [20], particularly high-density lipoprotein (HDL), accounting for its multiple functions in cholesterol metabolism such as removal of peripheral unesterified cholesterol, steroidogenesis and bile acid synthesis and secretion. SR-BI stimulates the bi-directional flux of free cholesterol (FC) between cells and lipoproteins, an activity that may be responsible for net cholesterol efflux from peripheral cells as well as the rapid hepatic clearance of FC from plasma HDL. In hepatic cells, SR-BI also mediates the selective uptake of cholesteryl ester (CE) from HDL, a process by which HDL CE is taken into the plasma membrane without degradation of the HDL particle [21]. Through lipid uptake, SR-BI increases cellular cholesterol mass and alters cholesterol distribution in plasma membrane domains [22], [23]. SR-BI mediates binding of the E2 [7], one of the two glycoproteins exposed at the surface of HCV particles, and, as a multiligand lipoprotein receptor, can also induce binding of HCV associated to LDL [24]. Intriguingly, we, and others, have demonstrated that HDL enhances infectivity of HCVpp and HCVcc [25], [26], [27], [28], [29], [30]. This original mechanism is controlled by the HCV glycoproteins, and, more particularly, by conserved residues of the hypervariable region-1 (HVR1) [25], [29], a 27 amino-acid peptide located at the amino-terminus of E2. HDL-mediated enhancement of infection clearly involves SR-BI but this occurs neither through a direct binding of HDL to HCV particles nor through increase of HCV binding to SR-BI [25], [27], [29]. Since SR-BI locally increases cholesterol content of cell membranes by mediating lipid transfer from HDL, it has been proposed that HCV may exploit SR-BI physiological function to achieve its entry processes [25], [29]. However, direct evidence is missing that, by providing a docking port to HCV particle and/or by modulating post-binding events, SR-BI favors infection. Indeed, in contrast to CD81 and CLDN1 whose implications during HCV entry have been unambiguously demonstrated by mutational analysis in cells that were rendered susceptible to HCV entry upon their ectopic expression [9], [12], [13], the importance of SR-BI has only been addressed indirectly because of lack of cells in which similar complementation assays could be performed. Here we identified two cell types, of rat and human origins, that supported efficient HCV entry upon ectopic expression of SR-BI. Through the design of SR-BI mutants, i. e., in the extracellular and the cytoplasmic domains, we unravel important features of SR-BI functions regarding its involvement during HCV entry. Challenging the notion of liver tropism of HCV, most HCV receptors isolated so far are broadly expressed in different tissues, including those in which HCV does not replicate [2], [3], [4]. Particularly, the broadness of SR-BI expression makes difficult the investigation of the functional properties of this molecule in HCV infection, owing to the paucity of SR-BI-negative human cell lines in which susceptibility to HCV entry could be obtained upon ectopic expression. Furthermore, efficient SR-BI down-regulation in susceptible cell types, such as Huh-7 cells, is difficult to achieve without compromising cell viability (MD, DL, BB and FLC, data not published) and has raised different results between studies [14], [25], [29], [31], [32]. To overcome these difficulties, we screened a panel of human and rodent cell lines for absence or low SR-BI expression (Table 1). Aiming to design functional complementation assays, we ectopically expressed in these cells HCV receptors by transduction with a set of selectable retroviral vectors encoding human CD81, CLDN1 or SR-BI and, upon appropriate selection, we challenged these cells with HCV pseudo-particles (HCVpp). We detected one human liver endothelial cell line, SK-Hep1, and one rat hepatocarcinoma cell line, BRL3A, that became susceptible to entry with HCVpp-H77 (Table 1) and with HCVpp of other genotypes (Figure S1C) upon ectopic expression of SR-BI, provided hCD81 and hCLDN1 were also co-expressed, endogenously or ectopically (Figure 1 and Figure S1). While non hepato-carcinoma cells of human origin like e. g., 293T cells, have been rendered susceptible to HCV entry upon ectopic expression of hCLDN1 [9], this is the first report of a non human cell line that can be functionally complemented by HCV receptors, allowing efficient HCV entry. Over-expression of hSR-BI in SK-Hep1-CLDN1 cells that express very low endogenous SR-BI levels (Figure 1A and Figure S1A) resulted in ca. 10-fold increased HCVpp titers, i. e., titers that were only 2-fold lower than those obtained in Huh-7 cells (Figure 1B and Figure S1D). In contrast, no or undetectable expression of endogenous rat SR-BI could be detected by immunoblotting and by RT-qPCR in BRL3A cells (Figure S1A and S1B, Protocol S1). Furthermore, no or hardly detectable HCV entry could be found in BRL3A cells ectopically expressing hSR-BI only or expressing both hCD81 and hCLDN1 (BRL3A-CD81-CLDN1 cells), despite full entry susceptibility of control pseudo-particles pseudotyped with VSV-G glycoprotein (Figure 1B and Figure S1D). Expression of hSR-BI in BRL3A-CD81-CLDN1 cells allowed HCVpp entry at titers similar to those detected in PLC/PRF/5 and Hep3B human hepato-carcinoma cells (Figure 1B), used in previous reports [12], [13], [33], [34], and ca. 8-fold lower than those obtained with Huh-7 cells (Figure 1B), which are the most susceptible to HCV entry [12], [13], [14], [33]. Of note, co-expression of hCD81, hCLDN1 and/or hSR-BI did not modify total (Figure S1A) or cell surface (Figure S2) expression levels of either of these entry factors. Hence, our results unambiguously demonstrated for the first time that expression of SR-BI - in combination with CD81 and CLDN1 - is required to allow HCV entry and support the notion that hSR-BI is an essential entry factor of HCV. We used these complementation assays to characterize the properties of hSR-BI in HCV entry. HDL, the main ligand of SR-BI, enhances infection of HCVpp [25], [28], [29] and HCVcc [26], [27], [30] in SR-BI-positive human cells that are susceptible to HCV entry like, e. g., Huh-7, HepG2-CD81, PLC/PRF/5, SW13 or Hep3B cells. We found that HCVpp entry into both BRL3A-CD81-CLDN1-SR-BI and SK-Hep1-CLDN1-SR-BI cells was stimulated by HDL to levels comparable to those detected in human hepatoma cells (Figure 1C). No change of cell surface (co) -expression of hSR-BI and/or hCD81 could be detected upon incubation of these cells with HDL (Figure S2 and data not shown). Next, we confirmed the above findings using cell culture-derived HCV (HCVcc). In comparison to HCVcc infection of Huh-7. 5 cells, for which viral infectious titers (above 1×106 i. u. /ml) could be assessed by immunostaining for Core protein, the same viral stocks resulted in lower infectivity levels in SK-Hep1-CLDN1-SR-BI target cells (data not shown), precluding accurate determination of infectious titers by immuno-detection. Therefore, we used a sensitive and quantitative real-time RT-PCR (RT-qPCR) assay to measure changes in HCV RNA at 4 hr, 12 hr and 72 hr post-infection with HCVcc. Inoculation of HCVcc on SK-Hep1-CLDN1 and SK-Hep1-CLDN1-SR-BI cells yielded strong RT-qPCR signals at 4 hr post-infection, indicating binding and/or capture of viral particles [9], that progressively declined with 10–30 fold loss at 12 hr (Figure 2A). Yet, while HCV RNA decreased again by ca. 15-fold in the parental SK-Hep1-CLDN1 cells at 72 hr, the HCV RNA levels increased in SK-Hep1-CLDN1-SR-BI cells at 72 hr vs. 12 hr post-infection but were strongly reduced when such target cells were treated during 72 hr with HCV replication inhibitors (BILN2061, an NS3 protease inhibitor, or 2′-C-methyl-adenosine, an NS5B polymerase inhibitor) (Figure 2A). Altogether, these results indicated that the detection of HCV RNAs revealed true HCVcc entry of these cells, leading to viral replication, rather than just residual cell attachment of viral particles. Overall, the co-expression of SR-BI and CLDN1 in SK-Hep1 cells allowed ca. 10 to 20 fold increased HCV RNA detection at this 72 hr time point as compared to SK-Hep1 cells expressing CLDN1 alone or none of these entry factors (Figure 2B), consistent with results obtained with HCVpp (Figure 1B and Figure S1D). Importantly, addition of HDL during infection could stimulate HCV RNA detection in SR-BI-expressing SK-Hep1-CLDN1 cells but not in the parental cells (Figure 2B). In previous studies [25], [29], [35], it was proposed that one of the mechanisms by which HDL enhances infection could involve SR-BI physiological activity. To address this possibility, we first sought to demonstrate whether SR-BI expressed in the BRL3A and SK-Hep1 cellular backgrounds was functional and could mediate lipid transfer, i. e., selective uptake of 3H-CE-labelled HDL [36] and efflux of 3H-cholesterol to phospholipid cholesterol acceptors [37]. As shown in Figure 2C, while BRL3A-CD81-CLDN1 cells could not or hardly mediate lipid transfer most likely owing to undetectable SR-BI levels (Figure S1A and S1B), ectopic expression of hSR-BI in these cells resulted in efficient lipid uptake and efflux, as compared to rat hepatoma Fu5AH cells expressing rat SR-BI (Figure S1A and S1B) used as positive controls. Likewise, over-expression of hSR-BI in SK-Hep1-CLDN1 cells resulted in efficient cholesterol efflux as compared to parental cells (Figure 2C). Importantly, these results were consistent with the restoration of HDL-mediated enhancement of HCV entry upon ectopic expression of SR-BI (Figure 1C and Figure 2B). Altogether, these results established that BRL3A-CD81-CLDN1 and SK-Hep1-CLDN1 cells provide original and useful tools for SR-BI complementation assays and render for the first time mutagenetic approaches possible to study the roles of SR-BI in HCV entry. We tested a panel of well-characterized SR-BI mutants in receptor complementation assays in order to address the properties of its intracellular and extracellular domains. Upon introduction in BRL3A-CD81-CLDN1 or SK-Hep1-CLDN1 cells, each SR-BI mutant was studied for its capacity to mediate HCV-E2 binding, HCV entry and HDL-induced infection-enhancement. Because some mutations introduced into human SR-BI were originally characterized in the murine ortholog, which shares 79% identity with human SR-BI (data not shown), we also characterized lipid uptake and efflux mediated by these human SR-BI mutants. To address the functions of the SR-BI intracellular domain, we expressed several SR-BI mutants or isoforms in BRL3A-CD81-CLDN1 and SK-Hep1-CLDN1 cells. By adjusting the input of vectors used to transduce the mutant/chimeric receptors in these cells, we obtained cell surface expression levels comparable to that of wt SR-BI as detected by FACS analysis (Figure 3A). To investigate the capacity of these modified SR-BI receptors to mediate binding of HCV surface glycoproteins (Figure 3A), we used a soluble recombinant form of HCV E2 glycoprotein (sE2), which harbors determinants of binding to CD81 [38], [39] and to SR-BI [7]. Of note, sE2-based binding assays may not fully represent all the binding parameters of HCV particles to CD81 [9], [40], [41], [42]. Yet, we decided to use this assay since in previous studies [27], [35], [43], we found that SR-BI-binding of HCVpp parallels that of sE2 although the latter is more sensitive than binding of HCVpp. Importantly, all these different target cells induced comparable entry levels of control viral particles harboring the VSV-G glycoprotein (VSV-Gpp), with less than 30% variation of VSV-Gpp titers as compared to those detected on wt SR-BI-expressing cells (Figure 3B). Note that although Figure 3B provides the raw data, the small differences of VSV-Gpp titers between the different SR-BI mutant-expressing cell lines could be used to normalize HCVpp infectivity. First, we investigated the HCV entry properties of a chimeric SR-BI/CD36 receptor [44], [45], [46], in which the two transmembrane domains and cytoplasmic tails of SR-BI were replaced by those of CD36, a close homolog of SR-BI that mediates high-affinity HDL binding but not efficient lipid transfer [46]. Cells expressing wt CD36 did not induce sE2 binding (Figure 3A), as reported previously [7], nor did they allow HCVpp entry (Figure 3B). In contrast, as compared to wt SR-BI, the SR-BI/CD36 chimera mediated about 3-fold reduced sE2 binding, in agreement with the 3-fold reduction of HCVpp entry, after VSV-Gpp normalization. Despite this reduced basal HCV entry, this mutant receptor allowed HDL-mediated infection-enhancement at levels similar to those obtained with wt SR-BI (Figure 3C). To examine further the involvement of the SR-BI endodomain in HCV entry, we expressed in BRL3A-CD81-CLDN1 cells SR-BI forms harboring alterations of its C-terminal cytoplasmic tail, which contains signals associated to SR-BI expression, localization and/or function: ΔCterm, a SR-BI mutant lacking the C-terminal cytoplasmic tail [45], and SR-BII, an alternative mRNA splice variant of SR-BI with an entirely different cytoplasmic C terminus that promotes more rapid HDL/SR-BII endocytosis as compared to SR-BI and alternative signaling events [47], [48]. Both forms of SR-BI were previously shown to mediate efficient binding of HDL [45], [47] and to induce lipid transfer (Figure 3D). We adjusted SR-BII cell surface expression to levels similar to those of SR-BI, but albeit all our efforts the expression levels of the ΔCterm mutant remained two-fold reduced (Figure 3A). Similar to results obtained with the SR-BI/CD36 chimera, these altered SR-BI receptors induced reduced sE2 binding (by 2–3 fold) and HCVpp entry (by 2-fold) but wild type level of HDL-induced infection-enhancement (Figure 3A–3C). Altogether, the results obtained with SR-BII, SR-BI/CD36 or ΔCterm mutants indicated that while the cytoplasmic tail of SR-BI does not seem to be involved in stimulation of infection by HDL, it could influence the basal HCV entry efficiency. Furthermore, the results on sE2 binding suggested that the level of cell attachment of viral particles was altered for these mutants, which could reflect alterations of receptor affinity, density, localization and/or turnover at the plasma membrane. We therefore sought to investigate specific determinants of SR-BI cytoplasmic tail that could modulate HCV entry. We first generated a mutant SR-BI receptor, ΔAKL, in which we removed a carboxy-terminal motif of SR-BI that mediates interaction with PDZKI or CLAMP [49]. PDZKI is a four-PDZ-domain-containing protein that is associated with SR-BI in hepatocytes and that may stabilize SR-BI in the sinusoidal plasma membrane by modulating its intracellular transport, localization, assembly and scaffolding [49], [50]. Compared to wt SR-BI, we found that the deletion of PDZKI-associating motif slightly reduced mutant receptor expression and sE2 binding by less than 2-fold but had no or minor influence on HCV entry and HDL-mediated infection enhancement (Figure 3). Furthermore, when PDZK1 was knocked-down in Huh-7 cells using siRNAs, we found that the PDZK1 down-regulated cells induced HCV entry and infection-enhancement at levels identical to those detected in unmodified Huh-7 cells (Figure S3). Thus, PDZK1 down-regulation had almost no effect on HCV entry, in agreement with the results of AKL motif deletion. Next, we generated alternative cytoplasmic-tail mutants: SES, in which the endocytosis motif of SR-BII was functionally introduced [51], and 2CS, in which the two acylation sites of the SR-BI carboxy-terminal cytoplasmic tail were mutated [46]. Like the ΔAKL mutant, these alternative mutants allow efficient HDL binding [46], [51]. Despite similar cell surface expression and sE2 binding, as compared to wt SR-BI (Figure 3A), the SES and 2CS mutants induced about 2-fold reduced HCV entry (Figure 3B), hence suggesting a role of the endocytic trafficking and/or membrane localization of SR-BI in HCV entry. While these results were obtained in a rat hepato-carcinoma background, they were largely confirmed in the human background of SK-Hep1-CLDN1 cells expressing the different SR-BI mutants (Figure S4). Furthermore, we tested a subset of these SR-BI mutants in HCVcc infection assays. While CD36 expression in SK-Hep1-CLDN1 cells did not induce infection of HCVcc, the SR-BI/CD36 chimera and the SES mutant were functional, but, for the latter, infection was reduced in comparison to wt SR-BI (Figure 4), in line with results obtained with HCVpp infection assays. Finally, we found that HDL stimulated HCVpp entry (Figure 3 and Figure S4) and HCVcc (Figure 4) at similar levels for SR-BI cytoplasmic tail mutants as compared to wt SR-BI. Altogether, these results indicated that the C-terminal cytoplasmic tail of SR-BI modulates the basal HCV entry process, but seems not to influence HDL-mediated infection-enhancement. This latter observation is consistent with the fact that the SR-BI C-terminal mutants mediated efficient lipid transfer (Figure 3D). To address the functions of the SR-BI ectodomain, we expressed SR-BI mutants that exhibited reduced HDL binding and/or lipid transfer properties. The capacity of either mutant to mediate sE2 binding, HCV entry and HDL-mediated infection-enhancement was compared with wt SR-BI or with the E210G ectodomain mutant, exhibiting wt lipid transfer properties (Figure 5D). First, we expressed a shorter isoform of SR-BI (SR-BI-Short), produced by alternative splicing of SR-BI mRNA that removes 100-amino-acids of the ectodomain [18], and the M159R point mutant, targeting a motif conserved between mouse and human SR-BI that has been shown to reduce HDL binding and lipid transfer [52]. The decreased levels of lipid uptake and efflux were verified for each mutant (Figure 5D). Upon expression in BRL3A-CD81-CLDN1 cells, these modified SR-BI receptors mediated no (SR-BI-Short) or hardly detectable (M159R) sE2 binding (Figure 5A) and reduced HCVpp entry by over 10-fold, in comparison to wt SR-BI (Figure 5B). These results therefore highlighted the importance of E2 attachment to the SR-BI ectodomain in the HCV entry process. Moreover, these mutants were unable to induce infection-enhancement when HDL was added during HCVpp infection (Figure 5C), which could be due to their inability to mediate HCV binding or, alternatively, from their inability to bind HDL and/or to mediate lipid transfer. BLTs (block lipid transfer; BLT-1 to BLT-4) are small lipid transport inhibitors originally identified in a high-throughput chemical screen of intact mSR-BI-expressing cells [53]. They inhibit SR-BI-dependent selective cholesterol uptake and efflux from and to HDL, but do not block HDL binding. We, and others, previously showed that BLTs also inhibit HDL-mediated HCV infection-enhancement, which, together with alternative results using SR-BI blocking antibodies or SR-BI down-regulation, suggested the possibility that the SR-BI physiological activity is involved during HCV entry [25], [29]. Surprisingly, here we found that BLT-4, characterized in several previous studies [25], [29], inhibited sE2 binding to SR-BI-expressing BRL3A (Figure 6) and CHO (data not shown) cells, at the same concentrations as those that proved to be effective for HCV entry inhibition, i. e., 15–50 µM [25], [27], [29]. Similar inhibition of HCVpp infectivity and sE2 binding was detected with other BLTs (data not shown). While sE2 readily bound BRL-CD81-CLDN1 cells, no inhibition of sE2 binding by BLTs could be detected on those cells (Figure 6 and data not shown). Moreover, while co-expression of CD81 and SR-BI increased sE2 binding as compared to BRL3A cells expressing either entry factor, BLT-4 reduced sE2 binding to BRL-CD81-CLDN1-SR-BI at the levels detected on BRL-CD81-CLDN1 cells (Figure 6). These results indicated that BLTs specifically inhibited sE2 binding to SR-BI. Moreover, HDL did not increase sE2 binding to either SR-BI or CD81 and did not modify inhibition of sE2 binding to SR-BI by BLT-4 (Figure 6). The unexpected finding that BLTs inhibit sE2/SR-BI binding further lent support for a requirement of sE2 binding to SR-BI for HCV entry. However, since the use of BLTs could not unambiguously demonstrate that HDL-mediated infection-enhancement requires SR-BI-dependent lipid transfer, next, we expressed and analyzed effects of SR-BI ectodomain mutants E418R, Q402R and Q402R/E418R that have reduced lipid uptake properties [52], [54], as shown in Figure 5D. Similar levels of cell surface expression for either mutant could be detected by FACS analysis, as compared to wt SR-BI (Figure 5A). These SR-BI mutants exhibited 5–15 fold reduced sE2 binding (Figure 5A), which was correlated with a lower infectivity of HCVpp (Figure 5B), in agreement with results obtained with the M159R and SR-BI-Short mutants. When HDL was added during the HCV entry assay, we found that the extent of infection-enhancement (Figure 5C) was correlated to the capacity of these SR-BI mutants to mediate lipid uptake (Figure 5D). For example, while E418R that shows 60% reduced lipid uptake capacity induced wild-type HDL-mediated infection-enhancement, the most disabled lipid transfer mutants, Q402R and Q402R-E418R, had lost almost all infection-enhancement capacity (Figure 5C and 5D). Collectively, the results demonstrated that SR-BI functions as an HCV entry factor by providing both cell surface binding sites and lipid uptake activity. Importantly, these different mutants had reduced HDL binding levels [52], [54], which could not unambiguously discriminate between altered HDL binding vs. reduced lipid transfer, the reason for loss of HDL-mediated infection-enhancement induced by SR-BI. Therefore, we next generated the N173Q and G420H-G424H mutants that have impaired lipid transfer but normal HDL binding [55], [56], [57]. These mutants induced ca. 10-fold reduced sE2 binding (Figure 5A), which resulted in ca. 4–5 fold reduced infectivity (Figure 5B). Interestingly, while the N173Q mutant poorly induced HDL-mediated infection-enhancement, the G420H-G424H failed to support stimulation of infection induced by HDL (Figure 5C), in agreement with their strongly reduced capacity to mediate lipid transfer (Figure 5D). These data further supported the notion that the lipid transfer functions of SR-BI are required for HCV entry enhancement. These results, obtained in the background of BRL3A rat cells, were confirmed in the human background of SK-Hep1 cells (Figure S4). Furthermore, we performed HCVcc infection assays of SK-Hep1-CLDN1 cells expressing a subset of mutants of SR-BI extracellular domain (i. e., Q402R-E418R, N173Q and G420H-G424H) (Figure 4). We confirmed that these mutant receptors reduced infection in comparison to wt SR-BI, but completely abolished HDL-mediated infection enhancement. Several lines of evidence suggested that SR-BI plays a prominent role in HCV entry into cells. First, SR-BI provides both direct and ApoB-mediated interaction with HCV particles [7], [24], [58]. Second, antibody blocking or down-regulation of SR-BI inhibit HCV entry in permissive cells [12], [14], [25], [26], [29], [59]. Third, HDL, the major important ligand of SR-BI, stimulates HCV entry in human hepatocarcinoma target cells [25], [26], [27], [28], [29], [35]. Finally, using small molecules that inhibit the selective lipid transfer functions of SR-BI, named BLTs [53], it was proposed that besides providing a docking site for HCV particles, SR-BI physiological property, i. e., cholesterol uptake and/or efflux, could be exploited during HCV entry [25], [29]. Yet, despite this indirect evidence, functional complementation assays addressing the implication of SR-BI during HCV entry were lacking since no cell type in which SR-BI ectopic expression would restore HCV infection has been available. Aiming to directly address these different possible functions of SR-BI in HCV entry, we report here for the first time a sensitive functional complementation assay that allows studying this molecule by mutagenesis. By screening cells of human and non-human origins for absence or low SR-BI expression in which HCV entry could be restored by SR-BI ectopic expression, our data highlight one non-hepatoma human cell line and one hepatoma rat cell line in which HCV entry assays could be performed. Our results therefore clearly demonstrate that SR-BI is an essential entry factor, along with CD81 and CLDN1, mediating HCV entry. This is also the first report showing that HCV can enter non-human cells upon expression of HCV receptors. Importantly, we show that the selective lipid transfer properties of human SR-BI were fully functional in such heterologous cell backgrounds, allowing us to directly address the role of specific residues of SR-BI ecto- and endo-domains in HDL-mediated infection-enhancement. How HCV undergoes cell penetration following binding to its specific receptors remains ill defined. SR-BI alone or, alternatively, SR-BI interacting with the other HCV receptors may initiate cell penetration and/or mediate virus internalization. That HCVcc binds SR-BI-expressing CHO cells but not CD81-expressing CHO cells [9] may imply that a first contact with SR-BI is necessary before the viral particle can interact with CD81. SR-BI may induce HCV endocytosis by itself, as suggested by its capacity to mediate internalization of its natural ligands [21], [60], [61]. Interestingly, expression of SR-BII, a mRNA splice variant that differs from SR-BI at the C-terminus [18], which confers intracellular localization of SR-BII and rapid internalization of HDL [19], [47], reduces HCVpp entry as compared to SR-BI (this report). Along with findings of others, i. e., via SR-BII over-expression in Huh-7 cells [59], this indicates that SR-BI, rather than SR-BII, is a preferred receptor for HCV entry and that determinants of SR-BI cytoplasmic tail different from those controlling its endocytosis may regulate HCV entry. Additionally, deletion (ΔCterm mutant) or replacement (SR-BI/CD36 chimera) of SR-BI cytoplasmic tail also reduced its capacity to mediate HCV entry. Moreover, functional restoration of the SR-BII dileucine endocytic motif in the SR-BI C-terminal cytoplasmic tail (SES mutant), which induces rapid internalization of SR-BI/HDL complexes [51], did not increase HCV entry but rather reduced it. Altogether, these results suggested that if SR-BI initiates and/or promotes HCV endocytosis, it could be through its interaction with other HCV entry factors rather than via a classical binary virus/receptor complex. In agreement with this assumption, our data raise the possibility that determinants of the C-terminal cytoplasmic tail contribute to SR-BI HCV entry functions through modulation of its intracellular trafficking and/or membrane localization. The study of the ΔAKL mutant, which abrogates SR-BI interaction with PDZK1 that modulates its intracellular transport, localization, assembly and scaffolding [49], [50], did not affect HCV entry, consistent with the lack of effect of PDZK1 down-regulation in Huh-7 cells. However, as suggested by results with the 2CS mutant (C462S-C470S), which prevents SR-BI palmitoylation [46] and thus its potential association to lipid raft micro-domains, our results indicate that localization of SR-BI in specific micro-environments could play a role in HCV entry. Indeed, sub-cellular fractionation experiments showed that SR-BI localizes in plasma membrane lipid rafts [62] and/or caveolae [63], which may play a critical role in SR-BI-mediated transfer of lipids between HDL and cells [64], [65] and, possibly, HCV entry. Such low-density membrane microdomains are enriched in cholesterol and glycolipids, and have been involved in a number of transport and signaling events that could be important for virus endocytosis and intracellular transport [66]. Our study of SR-BI ectodomain mutants provides the first direct and functional evidence that HCV and HDL binding to SR-BI, and intact lipid transfer properties of SR-BI are required for SR-BI function as HCV entry factor. SR-BI-mediated uptake of HDL CE is a two-step process that requires high-affinity binding of HDL followed by incorporation of CE to the plasma membrane pool and subsequent transfer of the lipid to an inaccessible pool. CE uptake is followed by hydrolysis to free cholesterol by a neutral CE hydrolase. SR-BI-mediated lipid uptake leads to increase of cholesterol content of the target cell membrane [22], [23], [65] and activates distinct signaling pathways [67], which may provide different beneficial roles for HCV entry. First, using liposome-based in vitro fusion assays, HCVpp membrane fusion was shown to be facilitated when cholesterol is present in the target membrane [15]. By analogy with fusion processes of Flaviviruses and Alphaviruses that have been widely studied [68], cholesterol-enrichment of target membranes may induce specific curvature that could positively influence the early interactions of HCV fusion protein. Alternatively, local cholesterol enrichment may facilitate binding [69] and/or conformational changes [70] within the HCV glycoproteins that are required for membrane fusion processes. Second, HCVpp internalization was shown to be specifically accelerated by HDL [27]. As discussed above, this effect is likely to be indirect. Indeed, the internalization rate of HCVpp is significantly slower than that of pseudo-particles harboring the surface glycoproteins from murine leukemia virus, influenza virus [27], Semliki forest virus, or vesicular stomatitis virus [11], and has an half-life much longer than that of HDL internalization [71]. Furthermore, HDL added during the initial stage of infection suppresses an one-hour time lag during which cell-bound virions are not internalized [27]. This may reflect the time interval required to assemble a functional HCV receptor complex, which may be reduced upon SR-BI activation through modifications of the cell membrane. A possibility is that HDL/SR-BI interaction augments the rate of CD81 recruitment at virion-binding sites and/or internalization of HCV/CD81 complexes via a cholesterol-dependent pathway. In agreement with this assumption, that SR-BI mutants increasing internalization (SR-BII and SES mutant) are less effective than wt SR-BI to mediate HCV entry (see above) suggests that HCV internalization is likely driven by SR-BI interacting with other receptors rather than via SR-BI alone. In this respect, it is interesting that CD81 and SR-BI function cooperatively to initiate HCV infection [32], [72], that CD81-mediated HCV entry seems dependent on membrane cholesterol [72], and that SR-BI/HDL-mediated HCV entry enhancement still requires CD81 [25], [27]. Interestingly, both SR-BI and CD81 have been proposed as cell factors allowing Plasmodium sporozoite invasion and/or intracellular parasite development in mouse [73] and human [74] hepatocytes, perhaps through SR-BI-induced regulation of the organization of CD81 at the plasma membrane by mediating an arrangement permissive to penetration by sporozoites [73]. Yet, although SR-BI lipid transfer blockers, i. e., SR-BI antibodies and BLTs, reduce both Plasmodium and HCV infection [25], [29], [74], there seems to be important differences in the mechanisms involved. Indeed, in contrast to HCV surface glycoproteins, Plasmodium sporozoites do not seem to directly interact with SR-BI and/or CD81 [73], [75]. Furthermore, in contrast to HCV, Plasmodium sporozoites invasion is not enhanced by HDL [74]. Finally, while we demonstrated that cholesterol uptake mediated by SR-BI ectopically expressed in BRL3A-CD81-CLN1 cells is functional (Figure 2C), we did not notice up-regulation of CD81 cell surface expression and TEM localization whether these cells expressed or not SR-BI and following treatment with HDL (Figure S2 and data not shown), in contrast to other studies that revealed such CD81 changes in mouse hepatocytes [73]. These differences may reflect dissimilar properties of mouse vs. human SR-BI and CD81, of species-specific cholesterol transport processes and/or of the cellular backgrounds used [76]. Likewise, no CD81 changes could be detected in Huh-7 cells incubated in the presence or in the absence of HDL (Figure S2). Consistently, HDL did not enhance sE2 binding capacity to SR-BI and/or CD81 (Figure 6). Finally, recent results of others suggest that the association of CD81 with TEM is not essential for HCV entry (Dr Jean Dubuisson, Personal Communication). Alternatively, homo-oligomerization of SR-BI seems associated with functional expression of the selective HDL cholesteryl ester uptake pathway [77] and may contribute to the formation of a HCV receptor complex. Third, an essential component of HDL that seems responsible for infection enhancement at the level of HCV membrane fusion is the apolipoprotein C-I (ApoC-I) [28], [35], an exchangeable apolipoprotein that could be transferred from HDL to the HCV membrane during SR-BI-mediated lipid transfer and could predispose HCV envelope for fusion with a target membrane, via alterations of its outer phospholipid layer [35]. Further analysis of the HCV entry events mediated by HCV receptors and co-factors will be greatly facilitated by the availability of the novel functional receptor-complementation assay described in this report. Moreover, it opens the way to develop small animal models susceptible for HCV in which entry inhibitors can be tested in vivo. Huh-7 [78], PLC/PRF/5 human hepatoma (ATCC CRL-8024), Hep3B human hepatocellular carcinoma (ATCC HB-8064), BRL3A rat hepatocytes (ATCC CRL-1442) and 293T (ATCC CRL-1573) cells were grown in DMEM (Invitrogen) supplemented with 10% fetal bovine serum (FBS) (Invitrogen). Fu5AH rat hepatoma cells [79] were grown in Eagle' s MEM supplemented with 1% L-glutamine and 5% newborn calf serum. CHO (ATCC CRL-1582) and SK-Hep1 (ATCC HTB-52) cells were maintained in RPMI (Invitrogen) with 10% FBS. Retroviral vectors expressing human CD81 (GenBank accession number: NM_004356), Claudin-1 (NM_021101) and SR-BI (Z22555) or mutant SR-BI receptors were inserted in CNC MLV (murine leukemia virus) vector backbones (kind gift of M. Collins) harboring selectable marker genes for blasticidin, neomycin and hygromycin respectively. Construct details are available upon request. The CD36 was kindly provided by Brian Seeds [80]. The cDNAs encoding the SR-BI-Short [18] and SR-BII [47], [48] were based on the original sequence of human SR-BI [18] and were inserted in the CNC expression vector. The SRBI-CD36 [44], [45], [46], the ΔCterm [45], ΔAKL [49], SES [51] chimeras were previously described for rodent SR-BI and were used to derive the equivalent human SR-BI chimeras investigated in this work. Point mutants encoding the following SR-BI receptors: M159R, N173G, Q402R, E418R, Q402R-E418R, G420H-G424H, C462S-C470S (2CS) [46], [52], [54], [55], [56], [57] and E210G (MD and FLC, unpublished data), were introduced in human SR-BI cDNA by site directed mutagenesis (primer sequences are available upon request). All mutants were sequenced to ensure that the clones possessed only the expected mutation. Retroviral vectors containing CD81, CLDN1 and wt or mutant SR-BI receptors were produced from 293T cells as VSV-G-pseudotyped particles as described previously [81], [82]. Stable expression of either receptor in target cells was obtained by transduction with vector particle-containing supernatants of 293T producer cells, followed by antibiotic selection. The expression vector for the E1E2 glycoproteins of HCV strain H77 (AF009606) was described previously [33]. Viral pseudo-particles named HCVpp and VSV-Gpp harboured the glycoproteins of HCV and VSV, respectively, and were produced as described previously [33] by transfection in 293T cells of vectors encoding viral glycoproteins, packaging proteins, and GFP-transfer vector. Prior to harvest viral particles-containing supernatants, producer cells were incubated in DMEM containing 0. 1% FCS for 24 hrs. For infection assays, target cells were seeded 24 hr prior to inoculation. 2 hr prior to infection, target cells were pre-incubated in DMEM containing 0. 1% FCS. Then medium was removed and dilutions of viral supernatants were added to the cells and incubated for 4 hr. Where indicated, HDL (Calbiochem) was added to the infection reactions at 6 µg/ml of cholesterol. Supernatants were then removed and the infected cells kept in regular medium (DMEM, 10% FCS) for 72 hr before analysis of the percentage of GFP-positive cells by FACS analysis [33]. The infectious titers were expressed as GFP infection units (i. u.) per ml of HCVpp-containing medium. Infections were controlled by using non-enveloped particles, which resulted in background titers between 102 and 103 GFP i. u. /ml. Plasmid pJFH-1 displaying previously described mutations F172C and P173S in core, as well as N534K in E2 [83], was in vitro transcribed using the Megascript T7 kit (Ambion). After DNAse treatment, genomic RNA was purified by two acidic phenol/chloroform extractions and pelleted by isopropanol precipitation. Then, RNA was electroporated into Huh-7. 5 cells using Gene Pulser II apparatus (Biorad) and cells were cultured under standard conditions. Virus-containing medium was harvested, pooled and added to target cells as described above. Where indicated, HDL (Calbiochem) was added to the infection reactions at 0. 6 µg/ml of cholesterol. Infected cells were collected by trypsinization, and RNA was prepared (RNeasy; QIAGEN), reverse transcribed (iScript cDNA synthesis kit, Biorad) and quantified with HCV specific (5′-CTTCACGCAGAAAGCGTCTA and 5′-CAAGCACCCTATCAGGCAGT) and house-keeping primers targeting RSP11 in SK-Hep1 and Huh-7 cells (5′-GCCGAGACTATCTGCACTAC and 5′-ATGTCCAGCCTCAGAACTTC) or rat GAPDH in BRL3A cells (5′-GTTACCAGGGCTGCCTTCTC and 5′-GGGTTTCCCGTTGATGACC) using the Platinum SYR Green qPCR super mix kit from Invitrogen on an Applied 7000 apparatus. Binding of soluble E2 glycoprotein, derived from the H77-E2 was performed as previously described [27], [38]. Briefly, 5 µg/ml of sE2 harbouring a His-tag was incubated for 1 hr at 37°C with 106 target cells. The amount of cell-bound sE2 was determined by FACS analysis using 2 µg/ml of an anti-His tag antibody (pentaHis, Qiagen) and using Allophycocyanine (APC) -conjugated anti-mouse antibodies. The surface expression of hCD81 and hSR-BI was quantified by FACS analysis from 106 live cells using anti-CD81 mAb (clone JS81, Pharmingen) and anti-SR-BI mAb (CLA-1, BD Biosciences), respectively, added to cells for 1 hr in PBFA at 4°C. After washing, the binding of antibody to the cell surface was detected using RPE- or APC-conjugated anti-mouse antibodies. Lipid efflux assays were performed as previously described [37]. After plating, cells were labeled by incubation with 3H-cholesterol (1 µCi/ml) for 48 hr. Subsequently cells were incubated for 24 hr in the presence of BSA (0. 5%) and newborn calf serum (25%) for Fu5AH or fetal bovine serum (25%) for BRL3a or SK-Hep1, to allow equilibration of the label. After equilibration, cholesterol acceptors (20 µg phospholipid/ml of isolated HDL) were added in serum-free medium and incubated with cells for 4 hr at 37°C. Fractional cholesterol efflux (expressed as percentage) was calculated as the amount of the label recovered in the medium divided by the total label in each well (radioactivity in the medium+radioactivity in the cells) obtained after lipid extraction from cells in a mixture of 3∶2 hexane-isopropanol (3∶2 v/v). The background cholesterol efflux obtained in the absence of cholesterol acceptor was subtracted from the efflux values obtained with the test samples. Selective HDL-CE (cholesteryl ester) uptake was performed as previously described [36]. Cells were plated in 24-well tissue culture plates (106 cells/well). Two days after plating, cells were washed 3 times with PBS and once with serum-free medium. Cells were subsequently incubated in the presence of 3H-CE-labelled HDL (60 µg protein) diluted in serum-free medium at 37°C for 5 hr. At the end of incubation, the medium was removed and cells were washed 4 times with PBS and incubated in the presence of an excess of unlabelled HDL (100 µg protein) for 30 minutes. Cells were then washed 4 times with PBS and solubilized with 200 µl of NaOH 0. 2 N for 15 minutes at room temperature with gentle mixing. Protein content (20 µl) from each well was measured using the Bicinchoninic acid protein reagent (Pierce). The radioactive content of 100 µl of each cell lysate was measured by liquid scintillation counting. Selective uptake was calculated from the known specific radioactivity of radiolabelled HDL-CE and is expressed in µg HDL-CE/µg cell protein. | Title: Receptor Complementation and Mutagenesis Reveal SR-BI as an Essential HCV Entry Factor and Functionally Imply Its Intra- and Extra-Cellular Domains Summary: More than 180 million people are chronically infected by hepatitis C virus (HCV), a leading cause of liver failure and cancer, stimulating the need to fully define the biology of HCV infection for developing novel and effective therapeutics. During the first steps of infection, the virus is taken up and penetrates hepatocytes. HCV entry is thought to be a coordinated multi-step process mediated by specific factors, including CD81, Claudin-1, and the scavenger receptor BI (SR-BI). Whereas the involvement of CD81 and Claudin-1 was demonstrated by rendering susceptible cells that are otherwise refractory, SR-BI complementation assays were lacking, raising questions as to its functions during HCV entry. Here, we identify one hepatoma rat cell line, in which SR-BI complementation assay and targeted mutagenesis could be performed. We therefore demonstrate that SR-BI is an essential HCV entry factor. Our results shed light on SR-BI intracellular domain functions in HCV entry, and, further, emphasize the remarkable capacity of HCV to hijack the lipid transfer function of SR-BI, hence favoring infection. | 12,341 | 289 | lay_plos | en |
Summarize: FIELD OF THE INVENTION [0001] The present invention is directed to trays for the display of merchandise, particularly in supermarkets and other large stores. The invention is especially suitable for, but not necessarily limited to, merchandise display trays of the type that are mounted in cantilever fashion, for example as disclosed in U.S. Pat. No. 8,210,367, and which are provided with spring-operated pusher paddles that constantly urge the displayed merchandise forwardly as products are removed by customers from the front of the display. BACKGROUND OF THE INVENTION [0002] When loading or reloading product display trays of the type referred to above, the spring-loaded pusher paddle must be held in a retracted position while new product items are loaded into the tray. To enable store personnel to have both hands available for loading of product, it is typical to provide a means for mechanically locking the paddle in a fully retracted position while the loading operations are taking place. A variety of arrangements and mechanisms have been proposed for accomplishing this. One such mechanism is reflected in British patent publication 2290077, in which a vertically movable latch element is mounted on the back of a spring-urged pusher paddle. When the paddle is moved to a retracted position, the latch is depressed so that it engages the track and retains the paddle in position while products are loaded into the tray. When the tray is fully loaded, a push against the paddle in a backward direction releases the latch, which returns to an elevated position allowing the paddle to move forwardly to advance the product column. [0003] European patent EP 0986980 illustrates a basic arrangement in which the base portion of a pusher paddle is provided with a hook engageable with a recess provided in the back portion of the track. When the paddle is retracted for loading of the tray, the entire paddle is tilted backwards to press the hook into the recess and the lock the paddle. The paddle is later released by pressing it backward and tilting it forward to release the hook. [0004] U.S. Pat. No. 7,931,156 illustrates an arrangement similar to that of the British publication 2 290 077 in that a vertically movable latch element is mounted to the back of the pusher paddle. The latch can be depressed when the paddle is in a retracted position, in order to lock the paddle during reloading operations. When reloading is completed, the paddle is pressed rearwardly (either manually or as a result of being pressed backward after becoming fully loaded with packages) causing release of a latch spring and thus allowing the tray to move forwardly under the action of the paddle spring. [0005] US patent publication 2012/0211450, owned by the assignee of this application, Trion Industries, Inc., illustrates an arrangement in which a locking element is positioned against the back face of a flexible and tiltable pusher paddle. During normal operations, the paddle is in an upright position, in which the locking element is ineffective. For reloading operations, the paddle is pushed to the back of the tray, and its geometry is such that it tilts forwardly when in its rearward or reload position. In a forwardly tilted position of the paddle, the locking element grips guide rods forming the base of the tray and retains the paddle in a retracted position. When the paddle is tilted back to an upright position, either manually or by the loading of a final product package into a substantially full tray, the lock automatically releases and allows the paddle to move forwardly under the action of its spring. [0006] US patent publication 2013/0112634 discloses a mechanism in which a U-shaped locking element is inserted through slots in the face of the pusher and has locking elements extending to the rear that automatically engage the tray and lock the pusher when the pusher is moved to a retracted position. Rearward pressure on a portion of the locking element exposed in front of the pusher releases the locking elements and allows the paddle to be pushed forwardly by its spring. This arrangement has the disadvantage of automatically locking the paddle in a retracted position anytime it is moved to the rear of the base. When this happens without the store clerk noticing, the paddle may remain in its locked, retracted position and not function to push the product column to the front as intended. [0007] All of the above devices function at some level to allow a spring operated pusher paddle to be locked in a retracted position for reloading operations. However, all of them suffer from certain shortcomings, either from an operating standpoint or from extra cost and complication in the manufacture. SUMMARY OF THE INVENTION [0008] The present invention provides a novel and improved form of product display tray including a product pusher of relatively rigid construction which is biased in a forward direction by a coiled strip spring. The coiled strip spring is arranged in a known manner, with a coiled body portion thereof being positioned behind and bearing forwardly upon the product pusher, and a strip portion thereof extending forwardly in the tray and being anchored at the front of the tray. The new tray includes a novel and improved locking mechanism functioning in combination with the spring-driven pusher to accommodate manual locking of the pusher in a retracted position for reloading of the tray, along with either automatic or manual release of the pusher when reloading has been completed. [0009] The mechanism of the invention includes a locking element that is pivotally secured at the rear of the front panel of the paddle. The locking element has a portion, which can be referred to as an actuating arm, extending upwardly from the pivot axis directly behind the upright front panel, and a second portion, which can be referred to as a locking leg, extending rearwardly from the pivot axis. In accordance with a feature of the invention, the upwardly extending actuating arm of the locking element is interposed between the coiled body of the strip spring and the back of the pusher paddle. Accordingly, in the device of the present invention, the locking element is constantly urged by the coiled spring body into a position in which the rearwardly extending locking leg is held in an elevated position where it cannot make locking engagement with the base of the tray. [0010] In accordance with another aspect of the invention, the front panel of the pusher paddle has an opening which provides access to the actuating arm of the locking element. When the pusher paddle is in a retracted position, and the operator desires to actuate the locking device to hold the pusher in a retracted position, the operator can manually access the actuating arm through the panel opening. By pressing rearwardly on the accessible portion of the actuating arm, the operator can pivot the locking element into a position in which the locking leg engages the base of the tray and secures the paddle in a retracted position. Releasing the paddle, when desired, involves merely pushing rearwardly on the upright panel, either manually or by loading of a final package onto the tray. As soon as the pusher paddle is moved slightly to the rear, the pressure of the coiled spring body on the actuating arm causes the locking element to immediately pivot in a release direction and free the paddle for forward movement. [0011] In accordance with yet another aspect of the invention, a product display tray is provided with a unique design of a rigid pusher paddle. The pusher paddle is designed and constructed to be guided and supported by a plurality (typically four) spaced apart and parallel guide rods that extend longitudinally over the length of the tray to accommodate movement of the pusher paddle between front and back limit positions. Typically, the structure of the tray includes front and back transversely disposed base elements that support the front and back ends of the guide rods. Desirably, the configuration of the pusher paddle is such that it can be assembled with or removed from the guide rods without requiring removal of a base element in order to provide access to the ends of the rods. At the same time, and because of the spring forces applied to the rigid pusher paddle, it is important to assure that the pusher paddle remains assembled with the guide rods unless intentionally removed. To this end, the pusher paddle of the invention incorporates improved guide sleeves that slidably engage the rods and at least certain ones of which include special internal detent projections that require snap-on, snap-off assembly and disassembly, assuring that the pusher paddle will remain attached at all times to the guide rods unless intentionally removed. [0012] The arrangement of the invention is functionally optimal, in that positive action of the operator is required in order to lock the paddle in a retracted position. At the same time, the mechanism of the invention is highly simplified in nature and enables the paddle return spring to serve in the additional capacity of controlling operations of the locking element. [0013] For a more complete understanding of the above and other features and advantages of the invention, reference should be made to the following detailed description of a preferred embodiment of the invention, and to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS [0014] FIG. 1 is a front orthographic view, from above, showing a product display tray incorporating features of the invention. [0015] FIG. 2 is a back orthographic view of the tray of FIG. 1, with one side panel removed to show further details and showing the pusher paddle in a forward position. [0016] FIG. 3 is a side elevational view of the tray of FIG. 1, with one side panel removed to show further details and showing the pusher paddle in a retracted but unlocked position. [0017] FIG. 4 is a side elevational view, similar to FIG. 3, showing the pusher paddle of the tray in a retracted and locked position. [0018] FIG. 5 is a back orthographic view, similar to FIG. 2, showing the pusher paddle in a retracted and locked position. [0019] FIG. 6 is a front orthographic view, from above, showing the pusher paddle in a retracted and locked position. [0020] FIG. 7 is a front elevational view of the pusher paddle incorporated in the tray of FIG. 1. [0021] FIG. 8 is a side elevational view of the pusher paddle of FIG. 7 [0022] FIG. 9 is a back elevational view of the pusher paddle of FIG. 7. [0023] FIG. 10 is a back orthographic view, from above, of the pusher paddle of FIG. 7. [0024] FIG. 11 is a side elevational view of a locking element incorporated in the tray of FIG. 1. [0025] FIG. 12 is back elevational view of the locking element of FIG. 11 [0026] FIGS. 13 and 14 are front and back orthographic views respectively of the locking element of FIG. 11. [0027] FIG. 15 is a back elevational view of a modified form of locking element that can be used in the display tray of the invention. DETAILED DESCRIPTION OF THE INVENTION [0028] Referring to the drawings, the reference numeral 20 designates generally a product display tray such as used extensively in supermarkets and other stores. The illustrated tray assembly advantageously, but not necessarily, is of a type disclosed in U.S. Pat. No. 8,210,367, the content of which is incorporated herein by reference. In the illustrated tray assembly, the tray base 21, formed of longitudinally extending, parallel guide rods, is supported in cantilever fashion by laterally spaced apart side wall panels 22, 23. The sidewall panels include notches 24 at the back that engage and are supported by a rectangular mounting bar (not shown). Transversely disposed support rods 25, 26 are mounted at front and back end portions of the respective side wall panels 22, 23. These support rods slidably engage front and back base members 27, 28 such that the base members are supported by the sidewall panels 22, 23 while enabling lateral adjustment of the sidewall panels to accommodate packages of different sizes. [0029] Desirably, the front and back base members 27, 28 extend slightly below the bottom edges of the sidewall panels 22, 23, such that the trays may be directly supported on shelves where desired. Mostly, however, the trays are supported in cantilever fashion. [0030] In the illustrated form of tray, the tray base 21 is comprised of the front and back base members 27, 28 and a plurality of longitudinally extending guide rods 29 - 32 that are supported at their front and back ends by the base members 27, 28. Crossbars (not shown) extend underneath the guide rods adjacent each end and are welded thereto to form a rigid guide rod structure. The crossbars are received in transverse grooves in the base members 27, 28, preferably by a snap-in attachment, such that the base members and guide rods form a rigid, coherent structure. The outermost guide rods 29, 32 have upwardly bent portions 29 a, 32 a at their forward ends which mount a front barrier plate 33. In an illustrative but non-limiting example, the guide rods 29 - 32 may have a diameter of approximately 3/16 inch. [0031] A pusher paddle 34, details of which are shown in FIGS. 7-10, is mounted on the guide rods 29 - 32 for forward-backward sliding movement. A coiled strip spring 35 is positioned with a coiled body portion 36 thereof positioned behind the pusher paddle 34, with an uncoiled strip portion 36 a thereof extending through an opening 37 ( FIG. 10 ) at the base of the pusher paddle 34 and anchored at its forward end 38 by the front base member 27. The coiled spring 35, in a manner well known to those skilled in the art, applies forward pressure to the paddle to keep the displayed merchandise moving to the front portion of the tray as individual items are removed by customers. [0032] With reference to FIGS. 7-10, the paddle 34 is a one-piece molding of a suitable, relatively rigid plastic material, such as polyvinyl chloride. The paddle includes a front panel 39, which is generally vertically oriented and joins along its bottom edge with a horizontal base panel 40. A plurality of triangular gussets 41 extend between the back surface of the front panel 39 and the base panel 40 to maintain a rigid right angle relationship between the two panels. At its opposite side edges the paddle base 40 is formed with outwardly opening, horizontally disposed guide sleeves 42, 43 of generally U-shaped configuration. At their inner ends, the horizontal guide sleeves 42, 43 are of generally semi-cylindrical form, with their respective axes spaced apart a distance equal to the spacing of the outer guide rods 29, 32. Lower portions of the guide sleeve 42, 43 are of the same width as the base panel 40. However, upper portions 44, 45 of the guide sleeves extend rearwardly beyond the back edge of the base panel 40 and overlie the guide rods 29, 32 over a greater length to provide increased stability to resist backward forces applied during movement of the pusher paddle into a reload position at the back of the tray. By extending the upper portions 44, 45, but not the lower portions of the guide sleeves 42, 43 the paddle 34 can be retracted farther back in the tray for reloading, providing greater room for receiving packages for display. This is evident in FIGS. 4 and 5, for example, which show the extended upper portions 44, 45 overriding the back base member 28. In an illustrative but non-limiting example, the upper portions 44, 45 of the guide sleeves may have a length of about 1.4 inches, while the lower portion may be approximately one-half that length. [0033] For engagement with the inner rods 30, 31 of the base, the paddle 34 is provided with intermediate guide sleeves 46, 47 positioned symmetrically on opposite sides of the center line of the paddle 34. The guide sleeves 46, 47 are of a generally downwardly opening, U-shaped form and are angled divergently at an angle of approximately 30° from the vertical. Preferably, the intermediate guide sleeves 46, 47 are of a length equal to the width of the base panel 40 (e.g., in the above illustrative example, approximately 0.7 inch). At their upper ends, the guide sleeves 46, 47 are of semi-cylindrical form, with their respective axes located at a common level with the axes of the outer guide sleeves 42, 43. [0034] In order to mount the paddle 34 on the guide rods 29 - 32, the paddle is placed on a mid portion of the guide rods, and both the inner pair of rods 30, 31 and the outer pair 29, 32 are deflected outwardly a short distance to allow the rods to enter the bottom openings of the inner guide sleeves 46, 47 and the side openings of the outer guide sleeves 42, 43. When the guide rods are released from their deflected positions, they can be fully received in the recesses and be seated in the semi-cylindrical closed ends thereof. The four guide sleeves are of the size to closely receive the respective guide rods 29 - 32, while allowing free sliding movement of the paddle on the rods. In the illustrated and representative tray, the guide rods 29 - 32 may have a diameter of approximately 3/16 of an inch. However, it will be understood that the rod diameter may vary with the length of the tray and the anticipated weight of the products to be supported thereon. In all cases, the guide sleeves will be correspondingly sized to slide freely on the guide rods while effectively guiding the paddle 34 in its movements thereon. [0035] In accordance with an aspect of the invention, the downwardly opening inner guide sleeves 46, 47 are formed with detent projections 48, 49 which are positioned a short distance in from the open ends of the guide sleeves and serve to partially constrict portions of the guide sleeves in the manner to require forcible snap-in, snap-out assembly and disassembly of the inner guide rods 30, 31 with the pusher 34. The detent projections, which may extend fully or partially along the length of the recesses 46, 47, may constrict the recesses by, for example, 30%. Preferably, the exposed surfaces of the detent projections are disposed at inclined angles to the sides of the recesses. The arrangement is such the guide rods 30, 31 may be partially received in the recesses before encountering the detent projections. The rods must then be forcibly pressed into the recesses in order to deflect the projections and the recess sidewalls enough to allow passage of the guide rods. Likewise, in order to detach the inner guide rods 30, 31 from the paddle 34, the guide rods must be forcibly pressed outward in order to displace and clear the detent projections 48, 49. The described arrangement enables the paddle to resist the tilting action of the spring 35 and also allows the tray and paddle to be roughly handled by store personnel and customers without concern that the paddle will separate from the guide rods. This is accomplished in the present invention without the requirement of using pins, screws or other devices, achieving equivalent functionality without the extra cost and assembly time associated with the use of separate fastening devices. [0036] Effective retention of the sliding pusher paddle 34 on the guide rods is an important consideration, because considerable spring force is acting on the paddle, and it can become a potentially harmful projectile if it accidentally becomes detached from the guide rods. [0037] In accordance with another aspect of the invention, a novel and improved arrangement is provided for locking the pusher paddle 34 in a fully retracted position, against the action of the coiled spring 35, to accommodate reloading of the tray when necessary. The locking arrangement includes a locking lever 50, shown in FIGS. 11-14, which is pivotally mounted at the back of the pusher 34, closely adjacent to the base panel 40. The locking lever 50 includes an upwardly extending actuating arm portion 51 and a rearwardly extending locking leg portion 52 formed in part by side plates 53, 54. At their lower front corners, the side plates 53, 54 are provided with laterally outwardly extending pivot pins 55, 56 which are arranged to be received in pivot openings 57, 58 formed in lower forward portions of the innermost pair of gussets 41 ( FIG. 10 ). Locking lever 50 is a molded part, designed so that the side plates 53, 54 are joined in the upper portions thereof by a transverse front panel 59. The lower, forward portions of the side plates 53, 54 are free of cross connection and thus can be squeezed inwardly to allow the pivot pins 55, 56 to be inserted into the pivot openings 57, 58, providing a pivotal assembly of the locking lever 50 to the pusher paddle 34. The lateral spacing of the side plates is such that they straddle and confine the spring 35, as shown in FIG. 5. [0038] Flanges 60, 61 extend inwardly a short distance from forward edges 62 of the side plates 53, 54 and are engaged by the coiled body 36 of the spring 35 such that the spring at all times applies a forward pressure on the actuating arm 51 of the locking lever 50, urging it to pivot toward an upright or “release” position. In the normal or release position of the locking lever, the forward edges 62 of the side plates bear against the back surface of the pusher paddle 34 such that the spring acts through the locking lever to urge the paddle in a forward direction. [0039] As shown in FIGS. 11 and 13, the front panel 59 of the locking lever is offset forwardly from the forward edges 62 of the side plates 53, 54 and projects into an opening 63 formed in the front panel 39 of the pusher paddle 34. When the locking lever is in its release position ( FIG. 3 ) the panel 59 is approximately flush with the front surface of the pusher panel 39, where it is accessible for actuating the lever 50. When the pusher paddle 34 is moved to a fully retracted position, as in FIG. 4, the locking lever continues to be retained in its release position by the action of the spring body 36 on the flanges 60, 61, so that the paddle is not automatically locked in a retracted position. There are occasions when the paddle is retracted by store personnel for reasons other than reloading of the tray. In such instances, it is undesirable for the paddle to automatically lock in a retracted position because the locking action may not be noticed where it was not intended, causing the tray to malfunction by not maintaining a forward presence of the products. [0040] In the arrangement of the invention, when a store clerk moves the paddle 34 to a retracted position for reloading, he or she must intentionally lock the paddle by pressing the locking lever panel 59 rearwardly to pivot the locking lever rearwardly to the position shown in FIGS. 4 and 5. Downwardly projecting, forwardly opening hooks 64, at the backs of the side plates 53, 54 can then be engaged in a slot 65 in a base cover member 66 to secure the paddle 34 in its retracted position. [0041] Desirably, the pusher paddle 34 is provided with a stop element 67 which projects rearwardly from a position directly above the access opening 63 and is formed with a downwardly projecting flange 68 positioned to engage upper back portions of the actuating panel 59 of the locking lever 50, when the lever is displaced rearwardly a predetermined distance relative to the paddle 34. When the flange 68 is engaged by the panel 59, the hooks 64 are positioned at a proper level to be received in the slot 65 of the base cover. [0042] When a reloading operation has been completed, the pusher paddle 34 is released by displacing it rearwardly until the hooks 64 disengage from the slot 65. As soon as the hooks are disengaged, the locking lever 50 is automatically pivoted forwardly by the action of the spring body 36 against the flanges 60, 61 of the locking lever. Frequently, but not necessarily, the pusher paddle is displaced rearwardly upon placement of the final package into the tray. Otherwise, the operator manually displaces the paddle to release the lock. [0043] In a modified form of the locking lever 50, shown in FIG. 15, a single hook portion 164 extends continuously from one side plate to the other such that the rearward ends of the two side plates 53, 54 are rigidly connected. The locking lever of FIG. 15 functions in the same manner as that of the previously described embodiment. [0044] The mechanisms of the invention are advantageous in requiring intentional operator action to lock the pusher paddle in a retracted position. However, unlike with prior art devices, the desired functions of the locking mechanism do not require a special spring but are accomplished by an advantageous placement of the locking lever so that the force of the coiled strip spring, which is provided to impart forward biasing to the pusher paddle, can be harnessed to also provide rotational bias to the locking lever in a release direction. This is accomplished in the described embodiment by pivotally mounting the locking lever adjacent the bottom of the pusher paddle, with the coiled body of the spring pressing forward on an upwardly extending actuating arm of the lever. The spring acts to provide forward bias to the actuating arm of the locking lever and also acts through the locking lever to provide forward bias to the pusher paddle. Locking of the pusher paddle in a retracted position for reloading of the tray requires both that the pusher paddle be moved to a retracted position and additionally that the actuating arm of the locking lever be manually pressed backward, through the access opening 63 in the pusher paddle. [0045] The mechanism of the invention also provides improvements in the manner in which the pusher paddle is mounted on its guide rods. In an arrangement including at least four guide rods, the base of the pusher paddle is provided with outwardly opening, horizontally disposed U-shaped guide sleeves for the reception of the outermost guide rods. A pair of inner guide rods is received in downwardly divergently opening U-shaped guide sleeves, each of which is formed with an internal detent projection requiring forcible snap-in and snap-out assembly and disassembly. The guide sleeves are elongated relative to the diameter of the rods, providing stability to resist tilting forces imparted by the coiled spring and or by store personnel moving the paddle. Additionally, at least certain of the guide sleeves, including the outermost sleeves are further elongated in their upper portions, providing additional stability to resist rearward forces, as when moving the pusher paddle to a reload position, at the back of the tray. [0046] It should be understood, of course, that the specific embodiments of the invention herein illustrated and described are intended to be representative only, as certain changes may be made therein without departing from the clear teachings of the disclosure. Accordingly, reference should be made to the following appended claims in determining the full scope of the invention. | Summary: A product display tray, which is provided with a spring-actuated pusher paddle for urging a column of products forwardly, includes a manually operated locking element pivotally attached to the pusher paddle and normally urged to a "release" position by the action of the pusher spring. When the paddle is fully retracted, the locking element is manually pivoted into a locking position to engage the tray structure and retain the paddle in its retracted position. The pusher paddle includes special features to facilitate its assembly with, and stable retention on, longitudinal guide rods on which the paddle slides. A pair of downwardly and outwardly inclined U-shaped guide sleeves engage innermost support rods of the tray and have detent projections therein requiring forcible snap-in assembly for greater stability during operations. Selected guide sleeves are partially recessed in lower portions to accommodate overriding of base supports and enable greater retraction of the paddle. | 6,908 | 212 | big_patent | en |
Summarize: Krystal Barter created the Pink Hope charity in 2009 as she was recovering from a double mastectomy. Krystal Barter is Australia's answer to Angelina Jolie. Not only did she carry the same faulty BRCA1 gene that prompted her to undergo a double mastectomy, but the 31-year-old has also proved she has the same star pulling power of the Hollywood A-lister. The mother-of-three and founder of the Pink Hope charity has signed on a number of high profile Australians including Victoria's Secret Model Jess Hart and sister Ashley, the Prime Minister's wife Margie Abbott and the daughter of the country's richest woman Bianca Rinehart for her charity campaign. The charity's latest project, Bright Pink Lipstick Day, is a social media campaign that encourages more people to discuss their hereditary health. 'We're very fortunate to have these women. It's a huge honour to have the Prime Minister's wife leading the charge. To have someone of her calibre mean we're fighting for something that's right,' Ms Barter told Daily Mail Australia. 'These women have become like my friends and it's pretty amazing.' Other celebrities who have jumped on-board include Jesinta Campbell, Lisa Wilkinson, Laura Csortan, Natalie Gruzlewski, Kyly Clarke and Nicole Trunfio. Scroll down for video. Krystal Barter, 31, (fourth from right) has signed on the Prime Minister's wife, Margie Abbott (second from left) for her charity even Bright Pink Lipstick Day. Victoria's Secret Model Jess Hart and sister Ashley are among the high profile Australians to support Pink Hope - the country's only hereditary health charity. Bianca Rinehart (left), daughter of Australia's richest woman, and her friend Steph Adams, former Vogue UK art director, have also backed the Pink Lipstick campaign. Pink Hope, Australia's only hereditary health charity, will use Bright Pink Lipstick Day on September 26 as an opportunity to encourage people to find about their hereditary health in a bid to prevent breast and ovarian cancers. 'There's three questions people need to ask: Has anyone had cancer, at what age were they diagnosed and what type of cancer was it?' Ms Barter said. 'I know there's hundreds or thousands of people at risk of hereditary cancer. Bright Pink Lipstick Day encourages people to make a promise to kiss and tell.' Ms Barter was 22 when she found out she carried the faulty BRCA1 gene. She was just 25 when she had a double mastectomy - four years before Angelina Jolie famously revealed she underwent the procedure. Krystal Barter (left), pictured with Pink Hope ambassador Heidi and their daughters, was just 25 when she had a double mastectomy. Pink Hope, Australia's only hereditary health charity, will use Bright Pink Lipstick Day on September 26 as an opportunity to encourage people to find about their hereditary health. 'Growing up, every woman in my family was sick, that was normal,' she said. 'When they found changes in my breast tissue I said 'I'm not becoming a pin cushion for biopsies'... I wanted (my breasts) gone.' Ms Barter, who started Pink Hope as she recovering from her mastectomy, said she felt alienated because it wasn't a common procedure. 'But that changed when Angelina Jolie did it. I've seen a big shift within the past 12 months. Three days after Angelina Jolie made her announcement, the number of people accessing our services jumped 701 per cent,' she said. Former Miss Universe Renae Ayris will wear the pink lipstick designed by model Jess Hart specifically for Pink Hope Charity. Erin Holland is Miss World Australia's title holder. She's backing the #brightpinklipstickday campaign. The lipstick, worn here by TheyAllHateUs bloggers, will be sold at Priceline stores or on the charity's website. Ms Barter said she'll be wearing her pink lipstick tomorrow in memory of her grandmother, who died just two months. 'I was in my hospital bed having surgery when my nan passed away,' she said. 'I went in about 8 weeks ago to have my fallopian tubes and an ovary removed. She wanted me to have my surgery so she didn't tell me she was sick. 'I've had a very sick mum for a long time and I've had all these women in my family who are now not here or not 100 percent (because of cancer)… I'm trying to use our family story to make a positive impact.' Model Jess Hart designed a lipstick through her cosmetic brand LUMA especially for Pink Hope. It will be sold exclusively through Priceline stores nationwide or online at www.pinkhope.org.au for RRP $19.95 with all proceeds going to the Pink Hope Charity. Bright Pink Lipstick Day will take place on Friday, September 26. www.pinkhope.org.au | Summary: Krystal Barter was just 25 when she had a double breast mastectomy after realising she had the faulty BRCA1 gene. The 31-year-old from Sydney now actively campaigns for hereditary health awareness through her Pink Hope Charity. The mother-of-three has signed on a number of high profile Australians for the charity Bright Pink Lipstick Day. It's a social media campaign that encourages people to discuss their hereditary health. | 1,152 | 103 | cnn_dailymail | en |
Summarize: BACKGROUND OF THE INVENTION This invention relates to a process for the production of enzymatically active biocatalysts which re insoluble in aqueous media and which are particularly suitable for use in fluidised-bed or fixed-bed reactors. The carrying out of enzymatic reactions on an industrial scale has resulted in the appearance of biocatalysts which are insoluble in aqueous media. The reason for this is that the enzymes should not be deactivated after being used only once, which has resulted in their being fixed to an inert support or in their "immobilisation" to enable them to be physically separated from the substance to be treated or "substrate". Several methods for fixing enzymes to supports have been proposed: The enzyme is directly adsorbed onto a mineral material, such as ceramics, glass, silica, etc. The products obtained have the disadvantage of being unstable because the enzyme is only weakly fixed to the support. The enzyme is chemically bound to an organic support, such as a synthetic polymer (for example an aminoethyl cellulose according to British Patent No. 1,357,317) or a natural polymer (for example chitosan according to U.S. Pat. No. 4,094,743) by way of a bifunctional reagent, such as a dialdehyde, or a monofunctional reagent, such as a carbodiimide. The enzymes immobilised on a synthetic support do not have the requisite quality for use in foods. On the other hand, organic supports are not really suited to industrial processes because they are compressible and have a relatively low density and, because of this, they are difficult if not impossible to use in highthroughput fluidised-bed or fixed-bed reactors. In addition, it is necessary to ensure good contact between the enzyme and the substance to be converted, i.e. the substrate. This means that the enzyme is preferably immobilised on the outer surface and not in the pores or in the matrix of the inert support. The above-mentioned difficulties and restrictions affecting practical application are more severe if the reaction medium is viscous and contains colloidal or solid substances or impurities. Difficulties such as these are currently being encountered in the food industry. SUMMARY OF THE INVENTION We have found an advantageous enzyme immobilisation process which is suitable for use in the food industry and which is not attended by any of the disadvantages referred to above. The present invention provides a process for the production of an enzymatically active biocatalyst insoluble in aqueous media and particularly suitable for use in fluidised-bed or fixed-bed reactors, which comprises coating particles of a rigid and dense mineral material with a layer of chitosan, stabilising the coated particles with a bifunctional reagent and fixing an enzyme to the support thus treated. The mineral core used is selected from rigid, chemically inert mineral substances preferably having a porous surface, such as for example microporous particles of silica gel, metal oxides, such as TiO 2, ZrO 2, ceramics, etc. The particles are generally from 0.05 to 5 mm and preferably from 0.1 to 0.25 mm in diameter. The core is coated with chitosan which is a natural polymer obtained by the deacetylation of chitin at elevated temperatures in a strongly basic medium. Chitosan is insoluble in water except in the presence of an acid other than sulphuric acid. Chitin is the principal organic component of the protective exterior of the invertebrates (the carapace of crustaceans or the cuticle of insects) which is also found in the skeletal wall of certain lower forms of vegetable (mushrooms for example). It is a linear polymer of N-acetyle-D-glucosamine which has a high molecular weight (approximately 200,000) and is characterised by bonds of the β(1→ 4) type. Since the N-acetyl group is difficult to eliminate, deacetylation is never complete and generally varies from 50 to 85% in commercial products. It is there products which are known by the name of chitosan. In order to load the surface of the mineral particles with chitosan, the first step is to prepare an aqueous solution of chitosan in an acid, for example concentrated acetic acid (10 to 80% by weight and preferably 30 to 60% by weight), containing from 1 to 30 g and preferably from 4 to 10 g of chitosan per litre. The mineral particles are then added to the solution while stirring until a concentration of from 10 to 500 g of solid material per litre is obtained. The mixture is the degassed in vacuo, the suspension is left standing for a few hours and, after decantation, the coated particles are recovered by filtration. The particles thus recovered are then washed with water and dried in vacuo. The support thus obtained has substantially the same density as the mineral support, for example 0.33 g/ml in the case of silica gel, i.e. higher than that of chitosan (0.24 g/ml). Compared with chitosan alone, it has decisive advantages from the point of view of industrial application, namely: It is generally as active in enzymatic units per gram of dry weight as chitosan alone. This is explained by the fact that the active sites of the chitosan are better utilised because they are distributed over the surface of the particles. By virtue of its higher density, the volume which it occupies in a column is lower than that occupied by chitosan for the same weight or activity. The mineral core makes the catalyst much harder and more rigid and hence less compressible than chitosan. The catalyst is suitable for use in a fluidised bed which is compatible with industrial application. During fluidisation, the substrate may be converted by using high throughputs. The treatment of biological fluids (for example milk, whey, etc.) or fluids containing suspended colloids involves far less risk of clogging than fixed-bed treatment. Attempts to fluidise chitosan have been made, but without any success. Aggregates are formed and channelling occurs. The use of chitosan in a fixed bed also involves problems. When the throughput increases, the chitosan, because of its low density, tends to rise and to collect at the column outlet. The internal pressure increases and the process intensifies, resulting in a paid reduction of throughput and in clogging of the column. Another advantage of fluidisation lies in the fact that the particles of catalyst are in a state of permanent agitation in the substrate. Because of this, problems of diffusion are limited and enzymatic activity is maximal. Handling is much easier than with chitosan. The particles coated with chitosan are stabilised with a bifunctional reagent preferably selected from linear dialdehydes. The bifunctional reagent may be, for example, malonaldehyde, succinaldehyde, glutaraldehyde, adipaldehyde. It is preferred to use glutaraldehyde which has the advantage of being a readily available commercial product. The object of this operation is to "stabilise" the chitosan and/or to form a network of polymer around the layer of chitosan in order to fix it to the mineral core and to prevent the mineral core from peeling. DETAILED DESCRIPTION OF THE INVENTION In a first embodiment of the process which may be used when the enzyme is not sensitive to glutaraldehyde, i.e. does not lose its catalytic properties in the presence of glutaraldehyde, the support is introduced into an aqueous solution of glutaraldehyde having a concentration of up to 25% by weight. Enzymes which are not sensitive to glutaraldehyde include those which do not contain a thiol group in their active site. The treatment is preferably carried out at ambient temperature at a pH value in the range from 2 to 8, preferably in a buffer solution. The duration of the treatment depends upon the concentration of glutaraldehyde and generally amounts to between 31 minutes and a few hours. The whole is left to react, preferably in the absence of air, for example in vacuo, and the excess glutaraldehyde is eliminated by washing with water. The concentration and the reaction time are such that the surface of the support is covered with aldehyde groups chemically bound thereto, the fixed glutaraldehyde making up from 0.5 to 5% of the weight of the support, for example when the support is a silica gel. The support is thus stabilised. The enzyme containing functional groups capable of reacting with the free aldehyde groups of the stabilised support, for example the free amino groups carried by the lysine bonds, is then fixed by bringing the activated support into contact with an aqueous solution of the enzyme. The pH value of the enzyme solution has to be kept in the stability range of the enzyme used, for example by means of a suitable buffer solution. The reaction normally takes place at ambient temperature, a low temperature only having to be maintained in the case of sensitive enzymes. The non-fixed enzyme is then eliminated by washing with a buffer solution. To obtain a particularly stable catalyst, which is preferred when the catalyst is used in the form of a fluidised bed, the support already loaded with the enzyme may be subjected to an additional treatment with a bifunctional reagent, preferably glutaraldehyde, for example in the form of an aqueous solution having a concentration of up to 25% by weight. The effect of this additional treatment is to crosslink the whole and also to strengthen the bond between the enzyme and the support. A second embodiment of the process is carried out in cases where the enzyme loses its catalytic properties in the presence of glutaraldehyde, for example in the case of a yeast lactase containing thiol groups sensitive to oxidising agents. The support coated with chitosan and crosslinked as described above is treated by introduction into a solution containing from 0.01 to 1% by weight of glutaraldehyde and by reacting the free aldehyde groups with a compound containing an amine group, such as glycine, asparagine or lysine or, preferably, by reducing the free aldehyde groups, with sodium borohydride for example. After the aldehyde groups have been inactivated, the support is brought into contact with an enzyme, for example a yeast lactase, previously protected at the active site by a competing inhibiting compound, such as for example galactono-γ-lactone or glucono-γ-lactone in a concentration of from 20 to 50 mg/ml of reaction medium. This protective sugar does not affect the adsorption of the enzyme onto the support and is freed by an excess of lactose. The treatment is carried out in a suitable buffer solution, generally at a low temperature, for example in the range from 2 to 10° C., over a period of from 30 minutes to 24 hours, and the excess of enzyme is removed by washing with a buffer solution and then with water. In order to increase the stability of the enzyme, the enzyme is preferably bound chemically to the chitosan through a coupling agent, such as for example a carbodiimide or Woodward's reagent, 3-(2-ethyl-5-isoxazolo)-benzene sulphonate, which is capable of activating the carboxyl groups of the enzyme and of making them react with the free amino groups of the chitosan. The reaction takes place over a period of 1 to 48 hours at a temperature of from 2 to 25° C. and at a pH value kept in the range from 4 to 6.5 using from 10 to 50 mg of carbodiimide per ml of reaction medium. On completion of the reaction, the excess reagent and the urea produced by the reaction are removed by washing with a suitable buffer solution and then with water. Alternatively, instead of working in stages, the support, the inhibiting compound, the enzyme and the carbodiimide may be contacted at one and the same time. The product obtained by the process according to the invention has an enzymatic activity approaching that of the corresponding free enzyme - a property which is rarely preserved in conventional fixing processes. In addition, the product remains stable for several months and has a higher inactivation temperature than the corresponding free enzyme. As mentioned above, the product obtained by the process according to the invention may be used in enzymatic reactions instead of the corresponding free enzyme either in the form of a fixed bed (column) or, preferably, in the form of a fluidised bed. Its use in the food industry should not present any problems because chitosan is a natural organic substance. EXAMPLES The process according to the invention is illustrated by the following Examples in which the quantities and percentages quoted are by weight unless otherwise indicated. EXAMPLE 1 Loading of the support with chitosan 8 g of chitosan are dissolved in 300 ml of concentrated acetic acid and 400 ml of water. The mixture is stirred for 1 hour at 40° C. and then filtered through a cloth filter (106 μm) to eliminate the undissolved residues. The chitosan solution is placed in a desiccator and 120 g of a silica gel, particle diameter d p 100-125 μm, pore volume 1.2 ml/g, specific surface 320 m 2 /g) are added to it with gentle stirring which produces some foam. The resulting suspension is then left standing in a vacuum until the foam disappears. After leaving the mixture to stand overnight, the liquid is decanted and the silica gel coated with chitosan is recovered by filtration. After the silica gel has been gently washed with water, the support is oven-dried in vacuo overnight at a temperature of 70° C. Preparation of a stabilised immobilisation support 120 g of the above support (silica gel coated with chitosan) are introduced into a desiccator with 1600 ml of an aqueous solution containing 200 ml of a 25% glutaraldehyde solution. The suspension is gently stirred and then placed under a vacuum. After degassing, the suspension is left standing at atmospheric pressure for 2 hours during which it is periodically subjected to gentle stirring. The support is thus activated, which is reflected in a change in its colour from white to yellow-orange. The support is recovered by filtration and then carefully washed with water. Immobilisation of invertase on the stabilised support A solution of 15 mg of invertase (Maxinvert 200,000, a product of Gist-Brocades NV) in 100 ml of water is prepared and the pH value adjusted to 4 with a 0.1 M solution of HCl. 30 ml of this solution are mixed with 3 g of moist activated support prepared as described above. After the suspension has been gently stirred for 2 hours, the catalyst is recovered by filtration. The quantity of active enzyme is determined by measuring the hydrolytic activity on cane sugar. The 30 ml of initial solution contain 4.5 mg of invertase, the filtrate after fixing 0.48 mg and the catalyst 4.02 mg. The immobilisation yield amounts of 89%, no loss of activity during this process being detactable. EXAMPLE 2 Re-treatment of invertase 15 g of the moist catalyst prepared in accordance with Example 1 and containing 16 mg of active invertase is treated for 2 hours with a 1% solution of glutaraldehyde, the mixture being gently stirred, and the catalyst is recovered by filtration. After washing, the activity of the catalyst measured as described in Example 1 corresponds to 14 mg of active invertase, representing a yield of 87%. EXAMPLE 3 Immobilisation of a fungal lactase on a stabilised support 28 g of moist support activated in accordance with Example 1 are introduced into a glass column having a diameter of 2.5 cm and a height of 20 cm. The column is part of a recycling system equipped with an adjustable peristaltic pump and with a reservoir of which the contents are stirred by a magnetic stirrer. The inlet of the pump is connected to the reservoir whilst its outlet is positioned at the base of the column. The outlet at the head of the column returns the medium to the reservoir. This system is filled with 120 ml of an acidified aqueous solution having a pH value of 4. The pump is adjusted until the support is fluidised to a maximum height of 15 cm in the column. 0.6 g of lactase of Aspergillus niger (Rapidase, France, 200,000 units/g) are dissolved in the reservoir with the recirculation system in operation and the support is left in the fluidised state for 2 hours. Activity analysis carried out as described in Example 1 shows that 72% of the activity is present on the support whilst 20% remains in the filtrate after filtration and washing of the catalyst. EXAMPLE 4 Re-treatment of the immobilised fungal lactase 10 g of the moist lactase catalyst prepared in accordance with Example 3 are mixed with 50 ml of an aqueous solution containing 5% of glutaraldehyde and adjusted to a pH value of 4. This mixture is periodically stirred and the catalyst is recovered by filtration after 2 hours. Analysis of the activity of the catalyst (by hydrolysis of lactose) before the re-treatment indicates an activity corresponding to 21 mg of lactase preparation (Rapidase, France, 200,000 units per gram) per gram of moist catalyst whereas, after the retreatment, an activity corresponding to 19 mg per gram of moist catalyst is measured. This corresponds to a 90% preservation of activity. EXAMPLE 5 Immobilisation of trypsin on a stabilised support 1 g of silica gel coated with chitosan (as in Example 1) is suspended in 20 ml of sodium acetate buffer (0.5 M; pH 6.0). 5 ml of glutaraldehyde (25% aqueous solution) previously diluted in a ration of 1:1 with the same buffer are then added. This activating treatment is continued for 30 minutes with gentle stirring at ambient temperature (25° C.). The material thus activated is washed several times with distilled water to eliminate the residual glutaraldehyde. 50 mg of crystallised bovine trypsin (Merck) are dissolved in 20 ml of sodium borate buffer (0.1 M; pH 8.0) containing calcium chloride (20 mM). The trypsin solution is then added to the chitosan-coated silica gel prepared before hand. The whole is then left standing overnight at 4° C. with gentle stirring (rotary stirrer). The enzyme-coated support is then separated from the solution by centrifuging or filtration and washed several times in succession with a) sodium borate buffer (0.1 M; pH 8.0) containing sodium chloride (0.15 M), b) sodium borate buffer (0.1 M; pH 8.0) and c) distilled water until the adsorption at 280 nm (UV spectrometer) of the wash waters is zero. The enzymatic activity of the soluble trypsin is determined using as substrate N-α-benzoyl-L-arginine-p-nitroanilide (L-BANA) hydrochloride in a concentration of 1 mM in (tris-hydroxymethyl-aminomethane)-HCL buffer (50 mM; pH 8.0) at a temperature of 25° C. The p-nitroaniline released by the enzymatic hydrolysis reaction is determined by UV spectrophotometry at 405 nm. 1 unit of trypsin activity (1IU) corresponds to the quantity of enzyme which releases 1 micromole of p-nitroaniline per minute under the prevailing conditions. The activity of the immobilised trypsin is determined by the same method, but in a stirred bed, using an intermittent measuring apparatus similar to that described in Methods in Enzymology, 44, 344-345 (1976). The quantity of enzyme fixed to the support is indirectly obtained by calculating the difference between the quantity of enzyme initially added and the quantity of enzyme which remains unfixed on the basis of the protein concentrations determined by the Folin-Lowry method (J. Biol. Chem. 193, 265, 1951). The preparation obtained contains 35.2 mg of trypsin per gram of support and has an enzymatic activity of 72 international units (IU) per gram of support. The fixing yield amounts to 63.7%. The specific activity of the immobilised trypsin amounts to 2.04 IU/mg of immobilised enzyme wheras the specific activity of the soluble enzyme amounts to 2.26 IU/mg. EXAMPLE 6 Stabilisation of the support for the immobilisation of enzymes sensitive to glutaraldehyde 40 g of support coated with chitosan in accordance with Example 1 are dispersed in 150 ml of potassium phosphate buffer (50 mM; pH 6.5). 1.5 ml of glutaraldehyde (25% aqueous solution, Fluka AG, pract.) are added and the whole left to react for 30 minutes at ambient temperature with gentle rotary stirring. The support is then separated from the solution by filtration (50 μm mesh metal screen) or centrifuging and is then washed repeatedly with distilled water. The support is re-suspended in 150 ml of the above-mentioned buffer. 500 mg of solid sodium borohydride are added in portions. The whole is then left to react for 30 minutes under the same conditions. The support is recovered by filtration, washed with distilled water, centrifuged and then used for the immobilisation of enzymes as described in Examples 7 and 8 below. EXAMPLE 7 Immobilisation of a neutral yeast lactase by adsorption 40 g of support stabilised in accordance with Example 6 are dispersed in 150 ml of potassium phosphate buffer (50 mM; pH 6.5) containing 0.1 mM of manganese chloride and 0.02% of sodium oxide. D-galactono-γlactone (Kock-Light Lab.) is added in a final concentration of 0.1 M. The pH value of the medium is adjusted to 6.5 if necessary. 6 ml of a solution of yeast lactase (Maxilact LX 5000, a product of GistBrocades NV) are then added, after which the medium containing the enzyme and the support is stirred for 16 hours. The support is separated from the medium by filtration and then washed successively with 500 ml of potassium phosphate buffer (50 mM; pH 6.5) and 0.1 mM manganese chloride; 500 ml of the same buffer additionally containing 50 mM of potassium chloride; distilled water (3 x 500 ml). The support having lactase activity is stored in the buffer first mentioned (phosphate-manganese-azide). The soluble and the immobilised enzymatic activity are determined by UV spectrophotometry using as substrate a 5 mM solution of o-nitrophenyl-β-galactopyranoside (ONPG) at 30° C. The o-nitrophenol released by the enzyme is determined at 405 nm (ε M θNP:1097 M -1 cm -1 at pH 6.5). The activity of the immobilised enzyme is determined as described in Example 5 using the abovementioned substrate. One internal unit (IU) of lactase activity corresponds to the release of one micromole of o-nitrophenol per min. under the conditions indicated. The immobilised lactase has an activity of 423 IU/g of dry support. EXAMPLE 8 Immobilisation of a neutral yeast lactase by covalence The enzyme adsorbed in accordance with Example 7 may be fixed more firmly to its support by an additional treatment with carbodiimide. After the lactase and its support have been in contact for 30 minutes under the conditions described in Example 7, 2.5 g of carbodiimide 1-cyclohexyl-3-(2-morpholinoethyl)-carbodiimide of metho-p-toluidene sulphonate (Sigma Chemicar Co.) are added in small portions with stirring (rotary stirrer), the pH-value being kept at 6.5 first for 2 hours at ambient temperature and then for 16 hours at 4° C. Washing is then carried out in the same way as in Example 7. The lactase activity of the support determined as in Example 5 amounts to 285 IU/g of dry support. EXAMPLE 9 Hydrolysis of whey Deproteinised whey is pumped upwards at 50° C. through the column according to Example 3 filled with catalyst re-treated in accordance with Example 4. An 18% reduction in the activity of the catalyst is observed during the first 12 hours. After this initial reduction, it was found by analysis after one week that the activity of the catalyst remains stable under the treatment conditions specified above. EXAMPLE 10 Continuous hydrolysis of skimmed milk 90 ml of a biocatalyst suspension according to Example 8 are introduced into a 2.5 cm diameter column. The height of the enzyme bed is 18.3 cm. Sterilised (UHT) skimmed milk is pumped upwards through the column at a rate of 180 ml per hour. Under these conditions, the enzyme bed is fluidised and reaches a height of 25.5 cm. The temperature of the system is kept at 6.2° C., the degree of hydrolysis of the lactose amounting to 92%. After 275 h continuous operation (except for a few hours washing with a suitable detergent every 2 to 3 days), the residual activity of the catalyst is 85% of its initial activity. | Summary: Enzymatic catalysts are produced from mineral particles coated with chitosan. The enzymes may be directly absorbed onto the surface after a cross-linking treatment to stablize the coating or immobilized by chemical bonds after a treatment with a bifunctional reagent, for example with glutaraldehyde. The stability of the biocatalyst is advantageously increased by retreatment with a bifunctional reagent after immobilization of the enzyme. Enzymes sensitive to glutaraldehyde are fixed by a carbodiimide. The catalysts thus prepared are insoluble in aqueous solutions. The particles are rigid and incompressible and are suitable for use in fixed-bed and fluidized-bed reactors. The immobilization yield may reach 90% depending on the circumstances. | 6,040 | 176 | big_patent | en |
Write a title and summarize: SECTION 1. EXCEPTIONS FOR SHORT-SUPPLY SITUATIONS. (a) In General.--Chapter 1 of subtitle C of title VII of the Tariff Act of 1930 (19 U.S.C. 1675) is amended by adding at the end the following new section: ``SEC. 752. EXCEPTIONS FOR SHORT-SUPPLY SITUATIONS. ``(a) In General.-- ``(1) Petition.--If a short-supply petition is filed under this section and the administering authority determines that a short-supply situation exists with respect to a particular product which is within the same class or kind as merchandise that is the subject of an order or finding described in paragraph (2), the administering authority shall suspend the order or finding and shall authorize the importation of additional quantities of the product free of duties, estimated duty deposits, reporting requirements, or other restrictions, unless the administering authority determines that such imports will erode the pricing structure of the domestic merchandise that is comparable to the class or kind of merchandise subject to an order or finding. ``(2) Order or finding.--An order or finding described in this paragraph is-- ``(A) an antidumping order issued under section 736, ``(B) a finding issued under the Antidumping Act, 1921, or ``(C) a countervailing duty order issued under section 706 or 303. ``(b) Factors.--In determining whether a short-supply situation exists in the United States with respect to a product, the administering authority shall consider all relevant factors, including-- ``(1) if there is domestic production of the product with respect to which the short-supply petition has been filed; ``(2) to the extent information is available, the recent levels of capacity utilization of domestic facilities producing the product; ``(3) the quantity of the product requested in the short- supply petition and the ability of domestic producers to supply the product in such quantity; ``(4) the reasonableness of the specifications requested by the purchaser or end-user of the product; and ``(5) the time the product can be delivered to the purchaser or end-user. ``(c) Procedures.-- ``(1) Petitions.--An interested party may file with the administering authority a petition requesting a determination under this section at any time an order or finding described in subsection (a)(2) is in effect. The petition shall be in such form and contain such information as the administering authority requires. ``(2) Publication.--If the administering authority finds that a petition filed under paragraph (1) contains adequate information, the administering authority shall promptly publish in the Federal Register a notice that a determination under this section is under consideration. ``(3) Comment.--The administering authority shall provide opportunity for comment by interested parties regarding issues raised in the petition. ``(4) Certification.--The petitioner and any interested party submitting information shall certify that the information contained in the petition (or submission, as the case may be) is accurate and complete to the best of the petitioner's or party's knowledge. ``(5) Consultations.--In making a determination under this section, the administering authority shall consult with domestic users of the product. ``(d) Determination.-- ``(1) In general.--In any case in which the administering authority finds that a short-supply petition contains adequate information, the administering authority shall determine, not later than the day specified in paragraph (2)-- ``(A) if a short-supply situation exists in the United States with respect to the product; and ``(B) if the determination under subparagraph (A) is affirmative, the quantity of the product, if any, that may be imported into the United States without regard to the antidumping or countervailing duty order that would otherwise apply. In making the determination under this subparagraph, the administering authority may consider whether allowing particular quantities of the product to be imported without regard to the antidumping or countervailing duty order will erode the pricing structure of the domestic merchandise that is comparable to the class or kind of merchandise subject to an order or finding. ``(2) Time limit for making short-supply determination.-- The administering authority shall make a determination described in paragraph (1) not later than-- ``(A) the 15th day after the date the petition is filed if-- ``(i) the administering authority authorized the importation of additional quantities of the product during each of the 2 years preceding the date the petition is filed, or ``(ii) the administering authority finds, on the basis of available information (without regard to whether such information is available as part of the petition under review), that the product is not produced in the United States; or ``(B) the 30th day after the date the petition is filed if clause (i) or (ii) of subparagraph (A) does not apply, except that if a petition under this section is received more than 30 days before the issuance of an antidumping or countervailing duty order with respect to the product, the administering authority may make a short-supply determination at the time and as part of such order. ``(3) Rebuttable presumption.--If a petition is filed under this section, there shall be a rebuttable presumption that the short-supply situation alleged in the petition exists. ``(4) Short-supply allowance upon failure of a domestic producer to supply.--If the administering authority determines that a short-supply situation does not exist because a producer in the United States states that it is willing and able to supply the product in the quantity requested at the specifications, price, and delivery date requested, and the producer fails to supply the product as promised, the administering authority shall, within 3 days of being notified of the failure, grant a short-supply allowance for the quantity the domestic producer failed to supply. ``(e) Notice.--The administering authority shall publish in the Federal Register notice of each determination made under this section and the reasons therefore. ``(f) Definitions and Special Rules.--For purposes of this section: ``(1) Interested party.--The term `interested party' means-- ``(A) a United States producer or consumer of the product; ``(B) a United States importer or distributor of the product; and ``(C) a foreign exporter or producer who will supply the product to a United States producer, consumer, importer, or distributor. ``(2) Product.--The term `product' means the product for which a short-supply allowance is requested, or material which possesses the same physical characteristics and performance standards and which can be used for the same application without imposing any significant alteration costs for the consumer. ``(3) Reasonable specifications.--The term `reasonable specifications' means specifications that are developed in the ordinary course of business. The administering authority shall apply a rebuttable presumption that specifications are reasonable whenever such specifications have been in use either-- ``(A) prior to the filing of an antidumping or countervailing duty petition; or ``(B) more than two years. ``(4) Erode the pricing structure.--The term `erode the pricing structure' means United States prices for the domestic merchandise comparable to the class or kind of merchandise subject to an order or finding will be suppressed by reason of the importation of specified quantities of the product pursuant to a short supply allowance. The Secretary shall apply a rebuttable presumption that the imported product will not erode the pricing structure of the comparable domestic merchandise whenever-- ``(A) no United States producers have produced a product meeting the reasonable specifications within the last six months, nor have any United States producers either qualified to supply products meeting such specifications (if such qualification is normally required) or signed contracts that would require the delivery of such products within the next six months; or ``(B) domestic consumption of the product exceeds domestic production by more than fifty percent, and the quantity of product covered by a short supply determination is less than half of the difference between domestic consumption and domestic production. In considering whether a short-supply determination would erode the pricing structure, the administering authority shall consider, among other factors-- (A) the quantity of short supply relief approved within the applicable class or kind of merchandise; and (B) the interchangeability between products subject to short-supply determinations and other products within the applicable class or kind of merchandise. ``(5) Short-supply allowance.--The term `short-supply allowance' means an authorization by the administering authority to permit importation into the United States, including a foreign trade zone, of a quantity of product free of duties imposed pursuant to an antidumping or countervailing duty order issued under this title.''. (b) Clerical Amendment.--The table of contents for title VII of the Tariff Act of 1930 is amended by inserting after the item relating to section 751 the following new item: ``Sec. 752. Exceptions for short-supply situations.''. | Title: To amend the Tariff Act of 1930 to provide relief from antidumping and countervailing duty orders in cases of short supply Summary: Amends the Tariff Act of 1930 to require the administering authority, whenever it has determined upon the filing of a short-supply petition that a short-supply situation exists with respect to a particular product within the same class or kind as merchandise that is the subject of an antidumping duty order or finding, or a countervailing duty order, to authorize the importation of additional quantities of such merchandise free of duties, estimated duty deposits, reporting requirements, and other restrictions, unless it determines that such imports will erode the pricing structure of domestic merchandise comparable to the class or kind of merchandise that is subject to such order or finding. Requires the administering authority, whenever it finds that a short-supply petition contains adequate information, to determine: (1) if a short-supply situation exists in the United States with respect to a product; and (2) if an affirmative determination is made, the quantity of the product, if any, that may be imported into the United States without regard to the applicable antidumping or countervailing duty order. Requires the administering authority, if it determines that a short-supply situation does not exist because a U.S. producer states that it will supply the product in the quantity requested, and such producer fails to supply such product as promised, to grant a short-supply allowance for the quantity such producer failed to supply. | 2,139 | 346 | billsum | en |
Summarize: Two policemen have been charged with brutally beating a man, leaving him with broken bones and needing stitches, after his girlfriend found a video which showed they had savagely attacked him. Najee Rivera was left covered in blood and with an eye swollen shut after police claimed they had been forced to restrain him after he slammed one into a wall when they pulled him over in North Philadelphia. Officers had believed Kevin Robinson and Sean McKnight's version of events until Mr Rivera's girlfriend investigated the incident herself and found it was in fact the two police officers, rather than her boyfriend, who had been violent. Najee Rivera was left bruised after he was beaten by two police officers who stopped him in Philadelphia and falsely claimed he had been violent, until Mr Rivera's girlfriend found a video proving police attacked him. Both have been charged with aggravated assault, conspiracy and related crimes. The video, found by Mr Rivera's girlfriend Dina Scannapieco at a barber's shop, showed the two policemen punching and using batons to beat the 23-year-old, the Inquirer reported. Police admitted the incident had not been investigated and the two officers had been believed without question. They may now review the way they deal with situations where someone arrested has been injured. On May 29, 2013, Mr Rivera was pulled over by police for for running a stop sign on his scooter near Seventh and Cambria Streets in Fairhill. Seeing the two officers armed with batons, he fled and they chased him. On the 2700 block of North Sixth, a surveillance camera caught them knocking Rivera from his scooter, then grabbing and hitting him with fists and batons. During the video Mr Rivera's screams can be heard. The officers had claimed that Mr Rivera had fled after being stopped and then lost control of his bike, falling off in North Sixth. They then said he had slammed Robinson against a wall and attacked them 'with elbows.' He was then taken to Episcopal Hospital and the two officers' filed charges against him for assault and resisting arrest. Kevin Robinson (left) and Sean McKnight (right) have been charged with aggravated assault and suspended. Mr Rivera was left needing stitches to his face and with a broken bone in his eye socket. But when Miss Scannapieco went to the hospital and found her boyfriend beaten and covered in blood she did not believe the police's version and decided to turn detective herself. She went back to the 2700 block of North Sixth and found her boyfriend's blood covering the pavement. After asking around she managed to get hold of a surveillance video from a barber's shop which showed the brutal attack by the two officers. They eventually handed themselves in and were suspended from duty and are likely to be dismissed. District Attorney Seth Williams said: 'This type of behavior has absolutely no place in our city, and I will prosecute these two officers to the fullest extent of the law.' In August 2013 all the charges against Mr Rivera were dropped. Police Commissioner Charles Ramsey said before the video surfaced the officers' version of events had been accepted without question. He admitted the department should have investigated the area after the incident - a process which usually only takes place after an internal complaint is made. He said McKnight and Robinson do not represent the majority of officers on the 6,500-strong force. But, he admitted, he could not guarantee all officers stick within the parameters of the law. He said: 'We've got to root them out.' Mr Rivera said he has struggled to move on since the attack and had lost his job. He added: 'Every time I get next to a cop or a cop is behind me, I get a little panic attack. And it's sad, because every cop ain't bad.' Public Defender Bradley Bridge said his office is now to review arrests made in the past in light of the charges against the two officers. In 2012, Robinson was accused of beating 28-year-old Darren Trammell during an arrest. Robinson was cleared by the Internal Affairs department but months later Trammell was also cleared of any wrongdoing. The city settled the case for $125,000 | Summary: Najee Rivera was arrested by police in 2013 and was left badly bruised. Officers claimed he had resisted and slammed one into a wall on arrest. But Mr Rivera's girlfriend did not believe her partner had attacked an officer. She went back to scene in Philadelphia and found his blood on pavement. A surveillance video captured the officers beating Rivera with their batons. Both charged with aggravated assault and conspiracy for the assault. Police said they should have investigated how Rivera came to have broken bones and bruising after arrest and will change the approach to incidents. | 948 | 128 | cnn_dailymail | en |
Summarize: SACRAMENTO (CBS13) — Wal-Mart is facing questions tonight after CBS13 learns the company draws its bottled water from a Sacramento water district during California’s drought. According to the label, the water comes from the Sacramento Municipal Water Supply. This comes on the heels of Starbucks opting to move sourcing and production of its Ethos bottled water from California to Pennsylvania. While the label reads Great Value, the fine print reveals the bottled water is anything but a deal, especially for Sacramento residents. “Either they were unaware, uninformed or unintentionally did this,” said public relations expert Doug Elmets. “It could be all three of those. Whatever it is, it’s a bad move and they need to correct it and they need to do it quickly.” RELATED: Visit California Drought Desk for complete drought coverage According to its own labeling, the water in the gallon jugs appears to come from Sacramento’s water supply. Sacramento sells water to a bottler, DS Services of America, at 99 cents for every 748 gallons—the same rate as other commercial and residential customers. That water is then bottled and sold at Walmart for 88 cents per gallon, meaning that $1 of water from Sacramento turns into $658.24 for Walmart and DS Services. For comparison, the city of Sacramento says the average family uses 417 gallons of water a day. Elmets wonders if this perfectly legal business operation will get a big thumbs-down from California consumers. This comes as Sacramento-area water districts are preparing to enforce residential water-use cuts as high as 36 percent. “It’s certainly leaving a bad taste in everyone’s mouth when you can’t fill up a swimming pool, if you’re building a new home in West Sacramento; you can’t water your lawn if you’re living in this region. And to find out they’re making a huge profit off of this, it’s just not right,” Elmets said. RELATED: Simple Water-Saving Tips He says Wal-Mart should take a page out of Starbucks’ game plan. The coffee giant moved production of Ethos bottled water after news its water was pumped out of Placer County and bottled in Merced. “The reaction should be immediate. And that is to find another supplier outside of California that can be able to meet the needs that they have and also the needs of the consumer,” he said. Wal-Mart sent a statement reading in part, “We have and continue to work with our suppliers to act responsibly while meeting the needs of customers who count on us across California.” CBS13 contacted the Sacramento water district on Friday, but were told its media specialist will get back to us next week. Bay Area & State Crystal Geyser to tap Siskiyou County groundwater Photo: Michael Macor, The Chronicle Shara Fish of Mount Shasta carries bottles filled with spring water from the headwaters of the Sacramento River in Mount Shasta, Calif., on Tues. April 28, 2015. Crystal Geyser is opening a bottling plant nearby without any environmental review or limits at a time when everyone else in the state is being asked to drastically cut water use. California's non-existent laws on groundwater use allow this. Shara Fish of Mount Shasta carries bottles filled with spring water... A private water bottling company will soon be sucking up thousands of gallons a day from an aquifer that feeds the Sacramento River, the primary source of drinking water for millions of thirsty Californians struggling to cope with a four-year drought. Residents who have faced increased water use limits amid fourth year of drought push for greater regulation of water-bottling industry Walmart is the latest company found to be sourcing its bottled water from drought-stricken California, as state residents push for greater regulation of the bottling industry. Starbucks was moved to alter its bottling practices in California last week and Mount Shasta community members are fighting the opening of a major bottling plant by California-based company Crystal Geyser. Then on Friday, an investigation by CBS13 in Sacramento found that Walmart’s bottled water comes from the Sacramento municipal water supply. The revelations come as state residents face increased water use limits during the fourth year of drought in the state. State governor Jerry Brown signed an executive order last week that calls for a 25% urban water reduction across the state. “It’s only logical that as the governor has asked all Californians to reduce their water consumption that he holds extractive industries like bottled water companies to the same standard, yet he hasn’t asked anything of them,” said Adam Scow, the California director of Food & Water Watch, which is calling for a moratorium on bottling water. There is little oversight or monitoring of bottling plants in the state, which are also operated by major corporations including Nestle, Coca-Cola and Pepsi. About 1% of state water is used in industry, and the bottling industry represents an even smaller fraction of that, according to the US Geological Survey. Walmart, like other large companies, draws water from municipal supplies to keep costs down. A Walmart spokesperson said that the company is “very concerned” about how the drought is affecting its customers and associates. “We share those concerns and are tracking it closely,” the spokesperson said. “Our commitment to sustainability includes efforts to minimize water use in our facilities. We have and continue to work with our suppliers to act responsibly while meeting the needs of customers who count on us across California.” Starbucks was pushed to stop sourcing its Ethos bottled water from California after Mother Jones discovered that it had been drawing water from Placer County. Starbucks said it would move production to a supplier in Pennsylvania over the next six months. It is also looking for alternative suppliers for its west coast distribution. “At the end of the day, bottling the public’s water for private profit is not in the public interest,” said Scow. He said the practice has a negative effect on local watersheds, that the oil and energy used to make plastic bottles and transport them across the nation are harmful to the environment and that there is a huge waste problem with plastic bottle disposal. Crystal Geyser, a bottled water company headquartered in San Francisco, announced it is opening a new plant near Mount Shasta, which feeds water into the Sacramento River. The company does not need to obtain a permit to draw the water and there is not a requirement to conduct an environmental impact report. Raven Stevens, community liaison for the Gateway Neighborhood Association, told the San Francisco Chronicle that the top concern is that there is little regulation for bottling plants. “Crystal Geyser in one day plans to pump more water than any three of my neighbors will use in an entire year,” Stevens said. “The entire state is under a 25% cut, farmers are letting fields go fallow and we don’t have one piece of legislation regulating water bottling.” | Summary: First Starbucks, now Walmart is awash in complaints about its bottled water operation in Sacramento, which has been hard-hit by conservation measures amid California's drought. CBS13 reports the company's Great Value brand water comes from the Sacramento Municipal Water Supply and is sold to bottler DS Services of America at 99 cents per 748 gallons before it lands on Walmart's shelves with a price tag of 88 cents per gallon, earning the two companies $658.24 for those 748 gallons. Walmart tells the Guardian it is "very concerned" about the drought, but "our commitment to sustainability includes efforts to minimize water use in our facilities. We continue to work with our suppliers to act responsibly while meeting the needs of customers." Still, the transaction is "certainly leaving a bad taste in everyone's mouth," a PR expert says. "You can't water your lawn if you're living in this region. And to find out they're making a huge profit off of this, it's just not right." Though the US Geological Survey notes the bottling industry uses less than 1% of state water, some say the plants aren't properly monitored. "The entire state is under a 25% cut, farmers are letting fields go fallow, and we don't have one piece of legislation regulating water bottling," a rep for the Gateway Neighborhood Association tells the San Francisco Chronicle. Residents of Mount Shasta are now campaigning against a planned bottled water plant from Crystal Geyser, which doesn't need to submit an environmental impact report or a permit to tap the area's water. | 1,521 | 365 | multi_news | en |
Summarize: (CNN) Video from Las Vegas' Mandalay Bay resort -- from its valet area, elevators, restaurants, gambling floors and hallways -- show that in the days before Stephen Paddock committed the worst mass shooting in modern American history, he did nothing terribly remarkable. The gunman, who took his life after killing 58 people and wounding hundreds of others last year by spraying bullets from his 32nd-floor room, comes and goes from the hotel, each time returning with more suitcases and bags, video footage released by the hotel's parent company shows. Over seven days, Paddock, 64, also returns to his home in Mesquite, Nevada, and stops at The Ogden condominium complex, about 6 miles from the hotel, the paper reported. On two occasions, he is seen in a Mandalay Bay elevator, leaving the hotel with some of his rollaboards. JUST WATCHED FL shooting revives Vegas survivors' trauma Replay More Videos... MUST WATCH FL shooting revives Vegas survivors' trauma 03:10 During that week, Paddock or the hotel's bellmen tote 21 suitcases, two small bags, a laptop bag and a white container to his room, the perch from which he perpetrated his October 1 massacre on a country music festival across the street from the hotel, the video shows. Read More Hotel Releases Video Of Las Vegas Shooter In Days Leading To Massacre Hide caption Stephen Paddock shown at VIP check-in at the Mandalay Bay resort in Las Vegas on Sept. 25. Previous Next MGM Resorts International Hide caption Paddock shown at the casino slots at the Mandalay on Oct. 1, the day of the shooting. Previous Next MGM Resorts International Hide caption Paddock in an elevator at the Mandalay Bay on the Las Vegas Strip on Sept. 25. Previous Next MGM Resorts International Hide caption Paddock moving more suitcases to his room on Sept. 27. Previous Next MGM Resorts International Hide caption Stephen Paddock smiles as a valet helps him transport luggage to his hotel room on Sept. 26. Previous Next MGM Resorts International Hide caption Paddock shown in the Mandalay Bay hotel on Sept. 28, two days before the shooting. Previous Next MGM Resorts International 1 of 6 i View slideshow Stephen Paddock, the man who rained bullets down on a crowd of concertgoers last October, killing 58 people, appears in newly released surveillance video to be an ordinary hotel guest and casino patron in the days leading to the massacre. Video and stills provided by MGM Resorts International of the Mandalay Bay resort where Paddock stayed shows him checking in at the hotel lobby, escorted by a valet and gambling in the casino. He is also seen wheeling large suitcases into his room that contained the arsenal – in all, 23 assault-style rifles and a handgun – that were recovered from his room after the attack. Washington Post/MGM Resorts International YouTube Records show that Paddock made several trips between one of his homes, in Mesquite, Nevada, to the hotel, apparently to transport the weapons. All the while, his demeanor suggests no clue that on Oct. 1, six days after checking in, he would use his 32nd-floor suite as a perch from which to carry out the deadliest mass shooting in modern U.S. history. "In the interest of providing greater context around Stephen Paddock's actions in the days leading up to October 1, MGM Resorts has released these security videos and images," MGM said in a statement accompanying the release of the images. "As the security footage demonstrates, Stephen Paddock gave no indication of what he planned to do and his interactions with staff and overall behavior were all normal," it said. "MGM and Mandalay Bay could not reasonably foresee that a long-time guest with no known history of threats or violence and behaving in a manner that appeared outwardly normal, would carry out such an inexplicably evil, violent and deadly act." In addition to the 58 he killed, Paddock, a 64-year-old retired accountant and real-estate investor, wounded hundreds before police reached his room and found him dead from a self-inflicted gunshot wound. Police have been unable to develop a clear motive for the attack and the surveillance images released on Thursday appear only to deepen that mystery. Published on Mar 22, 2018 MGM Resorts released surveillance video of Stephen Paddock, who stayed at the Mandalay Bay Resort and Casino leading up to the shooting where he killed 58 people and wounded more than 500 on Oct. 1, 2017. Subscribe to The Washington Post on YouTube: http://bit.ly/2qiJ4dy Follow us: Twitter: https://twitter.com/washingtonpost Instagram: https://www.instagram.com/washingtonp... Facebook: https://www.facebook.com/washingtonpost/ | Summary: New surveillance video of Stephen Paddock in the days before he killed 58 people from his hotel room window in Las Vegas shows nothing out of the ordinary, and that's what troubles Randy Sutton. "A guy who can order lunch knowing that he's going to kill people... that's not normal," the retired Las Vegas Metropolitan Police Department lieutenant tells CBS News, adding that Paddock's calm demeanor "is the true mark of a sociopath." NPR reports MGM Resorts says it released the surveillance footage "in the interest of providing greater context around Stephen Paddock's actions" in the six days he was at the hotel and casino prior to the October shooting. "As the security footage demonstrates, Stephen Paddock gave no indication of what he planned to do and his interactions with staff and overall behavior were all normal," MGM Resorts says in a statement. The footage shows Paddock eating sushi, watching TV, visiting the hotel VIP desk, and gambling, appearing to prefer video screens to human opponents, CNN reports. Paddock is seen checking into his room, tipping hotel staff, and buying snacks. The footage from security cameras also shows Paddock repeatedly coming and going from his room with luggage. He brought 23 guns to the room in at least 22 pieces of luggage during his stay, but even then the footage shows him using different bellhops to avoid suspicion. The footage brings authorities no closer to discovering a motive for the shooting, and Sutton doesn't think they'll ever find one: "Why would a guy who supposedly has a fairly happy, successful life... has plenty of money, has a home, has a girlfriend... what goes on inside a brain like that that suddenly triggers a mass murder?" | 1,093 | 381 | multi_news | en |
Summarize: FIELD OF THE INVENTION [0001] The present invention generally relates to an improved comfort device to be used with a nasal mask. In particular, the device is useful in combination with masks which are used for the treatment of respiratory conditions and assisted respiration. The invention assists in fitting the mask to the face as well. BACKGROUND OF THE INVENTION [0002] Nasal masks are commonly used in the treatment of respiratory conditions and sleep disorders by delivering a flow of breathable gas to a patient to either assist the patient in respiration or to provide a therapeutic form of gas to the patient to prevent sleep disorders such as obstructive sleep apnea. These nasal masks typically receive a gas through a supply line which delivers gas into a chamber formed by walls of the mask. The mask is generally a semi-rigid mask which has a face portion which encompasses at least the wearer's nostrils. Additionally, the mask may be a full face mask. The mask is normally secured to the wearer's head by straps. The straps are adjusted to pull the mask against the face with sufficient force to achieve a gas tight seal between the mask and the wearer's face. Gas is thus delivered to the mask through the aperture to the wearer's nasal passages and/or mouth. [0003] One of the problems that arises with the use of the mask is that in order for the straps to be tight, the mask is compressed against the wearer's face and may push unduly hard on the wearer's nose. Additionally, the mask may move around vis-à-vis the wearer's face. Thus, there has been provided a forehead support, which provides a support mechanism between the mask and the forehead. This forehead support prevents both the mask from pushing too strongly against the wearer's nose and/or facial region as well as minimize movement of the mask with the addition of a contact point between the mask and the wearer's head as well as minimize uncomfortable pressure points of the mask. Additionally, the forehead support may prevent the air flow tube from contacting the wearer's forehead or face. [0004] Prior to the present invention, the forehead supports were generally a single cushion with a single contact point which may be adjustable by rotation of a screw, with the single cushion pushing on the forehead at a single point. This is oftentimes uncomfortable for the patient, and the adjustability of the distance of the pad for different forehead protuberances oftentimes was difficult if not impossible to be performed. Additionally, a single contact point does not provide necessary lateral support to the mask. Finally, a single contact point may apply too much pressure at the single point. [0005] Examples of prior art nasal masks are shown in U.S. Pat. Nos. 4,782,832 and 5,243,971. [0006] There is a need for an improved forehead support for nasal and facial masks which adjusts to different angles on the face. [0007] There is a need for a forehead support for nasal masks which may be adjusted to different forehead shapes. [0008] There is a need for a multi-point forehead support for nasal masks. [0009] These and other advantages will be described in more detail below. SUMMARY OF THE INVENTION [0010] The present invention is directed to an improved forehead support for nasal and facial masks. In particular, the present invention utilizes a dual cantilevered forehead-support which preferably utilizes dual contacts which are arranged at an obtuse angle with respect to one another and which may be easily adjusted for different forehead protuberances. Preferably, the forehead support has two arms extending from the mask or gas supply line, with the two arms engagable into a bridge system wherein the arms may be adjusted to different positions on the bridge allowing optimal positioning of the mask on the face. This achieves even pressure of the mask on the face. The mask also provides an excellent fit which limits movement of the mask during sleep. The forehead support is adjustable such that the support is closer or further away from the front plane of the facial mask. The bridge supports the pad or pads which contact the wearer's forehead. The support also may allow the mask to be secured such that more pressure is applied to one area of the mask, to seal a leak for example. [0011] The present invention allows the mask user to adjust the angle of the mask to the face. This is possible due to the two point contact of the forehead support to the forehead working in combination with the point of contact of the mask to the face. The system thus has three points of contact, wherein the forehead pads provide two contact points and the mask to the face is a third point of contact. Adjusting the angle of the forehead pads or the distance of the legs to the forehead pads adjusts the angle of the mask vis-à-vis the face of the user. This unique system provides a mask system which can be adjusted to fit the different face angles or profiles required by users. BRIEF DESCRIPTION OF THE DRAWINGS [0012] [0012]FIG. 1 is a perspective view of the forehead support of the present invention attached to a mask, headgear and a gas supply tube. [0013] [0013]FIG. 2 is a perspective view of the forehead support of the present invention removed from the mask and gas line. [0014] [0014]FIG. 3 is an exploded view of the forehead support of the present invention. [0015] [0015]FIG. 4 is a side view of the present invention secured to a mask. [0016] [0016]FIG. 5 is a top view of the forehead support of the present invention in a first position. [0017] [0017]FIG. 6 is a top view of the forehead support of the present invention in a second position. [0018] [0018]FIG. 7 is a top view of the forehead support of the present invention in a third position. [0019] [0019]FIG. 8 is a top view of the forehead support of the present invention in a fourth position. [0020] [0020]FIG. 9 is a front view of the bridge of the present invention. [0021] [0021]FIG. 10 is a single pad of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT [0022] [0022]FIG. 1 shows a general perspective view of the forehead support 10 of the present invention. The forehead rest or support 10 is attached to an extending airflow tube 12 from the mask 14. The mask 14 and forehead support 10 are shown with headgear 16 which secures the mask 14 to the head of a patient. The headgear 16 may take a variety of forms, with one example being shown as 16. As can be seen in FIG. 1, preferably the headgear 16 loops through the forehead support 10 at 18 and 20. This pulls the forehead support 10 against the forehead, thus creating a snugly fitted mask 14 and also provides a stabilizing member for the mask 14. [0023] The mask 14, shown in FIG. 1 is merely one example of a mask which can be used with a forehead support, but any respiratory mask could be used. A full face mask which may cover the entire face or just both the nose and mouth could be used, for example. Additionally, the airflow tube 12 could be extending from the bottom of the mask 14, thus the tube 12 supporting the forehead support 10 would terminate above forehead support 10. If the airflow tube 12 extended in a downward or other direction from the mask 14, then preferably a post would extend up from the mask 14 (this post position is referenced as 22 ). This post 22 would terminate slightly above where forehead support 10 is shown secured to tube 12. Thus the forehead support 10 would be secured to the post in this alternative embodiment. [0024] [0024]FIG. 2 discloses the preferred construction of the forehead support 10 of the present invention. The forehead support 10 has pads 24 and 26. These pads 24 and 26 are the actual contact points of the forehead support 10 to the forehead. Pads 24 and 26 are preferably made of a deformable elastomeric material which retains its original shape upon release of pressure and provides the wearer with increased comfort and stability. As can be seen in the preferred embodiment, the forehead pads 24 and 26 have an annular interior construction with two retaining walls 28 and 30. The retaining walls 28 and 30 provide structural integrity to the forehead contact support pads yet allow the pads to be deformed. The deformation preferably occurs by deflection of the pad walls. The pads also may be solid pads. The support pads 24 and 26 are mounted to the bridge 32. The bridge 32 provides basically three purposes to the forehead support 10. First off, it acts as a securing means for forehead pads or cushions 24 and 26. Second of all, it has annular spaces 18 and 20 which receive the optional headgear 16 shown in FIG. 1. Finally, it receives arms 34 and 36, which may be adjusted, as described below. The bridge 32 and arms 34 and 36 operate in a cantilever fashion and are preferably made of a polymeric material, which may be easily molded, preferably injection molded. Arms 34 and 36 are secured to bridge 32 by an adjustable locking mechanism which is better illustrated in the figures below. Additionally, arms 34 and 36 join together to create an annular space 38 which may receive airflow tube 12 which is preferably connected to a flow generator to generate breathable air or some type of therapeutic gas. Arms 34 and 36 preferably create an operational hinge. The tube 12 may be an axis of this hinge. The hinge could also be a flexible membrane and not a rotational or axial hinge. Alternatively, the tube may extend through annular space 38 and terminate as described above (in the “post” embodiment) if the air flow tube is connected to another port on the mask. [0025] [0025]FIG. 3 is an exploded view of FIG. 2 and shows the forehead support 10 in greater detail. FIG. 3 discloses how bridge 32 is configured such that forehead pads 24 and 26 may be secured thereto. In particular, tongues 40, 42, 44 and 46 all engage forehead pads 24 and 26 by entering the interior space of the pads. This is shown in FIG. 2 wherein tongues 42 and 46 are shown securing pads 24 and 26 respectively by entering the annular space of the pads 24 and 26. Additionally, there may be engaging surfaces such as 48, 50, 52 and 54, as shown in FIG. 3, which engage an inner side wall of forehead pads 24 and 26. The means by which the forehead pads are secured to the bridge 32 can be done in many manners, and one skilled in the art can come up with numerous methods of achieving this securement. Two sided tape may be used, protruding pegs and apertures on the forehead pad may be used or many other methods. What is desirable is that the forehead pad(s) may be replaced after extended use or, in a clinical setting, with each new patient. The method of securement of the pad(s) to the support is not a limiting feature of the present invention. [0026] The type of forehead pad may also vary, it may include a solid foam sponge, a stuffed pad, a dual durometer foam which may be a single pad or multiple pads attached together, or many other known pads which would impart comfort when placed directly on the forehead. Finally, a single pad which extends all the way across bridge 32 may be used or more than two pads may be used. [0027] Bridge engaging pins 56, 58, 60 and 62 are shown in FIG. 3. As will be more apparent in the figures below, these engaging pins provide for the adjustability of the forehead support 10 of the present invention. There are pin receiving means located on the bridge 32 which receive pins 56, 58, 60 and 62. The pins 56, 58, 60 and 62 are merely one example of how the arms 34 and 36 may be secured to bridge 32. There are other designs which would work just as well as the pin designs. Such designs are known to those skilled in the art. Additionally, there is a space or recess at arms 34 and 36 shown clearly on arm 34 as 64. The purpose of this space 64 is so that the user may compress arm 34 and thus press 56 and 58 together by pressing on surfaces 66 and 69. The purpose of the compression is such that the distance between prongs 56 and 58 is decreased and thereby they may be inserted and locked into bridge 32. The structure and method of this insertion will be described in further detail below. [0028] [0028]FIG. 4 is a side view of the mask 14 and forehead support 10 of the present invention. The mask is shown as 14 with a dotted line showing the nose of a wearer 70 and the dotted line showing the forehead 72 of the wearer. Pad 26 is shown compressed by the forehead of the individual wearing the mask. [0029] [0029]FIG. 5 is a top view of the forehead support 10 of the present invention taken along lines 5 of FIG. 4. Also, the mask 14 is not shown in FIG. 5. This figure illustrates the forehead support 10 in a position wherein the forehead support is the closest to the tube 12 (shown as merely a space in FIGS. 5 - 8 ). The bridge 32 is shown essentially in contact with tube 12. The pins 56, 58, 60 and 62 are shown in their furthest position from the center of the bridge 32. This position may be utilized by someone with a large, protruding or bulbous forehead, or a high nasal bridge, or someone who prefers the airflow tube to be snug against their forehead. [0030] [0030]FIG. 6 shows the same forehead support in the next position, wherein the bridge 32 is moved away from tube 12 such that there is a gap 74 between bridge 32 and tube 12. As is visible from the figure, the forehead support 10 is now moved further away from tube 12, and is positioned differently than in FIG. 5. This may be configured to fit someone with a less protruding forehead, or someone who wants the flexible tube further from their head than is possible in FIG. 5. [0031] [0031]FIGS. 7 and 8 show the third and fourth position for the forehead support of the present invention. Although the present embodiment shows a four-positioned forehead support, the number of slots, shown as 76, 78, 80, 82, 84 86, 88 and 90 may be varied. There may be more or fewer slots, or there may just be one single slot wherein pins 56 and 58 slides transversely across bridge 32 and has locking recesses located along the slide. Additionally, the adjustments do not have to be uniform. In other words, the right side may be adjusted to slot 88 where the left side may be adjusted to slot 84 for some particular patient. There may also be more slots or adjustments on one side of the bridge as compared to the other side of the bridge. Finally, the arms may be coupled such that movement of just one arm moves the other arm in a likewise manner. [0032] [0032]FIG. 9 shows an isolated view of bridge 32. The slots 76, 78, 82, 84, 86, 88 and 90 are visible from this view. The slots are configured such that prongs 56, 58, 60 and 62 may be inserted therein. There is a mirror set of slots on the upper portion of bridge 12 which are not visible in FIG. 9. Again, there can be additional slots, fewer slots, or different methods of locking the arms 34 and 36 to various positions along the bridge 32. What is important to the present invention is that the bridge 32 with the accompanying pads 24 and 26 may be positioned to a variety of distances between the tube 12 and the pads 24 and 26. Additionally, the pad may be one continuous pad, three pads, five pads, four pads, etc. There also may a double bridge used, wherein there could be a total of two or more pads with two bridges. [0033] [0033]FIG. 10 is a perspective view of the preferred forehead pad of the present invention. As indicated above, there could be many shapes or variations of a forehead pad and type of forehead pad or the shape of forehead pad is not limited in the present invention. [0034] It is to be understood that while the invention has been described above in conjunction with preferred specific embodiments, the description and examples are intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. | Summary: An adjustable forehead support for a nasal mask. The present invention discloses an adjustable forehead support for a nasal or full-face mask wherein the forehead support may be adjusted for the different shapes and sizes of a facial profile. The forehead support utilizes a dual-arm system which adjusts the position of the forehead support vis-à-vis the mask and/or air flow tube. The angle of the mask to the face may be adjusted with the present invention. | 4,422 | 107 | big_patent | en |
Summarize: BACKGROUND OF THE INVENTION During surgical procedures such as cardiopulmonary bypass operations it is possible to replace the function of the lungs with an extracorporeal blood oxygenator. Venous blood is passed in an extracorporeal circuit through the oxygenator, arterialized (i.e. oxygenated) and returned to the patient's body. One well known type of blood oxygenator is the bubble oxygenator in which treating gas (e.g. oxygen) bubbles are created and brought into direct contact with the venous blood stream, with resulting mass transfer of oxygen from the bubbles to the blood and of carbon dioxide from the blood to the bubbles. Although bubble blood oxygenators have been employed for many years with considerable success, their use is characterized by an inherent disadvantage, which is the need to create a blood foam to accomplish gas transfer. The bursting of gas bubbles into the blood stream during the creation of the foam may give rise to deleterious hemolysis. Furthermore, the blood foam must be thoroughly treated after oxygenation, typically in a defoamer and an arterial filter, to remove gaseous bubbles and emboli before the arterialized blood can be returned to the patient. Another well known type of blood oxygenator, the membrane oxygenator, does not require formation of a blood foam to accomplish gas transfer. Blood and treating gas streams flow in the oxygenator separated by a semipermeable membrane, through which oxygen passes to the blood, carbon dioxide passes from the blood, while water and other non-gaseous blood components do not pass. In designing a membrane oxygenator for use in typical extracorporeal circuits, it is a desired goal to provide adequate gas transfer capacity to process the anticipated blood flows (from about 2 liters/min. to about 6 liters/min.) while maintaining a compact size for convenient handling, priming and operation, avoiding excessive blood and treating gas pressure drops and preventing significant trauma to blood components. Blood membrane oxygenators of the general type having a pleated, semipermeable membrane held in a housing with support screens positioned in alternating blood and oxygen passageways are known (see, for example, U.S. Pat. Nos. 3,560,340; 3,612,281; 3,780,870 and 4,199,457). However, none of the membrane oxygenators disclosed in said U.S patents fully satisfy all of the criteria set forth above in the preceding paragraph. U.S. Pat. No. 4,028,252 discloses a blood dialyzer containing a single sheet of membrane and a single length of non-woven support material accordion-folded together to form alternating blood and dialysate flow paths separated by the membrane, with the support material being capable of interdigitation when folded upon itself. Accordingly, the support material is located on only one side of the membrane in this prior art dialyzer. U.S. Pat. No. 213,858 discloses the use of three-layer non-woven "supporting nets" in blood dialyzers and oxygenators, adjacent units of which are capable of interdigitation. However, even when such interdigitation occurs, the flow passageway defined by two portions of membrane separated by one of the supporting nets is at least about as thick as the middle layer of the supporting net and thus occupies more volume than desired in an extracorporeal blood oxygenator. SUMMARY OF THE INVENTION The present invention comprises a mass transfer device for the treatment of blood, e.g. a blood oxygenator or blood dialyzer, comprising a housing; a pleated, selectively permeable membrane disposed within the housing in substantially rectangular folds defining first and second sets of alternating pockets for the flow of blood and a treating fluid; a plurality of discrete non-woven support screens having substantially the same width as said folds, with one of said screens being disposed within each of said pockets of said first and second sets, said membrane and screens being held in said housing as a compacted stack compressed in a direction normal to the substantially rectangular surfaces of said folds with the screens disposed within adjacent blood and treating fluid pockets and separated by the membrane being substantially interdigitated, and with said support screens consisting essentially of a first layer in a first plane of first strands spaced apart and substantially parallel to one another and a second layer in a second plane of second strands spaced apart and substantially parallel to one another, said first layer and said second layer being bonded together at points of contact and said first strands being oriented with respect to said second strands at an angle of from about 45° to 90°; blood inlet and outlet means in the housing adjacent opposed ends of said stack in communication with the first set of pockets, thereby establishing overall blood flow paths in the first set of pockets along the length of said pockets; and treating fluid inlet and outlet means in the housing adjacent opposed ends of said stack in communication with the second set of pockets, thereby establishing overall treating fluid flow paths in the second set of pockets along the length of said pockets. When the treating fluid is an oxygen-containing gas, the novel mass transfer device is a highly efficient membrane blood oxygenator. The interdigitation of adjacent support screens allows for the compression of the stack of pleated membrane and screens into a small prism-shaped volume, without reducing the membrane surface area available for mass transfer. As a result of its low volume, the oxygenator is easy to handle and operate and requires only a minimal amount of blood or other liquid for priming. High oxygen and carbon dioxide transfer rates between the blood and treating gas are attainable. The interdigitation of pairs of adjacent screens, with a membrane fold trapped between each pair, creates thin, highly convoluted local flow paths in the blood and gas pockets, thereby causing a high degree of beneficial fluid mixing and crossflow of blood and treating gas in said pockets. Because diffusion through the blood streams will usually be the rate-determining step for gas transfer in the oxygenator, improved mixing characteristics in the blood flow pockets are particularly significant. Treating gas and blood pressure drops across the oxygenator are quite acceptable and trauma to blood components is minimal. Preferably, in order to maximize the advantageous fluid flow characteristics in the blood and treating gas pockets, the first strands and the second strands in the blood pocket and treating gas pocket support screens are all oriented at acute angles of from about 20° to about 70° with respect to the fold lines of the membrane. The mass transfer rates in a device of the invention can be further improved without excessively increasing the blood pressure drop across the device by providing appropriate shims between the two opposed side walls of the oxygenator housing and the compacted stack of membrane and screens. Each of these two shims is centrally disposed between the ends of the stack, is at least about as wide as the stack, has a length of from about 10% to about 50% of that of the stack and has a thickness of from about 1% to about 10% of the height of the compacted stack. Additionally, blood and treating fluid pressure drops across a mass transfer device of the type disclosed herein can be reduced and fluid distribution over the width of the pockets improved by providing appropriate transversely-extending cut-out regions in the corresponding support screens adjacent the opposed ends thereof. DETAILED DESCRIPTION OF THE INVENTION The invention will be described in detail with reference to a preferred embodiment thereof, which is an extracorporeal membrane blood oxygenator in assembly with an integral heat exchanger. Reference to this embodiment does not limit the scope of the invention, which is limited only by the scope of the claims. In the drawings: FIG. 1 is a perspective view of an assembly of a membrane blood oxygenator of the invention and an integral heat exchanger, shown schematically in position in a typical extracorporeal blood circuit; FIGS. 2 and 3 are exploded perspective views of the assembly of FIG. 1; FIG. 4 is a side plan view of the assembly of FIG. 1; FIG. 5 is a top plan view of the assembly of FIG. 1; FIG. 6 is a section view, taken along line 6--6 in FIG. 5; FIG. 7 is a section view, taken along line 7--7 in FIG. 4; FIGS. 8, 9 and 10 are section views taken along 8--8, 9--9 and 10--10 in FIG. 4; lines FIG. 11 is a view, partially in exploded form, of the stack of pleated membrane and support screens in the oxygenator of FIG. 1; FIGS. 12 and 13 show alternative designs for the transversely-extending cut-out regions in the support screens in the oxygenator of FIG. 1; and FIG. 14 is a perspective view of three adjacent support screens in the compressed stack shown in FIG. 11 and the two adjacent membrane folds held between said screens, with schematic representation of the local blood flow paths through one of the blood pockets in the oxygenator of FIG. 1. A disposable assembly of a blood membrane oxygenator 1 of the invention and an integral heat exchanger 3 is shown in FIGS. 1 to 10. This assembly is adapted to be incorporated in an extracorporeal blood circuit in the vertically-extending orientation shown in FIG. 1. Oxygenator 1 comprises a housing 5 in the general shape of a rectangular prism, a blood inlet 19 and a treating gas outlet 21 adjacent the bottom end of the housing, and a treating gas inlet 23 and a blood outlet 25 adjacent the top end of the housing. Housing 5 includes a top wall 7, a bottom wall 9, opposed side walls 11 and 13, a front wall 15 and a rear wall 17. Integral heat exchanger 3, which does not constitute a part of the present invention, treats the venous blood upstream of the oxygenator 1 and is provided with a cooling water inlet 27 and a cooling water outlet 29, both of which include a quick-disconnect fitting, and a heat exchanger blood inlet 31. As shown in FIG. 1, a sample port 33 and a temperature probe 35 may be provided in or near the heat exchanger blood inlet 31. Heat exchanger 3 includes a single cooling fluid-conducting tube 6 provided with a continuous hollow helical rib forming a helical flute and a plastic coil-supporting core piece 4. The venous blood, which divides and flows downwardly through heat exchanger 3 along the four turas of coil 6 (note arrows in FIG. 1), is constrained by the surfaces of coil 6, core piece 4, blood manifold plate 55 and retainer plate 57 to follow locally the track defined by the helical flute. As a result, an extended contact time between the venous blood and coil 6 can be realized. Rear wall 17 and approximately one-half of each of top wall 7 and bottom wall 9 of housing 5 are formed by a gas manifold plate 37, which plate includes in single piece construction therewith treating gas inlet 23, a treating gas inlet manifold 39, treating gas outlet 21 and a treating gas outlet manifold 41. Each of manifolds 39 and 41 contains a constant cross-sectional diameter portion 47, 51 adjacent the treating gas inlet or outlet and a tapered portion 49, 53 removed from said inlet or outlet. This manifold configuration serves to prevent formation of zones of fluid stagnation within the manifolds. Side walls 11 and 13 of housing 5 are formed, respectively, by pressure plates 43 and 45. Approximately one-half of each of top wall 7 and bottom wall 9 and a portion of front wall 15 of housing 5 are formed by a blood manifold plate 55. The remainder of front wall 15 is formed by a retainer plate 57 (see FIGS. 6 and 9). Plate 55 includes in single piece construction therewith blood outlet 25, a blood outlet manifold 59, heat exchanger blood inlet 31 and a heat exchanger housing wall 61. The cooling water coils of heat exchanger 3 are held between plate 57 and wall 61. In order to prevent formation of zones of fluid stagnation therein, manifold 59 is tapered with decreasing cross-sectional diameter away from blood outlet 25. As shown in FIG. 1, a sample port 67 may be provided in blood outlet 25 and a temperature probe 69 in manifold 59. The blood inlet of oxygenator 1 (and also the blood outlet of heat exchanger 3) is a substantially rectangular slot 19 in retainer plate 57. Oxygenator 1 also includes a pleated, selectively permeable membrane 71 disposed within housing 5 in rectangular folds parallel to walls 11 and 13. These folds define first and second sets 73 and 75 of alternating pockets for the flow of blood and a treating gas, respectively. The fold lines of pleated membrane 71 are situtated adjacent walls 15 and 17 of housing 5. Blood inlet 19 and blood outlet 25 are in fluid communication with the first set 73 of pockets, while treating gas inlet 23 and treating gas outlet 21 are in fluid communication with the second set 75 of pockets. Thus, overall countercurrent blood and treating gas flow paths are established in sets 73 and 75, respectively, of pockets along the length of said pockets. In a membrane blood oxygenator such as oxygenator 1, the membrane should be permeable to oxygen and carbon dioxide, but impermeable to water and other non-gaseous blood constituents. Any of the known types of membrane materials conventionally employed in blood membrane oxygenators may be utilized in a blood oxygenator of the present invention. As only one example, membrane 71 of oxygenator 1 may be made of a microporous polypropylene membrane material sold by Celanese Corp. (New York, N.Y.) under the trade name Celgard. A very important feature in the design of oxygenator 1 is the presence, in each of the pockets of sets 73 and 75, of a discrete non-woven support screen, e.g. 77, 79 and 81, having substantially the same width as the rectangular folds of membrane 71. Preferably, in order to improve the distribution of fluids into the various pockets in the two sets 73 and 75 and to reduce pressure drops, these support screens are made to be slightly wider (by from about 0.02 in. to about 0.03 in.) than the membrane folds. As a result, the screens will be exposed in the vicinity of inlet 19 and manifolds 39, 41 and 59. Also, the support screens preferably have substantially the same length as said rectangular folds. In oxygenator 1, membrane 71 and its associated support screens are held in housing 5 as a compacted stack 83 compressed by side walls 11 and 13 in a direction normal to the rectangular surfaces of the support screens and membrane folds (see FIGS. 8 to 10). The opposed ends of stack 83 are situated adjacent walls 7 and 9, while the top and bottom of stack 83 are situated adjacent walls 11 and 13, respectively. Three of the support screens utilized in oxygenator 1 are shown in detail in FIG. 14, with two adjacent folds of membrane 71 held between them. It is to be understood that the actual stack of membrane folds and support screens in oxygenator 1 extends above and below the partial assembly depicted in FIG. 14. Each of the support screens in stack 83, e.g. screen 77, consists of a first layer, e.g. 85, of straight strands in a first plane spaced apart and parallel to one another and a second layer, e.g. 87, of straight strands in a second plane spaced apart and parallel to one another. The strands of said first layer are bonded to the strands of said second layer at their points of mutual contact, e.g. by adhesive or fusion bonding, and the strands of the first layer are oriented with respect to the strands of the second layer at an angle A of from about 45° to 90°. Angle A is substantially the same in every screen in stack 83. Preferably, the strands of the support screens in stack 83 are of cylindrical crosssection, with the strands in both layers of the screens in the set of blood pockets 73 having the same crosssectional diameter d 1 and the strands in both layers of the screens in the set of treating gas pockets 75 have the same cross-sectional diameter d 2, and d 1 and d 2 each being of from about 0.008 in. to about 0.016 in. Most preferably, d 1 is equal to d 2. In both the blood pocket and treating gas pocket support screens, the individual parallel strands in each of the two layers are preferably separated by from about 0.05 in. to about 0.10 in. As one example, the support screens in stack 83 may be cut from the same sheet of an open mesh polymeric material such as the extruded medical grade non-woven open mesh polypropylene screen material sold by NSW & Co. (Roanoke, Va.) under the tradename Polynetting, with the cutting lines in said sheet of the longitudinal edges of the blood screens all being substantially parallel, the cutting lines in said sheet of the longitudinal edges of the treating gas screens all being substantially parallel, and the cutting direction of the blood screen longitudinal edges being substantially perpendicular in said sheet to the cutting direction of the treating gas screen longitudinal edges. Alternatively, the two sets of support screens may be cut from different non-woven stock materials, with the strand pattern in the stock material from which the blood pocket support screens are cut being a mirror image of the strand pattern in the stock material from which the treating gas pocket support screens are cut. When assembled in stack 83 with the folds of membrane 71, adjacent support screens line up in the manner shown in FIG. 14, i.e. with the strands of each layer in each screen, e.g. screen 79, substantially parallel to the strands of the adjacent layer in the next screen in the stack, e.g. screens 77 and 81. As a result of this orientation, the support screens disposed within adjacent blood and treating gas pockets in oxygenator 1 become substantially interdigitated when the assembly of membrane and screens is compressed (e.g. by pressure plates 43 and 45) in a direction normal to the rectangular surfaces of the folds of the membrane. As used herein, the term "substantially interdigitated" means that two adjacent support screens are interdigitated over at least 50 percent of their common interfacing gross surface area. The substantial interdigitation of adjacent support screens in oxygenator 1 has several important benefits. First of all, for a particular membrane surface area available for mass transfer, the volume of stack 83 and thus of oxygenator 1 is greatly reduced. As a result, the manufacturing, shipping, handling, setting up, priming, operation and disposal of the oxygenator are facilitated. Additionally, the interdigitated support screens create networks of thin, highly convoluted flow paths in the blood and treating gas pockets (see, for example, the multitude of interconnected blood flow paths depicted by arrows in FIG. 14 in the pocket containing support screen 77). As the blood and treating gas pass along their thin convoluted flow paths, a high degree of intraphase fluid mixing occurs within the various flow pockets along with a high degree of crossflow of the blood and treating gas in adjacent pockets. The net result is a highly efficient mass transfer of oxygen to, and carbon dioxide from, the blood with minimal trauma to blood constituents (e.g. minimal hemolysis) and acceptable blood and treating gas pressure drops across the oxygenator. Preferably, the support screens are cut so that the strands in both layers of the blood pocket and treating gas pocket support screens are all oriented at acute angles of from about 20° to about 70° with respect to the fold lines of membrane 71. Since the overall flow paths of blood and treating gas are parallel to these fold lines, the strands oriented in such a manner act as a very highly effective series of flow distributors, thereby further enhancing the advantageous flow characteristics in the blood and treating gas pockets and essentially eliminating any tendency for channeling to occur. More preferably, the strands in both layers of the blood pocket support screens are oriented at substantially the same acute angle with respect to the fold lines of membrane 71 and the same is true for the strands in both layers of the treating gas pocket support screens (note angles B 1 and B 2 in FIG. 11). Since extensive flow distribution of blood is more important than that of treating gas, angle B 1 (blood screens) is most preferably greater than angle B 2 (treating gas screens). Another highly advantageous feature of oxygenator 1 is depicted in FIG. 11. Each of the support screens in the stack 83 is provided with a pair of transversely-extending slots, e.g. slots 97 and 99 in screen 77 and slots 101 and 103 in screen 79, one adjacent each opposed end of the screen. The slots in the blood pocket support screens in stack 83 are located directly below blood inlet 19 and blood outlet manifold 59, while the slots in the treating gas pocket support screens in stack 83 are located directly above treating gas inlet manifold 39 and treating gas outlet manifold 41. The slots in the support screens disposed in set 73 of blood pockets are tapered with decreasing width away from blood inlet 19 and blood outlet manifold 59 and may, as shown in FIG. 11, be substantially trapezoidal. The slots in the support screens in set 75 of treating gas pockets may also be tapered with decreasing width away from rear wall 17 but are not necessarily so tapered and may, as shown in FIG. 11, be substantially rectangular. Alternatively, any other type of transversely-extending cut-out regions may be formed in the various support screens, such as the series of circular holes, e.g. 181, with decreasing diameter shown in FIG. 12 for blood pocket screens and the series of circular holes, e.g. 183, with constant diameter shown in FIG. 13 for treating gas pocket screens. The cut-out regions in the support screens may be formed with a steel rule die simultaneously with the cutting of the screens from a sheet of open mesh stock material. The purpose of the transverse cut-outs in the blood pocket and treating gas pocket support screens is to enhance the distribution of blood and treating gas across the width of said pockets. Such enhanced fluid distribution results in a full efficient utilization of membrane surface area for mass transfer and in reduced blood and treating gas pressure drops across the oxygenator. Although this aspect of the invention is preferably practiced with the non-woven, interdigitated support screens of oxygenator 1, it is to be understood that its contemplated scope of applicability is not so limited. Thus, transversely-extending fluid distribution cut-out regions according to this aspect of the invention might be provided in, for example, woven and/or non-interdigtated support screens disposed within the alternating blood and treating gas pockets defined by a pleated, selectively-permeable membrane of any blood membrane oxygenator of this general class. Still another highly advantageous feature of oxygenator 1 is the presence of two substantially identical shims 89 and 91 centrally disposed between the ends of stack 83 and maintained in compression between the top and bottom of stack 83 and side walls 11 and 13 (see FIG. 7). The shims may be discrete elements or integral portions of shim plates such as plates 93 and 95. Each of shims 89 and 91 has at least about the same width as stack 83, a length of from about 10% to about 50% of that of said stack, preferably from about 20% to about 40%, and a thickness (dimension T in FIG. 7) of from about 1% to about 10% of the height of the compacted stack of membrane folds and support screens (i.e. the distance between the top and bottom of the stack) at the ends of the stack, preferably from about 2% to about 5%. Shims 89 and 91 serve to further compress stack 83 in a direction normal to the rectangular membrane folds so as to increase the extent of contact between blood and membrane and further reduce the thickness of the local fluid flow paths, thereby serving to increase the mass transfer rates to and from the blood. However, unlike the shims in prior art oxygenators that extend over a great majority of the length of the overall blood flow paths (see U.S. Pat. Nos. 3,522,885; 3,879,293; 4,219,422 and 4,304,669), the shorter shims 89 and 91 do not give rise to an excessive increase in the blood pressure drop across oxygenator 1. Most preferably, each of shims 89 and 91 has a thickness of about 2% of the height of compacted stack 83 and a length of about one-third of the length of said stack. In the oxygenator shown in the Figures, shim plates 93 and 95 abut a grid of longitudinal and transverse inwardly-extending spacers, e.g. 96 and 98, provided in pressure plates 43 and 45 over the full length and width of said plates to provide stability against buckling of said pressure plates. The manufacture of oxygenator 1 is quite simple. Blood manifold plate 55, gas manifold plate 37, pressure plates 43 and 45, retainer plate 57 and shim plates 93 and 95 are preferably injection molded parts made of a transparent thermoplastic material such as a polycarbonate. A heat exchanger preassembly may be constructed by fixedly (e.g. adhesively) securing the heat exchanger cooling water coil 6, the coil-supporting core piece 4, blood manifold plate 55 and retainer plate 57 together to form an integral assembly. Membrane 71 may be pleated by folding it about a stack of rectangular folding plates held in a first fixture. The assembly of the membrane and folding plates is then removed and placed in a second fixture, in which the folding plates are replaced one-by-one with the appropriate support screens in the sets 73 and 75 of blood and treating gas pockets. Next, with shim plates 93 and 95 and pressure plates 43 and 45 in position, the resulting assembly of membrane and support screens may be compressed in a hydraulic press to effect the substantial interdigitation of the support screens and form the compacted stack 83. Then, with a thixotropic potting material, e.g. thixotropic polyurethane, applied between manifolds 39 and 41 and between inlet 19 and manifold 59 to the surfaces of gas manifold plate 37, blood manifold plate 55 and retainer plate 57 destined to be closely proximate the folded edges of membrane 71, gas manifold plate 37 and blood manifold plate 55 are fit onto pressure plates 43 and 45. For this purpose, tongues 113, 115, 117, 119, 121, 123, 125 and 127 are provided in plates 37 and 55 which are received within corresponding grooves provided in pressure plates 43 and 45 (plate 55 is also provided with four tongues, not shown in the figures, equivalent to tongues 113, 115, 117 and 119 of plate 37). The compression from the hydraulic press is then released, thereby completing the formation of housing 5 around stack 83. When the thixotropic potting material hardens, it forms shunt blocks 105 and 107. The purpose of these two shunt blocks is to prevent the shunting of blood and treating gas along plates 37 and 57 outside the fold lines of the membrane and thus maintain the integrity of the individual blood and treating gas pockets. Finally, a top seal 109 may be formed by spinning the assembly of oxygenator and heat exchanger in a centrifuge while horizontally oriented with the top wall 7 of the housing 5 facing away from the center of rotation of the centrifuge and a low viscosity potting material, e.g. polyurethane, conducted to the assembly during centrifugation from a rotating dispensing container via a tube connected to the treating gas inlet 23. After hardening of the potting material, the position of the assembly in the centrifuge is reversed and the same procedure followed, with the low viscosity potting material applied through treating gas outlet 21, to form bottom seal 111. The purpose of seals 109 and 111 is to prevent direct contact between the blood and treating gas streams. In operation, oxygenator 1 of the invention is maintained in a vertical orientation as shown in FIG. 1 with a water input tube 22 connected to inlet 27, a water output tube 24 connected to outlet 29, a treating gas (preferably oxygen or oxygen mixed with air) input tube 26 connected to inlet 23 and a treating gas outlet tube 28 connected to outlet 21. Typically, the principal flow of venous blood from the patient is collected in a venous reservoir 30 along with the output from a cardiotomy reservoir/filter device, a tube 32 carrying the output from the venous reservoir 30 is connected to a blood pump 34, a blood pump output tube 36 is connected to inlet 31, the input treating gas is at essentially atmospheric pressure and an arterialized blood tube 38 leading to an arterial filter is connected to outlet 25. After passing through the arterial filter the arterialized blood is returned to the patient. The assembly of oxygenator 1 and integral heat exchanger 3 is primed, e.g. with sterile saline solution, through inlet 31. Preferably, said assembly is temporarily tilted, so as to tilt inlet 31 by about 30° from horizontal, during the priming step. During a cardiopulmonary bypass operation the patient's blood is cooled in the heat exchanger 3 to a temperature well below the physiological temperature. Subsequently, at the end of the operation, the patient's blood must be rewarmed in the heat exchanger to the physiological temperature. Since the assembly of oxygenator 1 and integral heat exchanger 3 is made of relatively in expensive materials and is of simple construction, it may be disposed after a single use. A mass transfer device of the present invention may also be used as a blood dialyzer, with a dialysis liquid serving as the treating fluid. In one specific example of a blood membrane oxygenator 1 of the invention (Example I), 120 Polynetting support screens (60 in blood pockets and 60 in treating gas pockets), each with an overall length of 12 in., an overall width of 3 1/16 in. and a gross surface area of 36 3/4 in. 2, are disposed in a compressed stack with 121 Celgard membrane folds. The membrane has a thickness of about 0.002 in. and a nominal pore size of about 0.2 microns. The compressed stack 83 has a volume of 480 cc. and a height at its ends of 2.4 in. The total membrane surface area is 2.4 m. 2. Each support screen consists of two fusion-bonded layers of 0.012 in. diameter parallel strands, with the strands of the first layer oriented at about 60° with respect to the strands of the second layer and the individual strands in each layer separated by about 0.06 in. The overall thickness of each screen is about 0.022 in. All the support screens in the oxygenator are cut from the same non-woven open mesh stock material. However, the cutting direction of the longitudinal edges of the blood pocket support screens in the stock material is perpendicular to the cutting direction of the longitudinal edges of the treating gas pocket support screens in the stock material. Additionally, the screens are cut from the stock material so that all strands in the blood pocket support screens are oriented at an angle of about 60° with respect to the fold lines of the membrane and all strands in the treating gas pocket support screens are oriented at an angle of about 30° with respect to the fold lines of the membrane. As shown in FIG. 11, the support screens in the blood pockets are provided with trapezoidal transverse slots adjacent their two opposed ends and the support screens in the treating gas pockets are provided with rectangular transverse slots adjacent their two opposed ends. In this device, each of the two shims 89 and 91 has a thickness of about 2% of the height of compacted stack 83 at the ends of said stack and a length about one-third that of said compacted stack. In vitro gas transfer and hemodynamic testing has been performed with the particular oxygenator described above as Example I. Oxygen was used as the treating fluid. As the blood flow rate in this device was increased from 2 liters/min. to 6 liters/min., with the ratio of blood volumetric flow rate to oxygen volumetric flow rate held constant at 1:1, the oxygen transfer rate increased linearly from 125 ml./min. to 325 ml./min., the carbon dioxide transfer rate increased linearly from 125 ml./min. to 290 ml./min. and the blood pressure drop across the assembly of oxygenator 1 and integral heat exchanger 3 increased linearly from 60 mm Hg to 180 mm Hg. Minimal hemolysis was observed. | Summary: A novel device for mass transfer across a membrane is disclosed, which is particularly suitable for use as a blood oxygenator. The novel device is of the type having a pleated, selectively permeable membrane defining first and second sets of alternating pockets for the flow of a fluid to be treated (e.g. blood) and a treating fluid (e.g. oxygen), and a discrete support screen disposed within each of the pockets of said first and second sets. Of considerable importance is the feature that the support screens are designed to be substantially interdigitated when the assembly of membrane and support screens is held as a compressed stack within the housing of the device. The novel mass transfer apparatus may be utilized as a compact blood oxygenator with excellent gas transfer rates, low pressure drops and negligible trauma to blood components. | 7,966 | 174 | big_patent | en |
Summarize: Sexual harassment claims against yet another powerful man in media inspired New York Times White House correspondent Glenn Thrush to post an impassioned note on his Facebook page in October, calling on his fellow journalists to stand by women entering the field. In the post, which linked to an article about the latest accusations against political journalist Mark Halperin, Thrush wrote, “Young people who come into a newsroom deserve to be taught our trade, given our support and enlisted in our calling — not betrayed by little men who believe they are bigger than the mission.” It was a noble statement — but some Washington journalists I spoke to say it rings hollow, given Thrush’s own behavior with young women in the industry. “He kept saying he’s an advocate for women and women journalists,” a 23-year-old woman told me, recounting an incident with Thrush from this past June. “That’s how he presented himself to me. He tried to make himself seem like an ally and a mentor.” She paused. “Kind of ironic now.” Thrush, 50, is one of the New York Times’s star White House reporters whose chronicles of the Trump administration recently earned him and his frequent writing partner Maggie Haberman a major book deal. Thrush and the young woman met at her colleague’s going-away party at a bar near the Politico newsroom, she told me, and shared a few rounds of drinks in a booth. The night, she said, ended on a Washington street corner, where Thrush left her in tears after she resisted his advances. The encounter was troubling enough to the woman that her friend Bianca Padró Ocasio, also 23 and a journalist, confronted Thrush about his behavior via text message the next day. “I want to make sure you don’t lure young women aspiring journalists into those situations ever again,” she texted. “So help me out here. How can I do that?” Thrush was apologetic but defensive. “I don’t lure anybody ever,” he wrote, according to screenshots provided by Padró Ocasio. “I got drunk because I got some shitty health news. And I am acutely aware of the hurdles that young women face in this business and have spent the better part of 20 years advocating for women journalists.” If Thrush is acutely aware of what young women face in the business of political journalism, he should also know it’s because he himself is one of the problems women face. Five years ago, when Thrush and I were colleagues at Politico, I was in the same bar as Padró Ocasio’s friend — perhaps the same booth — when he caught me off guard, put his hand on my thigh, and suddenly started kissing me. Thrush says that he recalls the incident differently. Three young women I interviewed, including the young woman who met Thrush in June, described to me a range of similar experiences, from unwanted groping and kissing to wet kisses out of nowhere to hazy sexual encounters that played out under the influence of alcohol. Each woman described feeling differently about these experiences: scared, violated, ashamed, weirded out. I was — and am — angry. Details of their stories suggest a pattern. All of the women were in their 20s at the time. They were relatively early in their careers compared to Thrush, who was the kind of seasoned journalist who would be good to know. At an event with alcohol, he made advances. Afterward, they (as I did) thought it best to stay on good terms with Thrush, whatever their feelings. “I apologize to any woman who felt uncomfortable in my presence, and for any situation where I behaved inappropriately. Any behavior that makes a woman feel disrespected or uncomfortable is unacceptable,” Thrush said in a statement emailed to me on November 19. In interviews with about 40 people in and around media who know Thrush, I got a picture of a reporter whose title doesn’t capture his power and stature. People who’ve worked with him say he can get a writer’s name in front of the right editor, if he wants. Newsroom leaders care what he thinks. Some reporters said Thrush had used his connections to help them land jobs or develop new sources. When just sitting at a bar with a powerful man comes at a price The downfall of Hollywood titan Weinstein has been a catalyst for a movement to stamp out workplace harassment, particularly the variety that pits powerful men against much less powerful women. They are facing consequences for their behavior like never before, including men in media. Halperin lost a coveted book deal. NPR news chief Michael Oreskes resigned. Leon Wieseltier lost funding for his new magazine. And Lockhart Steele, the editorial director of Vox Media, Vox’s parent company, was fired for misconduct. Thrush wasn’t my boss at Politico. He was a reporter and I was an editor. We were on different teams and hardly crossed each other’s paths. But he was an incredibly influential person in the newsroom and in political journalism, a world I was still trying to break into in a meaningful way at the time. It wasn’t that Thrush was offering young women a quid pro quo deal, such as sex in exchange for mentorship. Thrush, just by his stature, put women in a position of feeling they had to suck up and move on from an uncomfortable encounter. On that night five years ago, I joined Thrush and a handful of other reporters for a few rounds at the Continental, a Politico hangout in Rosslyn, Virginia. At first, nothing seemed strange, until the crowd had dwindled down to Thrush, me, and one other female colleague. Thrush tossed a $20 bill at her and told her to take a cab and leave us, “the grown-ups,” alone. He slid into my side of the booth, blocking me in. I was wearing a skirt, and he put his hand on my thigh. He started kissing me. I pulled myself together and got out of there, shoving him on my way out. In the morning, Thrush sent me an apologetic email. I didn’t save it, but I recall it as similar to the one he would later send to Padró Ocasio’s friend in June. He said he was sorry, but he didn’t say for what, exactly. A few hours later, I saw him in deep conversation with a number of men I worked with. My gut told me something was up. I worried he was covering his tracks by spreading a rosy version of the night. As many people told me in the course of reporting this story, Thrush is a talker — or, as many put it, “a bullshitter.” He likes to hear gossip, and he likes to spread it. Gradually, things in the office started to change for me. Certain men in the newsroom, I thought, started to look at me differently. Some of their comments seemed a bit too familiar or were outright offensive. I had a nagging sense that I just wasn’t as respected as I used to be. I started to think maybe I shouldn’t be in journalism if I couldn’t hang in a tough newsroom. I found myself on edge, nervous and anxious all the time. I started to believe I had brought this all on myself. In the course of reporting this story, I was told by a male reporter who’d worked at Politico at the time that my instinct was right. He said that the day after that night at the bar, Thrush told him about the incident, except with the roles reversed. I had come onto him, the reporter said Thrush told him, and he had gently shut it down. In a statement, Thrush denied that he disparaged me to colleagues at Politico. He said that “the encounter described [in this story] was consensual, brief, and ended by me.” The source said that Thrush frequently told versions of this story with different young women as the subject. He would talk up a night out drinking with a young attractive woman, usually a journalist. Then he’d claim that she came onto him. In his version of these stories, Thrush was the responsible grown-up who made sure nothing happened. There was no conventional HR office at Politico at the time (a VP of human resources position was created there in 2016). So I brought my concern about the night to an experienced colleague right after the incident. When I believed rumors were damaging my standing in the office a few months later, I told a very senior editor. I was under the impression that nothing could be done. A spokesperson for POLITICO Brad Dayspring emphasized that no formal complaint ever reached the general counsel’s desk and that both the colleague and senior editor in question had left POLITICO years ago. Women have a very different story to tell One former Politico staffer told me that she’d become worried about her reputation after an encounter with Thrush sometime in the winter of 2012-’13. The scene was, again, a Politico going-away party. She said she and Thrush spoke most of the night, until they ended up the last two of the party left in the bar. She says she’d had a lot to drink and Thrush offered her a ride home. Her recollection of the details is fuzzy, but one way or another, he ended up in her place. “I had alcohol blur,” she says. But Thrush was far from being the grown-up who prevented things from going too far; instead, she says, she was the one to raise objections. “I remember stopping him at one point and saying, ‘Wait, you’re married.’” After that, she says, he left almost immediately. “I remember that by the time he left, I didn’t have much clothes on.” The woman says she was struggling at Politico at the time, and she wondered if gossip might have made her situation worse. “I don’t know if he told other male reporters or editors. Did that shade their opinion of me? There’s no way to know.” She says she doesn’t believe she was pressured or that she’s a victim. But she also says she wants others to know about what happened. “The only regret I have is not telling more women. I told two. What if I had told five?” One of the two women she told at the time shared with me her recollection of the conversation. “I remember she kept reemphasizing that they were both really drunk, that it was consensual,” the friend said. “And she did not believe it was an assault. But I do remember she was very rattled and upset and ashamed of what she saw as her role in it.” Another woman described to me a 2013 Politico party that she attended in her early 20s. She said she was standing alone, Thrush came up to talk to her, and suddenly he leaned in and landed a wet kiss on her ear. “It all happened very quickly. And he leaned in very quickly,” she said. “At the time, I remember thinking … adults sometimes kiss each other on the cheek. Then sometimes they miss and slobber on your ear. It was my way of thinking this wasn't as weird as I thought.” Over time, the “whisper network” of warnings about Thrush has grown louder A 21-year-old woman arrived in Washington last year to intern in a journalism organization. She heard from people who don’t even work with Thrush to be careful. An employee at the Washington Post told her about him when she first arrived. A few months later, she says, a reporter at Roll Call warned her about him, too. She passed on the intel to four other female interns. Multiple young women journalists I spoke to said that they’d heard serious warnings about Thrush from friends. The word among women just starting in Washington, they said, is to be careful if you meet him at an event with alcohol, or if he sends you a direct message on Twitter. (Thrush suspended his Twitter account in September, saying it was too much of a distraction.) There’s something endearing and inspiring about interns who self-organized to guard themselves and each other against advances offered under guise of praise and professional advice — but there’s also something sad about a world in which the savvy move is to teach a young woman not to trust an older man who has something nice to say about her work. And whispers don’t fix everything. When Bianca Padró Ocasio’s friend found herself at the bar with Thrush in June, with him asking her to leave and go to another bar with him, she went to the bathroom and texted Padró Ocasio and another female friend, both of whom were also in journalism. “I’m drunk,” she texted, as saved screenshots of the messages show. “I’m nervous about this Glenn situation.” The friends urged her to call an Uber. “I am,” she responded. “I need to go home.” “Who else is there??” one friend asked. “Is there a woman you can uber home with?” Instead, the woman ended up leaving the bar with Thrush, who suggested they walk off some of their drinking — get some fresh air. He repeatedly tried to take her hand as they walked, she recalls, but she kept pulling it away. They crossed the Key Bridge from the Virginia neighborhood where Politico’s office is located into Georgetown. He led her down an incline to a dimly lit path along the old C&O Canal bed. He kissed her, she says, and she panicked. Then her phone rang, jolting her. It was Padró Ocasio. “I felt very protective of her,” Padró Ocasio said, describing the call. “I thought, she’s drunk right now. If I don’t do something, I’m not going to forgive myself.” The young woman ordered an Uber — the receipt shows it was about 11 pm — and says she planned to call Padró Ocasio back once inside the car. In the few minutes she waited, she said, Thrush walked back over to her and started to kiss her again. She began to cry. When Thrush saw, he abruptly walked off, waving his hand flippantly, and left her alone to wait for her ride, she said. Padró Ocasio’s friend received an email from Thrush the next morning with the subject line, “Nice meeting you!” followed by, “(And apologies?).” She responded congenially. “It was nice meeting you too! (And no worries haha).” She also met him a few weeks later at a tea shop near the White House, a meeting they’d discussed the night at the bar. Thrush sent her a few critiques of her stories. She said she feels that despite her misgivings, she has to stay on good terms with him since he is connected. “I hate feeling obligated to make him think I think everything is fine,” she said. “It’s been this thing hanging over me. I feel like I have to be nice to this person just because he knows people.” In his emailed statement, Thrush said that the night in June with the young woman was the last time he’s had a drink. He wrote: The June incident [described above] was a life-changing event [for me]. The woman involved was upset by my actions and for that I am deeply sorry. Over the past several years, I have responded to a succession of personal and health crises by drinking heavily. During that period, I have done things that I am ashamed of, actions that have brought great hurt to my family and friends. I have not taken a drink since June 15, 2017, have resumed counseling and will soon begin out-patient treatment for alcoholism. I am working hard to repair the damage I have done. “I feel really strongly about not creating a toxic environment” In the course of his text dialogue with Padró Ocasio about the incident with her friend, Thrush wrote, “I feel really strongly about not creating a toxic environment.” Back at Politico years ago, Thrush’s behavior contributed to a toxic environment I experienced. Dozens of people told me that Politico has changed dramatically since Carrie Budoff Brown took over a year ago as the publication’s editor. Multiple men and women who work for her say her standards are high and she has no time for the kind of behavior I described. Budoff Brown was at the going-away party in June where Thrush was in the booth with the 23-year-old woman. She told me she noticed them talking but, like other attendees I talked to, she didn’t know that anything happened afterward. “I was disappointed in Glenn but had no reason to think that anything would progress beyond the bar that night,” she said. “And I am saddened to learn in the course of your reporting that it did.” “Great journalism and great business require a great workplace. My colleagues and I have worked hard to nurture a newsroom where people are supportive, good to each other, and where mutual respect is the way of life. We have zero tolerance for anything else.” By the time of the June incident, Thrush was gone from Politico anyway — off to the New York Times, which has hired many of Politico’s top reporters over the years. But now he will be on hiatus pending a Times investigation that was sparked by my reporting for this story. "The behavior attributed to Glenn in this Vox story is very concerning and not in keeping with the standards and values of The New York Times,” said Eileen Murphy, the senior vice president of communications for the New York Times, in a written statement. “We intend to fully investigate and while we do, Glenn will be suspended. We support his decision to enter a substance abuse program. In the meantime, we will not be commenting further.” It’s the Times itself, of course, that has done so much to spark the current conversation around harassment with its exposés on Harvey Weinstein and Louis C.K. There’s probably no loftier perch in all of political journalism from which one could teach the trade and enlist young women into the calling — or, as the case may be, betray them. The New York Times has suspended its star White House reporter Glenn Thrush in response to allegations of sexual misconduct published by Vox. The Times will assign him to a new beat when he returns, executive editor Dean Baquet announced on Wednesday. Thrush will also receive “training designed to improve his workplace conduct,” according to the email sent to staff by Baquet. A spokesperson declined to elaborate on what the training will involve. The decision is a response to a story I wrote this November about Thrush’s conduct over the past five years. I described how Thrush, 50, has positioned himself as a champion of women in journalism, but has also targeted young women, including me, at industry functions: Three young women I interviewed, including the young woman who met Thrush in June, described to me a range of similar experiences, from unwanted groping and kissing to wet kisses out of nowhere to hazy sexual encounters that played out under the influence of alcohol. Each woman described feeling differently about these experiences: scared, violated, ashamed, weirded out. I was — and am — angry. Details of their stories suggest a pattern. All of the women were in their 20s at the time. They were relatively early in their careers compared to Thrush, who was the kind of seasoned journalist who would be good to know. At an event with alcohol, he made advances. Afterward, they (as I did) thought it best to stay on good terms with Thrush, whatever their feelings. I also wrote about how Thrush liked to talk about young women with male colleagues in the Politico office, describing how he said he had to bat them away after they came onto him. He told this same story many times, a source said, including about me. Thrush says he remembers the personal incident I described differently, and he denies he disparaged me in the newsroom. He also offered conciliatory words for other women. “I apologize to any woman who felt uncomfortable in my presence, and for any situation where I behaved inappropriately,” Thrush wrote. “Any behavior that makes a woman feel disrespected or uncomfortable is unacceptable.” The article attempted to show how the actions of a powerful man affect women at work, well after the specific incident. I wrote how the rumor he started seeped into the newsroom and changed how men treated me. Another woman told me how powerless she felt after an unwanted encounter with him: “I hate feeling obligated to make him think I think everything is fine,” she said. “It’s been this thing hanging over me. I feel like I have to be nice to this person just because he knows people.” Thrush joins a laundry list of other powerful men in media who’ve recently been accused of sexual misconduct or sexual harassment. Thrush’s is the first prominent case where the accused did not lose his job. Baquet told Times staff that the company does not condone Thrush’s behavior but that they do not think it warrants firing him, either. Thrush is currently on a two-month unpaid suspension. The Times suspended him in November pending an investigation. He’ll be able to return in January. “Each case has to be evaluated based on individual circumstances,” Baquet wrote. “We believe this is an appropriate response to Glenn’s situation.” Baquet is tapping into the broader question of what to do with men who “aren’t Weinstein,” as many have come to put it. These men aren’t accused of rape, like movie mogul Harvey Weinstein, but they’ve also done something terrible to a colleague (or colleagues) in the industry or a co-worker in the office. We know what to do when the accusations are monstrous. But what do we do when accusations are bad, or even terrible, but fall below the bar set by the worst of the worst? Thrush is an early test. Read Baquet’s full statement: The New York Times said on Wednesday that Glenn Thrush, one of the paper’s most prominent political reporters, would remain suspended until late January and then be removed from the team covering the White House after he faced allegations of inappropriate sexual behavior. The decision came a month after the website Vox published a report that contained allegations from four female journalists of inappropriate behavior by Mr. Thrush. After learning Vox planned to run its article, which was published on Nov. 20, The Times began an investigation into Mr. Thrush’s conduct. The inquiry was led by Charlotte Behrendt, a lawyer in the Times newsroom, and involved interviews with more than 30 people in New York and Washington, both inside and outside The Times, according to a person briefed on the process. Ms. Behrendt compiled a report with her findings that was reviewed by Dean Baquet, the executive editor, and a group of top editors. Mr. Thrush was told of the decision on Wednesday during a meeting with Mr. Baquet. In a statement, Mr. Baquet said the company had completed its inquiry and found that Mr. Thrush had “behaved in ways that we do not condone.” | Summary: Political reporter Glenn Thrush has "acted offensively" toward women-but not so offensively that the New York Times believes he should be fired, executive editor Dean Baquet says. The Times says Thrush, who has been on the paper's White House beat since January and was suspended without pay after accusations of sexual misconduct surfaced a month ago, will be suspended for another month, and will be removed from the White House team when he returns. Baquet says Thrush, 50, is independently undergoing counseling and substance abuse rehab, and will also be given "training to improve his workplace conduct." In a Vox story last month, four women described unwanted kissing and touching from Thrush. "We understand that our colleagues and the public at large are grappling with what constitutes sexually offensive behavior in the workplace and what consequences are appropriate," Baquet said. "Each case has to be evaluated based on individual circumstances. We believe this is an appropriate response to Glenn's situation." At Vox, Laura McGann, one of the young journalists Thrush targeted, describes the case as an "early test" of what organizations do with men who are accused of sexual misconduct but who "aren't Harvey Weinstein." "We know what to do when the accusations are monstrous," she writes. "But what do we do when accusations are bad, or even terrible, but fall below the bar set by the worst of the worst?" | 5,191 | 314 | multi_news | en |
Summarize: Introduction Since FY2008, federal highway user taxes and fees have been inadequate to fund the surface transportation program authorized by Congress. Although the 2015 surface transportation act addressed the revenue shortfall through FY2020 by authorizing the use of general funds for transportation purposes, the Congressional Budget Office (CBO) projects that after FY2020 the gap between dedicated surface transportation revenues and spending will average $20 billion annually. The search for revenue to fill this gap may revive congressional interest in tolling as a means of financing transportation projects without federal expenditures. Although states are free to impose tolls on roads, bridges, and tunnels that have been built and maintained without federal assistance, federal law limits the imposition of tolls on existing federal-aid highways, especially on the Interstate Highways. This report explains current federal policies governing tolling and discusses issues related to increasing the use of tolls as a source of revenue for surface transportation projects. A Brief History of Tolling on Federal Roads In some states, mostly in the Northeast and the mid-Atlantic region, many of today's highways were originally toll roads, often built and operated by private investors. While tolling often made it possible to build or improve roads at minimal cost to taxpayers, many of these roads failed due to overly optimistic revenue expectations, inability to attract sufficient investment to pay for improvements, competing capacity, and toll avoidance and the related cost of enforcement. Over time, toll roads came to be regarded as obstacles to the free flow of commerce. When it established the forerunner of today's federal-aid highway program in 1916, Congress emphasized the principle that roads should be free. Section 1 of the Federal Aid Road Act (39 Stat. 355) provided that "all roads constructed under the provision of this Act be free from tolls of all kinds." The Oldfield Act of 1927 (44 Stat. 1398) opened the door to tolls by permitting the use of federal funds to build toll bridges as long as they were operated by the states or their political subdivisions. However, the federal Bureau of Public Roads continued to oppose the use of federal funds on toll roads. Consequently, when states, mainly in the Northeast, undertook expressway construction in the decade after World War II, they built toll roads without federal aid. By January 1, 1955, there were 1,239 miles of completed "arterial toll roads" in the United States, another 1,382 miles were under construction, and 3,314 miles were being planned or studied. Many of these roads were on routes of the planned Interstate system. Although the Bureau of Public Roads supported the building of new Interstate Highways as free roads, it did recommend that existing toll roads that met its engineering standards and followed the routes of proposed Interstate Highways be incorporated into the new network. The tolling prohibition was reiterated in the Federal-Aid Highway Act and Highway Revenue Act of 1956 (P.L. 84-621; 70 Stat. 374), which authorized 13 years of funding for construction of the Interstate Highway system, created the Highway Trust Fund (HTF) as the source of federal funds for state road construction, and raised tax rates on motor fuels to help fund it. The fuel and other highway taxes that were now dedicated to the HTF were seen as a close proxy for a user-payer system of financing federal-aid roads. The increased flow of federal funds, heavily weighted toward the Interstate Highways, effectively stopped the development of new toll roads by the states. Thirty-five years later, the Intermodal Surface Transportation Efficiency Act of 1991 (ISTEA; P.L. 102-240 ) opened non-Interstate federal-aid highways to tolling, but allowed existing roads or bridges to be tolled only after being reconstructed. This effectively linked tolling to capacity additions or road improvements. Both the 1998 Transportation Equity Act for the 21 st Century (TEA-21; P.L. 105-178, as amended by P.L. 105-206 ) and the Safe, Accountable, Flexible, Efficient Transportation Equity Act: A Legacy for Users ( P.L. 109-59 ; SAFETEA) allowed tolling on high-occupancy vehicle (HOV) lanes, established pilot projects for tolling of a limited number of Interstate system routes, and allowed limited use of tolls that vary according to the level of traffic, known as congestion pricing. The Moving Ahead for Progress in the 21 st Century Act (MAP-21; P.L. 112-141 ), enacted in 2012, reinforced the encouragement of tolls on HOV lanes and congestion pricing. It allowed new Interstate system routes or route extensions to be built as toll roads, but continued to block tolling of most existing Interstate Highway lane capacity. MAP-21 retained two pilot programs, one encouraging the use of pricing to control congestion and another allowing Interstate route segments in three states to be converted to tolling as part of their reconstruction. The Fixing America's Surface Transportation Act (FAST Act; P.L. 114-94 ), enacted in December 2015, clarified that public authorities generally, as opposed to solely state agencies, may impose tolls on single-occupant vehicles using HOV lanes. It modified the TEA-21 pilot program allowing existing Interstate Highway segments in three states to be subject to tolls to finance reconstruction by providing that federal approval lapses if the selected states have not started construction within three years of approval. The law also included two provisions related to the setting of rates. One mandates that intercity buses that serve the public have the same access to toll roads and pay the same rates as public transportation buses. The other requires public authorities operating high-occupancy toll lanes (HOT lanes) on the Interstate system to consult with the metropolitan planning organizations concerning the placement and amount of tolls on the facility. Other than these changes, the FAST Act continued the general federal government policy of not regulating toll rates. Current Law Table 1, below, briefly describes active federal tolling programs. An important attribute of federal tolling policy is that all conversions of existing federal-aid highways, bridges, or tunnels to toll facilities require that the facility be reconstructed, restored, rehabilitated, or replaced (unless the conversion occurs under the Value Pricing Pilot Program). The decision to convert a free facility to a tolled facility must be made prior to completion of the qualifying reconstruction project. According to the Federal Highway Administration (FHWA), once physical construction is completed it is too late to make the decision to toll, unless an additional qualifying reconstruction or rehabilitation project is undertaken. Financial Realities of Toll Roads Whether it is built or operated by a government agency or by private investors, a toll road must have sufficient traffic willing to pay a high enough toll to cover construction, maintenance, and toll collection costs if it is to be financially successful. Most roads on the federal-aid system are not likely to pass that test. In rural areas, highways often do not have enough traffic to cover the cost of building toll-collection infrastructure and collecting tolls. While urban roads typically have more traffic, they may not be able to generate sufficient toll revenue to make the facilities self-sustaining. Some publicly owned toll roads have been financially successful, generating sufficient revenue to pay for capital improvements and operations, and, in some cases, to contribute to the cost of other highway activities and even to public transportation activities. Other public toll facilities, however, have struggled. One recent example is the 8 miles of express toll lanes built by the Maryland Transportation Authority on I-95 north of Baltimore. In the seven months following their opening in December 2014, the toll lanes produced $6 million in revenue before operating expenses, far from enough to cover the cost of financing the $1.1 billion project. The state government has had to use other funds to make up the difference. Recent federal policy has encouraged the use of tolling to attract private investment into highway and bridge construction, but a number of private toll roads have proven to be financial failures. The Pocahontas Parkway, an 8.8-mile-long toll road near Richmond, VA, that opened in 2002, has persistently been unable to service debt due to low traffic volumes; in June 2012, its private operator wrote off the entire value of its investment in a 99-year concession, and eventually transferred the lease to a new operator. SH-130, a 90-mile, four-lane toll road near Austin, TX, has had much lower traffic volumes than forecast when it opened in 2012, and the Texas Department of Transportation ended up subsidizing truck tolls in an effort to help make the privately owned project viable. Despite the subsidy, in March 2016 the toll road operator, SH 130 Concession Co., and two affiliates filed for Chapter 11 bankruptcy protection. Other toll roads that have sought bankruptcy protection include the South Bay Expressway in San Diego, CA, and the Indiana Toll Road. All of these financial failures were public-private partnerships (P3s) that were formed based, at least in part, on overly optimistic forecasts of the revenue that would be provided by tolls. Their widely publicized difficulties have made investors more cautious about projects reliant on toll revenue. In some cases, private-sector investors have conditioned their participation in P3s on "availability payments," regular payments from the sponsoring government entity to the private entity. This reduces the risk to the private entity, but leaves the public entity at risk if toll revenue falls short of expectations. Billing and Operating Costs Using tolls to support transportation expenditures may be a comparatively inefficient form of funding because of high administrative costs. Collecting federal motor fuels taxes is estimated to cost about 1% of the amount collected. The process is administratively simple, because nearly all the federal fuels taxes are collected at the terminal "rack" from only 850 registered taxpayers nationwide, rather than at a large number of retail gasoline stations. The small number of collection points also facilitates enforcement. The administrative costs of toll collection appear to be significantly higher than the cost of fuel-tax collection. Determining the true cost of toll collection is difficult because, as noted in a 2007 report for the Transportation Research Board, some costs are not readily identified in agencies' financial reports, such as a portion of general administrative costs and pension expenses attributable to tolling. Published figures thus likely understate true collection costs. Even so, at the seven agencies examined, the study estimated that toll collection cost from 16.5% to 92.6% of the amount collected. Most toll facilities now collect a majority of their tolls from customer accounts that are debited when an electronic sensor detects a transponder in a vehicle passing beneath a gantry. In principle, the cost of operating an electronic tolling system should be much lower than the cost of manual collection, due to obvious personnel savings. However, many toll facilities continue to employ collectors to receive cash tolls. Those with no provision for collecting cash tolls normally bill drivers without transponders by mail at the address associated with the license plate on the vehicle, often at a higher rate to cover the cost of mailing the bill. Recent financial reports from public agencies indicate that even with extensive use of electronic tolling, collecting highway tolls costs between 8% and 11% of the amount collected (see Table 2 ). The annual report of the New Hampshire turnpike system breaks out some of the costs of electronic tolling in detail, including bank and credit card fees (2.7% of revenue collected from the electronic system), fees paid to process electronic transactions (7.3%), and the in-vehicle transponders furnished to drivers (0.7%). The agency's total operating costs for electronic tolling in FY2015, not including enforcement costs and depreciation of the electronic tolling infrastructure, were 10.6% of revenues collected electronically. Tolling and Highway Funding Highway toll revenue nationwide came to $14.35 billion in FY2014, according to FHWA. While the amount of toll revenue has grown significantly in recent years, toll revenue as a share of total spending on highways has been relatively steady for more than half a century, in the range of roughly 5% to 6%. On average, facility owners collected $2.36 million per mile of toll road or bridge in FY2014, but revenue per mile varies greatly among toll facilities. All revenue from tolls flows to the state or local agencies or private entities that operate tolled facilities; the federal government does not collect any revenue from tolls. However, a major expansion of tolling might reduce the need for federal expenditures on roads. There are three possible means of increasing revenue from tolling: Increase the extent of toll roads. FHWA statistics identify 6,088 tolled miles of roads, bridges, and tunnels as of January 1, 2015, a net increase of 1,367 miles, or 29%, over 1990. These figures indicate that the extent of toll roads has been growing by 54.7 miles per year, on average, adjusting for the fact that some previously tolled roads have become toll-free. Toll-road mileage comprises only 0.6% of the 1,016,964 miles of public roads eligible for federal highway aid. While there may be many existing roads on which tolling would be financially feasible, proposals to place tolls on existing roads have encountered strong opposition in several states, including Missouri, North Carolina, Texas, and Virginia. The vast majority of mileage on the federal-aid system probably has too little traffic to make toll collection economically viable. Increase toll-road usage. In the aftermath of the recession that began in 2007, the number of vehicle miles traveled in the United States fell below pre-recession levels until 2014. In 2015, vehicle miles traveled increased by 3.5% over 2014. Despite this recent growth in travel, demographic trends and social changes, such as the increased popularity of center-city living among young people, suggest that personal motor vehicle use may grow more slowly in future years than it did in 2015. If that proves to be the case, higher traffic volume may contribute little to increased toll revenues in the long run. Increase the average toll per mile. Toll rates are often significant political issues at the state and local levels, especially when toll revenue is used for purposes other than building and maintaining the toll facility. Trucking interests frequently raise opposition to rate changes that increase truck tolls relative to automobile tolls. On publicly owned facilities, political concerns may lead to toll reductions, as occurred on bridges operated by the Delaware River Port Authority and the Maryland Transportation Authority in 2015. Where roads are operated by private concessionaires, the operators' contracts with state governments typically specify the maximum rate at which tolls can rise. Additionally, large increases can encourage motorists to use competing non-tolled routes. These factors suggest that imposing tolls on individual transportation facilities is likely to be of only limited use in helping states overcome reductions in federal grants should Congress deal with the shortfall in motor fuels tax revenue by reducing the size of the federal surface transportation program. Further, some states, particularly those with low population densities, may have few or no facilities suitable for tolling. Tolls may be an effective way of financing specific facilities, especially major roads, bridges, or tunnels that are likely to be used heavily and are located such that the tolls are difficult to evade, but they seem likely to be less effective in providing broad financial support for surface transportation programs. Tolling the Interstate Highway System One way of estimating the revenue that could be raised by tolling the Interstate Highways is to assume that the public would pay the same average annual amount per mile, $2.35 million, as is raised on existing U.S. toll roads and bridges. In this case, tolling all Interstate Highways would be expected to raise roughly $112 billion per year. Of this, approximately $8 billion is already captured by existing toll facilities, leaving around $104 billion of new revenue. This would be more than enough to maintain and operate the proposed toll network. However, it is doubtful that this average could be supported over the entire length of the Interstate system. This is because a large proportion of current toll revenue is collected on heavily traveled roads and bridges in urban areas. The rural Interstates that account for a majority of Interstate Highway mileage carry far less traffic, and may be unable to produce so much revenue per mile. In addition, excessively high tolls could lead users to seek alternative routes. In cases where an Interstate carries little traffic, the costs of building and maintaining the toll collection system might be large relative to the revenue that could be realized. One option for expanding tolling on the Interstates would be for Congress to require tolling only as Interstate system roads and bridges are rebuilt with federal assistance. As many of these roads are not in need of near-term reconstruction, the evolving Interstate system toll network would expand over time. The corresponding reduction in federal-aid highway program spending would also be gradual. To accelerate the conversion, bonds might be issued to fund construction costs up-front, with toll revenues from the newly rebuilt facilities then used to pay for the interest and bond retirement costs. A less ambitious alternative would be to convert only the urban Interstates. Approximately 8.4% of the roughly 18,500 miles of urban Interstate Highways are tolled already, leaving over 17,000 miles of road available for conversion to toll roads. Assuming tolls would be imposed at rates that generate the current average of $2.35 million per mile, tolling the currently free urban Interstates might produce nearly $40 billion in annual revenue, nearly as much as the highway account of the HTF now receives from motor fuels taxes. However, it is doubtful that such a large sum could be realized once operating and collection costs are covered. Also, it is likely that some urban Interstate Highways will not generate sufficient revenues to pay for all their costs. There could, again, be concerns about cross-subsidization if tolls paid on urban roads were used to build and maintain toll-free roads elsewhere. In recent years, federal funds obligated for projects on the 47,662-mile-long Interstate system have accounted for 27% to 32% of total annual federal-aid highway obligations, or about $11 billion to $12 billion annually (in 2014 dollars). Hypothetically, if all Interstate Highways could be instantly converted to a self-sustaining toll network and received no further federal funding, expenditures under the remaining federal-aid highway program would fall from an average of about $42 billion per year to around $30 billion. This would bring federal highway program spending more in line with motor fuels tax revenues. This assumes, however, that tolls could be set high enough to support all the physical infrastructure and operating costs of such a massive toll network, and also that drivers continued to pay federal motor fuels taxes for fuel used while driving on toll roads that do not receive federal funds. Costs of establishing tolling across the Interstate system are likely to be great. States would need to construct gantries above roads and entrance and exit ramps at thousands of locations to hold toll-collection equipment and cameras to identify toll violators, in addition to building communications infrastructure. If tolling were introduced in conjunction with reconstruction of Interstate Highway segments, estimates of the road building costs involved range from $1 trillion to $3 trillion. The use of bond financing would add interest expense. However Congress chooses to proceed, the conversion of a significant portion of the Interstate Highway system from free roads to toll roads would take a number of years. Studies would need to be conducted to identify the best locations to collect tolls, equipment would have to be ordered, and physical infrastructure such as road-spanning gantries and communications structures would need to be designed and constructed. Increased use of tolling would therefore be unlikely to have a significant impact on the need for taxpayer funding over a 5- or 10-year time frame. Increased Use of Tolling to Encourage Innovative Finance The revenue stream provided by tolling can be used to support highway projects that rely on debt finance and private equity investment, both of which have long histories in toll road construction. In recent years, Congress has encouraged the use of innovative financing mechanisms such as public-private partnerships (P3s), which may use toll revenues in several ways. Toll revenues can be used to service municipal bonds that state and local agencies have issued to pay for highway projects. The federal government supports this spending by providing a tax exclusion of the interest paid on the bonds. The tax exclusion results in a loss of revenue to the federal government. Private activity bonds, in which a state or local government acts as a financial conduit for a business or individual (such as a P3), can also be serviced with toll revenues. The Transportation Infrastructure Finance and Innovation Act (TIFIA) provides federal credit assistance, including loans, to leverage nonfederal funding, which may include investment from the private sector. Under the FAST Act, TIFIA is authorized to spend $1.44 billion over five years to cover the federal government's cost of providing the subsidized credit. Each $1 of budget authority can support approximately $10 in loans. TIFIA requires that each proposed project have a dedicated revenue stream to repay the loan. For highway projects, toll revenues are the most commonly proposed revenue source. Toll revenues could also support loans for highways and bridges provided from a National Infrastructure Bank, should one be established. The creation of a well-funded National Infrastructure Bank could thus lead to an expansion of toll roads. Any expansion of tolling due to increased use of innovative financing for highway construction, maintenance, and operation would occur over an extended period of time. In any event, toll-supported innovative financing is likely to provide only a small proportion of highway spending needs unless Congress requires its use in large-scale reconstruction of Interstate Highways. Tolling Policy Issues How Could an Interstate System Conversion Be Accomplished? The current federal-aid highway program is essentially a state-run federal grant program, and states have ownership of the federal-aid highways within their borders. Any immediate conversion of highways to toll roads would necessarily be at individual states' discretion, with federal participation limited to technical assistance and a suggested conversion schedule. This would likely lead to a piecemeal outcome, as some states might convert quickly, some slowly, and some not at all. Congress could insist on a much stronger federal role by making the provision of federal highway grants to a state contingent on the state implementing a program of converting Interstate Highways to toll roads. FHWA might then take the lead in determining the sequence of reconstruction and conversion of Interstate Highways. This paradigm would have the advantage of assuring that all states would begin imposing tolls at roughly the same time, and federal leadership would likely not allow the outbreak of "toll wars" among the states, whereby states attempt to impose toll rates in a way that shifts the burden of the toll to their neighbors or interstate travelers generally. Under federal oversight, the operation of the converted highways might still be under the auspices of the states, which could operate them directly, through a toll authority, or perhaps under contract to a private operator. Whether or not implementation of tolls were linked to reconstruction of existing roads, creation of tolling systems would require up-front investments in gantries, equipment to read transponders in vehicles, communications infrastructure, software to process toll payments, and enforcement. This would have to be done before the tolls are collected. How Would Tolls Be Regulated? Under current law, FHWA approval is needed for initial implementation of tolls on roads and bridges that have received federal aid, but the federal government has no jurisdiction over toll rates. The Surface Transportation and Uniform Relocation Assistance Act of 1987 ( P.L. 100-17 ; H.Rept. 100-27) requires only that bridge tolls "shall be just and reasonable." More widespread use of tolls is likely to raise significant questions about equity. These might arise in a variety of contexts. Motorists from states with comparatively low tolls might find it unfair that other states charge comparatively high tolls. Some existing facilities offer preferential toll rates to residents of particular jurisdictions; if that practice were to become widespread, it could burden interstate travel and commerce. States may be tempted to collect tolls at state borders rather than at internal locations where more residents would be affected, effectively taxing interstate travel at higher rates than in-state travel and in some cases putting out-of-state companies at a competitive disadvantage against local companies. Truck tolls are invariably higher than auto tolls, sometimes much higher: crossing the George Washington Bridge from New Jersey to New York at an off-peak hour costs $10.50 for a car with an electronic transponder, but $68.00 for a standard tractor-trailer rig. Trucking interests generally oppose additional tolling, largely out of concern that political considerations will make it easier to raise tolls on trucks than on cars; they generally prefer higher fuel taxes whose revenues are dedicated to highway improvement. One reason for the preference for fuel taxes is that studies have concluded that funding highways with motor fuels taxes provides trucks a cross-subsidy from automobile users' gas tax payments. Proposals for a major expansion of tolling of federal-aid highways are likely to lead to discussion of a federal role in rate-setting. The FAST Act involved the federal government in toll rates for the first time, mandating that intercity buses serving the public have the same access to and pay the same rates as public transportation buses, and requiring public authorities operating high-occupancy toll lanes on the Interstate system to consult with affected metropolitan planning organizations on the placement and amount of tolls. Deeper federal involvement might include a federal framework of regulatory standards or a more precise definition of the requirement in current law that tolls be "just and reasonable," along with provision for the enforcement of that requirement. In such a case, Congress would need to clarify which federal agency would be responsible for enforcing tolling regulations and overseeing toll rates. Will Tolling Increase Transportation Spending? Proponents often advocate tolling as a means of increasing total spending on surface transportation infrastructure. It is possible, however, that any increase in toll revenue could be offset by declining spending on surface transportation at the local, state, and federal levels. Congress has at times sought to condition federal support for states' highway spending on "maintenance of effort" by state governments. Imposing similar requirements in conjunction with a large increase in the use of tolling would require increased federal monitoring of state and local transportation expenditures. Toll Credits An existing federal program, the toll credit program, has for many years allowed states to count expenditures of toll revenues on capital investments serving interstate travel as part of a state's required match for federal highway grants. Although the statute states that the credit "shall not reduce nor replace State funds required to match Federal funds for any program under this title," some states have come to rely heavily on toll credits to meet their matching share requirements. A major expansion of Interstate Highway tolling could also expand the use of toll credits nationwide. This raises the possibility that states could provide less taxpayer funding for their matching shares of federal formula grants, unless other changes are made in the law. Mileage-Based Road User Charges as an Alternative to Tolls A mileage-based road user charge would be a toll-like charge on each mile driven. It has been advanced as an alternative to the federal and state motor fuels taxes that now support highway spending. As generally proposed, a mileage-based charge would be imposed for the use of any road within a state or nationwide, whereas tolls are imposed only on specific highway segments. Most existing highway tolls are based on weight and distance traveled, and road user charges could be structured in a similar manner. Both electronic tolls and mileage-based road user charges could be used to implement congestion pricing, in which drivers are charged more for using a road at a busy time. However, a number of widely criticized aspects of mileage-based charges, such as the difficulty of accommodating drivers who lack credit card accounts to which the charges could be billed and concerns that the vehicle tracking system would invade drivers' privacy, have generally been less prominent in discussions of tolling. | Summary: Toll roads have a long history in the United States going back to the early days of the republic. During the 18th century, most were local roads or bridges that could not be built or improved with local appropriations alone. During the tolling boom of the late 1940s and early 1950s, the prospect of toll revenues allowed states to build thousands of miles of limited-access highways much sooner than would have been the case with traditional funding. The imposition of tolls on existing federal-aid highways is restricted under federal law, and while new toll facilities have opened in several states, some of those projects have struggled financially. The failure of federal highway user taxes and fees to provide sufficient revenues to fund the surface transportation program authorized by Congress beginning in FY2008 renewed interest in expanded toll financing. The recently passed five-year surface transportation act, the Fixing America's Surface Transportation Act (FAST Act; P.L. 114-94), made few changes in tolling policy. Nonetheless, the Congressional Budget Office (CBO) projects that annual highway revenues, mostly from motor fuels taxes, will fall an average of $20 billion short of the amount needed to sustain the current federal surface transportation program between FY2021 and FY2025. This impending shortfall could again revive congressional interest in tolling. Congress could achieve an expansion of tolling in several ways. At one extreme, it could simply encourage tolling pilot projects on federal-aid highways, of which relatively few have been implemented to date. At the other extreme, Congress might authorize states to toll federal-aid highways as they see fit, or even require that Interstate Highway segments be converted to toll roads as they undergo reconstruction in the future, eventually turning all Interstates into toll roads. Whatever policies Congress adopts, tolls are likely to play only a limited role in funding surface transportation projects. The costs of toll collection on many existing toll roads exceed 10% of revenues even if all tolls are collected electronically, not including the cost of toll collection infrastructure. This compares unfavorably to the cost of collecting the existing federal motor fuels taxes, estimated to be about 1% of revenues. Many roads may not have sufficient traffic willing to pay a high enough toll to cover construction, maintenance, and toll collection costs. The availability of competing non-tolled routes may allow motorists to evade tolls. In addition, political concerns often limit the ability of operators to raise toll rates. Beyond a requirement that bridge tolls "shall be just and reasonable" and a provision limiting tolls on over-the-road buses, current federal law provides no role for the federal government in regulating toll rates or practices. A number of states offer preferential tolls for in-state residents or residents of particular localities. Some states have attempted to collect tolls at borders rather than at internal locations where more residents would be affected, and in a number of places trucking interests have complained that truck tolls are excessive compared to auto tolls. More widespread use of tolls is likely to raise questions about the extent to which tolling should be subject to federal oversight. | 6,364 | 700 | gov_report | en |
Write a title and summarize: Japanese encephalitis (JE) virus (JEV) causes severe epidemic encephalitis across Asia, for which the live attenuated vaccine SA14-14-2 is being used increasingly. JEV is a flavivirus, and is closely related to dengue virus (DENV), which is co-endemic in many parts of Asia, with clinically relevant interactions. There is no information on the human T cell response to SA14-14-2, or whether responses to SA14-14-2 cross-react with DENV. We used live attenuated JE vaccine SA14-14-2 as a model for studying T cell responses to JEV infection in adults, and to determine whether these T cell responses are cross-reactive with DENV, and other flaviviruses. We conducted a single arm, open label clinical trial (registration: clinicaltrials. gov NCT01656200) to study T cell responses to SA14-14-2 in adults in South India, an area endemic for JE and dengue. Ten out of 16 (62. 5%) participants seroconverted to JEV SA14-14-2, and geometric mean neutralising antibody (NAb) titre was 18. 5. Proliferation responses were commonly present before vaccination in the absence of NAb, indicating a likely high degree of previous flavivirus exposure. Thirteen of 15 (87%) participants made T cell interferon-gamma (IFNγ) responses against JEV proteins. In four subjects tested, at least some T cell epitopes mapped cross-reacted with DENV and other flaviviruses. JEV SA14-14-2 was more immunogenic for T cell IFNγ than for NAb in adults in this JE/DENV co-endemic area. The proliferation positive, NAb negative combination may represent a new marker of long term immunity/exposure to JE. T cell responses can cross-react between JE vaccine and DENV in a co-endemic area, illustrating a need for greater knowledge on such responses to inform the development of next-generation vaccines effective against both diseases. clinicaltrials. gov (NCT01656200) Japanese encephalitis (JE) virus (JEV) is the cause of around 68 000 cases of encephalitis per year in Asia, mostly in children [1]. JEV is a single stranded positive sense RNA virus of the family Flaviviridae, genus Flavivirus. The JEV genome is 11 kb comprising a single 10. 3 kb open reading frame encoding three structural proteins (core, C; pre-membrane, prM; envelope, E) and seven non-structural (NS) proteins denoted NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5 [2]. JEV is transmitted naturally among birds and pigs by Culex mosquitoes, with humans infected coincidentally as dead-end hosts. Ecological control of JE is, therefore, unrealistic: vaccination is the only reasonable prospect of preventing disease in humans [3]. JE vaccines are effective, have been available for many decades [4], and appear to protect through neutralising antibody (NAb) against JEV [5]. Early JE vaccines were inactivated; subsequently an infectious attenuated vaccine (JEV SA14-14-2) has been developed which is safe and immunogenic [6–8]. In JE endemic areas a single dose is 94. 5% to 99. 3% effective [9,10] and gives durable protection for up to five years [11,12]. The vaccine was prequalified by the World Health Organisation in October 2013 [13]. JEV co-circulates in many parts of Asia with the related flavivirus dengue virus (DENV), currently the target of several developmental vaccines. T cell and antibody responses to DENV are cross-reactive, with clinically relevant effects, both potentially beneficial and harmful [14]. The sequence of exposure to JEV and DENV may also be relevant; DENV partially protects against JE [15], whereas JEV may predispose to worse dengue disease [16]. Cross-reactivity between DENV and other flaviviruses is less well studied, though we have recently described highly cross-reactive CD8+ T cell responses between JEV and DENV in South India, associated with asymptomatic exposure to JEV [17]. In addition to their clinical use, live attenuated vaccines may serve as models for viral infection in humans and allow the study of the development of anti-viral immune responses [18,19]. Greater knowledge of cellular responses to both JEV and JE vaccine was identified as research priority in a JE vaccine Cochrane review [20]. A protective role for T cell responses against JE is not clearly established, but both animal and human studies suggest a role for the cellular response as well as NAb in protection and/or recovery from JE [17,21–23]. In JE endemic areas most of the population are exposed by adulthood [24]. Therefore, live JE vaccination may mimic repeated exposure to wild type JEV in an immune host, giving information on the T cell response to wild type JEV as well as the vaccine. Although the live JE vaccine is predominantly used in children, the repeated blood sampling required makes such studies impractical in this age group. For these reasons we conducted an exploratory study of T cell responses after vaccination of adults with a single dose of JE vaccine SA14-14-2 in South India, a JE endemic area. Because dengue and JE vaccines will ultimately be used together in much of Asia, and South India is also dengue endemic, we also sought to determine whether T cell responses to JE vaccine could cross-react with DENV (or other flaviviruses), and whether there were JEV-specific T cell responses. Here, we report the first description of T cell responses to live attenuated JE vaccine SA14-14-2 in humans. Healthy adults aged 18 to 50 years were recruited into the study by advertisement and word of mouth and vaccinated at the Indian Institute of Science (IISc) or National Institute of Mental Health and Neurosciences (NIMHANS), both in Bengaluru, Karnataka State, India. Any laboratory workers who were being vaccinated because of potential occupational exposure to JEV were eligible. Because of concern that recruitment would be insufficient, an interventional protocol was developed to enrol additional participants. Participants who were being vaccinated on this protocol were screened for anti-JEV NAb before trial entry as JE vaccination was deemed more readily justified if NAb was not detectable. Participants with positive NAb or ELISpot screening assays were included in an observational study [17]. Participants on the interventional protocol also had HIV, hepatitis B and C excluded before entry. Apart from the pre-vaccination screening, both sets of participants followed an identical protocol and were analysed as one group. Exclusion criteria were previous administration of JE vaccine, pregnancy, immunosuppression of any cause, allergy or adverse reaction to a vaccine or component of the investigational vaccine, previous episode of encephalitis, use of any other investigational drug or vaccine within 30 days of vaccination. This was an open label single arm study. The target sample size was 20, chosen to give a reasonable chance of representing common HLA types in the South Indian population. No power calculation was performed and no comparative analysis was pre-specified. The primary endpoint was a description of the timing, magnitude, specificity and cross-reactivity of the T cell response to JE vaccine SA14-14-2 up to 8 weeks after vaccination. The number of participants seroconverting to the vaccine (defined as NAb titre > 1: 10 if negative pre-vaccine, or a four-fold increase over baseline titre), geometric mean NAb titre, the number of adverse events occurring one month after vaccination and number of serious adverse events at any time were secondary endpoints. Data were analysed descriptively; statistics were performed using R version 3. 1. 2 (www. r-project. org). Pre-vaccine samples were collected before subcutaneous injection of 0. 5 ml attenuated JE vaccine SA14-14-2 (Chengdu Biological Products, China) over the deltoid by a study physician (lot numbers 201107C017-1,201107C021-2,201103C002-2 or 201206C030-2; derived from primary hamster kidney cells). Blood (40-50ml) was drawn at 1,2, 4 and 8 weeks and monthly thereafter (in some participants). Peripheral blood mononuclear cells (PBMC) and serum were separated and cryopreserved. Safety was assessed actively using weekly symptom diaries for the first four weeks and passively thereafter. Participants were asked about any symptoms at each contact up to six months and were telephoned at this point if face-to-face contact was not possible. Adverse events were graded 1 (symptoms but no change in behaviour), 2 (symptoms sufficient to interfere with usual daily activities), 3 (symptoms prompting medical consultation) or 4 (hospital admission). The study was conducted according to the principles of the Declaration of Helsinki. All participants gave written, informed consent separately for screening and then for administration of the vaccine. The protocol was approved by the IISc Institutional Human Ethics Committee (ref 5/2011). The observational study was also approved by the Liverpool school of Tropical Medicine ethics committee (ref. 10. 59). The interventional protocol was registered at clinicaltrials. gov (NCT01656200). A library of 18 amino acid peptides overlapping by 10 corresponding to the entire JEV SA14-14-2 open reading frame based on the two sequences available in Genbank in 2010, accession numbers AF315119 and D90195 (see S1 JEV peptide library), was synthesised commercially (Mimotopes). Peptides were dissolved in dimethylsulphoxide (DMSO) and pooled according to JEV proteins: C/prM, E (2 pools), NS1, NS2a/NS2b, NS3 (2 pools), NS4a/NS4b, NS5 (3 pools). For proliferation assays adjacent pools (except C/prM) were combined. In cross-reactivity assays, the following peptide sets, obtained through Biodefense and Emerging Infection (BEI) Resources, NIAID, NIH, were used: DENV1 Singapore/S275/1990 E (NR4551), NS1 (NR2751), NS3 (NR2752); DENV2 New Guinea C (NGC) prM (NR506), E (NR507), NS1 (NR508), NS3 (NR509); DENV3 Philippines/H87/1956 NS1 (NR2753), NS3 (NR2754); DENV4 Dominica/814669/1981 E (NR512), DENV4 Singapore/8976/1995 NS1 (NR2755), NS3 (NR2756); West Nile virus NY99-flamingo382-99 prM (NR433), M (NR434), E (NR435), NS1 (NR436), NS3 (NR439). JEV infected cell lysate was prepared from Vero cells which were infected with JEV P20778 (MOI 5), fixed with 0. 025% glutaraldehyde (Sigma), washed with phosphate buffered saline, suspended in MEM/10% FCS and sonified in a Branson cup-horn sonifier (Model 450, Branson Ultrasonics, Danbury, CT) as previously described [25]. The antigen preparation was diluted to a stock containing 4 μg/ml of JEV E protein and used at a final concentration of 80 ng/ml. Interferon-gamma (IFNγ) enzyme linked immunospot (ELISpot) assays were conducted as previously described [17], using 2 x 105 fresh PBMC in triplicate, with peptides at 3 μg/ml and a final DMSO concentration of 0. 5% (pools), or 3 μg/ml and DMSO <0. 001% (individual peptides). PBMC were cultured in 100 μl RPMI supplemented with 2mM L-glutamine, 100U/ml penicillin, 0. 1mg/ml streptomycin (sRPMI) and 10% fetal calf serum (FCS, R10). The cut-off for a positive ELISpot was at least 50 spot forming cells (SFC) /106 PBMC and twice the background count. Proliferation assays used cryopreserved PBMC which were thawed, then rested overnight before labelling with Carboxyfluorescein succinimidyl ester (CFSE) as previously described [17]. Briefly, PBMC were labelled at 5–10 x 106 cells/ml of pre-warmed phosphate buffered saline (PBS) /1μM CFSE at 37°C for 10 minutes, followed by quenching with five volumes of ice cold R10 and two washes. After eight days in culture with 3 μg/ml JEV peptide pools, cells were stained with near-infra-red (IR) viability dye (molecular probes), anti-CD3-AF700 (clone UCHT1), anti-CD4-PE (clone RPA-T4), anti-CD8-APC (clone RPA-T8) and anti-CD38-PE-Cy7 (clone HIT2) fluorescent antibodies (all from BD biosciences) for flow cytometry. Peptide epitope mapping was done either by ELISpot, using an additional blood sample if the volunteer was available, or by expanding short term T cell lines (TCL) using left over PBMC. For cross-reactivity assays, short-term T cell lines (TCL) were always used for reasons of consistency. PBMC (2 x 106) were cultured with 5 μg/ml JEV peptide pools, or 10 μg/ml individual peptide, to which responses had been detected in ELISpot assays, in 1 ml sRPMI supplemented with 10% human serum, 10% Natural T cell growth factor/IL2 (“T-stim, ” Helvetica Healthcare) and 20 ng/ml recombinant human IL7 (R&D systems). TCLs were expanded for 7–10 days in culture, rested overnight in R10 without peptide, then stimulated with peptides for six hours in the presence of 10 μg/ml brefeldin A (Sigma). Intracellular cytokine staining (ICS) assays were done using whole blood, TCL (6 hours) or PBMC (overnight), stimulated with JEV peptides (3–10 μg/ml), peptide pools (3 μg/ml), JEV infected cell lysate, or approximately 103. 4 to 104. 4 plaque forming units (PFU) of JEV SA14-14-2 in the presence of 10 μg/ml brefeldin A during the stimulation. Following stimulation (and red cell lysis in the case of assays using whole blood), cells were stained with near infrared viability dye (Invitrogen) at room temperature in the dark for 20 minutes, fixed with 2% formaldehyde at room temperature for 20 minutes, and cryopreserved at -80°C in PBS/1% bovine serum albumin/10% DMSO. Later, cells were incubated in FACS perm/wash buffer (BD) at room temperature for 20–30 minutes followed by staining in perm/wash buffer for 30 minutes at 4°C. Antibody clones used for anti-CD3, CD4 and CD8 were as above. Antibodies used for TCL ICS were: anti-CD3-FITC, anti-CD4-PerCP-Cy5. 5, anti CD8-APC, anti-IFNγ-PE or PE-Cy7 (clone 4S. B3), anti-IL2-PE (clone 5344. 111) and anti-TNFα-PE-Cy7 (clone MAb11). Antibodies used for ex-vivo ICS were: anti-CD3-AmCyan, anti-CD4-PerCP-Cy5. 5, anti-CD8-Horizon v450, Anti-CD14-APC-Cy7 (clone MφP9), anti-IFNγ-PE-Cy7, anti-TNFα-APC, anti-IL2-PE and anti-MIP-1β-FITC (clone D21-1351). MIP-1β was from R&D systems, all other antibodies were from BD. Flow cytometry was performed using a BD Canto (TCL ICS and proliferation assays) or Canto II (ex-vivo ICS) cytometer. Ex-vivo ICS responses were considered positive if the responding population was at least 0. 02% of the parent gate and double the negative control value. Proliferation responses were considered positive if the CFSElo/CD38hi responding subset were at least 1% of the parent gate and double the negative control value. Analysis of T cells stained for >2 cytokines was done using Simplified Presentation of Incredibly Complex Evaluations (SPICE) software version 5. 35 with pre-processing in Pestle version 1. 7 [26]. Screening assays before vaccination measured the ability of heat inactivated sera at two fold dilutions from 1: 4 to 1: 32 to prevent destruction of a monolayer of PS cells infected with 100 plaque forming units of JEV P20778. Fifty percent plaque reduction neutralisation titres (PRNT50) were measured using LLC-MK2 cells for all study samples together at the end of the study using the same batch of cells and JEV stock to minimize variation in the assay. For PRNT50, sera were heat inactivated and assayed according to the method of Russell et al [27]. Viruses used were JEV SA14-14-2 (expanded by three passages in C6/36 cells), DENV1 16007, DENV2 16681, DENV3 16562, DENV4 C0036/06. PRNT50 values were calculated by probit regression. Seventeen participants were recruited into the study (Table 1); nine participants were vaccinated for occupational reasons and seven were vaccinated on the interventional protocol. Median age was 25 years, range 20–39 years. One participant withdrew after a week, a second donated 5ml per sample so had limited assays performed; both remained in the study for safety. Therefore 17 participants were evaluated for safety, 16 for seroconversion, 15 for T cell immunogenicity over 8 weeks, and nine for immunogenicity beyond 8 weeks. Six adverse events in three participants were reported in total, in the first 4 weeks two grade 1 and two grade 2 adverse events occurred, two further grade 2 events occurred >4 weeks after vaccination (Table 1). Four were febrile illnesses (two within 4 weeks), the others were dizziness with, and without, headache. All adverse events recovered spontaneously and no serious adverse events occurred. Two participants vaccinated for occupational reasons were JEV seropositive (PRNT50 >1: 10) before vaccination. In addition, despite negative screening neutralizing antibody assays using PS cells, two participants on the interventional protocol were found to be seropositive when neutralising antibody measurements were repeated using PRNT50 after vaccination. Because NAb at baseline was allowed in the occupational vaccinees, these participants remained in the analysis. Ten out of 16 participants (62. 5%) seroconverted to PRNT50 >1: 10 or >4-fold increase over baseline (Fig 1A and S1 Fig). Of the four seropositive participants at baseline, two seroconverted with 7. 2 and 9. 7 fold increases in PRNT50. Therefore, 12 volunteers were sero-protected after vaccination (75%). Reciprocal geometric mean titre (GMT) at week 4 was 18. 5 overall but 51 among those who seroconverted. The reciprocal GMT of maximal responses among seroconverters was 61. 5. PRNT50 waned after vaccination and, of the nine participants with data 16–26 weeks after vaccination, only four (44%) had PRNT50 >1: 10. Participant VA001/1 had a positive IFNγ-ELISpot assay (NS3) at baseline (but was vaccinated because of PRNT50 1: 6 and laboratory work with JEV), but made additional responses after vaccination. In total, 13 out of 15 participants tested (87%) developed new IFNγ-ELISpot responses, peaking two weeks after vaccination with significant increases over baseline at weeks 1,2 and 4 (Fig 1B). However, there was variation amongst the participants with some mounting the peak response later (S1 Fig). Proliferation responses were available for 13 participants for at least two time points. Interestingly, T cell proliferation responses were detected in most participants before vaccination, despite negative ELISpot assays and/or PRNT50. Although five volunteers appeared to make new T cell proliferation responses over the course of the study (S2 Fig), proliferation responses were variable and overall there was no significant difference from baseline values at any time point (Fig 1C). Example flow cytometry data of CFSE assays over the course of the study are shown in supplementary figure S3 Fig. The function and characteristics of ex-vivo T cell responses were investigated further by intracellular cytokine staining (ICS) and flow cytometry in 13 participants with positive ELISpot assays; responses were detected in five (ELISpot is a more sensitive technique than ICS). CD4+ T cell responses were detected in three participants; CD4+ and CD8+ T cell responses in two. Flow cytometry data showing CD4+ and CD8+ T cell responses throughout the study from participant VA019/3 are shown in Fig 2, though sample limitation meant that we could not perform all these assays on every participant. Cytokine responses were small (Fig 3A) and polyfunctional T cell responses to JE vaccine were rare, in contrast to our recent findings in natural exposure and recovered JE [17]. In CD4+ T cell responses, IFNγ+ or IL2+ only populations dominated (Fig 3B), indicating that IFNγ-ELISpot alone may not detect all such responses. Participant VA001/1 (who showed a CD8+ T cell response at baseline) was an exception; we identified a polyfunctional (IFNγ/TNFα/IL2 triple positive) CD4+ T cell response at week 16 after vaccination. Most participants made IFNγ responses to >1 peptide pool (median five) and all viral proteins were targeted. The total magnitude of the ELISpot response correlated with the number of responding pools (Spearman’s R = 0. 78, p = 0. 0005, Fig 4A) indicating that there were no strongly immunodominant pools. Normalised to protein size, NS1 elicited responses most frequently (Fig 4B). In six participants, further experiments were conducted to identify some of the epitopes recognised after vaccination with JEV SA14-14-2. Responding peptide pools were either mapped ex-vivo by ELISpot, or short-term T cell lines (TCL) were expanded to peptide pools showing responses in ex-vivo assays. The peptide pools were then deconvoluted first into “mini-pools” of 6–10 peptides which were used to stimulate short term TCL in ICS assays (also allowing determination of the responding subset), followed by mapping down to individual peptides. Fifteen peptides were mapped (Fig 4C and Table 2) and a further six 46 to 90 amino acid regions (Fig 4D and Table 2) eliciting IFNγ responses were identified (participant VA023/1 had a response mapped to mini-pools only). In participant VA019/3 an antigenic region corresponding to amino acids 214–303, in prM, overlapped with peptide TRTRHSKRSRRSVSV, amino acids 209–223. The response to amino acids 214–303 was larger than the response to 209–223, making it unlikely the response to 214–303 was accounted for by only the 10 amino acid overlap. The peptides identified were mostly in the prM, NS1 and NS3 proteins (Fig 4C) with one identified in E protein. Table 2 shows all the peptides and antigenic regions identified. All four DENV serotypes were detected in Karnataka State in the two years prior to this study (S1 Data). Therefore, in some participants, we investigated whether the IFNγ responses identified cross-reacted with DENV. Two participants, VA012/3 and VA020/1, had responses that were not present before vaccination mapped to individual peptides by ex-vivo ELISpot assays. Partial peptide libraries from DENV serotypes 1,3 and 4 and complete libraries from DENV2 and WNV were available (see methods). To test for cross-reactive responses, short term T cell lines (TCL) were expanded by culturing PBMC from the volunteers in the presence of “T-Stim” (IL2), IL7 and the relevant JEV peptide at 10 μg/ml for 7–10 days. The same TCL were then stimulated with JEV peptide alongside variant peptides from DENV or WNV selected on the basis of a ClustalW protein alignment. Because the cells specific for the JEV peptide had expanded in culture (typically from around 0. 1% (Fig 3A) to 5% (Fig 5) ), a response to the variant peptide of equivalent magnitude to the JEV peptide indicates that it is likely to be the same cells being triggered by the variant peptide and the response is therefore cross-reactive. Participant VA012/3 had high levels of NAb to DENV4 and intermediate levels of NAb to DENV2 and DENV3 at baseline, and no detectable JEV NAb. This participant developed a CD8+ T cell response to peptide TAVLAPTRVVAAEMAEVL (NS3), subsequently mapped to APTRVVAAEM (S4 Fig panel A), very similar to a previously described partially mapped HLA B*07 restricted DENV4 epitope, LAPTRVVAAEME [28]. A short-term T cell line recognised the very close DENV1 sequence APTRVVASEM equally well (Fig 5A); the sequence in DENV2-4 is identical to JEV. Interestingly, this subject did not seroconvert to JE vaccine. Participant VA020/1, who had the highest titre of NAb to DENV1 with lower levels to DENV2 and DENV3 and no JEV NAb at baseline, developed a CD8+ T cell response to GATWVDLVL (E), based on overlapping peptide ELISpot assays and confirmed by flow cytometry with truncated peptides (S4 Fig panel B). This was confirmed by expanding a short-term TCL (Fig 5B); the epitope cross-reacted with a variant peptide conserved in DENV1 and DENV3. In a subsequent experiment variant peptides from DENV2 and DENV4 were not recognised, consistent with the serology assays suggesting DENV1 exposure (S4 Fig panel C). These responses represent either priming by JE vaccine that cross-reacts with DENV, or priming by DENV, boosted by JE vaccine, that cross-reacts with additional DENV serotypes because of close sequence similarity. Participant VA019/3 was DENV exposed (DENV2 PRNT50 1: 538), but also had JEV NAb (titre 1: 123) before vaccination. This participant had several CD4+ responses mapped by expanding short term TCL to responding pools in the ELISpot assays using 5 μg/ml equivalent concentration of each peptide. The short term TCL were then stimulated with smaller pools (“mini-pools”) followed by deconvolution down to individual peptides (Table 2), Finally, the same TCL were then tested with variant peptides from DENV and WNV. As before, because TCLs were expanded with JEV peptides, responses to variant peptides indicate cross-reactivity, though in this case all but one of the responses were JEV specific (Table 3). Participant VA001/1 carries the HLA B*15: 01 allele and had high levels of DENV2 NAb and intermediate levels to other serotypes at baseline (Fig 6A). Peptide ALRGLPVRY was mapped before vaccination, and a cross-reactive response was identified to the previously described HLA-B*15 restricted peptide ALRGLPIRY from DENV2/4 and WNV [29]. The corresponding vaccine library peptide VVAAEMAEVLRGLPVRY had a modest Val for Ala substitution corresponding to position 1 of the 9-mer (the same position as the NS3 peptide TAVLAPTRVVAAEMAEVL recognised by participant 012/3), and is predicted to bind the same HLA allele as the wild type peptide with slightly lower affinity (IEBD. com [30,31]). The ex-vivo IFNγ response to the pool containing this peptide did not change after vaccination or with seroconversion (Fig 6B), nor did the responses to the wild type and DENV peptides at week 16 (Fig 6C), though other responses developed. The SA14-14-2 peptide produced a smaller IFNγ response, though the response was still detectable (Fig 6C left panel). Short-term T cell lines expanded with JEV wild type peptide before and after vaccination (Fig 6D & 6E) confirmed that IFNγ responses were smaller to the vaccine peptide (Fig 6E). However, when analysed for additional cytokines, the total number of responding cells was similar, with the difference mostly accounted for by MIP-1β single positive cells (Fig 7A & 7B). MIP-1β may have a lower triggering threshold than other cytokines [32], suggesting that the vaccine variant epitope is less efficient than the wild type in this case. This represents an example where responses to DENV2/4 and JEV are highly cross-reactive with each other, but were less efficiently cross-reactive with the SA14-14-2 variant. Together, these data show that T cell responses induced to JEV vaccine SA14-14-2 can recognise wild type JEV, and that responses primed to natural flavivirus infection can cross-react with JEV vaccine SA14-14-2 in some instances. These data are consistent with our recent finding that CD8+ T cell responses to JEV are highly cross-reactive, whereas CD4+ responses are much less so [17], although the small number of participants in the present study prevents generalisation of these findings. We have shown that, in participants resident in a JE endemic area, T cell IFNγ responses are detectable after vaccination with JEV SA14-14-2, are modest in magnitude, peak within eight weeks of vaccination, and return to baseline levels by 4–6 months. Determination of epitope specificity and cross-reactivity in four participants showed that some responses to JE vaccine can cross-react with DENV, and in one case a variant epitope of SA14-14-2 was recognised less efficiently than the JEV wild type peptide by memory CD8+ T cells from a pre-existing response. Our study found a seroconversion rate of 62. 5%, sero-protection rate of 75% and GMT of 18. 5 four weeks after vaccination with a single dose of JEV SA14-14-2. This is lower than studies of single dose JEV SA14-14-2 in children, where the seroconversion rate is 80–99% and GMTs 4 weeks after vaccination range from 56–370 [7,8, 33]; or even higher after previous JEV exposure or vaccination in a DENV non-endemic area (Korea) [34]. However, our findings are consistent with a recently published clinical trial using SA14-14-2 in India in which 57. 7% of participants seroconverted at 4 weeks, including 54. 9% of adults aged 18–50, a similar age group to this study [35]. In the study of Singh et al., seroconversion in children aged 1–6 years was 58. 8%, suggesting it is the environment and not age driving this effect. The greater number of participants showing T cell responses than NAb, and the presence of proliferation responses at baseline, indicate that measuring NAb alone may not be the only potential test of JE-immunity. NAb titres to JE vaccines can fall below “protective” levels after vaccination in the presence of protection and rapid recall responses [36,37], a feature also observed following HBV vaccination, where B cell memory pools may be detected [38]. DENV circulates in South India where this study was conducted. Four participants in whom DENV PRNT50 were measured all showed neutralising antibody to DENV, indicative of past infection, as did a larger group recently recruited in Karnataka State, South India [17]. One possibility is that immune interference by DENV may account for the lower seroconversion rate after JEV SA14-14-2 in Indian adults. Experiments are underway to investigate the possibility of interference by DENV exposure. So far, five more participants have been tested for DENV3 NAb post JE vaccine, including two participants who did not seroconvert. Preliminary data suggest our study population is highly DENV exposed, and we have so far not identified any evidence of an increase in DENV NAb titres after JE vaccine, or an original antigenic sin type response. Cross-reactive T cells against DENV are readily detectable after natural infection or attenuated tetravalent dengue vaccine (TV003) [32,39] and have been associated with pathology [40] but also protection [41,42]. One hypothesis for the disappointing results with the new dengue vaccine, Dengvaxia, in some studies [43,44] is that, because the vaccine is a chimera based on yellow fever 17D, the appropriate T cell responses are not elicited [14]. In this study, as well as in our earlier work [17], we have observed a high degree of T cell cross-reactivity between JEV and dengue viruses in adults in this JE/dengue co-endemic area. This may reflect priming by multiple flavivirus exposures, whereby the most conserved epitopes, which receive the largest number of re-stimulations, are the most readily detectable. This is consistent with observations in a humanised animal model and following tetravalent vaccination [39,45]. However, this is not always seen in dengue endemic areas, where a sizeable fraction of the T cell response is directed against serotype specific epitopes even in populations with multiple DENV exposures [46]. Conservation between JEV and DENV epitopes and the cross-reactivity observed in most individuals who were tested here suggests that a better understanding of how such responses develop and whether they are protective would be of benefit. There may be strategies that could include such epitopes in next generation vaccines, such as a chimeric JEV/DENV vaccines [47,48], or heterologous prime/boost immunisation schedules with dengue and JE vaccines. The ex-vivo T cell cytokine profiles after vaccination in this study were different from those seen in our recent study of circulating memory T cell responses to JEV [17]. In our previous study, 75% of responding CD8+ T cell responses in healthy, JEV exposed people made two or more cytokines; CD4+ T cell responses were very infrequent. Compared with recovered JE patients, where CD4+ T cell responses were much more frequent, CD4+ T cell responses in this study showed many fewer TNFα secreting cells and cells making two or more cytokines; instead IFNγ and IL2 single positive cells dominated the response. High TNFα levels have been linked to mortality in JE [49], and this finding provides further support for our earlier observations linking CD4+ T cell derived TNFα with pathogenesis in JE. JE vaccination is effective even if the vaccine virus is relatively genetically distant from circulating virus [5] and protection may be long lasting even in the absence of NAb [50]. In our study, 10 individuals were NAb negative at baseline and had proliferation data available. Nine had T cell proliferative responses at baseline, reflective of ‘central’ memory (which presumably also make cytokines, though we did not measure this) rather than IFNγ-ELISpot assays, which, by virtue of their much shorter incubation period, are biased towards ‘effector’ memory [51]. The combination of proliferation in the absence of NAb and ELISpot responses may reflect a common, but hitherto unrecognised, state of long term immunity, mediated by long lived memory T cells [52]. In summary, here we have given the first description of T cell responses to JE vaccine SA14-14-2 in adults in a flavivirus endemic area, most of whom have evidence of prior adaptive immunity against JEV. We have shown that (i) T cell responses were detected in most volunteers after vaccination and cross-react with other flaviviruses; (ii) seroconversion after vaccination of adults with single dose JEV SA14-14-2 in an endemic area is relatively poor and (iii) T cell proliferative responses were detectable before vaccination in most volunteers, even if ELISpot and NAb assays were negative. T cell proliferation is worthy of investigation, in JEV naïve subjects, as an additional immunologic measure of response to vaccine [53]. To what extent prior exposure to related flaviviruses and associated T cell cross reactivity could influence vaccine responsiveness, especially in the B cell compartment, requires further study. Some of the questions surrounding the nature of the response to JEV SA14-14-2 can best be addressed in populations without extensive prior flavivirus exposure. | Title: Cellular Immune Responses to Live Attenuated Japanese Encephalitis (JE) Vaccine SA14-14-2 in Adults in a JE/Dengue Co-Endemic Area Summary: The Flavivirus genus member Japanese encephalitis (JE) virus (JEV), causes severe brain disease in tens of thousands of children across Asia every year. JE is vaccine preventable, and the immune response to JEV plays a major role in disease outcome. However, the response to JEV is hard to study as JE affects young children in rural areas. Related flaviviruses, such as dengue virus (which has no good vaccine), can influence the outcome of JE, probably due to cross-reactive immune responses. T cells (a subset of white blood cells) respond to virus infections, but we know little about the timing and nature of T cell responses to JEV after infection and whether T cells are protective against JEV. We used the live JE vaccine SA14-14-2 as a model to study the immune response to JEV. We found T cell responses frequently after JE vaccination. In this small group of volunteers, many of whom were exposed to dengue virus, most of the T cell responses tested cross-reacted between JEV and dengue virus. However, only about two thirds of people made antibody responses to the vaccine. Studying these responses could help design new vaccines for use against JE and dengue in Asia. | 9,160 | 307 | lay_plos | en |
Summarize: BACKGROUND OF THE INVENTION The present invention relates to a powered surgical cutter and more particularly to a sterile disposable powered surgical cutter particularly adapted to perform eye surgery by cutting and removing vitreous from inside the anterior aqueous chamber of the eye. The role of vitreous in retinal detachment has been recognized for many years, but the vitreous remained more or less untouched until Shafter (1958) replaced it with human vitreous implant. (D. M. Shafer, The Treatment of Retinal Detachment by Vitreous Implant Transactions American Academy Ophthalmology and Otolarying. 61:194-200, 1958). Later, Michaelson described in 1960 an instrument capable of cutting the vitreous bands. (Michaelson, Transcleral Division of Mid-Vitreous Membrane Under Visual Control, British Journal of Ophthalmology, 44:634-635, 1960). Cibis in 1964 replaced the vitreous with silicon and devised instruments for cutting the vitreous bands. (P. A. Cibis, Vitreous Transfer and Silicon Injection Transactions American Academy Ophthalomology and Otolarying. 68:983-997, 1964). Freeman, Schepens, and Anastopolous introduced their vitreous scissors in 1967 (Vitreous Surgery II Instrumentation and Technique Arch. Ophthal. 77:681-682, 1967). Kasner reported on Vitrectomy in 1968 (D. Kasner Vitrectomy: A New Approach to the Management of Vitreous Highlights Ophthalmology. 11:304-309, 1968 (published in July 1969)). In addition, Machamer, Buettner and Norton in 1970 developed a vitreous cutter-sucker infusion instrument (Vitrectomy--American Academy Ophthalmology and Otolarying. Las Vegas, 1970). A history of the development of such cutting devices is described in the AORN Journal, November 1973, Vol 18, No. 5 page 908 in an article entitled Pars Plana Vitrectomy, a New Treatment for Vitreous Disease. DESCRIPTION OF THE PRIOR ART The problems inherent in the techniques, methods and apparatus relating to vitreous removal are disclosed in the Annals of Ophthalmology, September 1974, page 947 in an article, entitled Anterior Vitrectomy in Cataract Surgery, Aphakic Keratoplasty and Patients with Vitreous Pathology Using a Simple Vitreophage, and in the American Journal of Ophthalmology, June 1974, page 824, in an article entitled Companied Ketratiplasty and Cataract Extraction. In accomplishing eye surgery in the anterior aqueous chamber it has been found that after the incision is made it is sometimes necessary to draw off vitreous or in turn add vitreous fluid. Apparatus for accomplishing these ends is discussed in both of the above-mentioned periodicals. Since vitreous is composed of hyaloronic acid and collogen fiber the substance cannot be removed by suction alone, and therefore, the vitreous fibers must be incised. Various vitreous cutting apparatus and concepts are well known in the prior art as disclosed by the following patent references. U.S. Pat. No. 3,734,099 discloses a hand held powered surgical cutter utilizing a cutter tip having an outer fixed tubular cutter in which an inner tubular cutter is rotated. The cutter tip is inserted into the eye and the inner cutter is rotated cutting the vitreous. The pieces of the severed vitreous are then removed through the interior of the inner tubular cutter to a disposal means. U.S. Pat. No. 3,618,861 discloses another similar hand held tubular cutting apparatus adapted to cut the vitreous in the eye and suck the cut vitreous to disposal means. The use of ultrasonic energy in a surgical instrument to cut the vitreous is taught by U.S. Pat. No. 3,806,787. The apparatus has a probe head with bores cut therein to receive both suction means adapted to remove material emulsified by the probe and fluid transfer means to transmit irrigation fluid into the eye. Another hand held vitreous cutter is disclosed in U.S. Pat. No. 3,732,858 which utilizes a rotating blade mounted in a tube to cut the vitreous material. As the vitreous is cut suction means draw the vitreous material back up through the tube housing of the cutting blade to an area for disposal. The apparatus is also shown in another embodiment adapted to be used with infusion means for submitting or directing fluid into the eye. The present invention represents an improvement over this previously identified prior art. One problem encountered with rotating blade assemblies is that the rotating blade can "spool" or "wind-up" the vitreous fiber around the blade. This may cause an excessive amount to be removed, with damage resulting to the interior of the eye. The use of a reciprocating vitreous cutter apparatus is disclosed in U.S. Pat. No. 3,776,238. This reference discloses a first tube containing an inner reciprocating cutter tube powered by an electromagnetic coil positioned on the handle of the tube. The cutting action of the apparatus depends upon the sharp end of the inner tube repeatedly striking the base plate at the end of the outer tube in the manner of a cleaver. This striking action in time dulls the cutter blade and in some instances damages the cutter blade. All of the previously disclosed apparatus must be sterilized after each operation. A common sterilization technique in hospitals is to sterilize the units with ethylene oxide. The construction of the prior apparatus is such that the cutter blade assembly which is hardest to sterilize, is difficult to reach in sterilizing processes, expensive to manufacture and is constructed to form a complex cutter assembly. Furthermore, the drive mechanism of the cutter blade assembly has to be sterilized after each use resulting in damage to the mechanism after repeated sterilization not to mention the time, labor and expense required for each sterilization. The present invention is thus constructed with a simple disposable reciprocating cutter assembly which can be disposed of preferably after only one use. The novel use of a removable protective bag which is sealed by the disposable cutter assembly to the drive housing prevents the drive housing from being contaminated so that the drive housing can be reused within minutes or within a minute after its use in the previous operation. Due to the protective sheath, the housing does not contact surgeon or patient. The drive unit can be used and reused indefinitely without sterilization, since the sterile sheath eliminates potential cross-contamination. Because of the self contained power source the instrument can be used in the field or in other remote places where power is not available. Thus the invention provides a sophisticated low cost sterile medical instrument available for use under any environment or condition. Additionally the self-contained power source provides additional convenience since no power cords or air lines are required in the operating room. SUMMARY OF THE INVENTION The surgical cutter of the present invention is an improvement over appartaus and methods previously disclosed in the prior art and comprises a drive housing having motor means and a power source mounted in the drive housing. An elongated external removable cutter assembly is attached to one end of the housing. The external cutter assembly comprises an outer housing mounted to the drive housing, a drive transfer assembly mounted in the outer housing, a closed end tubular blade housing secured to the outer housing and a reciprocating blade mounted within the tubular blade housing. The reciprocating blade is urged forward in the tubular blade housing by a cam and cam follower assembly which causes the blade to pass by an aperture formed in the closed end of the tubular blade housing. A coiled spring assembly urges the blade rearwardly in the tubular blade housing when the blade is not driven forward by the cam assembly. The reciprocation of the blade within the tubular blade housing beyond the opening will shear off tissue drawn into the opening formed in the end of the tubular housing and when used with suction provided by a syringe or other suitable suction means the cut material will be drawn through the interior of the cutter tip assembly into a suitable depository. This blade, therefore does not strike the end of the tube but rather cuts the vitreous by using the walls of the tube housing. A protective sheath is adapted to fit over the drive housing and into a channel formed on the end of the drive housing so that it engages the cutter assembly to form a fluid seal. The outer housing of the cutter assembly preferably has an end skirt construction which fits over the motor end of the drive housing and its associated sheath to seal or contain the non-sterile motor unit. Although the invention will be set forth in the claims the invention itself and the manner in which it may be made and used, may be better understood by referring to the following description taken in connection with the accompanying drawings forming a part hereof in which like reference numerals refer to like parts throughout the several views and in which: BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view showing the powered surgical cutter of the present invention; FIG. 2 is a perspective view of the disposable sterile sheath assembly used with the powered surgical cutter; FIG. 3 is a cross-sectional view of the disposable cutter head of the invention shown in FIG. 1; FIG. 4 is a side elevational view of the cam shown in FIG. 3; FIG. 4(a) is a rear elevational view of the cam shown in FIG. 4; FIG. 4(b) is a side elevational view of the cam shown in FIG. 4 after a quarter rotation. FIG. 5 is a cross sectional view of the cam follower shown in FIG. 3; FIG. 5(a) is a front elevational view of the cam follower shown in FIG. 3; FIG. 5(b) is a side elevational view of the cam follower shown in FIG. 5(a) after a quarter rotation: FIG. 6 is a side view of the motor end of the drive housing partially in section; FIG. 7 is a perspective view of the invention showing the instrument drive housing about to be placed in a sterile surgical receptacle; FIG. 8 discloses the instrument of FIG. 7 inside the sterile sheath with the end of the instrument and sheath partially shown in cross section to show the relation of the instrument with the sheath; FIG. 9 discloses the instrument with the cutter head placed on the sheath and drive housing and locked into position; FIG. 10 discloses a cross sectional view of the cutter head housing; FIG. 11 shows a cross sectional view of the drive housing; FIG. 12 discloses a partial enlarged cross sectional view of FIG. 11 taken along lines 12'--12'; and FIG. 13 discloses an enlarged side view of the end of the cutter head housing taken along lines 13'--13' of FIG. 10. DESCRIPTION OF THE PREFERRED EMBODIMENT Referring now to the drawings, the disposable surgical cutting instrument 10 of the present invention has a drive housing 12 of generally cylindrical form designed to be easily held in the surgeons hand. It should be noted at the outset that all parts of the invention which could possibly come in contact with the patient during an operation are sterilized and pyrogen free. A protective latex sheath 14 is adapted to be placed over the drive housing 12 to protect the non sterile drive housing from contaminating when a surgical operation is performed. A disposable cutting head 16 is mounted on the drive housing 12 in engagement with the sheath 14. The disposable cutting head is driven by a drive shaft of a micro motor mounted in the drive housing so that only the cutting head 16 and sheath 14 comes into contact with blood, vitreous and other materials during an operation. The drive housing 12 as shown in FIGS. 6-9, 11 and 12 is constructed of two components comprising a power source section 18 and a motor section 20. The power source section 18 has one end provided with an outer threaded surface 19 which is adapted to be screwed into a threaded inner surface 22 of the motor section to form the complete drive housing 12. A free seated coiled spring 24 is seated in one end of the power source section 18 and abuts against a battery 26 to urge the battery toward a standoff sleeve 28. The battery is slidably mounted in the housing for easy replacement and does not engage the standoff sleeve. The sleeve merely prevents electrical contact in case the battery is inadvertently installed backward. The standoff sleeve 28 is secured to a bulkhead 30 by adhesive means such as cement or press fit on the conductor. One end of the battery is engaged with a modified rivet contact 32 that is riveted in place. The bulkhead 30 is positioned within the motor housing section by a retaining ring 31 which is mounted in a channel cut in the housing. A set screw 34 contacts a motor support 36 mounted to the housing and holds the motor in place. A stripped wire 38 is bent and squeezed between the micromotor 40 and motor support 36 to form an electrical connection. The micromotor 40 is mounted in the motor housing and is electrically connected to the contact 32 by wire 42 so that when switch 44 is depressed an electrical contact is made between the battery and the micromotor, energizing the micromotor 40 to drive a hexagonal shaped drive shaft 46 of the micromotor. It should be noted that while the preferred embodiment discloses a hexagonal drive shaft 46, the drive shaft could be octagonal, square, flat or shaped in any other manner. The drive shaft end of the motor section forms a seat or channel 48 depending upon its construction and has two locking pins 50 protruding inwardly from the collar to fit bayonet slots 51 formed in the disposable cutting head 16. The drive housing is covered by using a sheath assembly 52 comprising a sleeve 54 having a tapered end 56 upon which the latex sheath 14 is stretched and mounted. The other end 58 of sleeve 54 is open and flanged outward so that the drive housing can be easily inserted into the mounted sheath. The flexible latex sheath 14 has an open end 62 formed with a lip 64 which fits into the seat 48 defined in the motor section of the drive housing. The other end 66 of sheath 14 is closed. After the drive housing 12 has been deposited into the protective covering of the latex sheath the sleeve 54 is removed and lip 64 is inserted into the seat 48 formed in the end of the housing. The cutter head 16 is constructed with a body 70 having a varying diameter axial bore 71 cut therethrough. The bore 71 is cut in a series of steps so that the diameter narrows after each step. The steps form shoulders 69, 72, 73 and 74. Shoulder 73 is adapted to seat retainer ring 92, and seal 100. The cutter head body 70 is provided with a second bore 75 and a tubular extension 76 axially aligned with the bore allowing a suction or irrigation device to communicate with bore 71. Thus a syringe 102 can be connected to the tubular extension 76 by a hose 104 to provide suction to a chamber portion 71(a) and the interior of tube 94 so that material severed by tube blade 95 travels through the tube into chamber portion 71(a), through bore 75 into a suitable disposal means such as the syringe 102. Alternatively, a saline solution or other suitable fluid can travel the same path through the cutter tube 94 to the eye. The body 70 has a generally tapered exterior surface and is cut at one end in an annular manner to optionally receive a skirt 77 which is cemented to the annularly cut end of the body. The outer surface of the annularly cut end or tip 78 is provided with two bayonet slots 51. When the tip 78 is inserted into the motor section, the tip 78 fits around the hexagonal drive shaft 46 of the micromotor with the skirt 77 projecting over the outer surface of the motor section and the latex sheath 14. A cam 80 also serving as a drive coupling member is positioned in the cutter body bore 71 and bears against retaining ring 93 which positions the cam in the cutter body bore 71. The cam 80 has an axial bore of hexagonal configuration at one end of its suitably shaped configuration to slidably receive and hold the drive shaft 46. The cam 80 has a smooth inclined cam face 82 which contacts a cam follower assembly 84 held against the cam face by a coil spring 86. The cam follower assembly 84 comprises a face 88 which is hexagonal in shape slightly smaller than the hexagonal bore of the body which permits axial movement of the cam follower assembly but not rotation of the cam follower assembly. In this manner rotary movement of the cam is converted to reciprocating movement of the cam follower. Bearing against the reverse side of face 88 is a spring 86 which is seated against retaining ring 92 mounted in the bore of the body. The cutting tube blade 95 is mounted in the bore in the stem of the cam follower and reciprocates therewith. The tube blade 95 is positioned within the outer stationary tube 94 fixed to the end of the nose body in a cap member 97. The inner cutting tube blade 95 and the outer tube 94 may be of any configuration such as round, square, hexagonal, oval, octogonal, etc., so long as they are matched for a close telescoping fit in the area where cutting takes place. The outer tube 94 has an aperture 98 which may be of any preferred shape or size in the side wall near the end of the outer tube to permit entry of the vitreous material when suction is applied. The relative length of the inner and the outer tube are such that the sharpened open end of the inner tube 94 passes across the aperture 98 with each down stroke of the cam. Each upstroke of the cam uncovers the aperture 98 to permit entry of the vitreous material. The upstroke is accomplished by the action of the coil spring 86 which is seated on retaining ring 92 pushing against the face of the cam follower and driving it towards the cam face. The down stroke action of the blade shears the vitreous material between the tube cutting end 99 of the inner blade 95 and the edge of the aperture. If desired the aperture 98 may be cut at an angle so as to provide the sharpest cutting surface possible. The cam follower assembly is mounted in the retainer ring which abuts a circular seal 100. The seal 100 prevents entry of foreign material from cavity 71(a) into the bore of the cutter head. The reciprocating cutter tube blade 95 is also provided with an aperture 101 which allows the sheared vitreous to be drawn upward through the inside diameter of the inner cutting tube and out through the opening 101 into the suction chamber 71(a) and then into the syringe 102. The external fixed thin walled tube 94 projects from the end of the body 70 with the distal end 99 being formed into a smoothly blended closure. The other end 103 of the outer tube 94 is open. The open end is preferably press fitted into nose bushing 97, but it can be cemented if desired. The clear plastic retainer ring 92 and seal 100 are mounted around the cam follower 84 to keep fluids from entering into the cavity housing the coupling means, thus preventing any leakage of vitreous material, fluid, blood or other materials past the shaft. The seal also prevents air from being drawn into the syringe via motor shaft leakage. The cam follower shaft 105 and ring 92 and seal 100 effectively seal off bore 71 to form the fluid receiving chamber 71(a). A syringe 102 is connected to the tubular extension 76 by flexible tubing 104 which is inserted over the tubular extension 76 on one end and onto a female luer-lok of the syringe on the other end. Thus, suction or fluid can be transmitted to tube 95. In the surgical operation and before the actual cutting of the vitreous is to take place, the surgeon takes the drive housing 12, drops it into the sleeve 54 made of a suitable material and into an associated sheath 14. The sleeve 54 is removed and sleeve lip 64 is inserted into the seat or channel 48 of the drive housing and the disposable plastic cutter head 16 is mounted on to the housing so that bayonet slots 51 cut into the cutter head are mounted over the pins 50 of the motor section with the cutter head then being depressed and turned so that it is locked into place on pins 50. Simultaneously, the outer skirt 77 extends down over the drive housing which is covered by flexible sheath 14. The lip 64 in combination with the drive housing and cutter head forms a fluid tight seal so that any fluid that might enter under skirt 77 is prevented from contacting the motor housing by sheath 14. The syringe 102 is then connected to the tubular extension 76 so that suction can be applied. When the opening is made in the anterior aqueous chamber the cutter tube blade 95 is inserted in the chamber. The surgeon depresses the switch 44 of the micro motor 40 through the protective sheath 14 thereby activating the motor and thereby rotating the cam 80 and reciprocating the cam follower 84 and associated tube blade. The tube blade 95 is constantly urged rearward through coil spring means 86 in the cutter head body. The spring means seats between the rear surface of the cam follower face and the cam follower retainer ring 92. As suction is applied to the instrument vitreous material is drawn into the aperture 98. The rapidly reciprocating spring loaded tube blade 95 fits flush against the aperture 98 and severs the vitreous. The suction carries the vitreous into the tube blade with the construction of the blade being such that the vitreous is passed through aperture 101 and is carried into chamber 71(a) of the cutter head and from there into a syringe or other suitable material disposal means. The cutter of the present invention, although specifically designed for eye surgery could also be used to remove any other body tissue in the same manner. Because of the sealed nature of the internal structure of the cutter head, foreign materials cannot proceed past the seal 100 or chamber 71(a) so that no foreign materials contact the hexagonal drive shaft or interior of the drive housing. After the operation has been completed the surgeon rotates the cutter head thereby releasing it from its bayonet connection and removes the head from the drive housing. The head is then thrown away and the latex protective sheath 14 is removed from the drive housing so that the drive housing is ready for the next operation. When the next operation is ready to begin a new sterile disposable cutter head and a new sterile disposable sheath are placed on the instrument as previously indicated so that no problem of sterilizing the instrument is incurred with the external parts of the instrument being maintained in a sterile condition. This effectively eliminates patient-to-patient cross contamination. In the foregoing description the invention has been described with reference to a particular preferred embodiment although it is to be understood that the specific details shown are merely illustrative and that the invention may be carried out in other ways without departing from the true spirit and scope of the following appended claims. | Summary: A surgical instrument comprising a housing with a motor and source of power contained in the housing. A removable sheath is placed over the housing and a cutter assembly is removably mounted to the housing so that the housing is protected from external materials and contamination. The cutter assembly has a body, a tube projecting from the body, a reciprocating blade positioned in the tube and a cam drive transfer mechanism mounted in the cutter body which transmits motion to the blade from the motor shaft. The tube defines an aperture in its side and the blade as it reciprocates in combination with the walls defining the aperture shears vitreous material entering the hole. A second passage is formed in the cutter body communicating with the tube to allow pressure differentials to be exerted to the tube. The cutter head and removable protective sheath are replaced after each successive operation in order to eliminate patient-to-patient cross contamination. | 5,588 | 198 | big_patent | en |
Write a title and summarize: Claude, un habitant du Val-d'Oise, nous fait part des faits suivants: « Le 26 septembre 2017, j'emprunte la ligne J du Transilien à La Frette-sur-Seine, avec un billet SNCF-RATP, que je valide, pour me rendre à la gare Saint-Lazare.... « Cf photo ci-dessus : les chiffres en violet prouvent que j'ai validé le ticket. A Saint-Lazare, je cherche à prendre la ligne 13 du métro, mais mon billet ne fonctionne pas. Je m'adresse au guichetier, qui constate qu'il s'est 'démagnétisé', et m'ouvre le portillon, afin que je passe. « Lorsque j'arrive à la station Champs-Elysées-Clemenceau, je suis contrôlé... et verbalisé, du fait que mon ticket est 'illisible par la machine, car démagnétisé'. J'essaie d'expliquer que je l'ai validé à La Frette, comme le montrent les chiffres en violet, mais le contrôleur ne veut rien savoir, et m'inflige une amende de 50 euros pour le motif de 'billet Illisible/déchiré' (photo-ci-dessous). Comme je refuse de payer immédiatement, il me dresse un PV en me réclamant 100 euros. « Quand je reviens le soir à Saint-Lazare, je repasse au guichet d'où l'on m'avait ouvert le portillon, à 14 heures. Le guichetier n'est pas le même. Mais, désolé de ce qui m'est arrivé, il me conseille de contester l'amende. « J'écris donc aussitôt au service client de la RATP. Le 3 octobre, celui-ci accepte, 'compte tenu des circonstances particulières décrites', de réduire le montant de l'amende à 50 euros. « Estimant toujours ne pas mériter cette amende, je m'adresse à la médiatrice de la RATP, Mme Betty Chappe. Elle me répond le 22 janvier. ».. Illisible donc non valide Voici ce que la médiatrice lui répond: « Le service client de la RATP indique (...) que vous avez été verbalisé pour le motif de 'Titre de transport non validé' » Or, le motif figurant sur le PV de Claude est 'billet Illisible/déchiré' « La RATP considère que vous avez été régulièrement verbalisé, conformément à la réglementation en vigueur et à son objectif de lutte contre la fraude. » « Ceci étant, continue la médiatrice, je note, après vérification du titre de transport joint à votre saisine, que le ticket mentionne bien qu'il permet de se rendre de la Frette-sur-Seine à Paris, avec un encrage indiquant une première validation. « Par ailleurs, j'ai constaté après vérification que le titre est illisible, ainsi, démagnétisé.» [La médiatrice veut sans doute dire illisible « parce que » démagnétisé.] Voici ce qu'elle ajoute : « Je porte à votre attention que l'agent de la RATP ayant procédé au contrôle de votre titre ne pouvait pas déduire sa validité, puisqu'en l'espèce, le ticket est illisible. L'agent de contrôle ne pouvait pas faire autrement que de procéder à une verbalisation. » Néanmoins, compte tenu de l'absence de passé infractionnel de Claude, la médiatrice indique avoir proposé à la RATP, qui l'a accepté, le classement sans suite de son PV. Mme Chappe précise : « Vous comprendrez que cette mesure est prise à titre tout à fait exceptionnel et ne saurait en aucun cas former jurisprudence... » Nous ne pouvons que nous réjouir pour Claude. Mais aussi nous inquiéter de cette précision : le ticket dûment validé qui se démagnétisera, au contact d'un téléphone portable ou d'une carte bancaire, sera présumé non valide, et son détenteur en infraction. On peut en outre se demander comment il se fait qu'un premier contrôleur, à Saint-Lazare, laisse le voyageur passer avec un billet démagnétisé, et qu'un second, à Champs-Elysées-Clemenceau, lui inflige une amende...... D’autres articles de Sosconso : Le « notaire qui décoiffe » rappelé à l’ordre ou Divorce : l’épouse faussaire condamnée à ses torts exclusifs ou L’ostréiculteur, la machine défectueuse et l’erreur de l’avocat 2/2 ou L’ostréiculteur, la machine défectueuse et l’erreur de l’avocat 1/2 ou Divorce : chaque parent doit respecter les droits de l’autre ou Elle se casse une dent au parc aquatique ou Sous le tapis, une trappe… ou Le propriétaire impute le jaunissement des peintures au locataire ou Musculation : la difficile mise en cause du club en cas d’accident ou Le syndic n’aurait pas dû appeler la police ou Le bailleur n’avait pas le droit d’évacuer les plantes vertes de sa locataire ou Il reçoit des allocations pour un logement qu’il n’occupe pas ou Joyeuses fêtes! | Title: Cent euros d'amende pour un ticket de métro démagnétisé Summary: Avant de prendre le train, Claude valide son billet SNCF-RATP, comme le prouvent les chiffres qui s'inscrivent dessus en violet. Pendant son voyage, le ticket se démagnétise. Un guichetier du métro laisse passer Claude, mais un contrôleur le verbalise. Une aventure qui se terminera avec l'indulgence du service client de la RATP. | 1,172 | 102 | mlsum_fr | fr |
Summarize: By. Louise Cheer. A video of two unsuspecting fast food employees who were the victims of a practical joke pulled by an Australian YouTuber has gone viral. So far the clip - which lasts for almost four minutes - of Tyson Williams performing the prank call has attracted more than 160,000 views. It involves Williams putting two Domino's Pizza employees on the phone to each other using the'merge calls' function on his mobile phone. Scroll down for video. A video of a Brisbane man pranking two Domino's Pizza employees has gone viral. In the footage, the Brisbane man dials the number of Domino's Pizza in Forest Lake - south of the Queensland capital - on his iPhone. A pizza chain employee named 'Ron' greets him and prepares to take his pick-up order. Williams - whose friend is having trouble keeping his amused laughter at bay off-camera - orders two deep pan pepperoni pizzas, two thin 'n' crispy Hawaiian pizzas, two cheesy breads and a 1.25-litre bottle of coke under the name of 'Rogan'. At one point, it looks like Williams is about to break his facade and lose his composure, but he keeps it together and tells Ron to hold on - saying he has to ask his friend what dessert he wants to order. While Ron is on hold, Williams then dials the number of the Acacia Ridge branch - also in Brisbane's south - of Domino's Pizza. Tyson Williams posted the video on YouTube and so far it has had more than 160,000 views. Two employees - one from the Acacia Ridge store (pictured) and one from the Forest Lake store - were victims of the prank. A 'Rhiannon' answers the phone and asks him: 'Would you like pick-up or delivery?' Williams tells her to hold and proceeds to take Ron off hold, and asks him to read the order back - but not before Williams merges the calls so Rhiannon thinks Ron is the one placing the order. What ensues is a lot of confusion on the part of both employees who don't realise that neither is placing an order, but trying to take an order. This is where Williams and his friend really start to get a kick out of the prank - trying to stifle their laughter. In the footage, Williams and his friend cannot contain their delight at the prank. After the prank, Williams and his friend burst out laughing, and jump up and down with joy. After about two minutes, the employees finally figure out what is going on. 'So you haven't called me?' Rhiannon said. Ron confirmed that he didn't and then added: 'Sounds like someone is stuffing us around.' The video ends with the employees hanging up, and Williams and his friend finally being able to laugh out loud freely | Summary: Brisbane's Tyson Williams has uploaded a four-minute video on YouTube. The video showing the prank has so far attracted more than 120,000 hits. Williams calls the Forest Lake store and then the Acacia Ridge store. He uses the'merge calls' function on his iPhone to orchestrate the trick. This meant when one of them read back the order it sounded like they were placing an order. It took the employees about two minutes to figure out what was happening. | 646 | 107 | cnn_dailymail | en |
Write a title and summarize: Host control of influenza A virus (IAV) is associated with exuberant pulmonary inflammation characterized by the influx of myeloid cells and production of proinflammatory cytokines including interferons (IFNs). It is unclear, however, how the immune system clears the virus without causing lethal immunopathology. Here, we demonstrate that in addition to its known anti-viral activity, STAT1 signaling coordinates host inflammation during IAV infection in mice. This regulatory mechanism is dependent on both type I IFN and IFN-γ receptor signaling and, importantly, requires the functional interplay between the two pathways. The protective function of type I IFNs is associated with not only the recruitment of classical inflammatory Ly6Chi monocytes into IAV-infected lungs, but also the prevention of excessive monocyte activation by IFN-γ. Unexpectedly, type I IFNs preferentially regulate IFN-γ signaling in Ly6Clo rather than inflammatory Ly6Chi mononuclear cell populations. In the absence of type I IFN signaling, Ly6Clo monocytes/macrophages, become phenotypically and functionally more proinflammatory than Ly6Chi cells, revealing an unanticipated function of the Ly6Clo mononuclear cell subset in tissue inflammation. In addition, we show that type I IFNs employ distinct mechanisms to regulate monocyte and neutrophil trafficking. Type I IFN signaling is necessary, but not sufficient, for preventing neutrophil recruitment into the lungs of IAV-infected mice. Instead, the cooperation of type I IFNs and lymphocyte-produced IFN-γ is required to regulate the tissue neutrophilic response to IAV. Our study demonstrates that IFN interplay links innate and adaptive anti-viral immunity to orchestrate tissue inflammation and reveals an additional level of complexity for IFN-dependent regulatory mechanisms that function to prevent excessive immunopathology while preserving anti-microbial functions. Influenza A virus (IAV) is a leading cause of respiratory infection and an ongoing threat to global health. Host clearance of IAV, which infects primarily airway epithelial cells, requires the development of both innate and adaptive immune responses [1,2]. Interestingly, recent studies have suggested that the host immune response rather than the cytopathic effect of viral infection plays the key role in driving tissue pathology and host mortality [3–5]. IAV triggers an acute pulmonary inflammation associated with the recruitment of inflammatory monocytes and neutrophils in infected lungs (reviewed in [6]). While it is clear that elevated neutrophil accumulation into infected lungs is associated with increased mortality following IAV infection [7,8], monocyte recruitment can be host protective or detrimental [9,10], suggesting that monocytes may play a multifactorial role in the infection. The current understanding of monocytes suggests that there are at least two major subsets: classical Ly6Chi and nonclassical Ly6Clo monocytes [11]. The classical Ly6Chi monocytes are known to mediate various inflammatory conditions [12] and accumulate in large numbers in IAV-infected lungs [13]. In contrast, nonclassical Ly6Clo cells have been shown to “patrol” the vasculature to clear damaged endothelial cells and contribute to tissue remodeling during the resolution phase of inflammation [14]. Interestingly, the patrolling Ly6Clo monocytes have been shown to differentiate into alternatively activated macrophages during Listeria monocytogenes infection [14]. However, the phenotype and function of Ly6Clo monocytes / macrophages (Mo/Mϕ) in IAV infection are currently unknown. In addition to recruiting myeloid cells, IAV induces the production of proinflammatory cytokines, including type I and II interferons (IFNs), in infected animals. The type I IFN family consists of ~20 different members believed to be important in anti-viral and cancer immunity [15], whereas the sole member of type II IFN, IFN-γ, plays a major role in activating Mo/Mϕ and protection against intracellular bacterial and parasitic infections (Reviewed in [16]). In contrast to its extensively studied function in initiating a cell-autonomous anti-viral state, the mechanisms by which IFN signaling regulates host tissue responses to IAV infection are poorly understood. Several recent studies have shown that viral-induced type I IFNs promote the accumulation of classical Ly6Chi monocytes into the airway and lungs of IAV-infected mice [17,18]. However, it is unclear whether these cytokines also regulate the function of pulmonary monocytes for the resistance to IAV infection. Moreover, the contribution of IFN-γ to IAV-induced pulmonary tissue inflammation is not clearly defined. We report in this study that type I IFN and IFN-γ signaling each play a pleiotropic role in the pulmonary inflammatory response to IAV. Importantly, IFN cross-regulation and cooperation are essential for the suppression of monocyte- and neutrophil-driven tissue inflammation. While antagonizing IFN-γ signaling to inhibit Mo/Mϕ activation, type I IFNs synergize with IFN-γ to inhibit neutrophil infiltration. Moreover, we demonstrate that in the absence of type I IFN signaling, Ly6Clo Mo/Mϕ become more proinflammatory than their Ly6Chi counterparts. Since the Ly6Clo Mo/Mϕ population is traditionally associated with tissue remodelling rather than inflammation, our findings also reveal an unrecognized pro-inflammatory potential for Ly6Clo Mo/Mϕ and suggest that IFNs dictate the homeostasis versus inflammatory function of mononuclear cells in viral infection. Sub-lethal, intranasal (i. n.) infection with influenza A/Puerto Rico/8 (PR8) virus in wild-type (WT) mice is characterized by a progressive weight loss that peaks at day 10, after which mice recover and clear the infection (Fig 1A and [19]). To investigate the function of IFNs in shaping the host response to IAV infection, we first examined IFN gene expression and observed that while in WT mice type I IFNs Ifna and Ifnb were both rapidly up-regulated at day 3 post-infection (p. i.), the sole type II IFN, Ifng, was not significantly induced until day 7 p. i. (Fig 1B). The expression of both type I and II IFNs declined to baseline levels by day 10 p. i.. In WT mice, the cellular immune response to IAV infection was characterized by the strong influx of monocytes that peaked at day 7 and then declined by day 10, at which point T cells became the dominant immune cell subset in lungs (Fig 1C). In contrast to WT controls, Stat1-deficient mice, lacking both type I IFN and IFN-γ signaling, displayed a neutrophil-enriched cellular response (Fig 1D), highlighting the critical importance of IFN signaling in orchestrating a protective tissue response to IAV infection. Next, we quantified the viral loads at days 3 and 7 p. i. using both qRT-PCR and classical plaque forming (PFU) assays. While mRNA copy numbers of viral nucleoprotein (NP) determined by qRT-PCR were comparable in WT and Stat1—/—mice, the latter animals showed a marginal increase (0. 4 log) in PFUs at day 7 (Fig 1E). The extent of defect in viral control in Stat1—/—mice observed is consistent with that reported previously [20,21], suggesting that the dysregulated tissue response in Stat1—/—mice cannot be explained fully by increased viral loads. To determine whether the altered pulmonary inflammation in infected Stat1—/—mice stems from dysregulated myelopoiesis in bone marrow (BM) or cell trafficking in the periphery, or both, we analyzed hematopoietic cells in the BM of infected WT and Stat1—/—mice by flow cytometry. The stem/progenitor cell populations are commonly defined as lineage-negative Sca1+cKit+ (CD117+) (LSK) cells [22,23]. However, since Sca1 expression is regulated by IFNs (S1 Fig and [22]), we omitted Sca1 staining in the analysis. We did not observe a significant difference in the percentage of lineage-negative CD117+ progenitor cells (Fig 1F), or mature BM-residing CD11b+Ly6G+Ly6Clo neutrophils and CD11b+Ly6G—Ly6Chi monocytes (Fig 1G) in infected WT and Stat1—/—mice, suggesting that IFN signaling plays a minimal role in regulating central myelopoiesis in the BM during IAV infection. To determine the relative contribution of type I and II IFNs to monocyte recruitment in IAV infection, we analyzed monocyte populations in the lungs of infected WT, Ifnar1—/—, Ifngr1—/—and Stat1—/—mice using flow cytometry. When compared to WT mice, Ifnar1—/— and Stat1—/—mice displayed a significant reduction in CD11b+Ly6Chi monocytes in the lungs at day 7 p. i. (Fig 2A, 2B and 2C). The difference is unlikely due to kinetic variations of the pulmonary response to IAV in IFN signaling-sufficient and deficient mice, as the significant influx of leukocytes into the infected lungs was not observed until day 7 p. i. in all groups (Fig 2B and 2C). In contrast to Ifnar1—/—animals, monocyte recruitment in Ifngr1—/—mice was largely unaffected, suggesting that type I IFN signaling alone is sufficient to trigger monocyte recruitment into infected lungs. We next determined whether type I IFNs act directly or indirectly on monocyte populations to regulate their trafficking to lungs. Lethally irradiated CD45. 1+ WT recipient mice were reconstituted with equal numbers of CD45. 1+ WT and CD45. 2+ Ifnar1—/—BM cells. After full reconstitution (8–10 wk), chimera mice were infected with IAV and the cellular response analyzed at day 7 p. i. (Fig 2D). We found that the defect in the recruitment of Ly6Chi inflammatory monocytes observed in Ifnar1—/—mice was not restored in CD45. 2+ Ifnar1—/—cells in mixed Ifnar1—/—and Ifnar1+/+ BM chimeric mice (Fig 2E). As such, the ratio of Ly6Chi / Ly6Clo monocytes in the CD45. 2+ Ifnar1—/—compartment was significantly lower than that in the CD45. 1+ Ifnar1+/+ compartment, indicating that direct type I IFN signaling in Ly6Chi monocytes is required for their recruitment into infected lungs (Fig 2F). We next examined whether type I IFN signaling regulates the phenotype and function of major populations of CD11b+ monocytes in IAV-infected lungs. Consistent with current knowledge of mononuclear phagocyte subsets [11], we observed that Ly6Chi monocytes in IAV-infected lungs displayed higher CCR2 expression than their Ly6Clo counterparts in WT and Ifnar1—/—mice (Fig 3A). Furthermore, expression of the integrin LFA-1 (CD11a), a key molecule responsible for the function of monocytes [24], was unchanged on either Ly6Chi or Ly6Clo cells irrespective of type I IFN signaling. Strikingly, however, loss of type I IFN signaling on Ly6Clo but not Ly6Chi populations resulted in significant increases in the expression of MHC-II (I-A), CD11c, CD16/32 and CD64, suggesting that in Ifnar1—/—mice, Ly6Clo Mo/Mϕ display a phenotype that is characteristic of activated proinflammatory monocytes. Consistent with this hypothesis, we found that Nos2, a known proinflammatory molecule produced predominantly by monocytes, was more highly expressed in the lungs of Ifnar1—/—mice than WT animals (Fig 3B), despite the reduction in Ly6Chi monocytes in Ifnar1—/—mice (Fig 2B). Consistent with Nos2 gene analysis, flow cytometric analysis revealed that there was a significant increase in NOS2-expressing cells in the lungs of infected Ifnar1—/—mice compared to WT animals (Fig 3C). Further analysis revealed that multiple mononuclear cells in IAV-infected lungs produced NOS2 (Fig 3D). However, while Ly6Chi monocytes were the major NOS2-producing cells in WT animals, both Ly6Chi and Ly6Clo subsets contributed to the NOS2 production in the lungs of infected Ifnar1—/—mice (Fig 3D and 3E). Paired analysis of the two monocyte subsets among individual mice demonstrated that in Ifnar1—/—animals, both the percentage of cells expressing NOS2 as well as the total quantity of NOS2 produced per cell was higher in Ly6Clo than Ly6Chi monocytes, suggesting that the former subset is more susceptible to type I IFN-dependent suppression (Fig 3F). Therefore, type I IFNs are able to regulate not only trafficking, but also the phenotype and effector function of mononuclear cells in the lung during IAV infection. Since the surface markers and NOS2 examined above are known to be highly sensitive to induction by IFN-γ [25–27], we suspected that IFN-γ might play a role in the up-regulation of these molecules in the infected Ifnar1—/—mice. Indeed, at day 3 p. i., a time point at which minimal levels of IFN-γ are produced (Fig 1B), there were no differences in the expression of I-A, CD11c or CD64 on Ly6Chi and Ly6Clo cells (S2 Fig). To demonstrate directly that IFN-γ is responsible for the up-regulation of the molecules, we compared the expression of I-A and NOS2 in Ly6Clo Mo/Mϕ of WT, Ifnar1—/—, Ifngr1—/—and Stat1—/—mice at day 7 following IAV infection. We found that the enhanced expression of I-A and NOS2 observed in lungs of Ifnar1—/—animals was completely abolished in Ifngr1—/—mice as well as Stat1—/—mice that lack both type I IFN and IFN-γ signaling pathways (Fig 4A and 4B), suggesting that up-regulation of I-A and NOS2 in the absence of type I IFN signaling is driven by IFN-γ. To determine whether type I IFNs act directly on monocytes to exert their suppressive effect, we analyzed NOS2 production in IAV-infected, mixed Ifnar1+/+ and Ifnar1—/—BM chimera mice and found that type I IFNs signal directly to suppress NOS2 production in both Ly6Clo (Fig 4C) and Ly6Chi (S3A Fig) mononuclear cells. Moreover, as we observed previously in Ifnar1—/—mice (Fig 3F), Ly6Clo Mo/Mϕ in BM chimera mice expressed higher levels of NOS2 than their Ly6Chi counterparts (S3B Fig), confirming that enhanced susceptibility to type I IFN inhibition is intrinsic to this Mo/Mϕ subset. We next determined whether the enhanced IFN-γ-inducible response in IAV-infected Ifnar1—/—mice was a consequence of increased IFN-γ production or signaling by examining the expression of Ifng and Ifngr1 in infected lungs. We found that although Ifng expression was comparable in the lungs of infected WT and Ifnar1—/—mice, Ifngr1 levels were significantly higher in Ifnar1—/—animals (Fig 4D), suggesting that enhanced IFN-γ signaling rather than IFN-γ production is responsible for the increased IFN-γ-inducible response in Ifnar1—/—mice. To test this hypothesis, we analyzed the cell surface expression of IFN-γ receptor 1 (CD119) by flow cytometry and found CD119 expression was significantly increased on Ly6Clo Mo/Mϕ of Ifnar1—/—mice compared to WT mice (Fig 4E and 4F). Therefore, the intrinsic regulation of IFN-γ receptor levels by type I IFNs appears to be a mechanism by which Mo/Mϕ activation is suppressed in the presence of type I IFNs. Our findings above suggest that type I IFN signaling is dominant over IFN-γ in the recruitment of Ly6Chi monocytes to the lungs of IAV-infected mice (Fig 2). To investigate the relative contribution of type I and type II IFNs on the STAT1-dependent suppression of neutrophil migration (Fig 1D), WT, Ifnar1—/—, Ifngr1—/—and Stat1—/—mice were infected with IAV and the relative abundance of neutrophils in each mouse strain determined by flow cytometry. Interestingly, we observed that both percentage and numbers of CD11b+Ly6G+ neutrophils were significantly elevated in the lungs of Ifnar1—/—as well as Ifngr1—/—mice compared to WT animals at day 7, but not day 3 p. i. (Fig 5A, 5B and 5C). Importantly, this defect was further exaggerated in Stat1—/—mice, suggesting a synergistic function of type I and II IFNs in suppressing neutrophil recruitment during influenza infection. Moreover, in contrast to the cell-intrinsic function of type I IFNs in monocyte migration described above (Fig 2D), we found that the percentage of CD11b+Ly6CloLy6G+ neutrophils was comparable among CD45. 1+ WT and CD45. 2+ Ifnar1—/—compartments before (S4 Fig) and following (Fig 5D) infection, suggesting that type I IFNs regulate neutrophil migration through a cell-extrinsic manner. Therefore, type I IFNs employ distinct mechanisms to regulate monocyte and neutrophil trafficking in IAV infection and act in concert with IFN-γ to prevent accumulation of tissue-damaging neutrophils at the site of infection. To investigate potential cell-extrinsic mechanisms responsible for the increased accumulation of neutrophils, we measured gene expression of the known neutrophil-attracting chemokine Cxcl1 and the cytokine Il1b in WT and IFN-signaling deficient animals. Stat1—/—mice displayed significantly higher expression of Cxcl1 and Il1b than in either Ifnar1—/—or Ifngr1—/—mice (Fig 5E), consistent with the notion that IFNs synergize to suppress neutrophil chemotactic chemokine/cytokine production in IAV infection. STAT1 is one of many transcription factors that can transduce both type I IFN and IFN-γ receptor signaling, but it can also mediate IFN-independent functions [28–30]. Therefore, it is possible that the increased neutrophilic influx in IAV-infected Stat1—/—mice, as compared to Ifnar1—/—mice, is independent of IFN-γ signaling. Moreover, it is unclear whether IFN-γ-dependent neutrophil suppression requires intact type I IFN signaling. Type I IFNs are known to regulate neutrophil recruitment by signaling directly in inflammatory monocytes to suppress their production of neutrophil chemoattracting chemokine Cxcl2 [31]. To address these questions, we generated Ifnar1—/—BM reconstituted WT chimera mice, which are deficient in type I IFN signaling in hematopoietic cells only. Similar to Ifnar1—/—mice, these chimeric mice also displayed defective pulmonary accumulation of Ly6Chi monocytes following IAV infection (S5 Fig). Ifnar1—/—BM chimera mice treated with anti-IFN-γ antibody at day 2 and 6 p. i. exhibited a marked reduction in I-A expression on monocytes when analyzed at day 7 (Fig 6A). This is consistent with our previous observation that IFN-γ augments MHC class II expression (Fig 4) and confirms that the mAb administration successfully blocked IFN-γ activity. Importantly, consistent with the results presented in Fig 5, we found both the proportion and numbers of neutrophils to be significantly elevated in the anti-IFN-γ antibody-treated mice compared to untreated animals (Fig 6B). We also enumerated neutrophils in the bronchoalveolar lavage (BAL) and observed a similar increase in neutrophils in the airway of anti-IFN-γ antibody treated mice when compared to untreated controls (Fig 6C), indicating that IFN-γ regulates neutrophil migration into both the lung parenchyma and bronchoaveolar air spaces independent of type I IFN signaling in inflammatory monocytes. These results suggest that IFN-γ produced by the adaptive immune response to IAV infection regulates the tissue inflammatory response in addition to its anti-viral activity [1]. To test this hypothesis, we infected WT and Rag2—/—mice, which lack B and T-cells, and analyzed the IFN-γ and neutrophil response at d7 p. i.. As expected, Rag2—/—mice displayed significantly reduced IFN-γ expression (Fig 6D) and increased Ly6G+ neutrophil accumulation in the lungs when compared to WT animals (Fig 6E). Together, our findings reveal a mechanism by which IFNs link innate and adaptive immune systems to orchestrate pulmonary inflammation for the resistance to IAV infection. While it is established that IFN-mediated resistance to viral infection in vitro is dependent on the inhibition of viral replication [32], the mechanisms by which IFNs protect against infection in vivo are less well understood. Nevertheless, recent studies have suggested that type I IFN signaling is important in regulating myeloid cell migration during viral infections [17,31,33], arguing that IFNs can play a broader role in anti-viral immunity beyond their well-established cell-intrinsic anti-viral activity. In this study, we report that type I IFN signaling is necessary, but not sufficient, to control the full scale of pulmonary innate responses to IAV. To this end, the functional interplay between type I IFN and IFN-γ signaling pathways is required for the regulation of both monocyte- and neutrophil-driven pulmonary inflammation (Fig 6F). The discovery that, in the absence of type I IFN signaling, IFN-γ promotes inflammatory functions of Ly6Clo Mo/Mϕ suggests that the interplay between innate and adaptive IFNs dictates the outcome of tissue inflammation for the resistance to IAV infection. The impaired Ly6Chi monocyte migration observed in infected Ifnar1—/—mice bears similarities with Ccr2—/—mice [10,18,34,35]. Indeed, the CCR2 ligands CCL2, CCL7 and CCL12 are all type I IFN-inducible and influence monocyte recruitment in a model of chronic inflammation [36]. A key difference between Ccr2—/—and Ifnar1—/—mice, however, is that CCR2 deficiency is favourable for infection outcome [10,18] whereas Ifnar1—/—deficiency leads to enhanced mortality compared to WT animals [17]. Therefore, type I IFNs must mediate other protective mechanisms beside the recruitment of Ly6ChiCCR2+ inflammatory monocytes in IAV infection. Unexpectedly, we discovered that type I IFN signaling plays a major role in suppressing mononuclear cell activation following IAV infection. Interestingly, this inhibition is particularly effective at suppressing the pro-inflammatory potential of Ly6Clo Mo/Mϕ. Our observation that Ifnar1—/—Ly6Clo Mo/Mϕ express higher levels of CD11c, MHC class II and NOS2 than their Ly6Chi (WT or Ifnar1—/—) counterparts is unexpected. These Ly6Clo cells resemble both phenotypically and functionally the inflammatory monocytes or TNF/iNOS-producing dendritic cells (Tip-DC) described in other inflammatory conditions (reviewed in [12]). Although Ly6Chi and Ly6Clo monocytes are considered to be phenotypically distinct lineages, and their developmental maturation is still under contention [37,38], our data demonstrate that both subsets can be activated by IFN-γ to mediate pro-inflammatory actions. Given these findings, it remains to be established whether CD11b+Ly6Clo Mo/Mϕ in lungs of IAV-infected mice represent a separate lineage or have developed from Ly6Chi monocytes as a result of the down-regulation of Ly6C expression upon entry into inflamed lung tissues as described in other models [33,36]. However, the latter scenario is unlikely to be the major mechanism accounting for Ly6Clo Mo/Mϕ accumulation in the absence of type I IFN signaling in our study, because of the significant difference in the numbers of total CD11b+ Mo/Mϕ in the lungs of infected WT and Ifnar1—/—mice. Our finding that type I IFNs differentially regulate neutrophil and monocyte trafficking in IAV infection is consistent with a previous report [17]. However, while the previous study analyzed exclusively the cells in the BAL, our investigation examined myeloid populations in both the BALF and lung tissues. Furthermore, in contrast to Seo et al, we did not observe any major changes in progenitor or mature myeloid cells in the BM and blood of IAV-infected Ifnar1—/—or mixed BM chimeric mice, suggesting that the IFNs play a major role in coordinating regional immunity rather than central myelopoiesis as proposed by Seo and colleagues [17]. This discrepancy may be explained by the fact that the previous study analyzed myeloid progenitor populations following infection of BM with IAV in vitro, an event not typically known to occur during natural infection [39]. Importantly, in addition to defining the function of type I IFNs, we have uncovered two novel functions of IFN-γ in the pulmonary response to IAV infection; the inhibition of neutrophil migration and the induction of monocyte activation. Interestingly, although IFN-γ is known to elicit direct anti-viral activity in infected cells [16] and is produced in high quantities following influenza infection, its function in IAV infection has been elusive. Numerous studies investigating lymphocyte function, viral clearance or survival of mice deficient in IFN-γ or IFN-γR1 collectively reported no appreciable differences compared to WT animals [20,40–42]. Therefore the current study reveals a functional role for IFN-γ in influenza infection and suggests that some IFN-γ functions are masked by type I IFN-dependent regulatory mechanisms. The role of type III IFNs in pulmonary inflammation was not examined in this report, it is possible that the cytokines also play a role in controlling innate cell trafficking and activation during IAV infection. Indeed, a recent study revealed that type III IFNs can regulate neutrophil migration and function in an experimental arthritis model [43]. Interestingly, while type III IFNs are shown to mediate immunity to viral infections, there exists a large degree of redundancy with type I IFNs [44–46]. Future studies investigating the involvement of type III IFNs in this process may provide further insight into the regulatory functions of the IFN system. Type I IFN production has previously been reported to suppress IFN-γ driven immune responses and resistance to intracellular bacteria [25,26], but it is unknown whether a similar mechanism is activated in viral infection. We demonstrate in this study that the IFN regulatory circuit also plays a pivotal role in the host response to IAV infection, particularly in preventing Ly6Clo Mo/Mϕ from IFN-γ-induced activation by regulating IFN-γR1 expression. The tightly controlled IFN-γ signaling in Ly6Clo Mo/Mϕ may explain why under some circumstance this monocyte population differentiates into alternatively activated macrophages [24], a process known to be susceptible to IFN-γ suppression [47]. Interestingly, the type I IFN cross-regulatory mechanism described here appears to function more actively in some components of the immune response to IAV infection than others, as the inhibitory effect of IFN-γ on neutrophil migration is not suppressed during IAV infection. Nevertheless, this and previous studies collectively suggest that inhibition of IFN-γ function by type I IFN signaling is an important regulatory mechanism operating under some infection and inflammatory settings, where both type I and II IFNs are produced [48]. We propose that in contrast to intracellular bacterial infection, where activation of infected monocytes by IFN-γ is essential for pathogen clearance, inhibition of IFN-γ by type I IFNs during influenza infection serves a host-protective role. Indeed, IFN-γ-inducible nitric oxide (NO) has been shown to play a major role in mediating pulmonary pathology in IAV infection [13,49–51] and, as such, must be tightly controlled to limit immune-mediated tissue damage. IFNs are potently induced by viral pathogens and mediate host immunity to infections. In this study, we demonstrate the cooperation and cross-regulation between type I and II IFN signaling pathways coordinate a multifaceted pulmonary inflammatory response to IAV infection. Interestingly, it is known that viruses have evolved mechanisms to counteract the host IFN system [52]. Therefore, our findings suggest that in addition to impairing cell-intrinsic anti-viral effector functions as proposed previously [53], blockade of type I IFN production or signaling by viral products may lead to dysregulated inflammation, thereby contributing to impaired disease resistance and possibly increased viral transmission. This hypothesis may explain why some highly virulent strains of IAV are associated with hyper-inflammatory responses [54,55] and suggests that targeted manipulation of IFN signaling pathways could lead to new therapeutic opportunities. C57Bl/6 (CD45. 2+) and CD45. 1+ (B6. SJL-Ptprca) mice were obtained from the Animal Resources Centre (ARC, Perth). Rag2—/—, Ifnar1—/—, Ifngr1—/—and Stat1—/—mice (all on C57Bl/6 background) were bred and maintained at the University of Sydney Bosch Rodent Facility. All mouse work was performed according to ethical guidelines as set out by the University of Sydney Animal Ethics Committee. All experiments within this manuscript were approved under protocol numbers 2013/5847 and 2013/5848. University of Sydney Animal Ethics Committee guidelines adhere to the Australian Code for the Care and Use of Animals for Scientific Purposes (2013) as set out by the National Health and Medical Research Council of Australia. Mice were anaesthetized by intraperitoneal (i. p.) injection with 2% 2-2-tribromoethanol (Avertin) and inoculated intranasally (i. n.) with 20 plaque forming units (PFU) of influenza A virus strain PR8 (A/Puerto Rico/8/1934 H1N1) in a volume of 50 μl. PR8 virus was a kind gift from A/Professor John Stambas (Deakin University, VIC., Australia). IAV was quantified by plaque assays with MDCK cells using standard methods. In brief, 0. 9 x 106 MDCK cells were seeded in each well of a 6-well culture plate. Lungs were homogenized in RPMI and clarified by centrifugation for 5 minutes at 2,000 g. Homogenates were serially diluted in RPMI and added to MDCK cell monolayers. After incubation for 45 minutes at 37°C, cells were overlaid with 1% w/v Avicel (FMC Biopolymer) in L15 media (Sigma Aldrich) containing 2 μg/ml TPCK-treated trypsin (Worthington Biochemicals) and incubated at 37°C, 5% CO2 for 3 days. Cells were subsequently washed, methanol fixed and stained with crystal violet before plaques were counted. Euthanized animals were perfused with 10 ml PBS and the lungs removed into 1 ml cold 2% FCS/RPMI. Single cell suspensions were made by dissociating the lungs with a scalpel blade and then incubated in 2% FCS/RPMI supplemented with 2 mg/ml of DNaseI (Sigma Aldrich) and Collagenase IV (Sigma Aldrich) for 30 minutes at 37°C. The digested lungs were then dissociated through a 70 μm cell strainer (Falcon) and red blood cells lysed with ACK lysis buffer (Life Technologies). Cells were counted using trypan blue exclusion. For bone marrow cells, femurs and tibias were removed and cleaned of flesh before the bone marrow was flushed out with 2% FCS/RPMI. Cells were pelleted at 300 g for 5 minutes and resuspended in ACK lysis buffer (Life Technologies) for 1 minute to lyse red blood cells. Cells were washed and resuspended in 2% FCS/RPMI before being counted by trypan blue exclusion. For BAL collection, a catheter attached to a 3-way stop cock and 5 ml syringe was inserted into the trachea and the lungs flushed with 5 x 1 ml of cold PBS supplemented with 2 mM EDTA. Cells were pelleted at 300 g for 5 minutes and the cells resuspended in 250 ul of 2% FCS/RPMI and stored at 4°C until used for flow cytometric analysis. BM chimeras were generated by lethally irradiating CD45. 1+ recipient mice with 10 Gy, followed by intravenous transfer of 2 x 106 BM cells from Ifnar1—/—mice into the tail vain. For mixed BM chimeras, irradiated CD45. 1+ recipient WT mice were reconstituted with a total of 2 x 106 BM cells from WT (CD45. 1+) and Ifnar1—/— (CD45. 2+) mice at a ratio of 1: 1. Mice received antibiotic-supplemented (Trimethoprim sulpha) drinking water for 3 weeks after irradiation. Mice were used at least 8 weeks after bone marrow reconstitution. For in vivo IFN-γ neutralization, mice received 500 μg of anti-IFN-γ monoclonal antibody XMG1. 2 intravenously on days 2 and 6 post IAV infection. Anti-IFN-γ clone XMG1. 2 hybridoma was expanded in 10% FCS/RPMI supplemented with Pen/Strep (Gibco) and affinity purified using protein G beads (GE Healthcare). Purified antibody was dialyzed into PBS and filter sterilized prior to injection into mice. Lung (1 x 106), blood (200 ul whole blood) or BM (4 x 106) cells were stained according to standard procedures. Briefly, cells were incubated for 30 minutes with UV Live/Dead stain according to the manufacturer’s instructions (Life Technologies). Cells were stained with the following antibodies in FACS wash (2% FCS/PBS): CD4 (clone GK1. 5), CD8 (53–6. 7), B220 (RA3-6B2), I-A/I-E (M5-114. 15. 2), Ly6G (1A8), Ly6C (HK1. 4), CD11b (M1/70), CD45. 1 (A20), CD45. 2 (104), NK1. 1 (PK136), Siglec-F (E50-2440), CCR2 (475301), LFA-1 (M17/4), CD119 (2E2), CD11c (N418), CD16/32 (93), CD64 (X54-5/7. 1), CD45 (30-F11), Lineage cocktail, CD117 (2B8), Sca1 (D7), CD48 (HM48-1), CD150 (Q38-480). The gating strategy used for identifying cell populations is shown in S6 Fig. Monocyte and macrophage populations were identified as CD4—CD8—B220—NK1. 1—SiglecF—Ly6G—CD11b+ and then categorized into Ly6Chi and Ly6Clo populations based on Ly6C expression. Neutrophils were identified as CD4—CD8—B220—NK1. 1—SiglecF—CD11b+Ly6G+. For intracellular NOS2 staining, single cell suspensions were incubated at 37°C for 3 hours prior to staining with surface marker antibodies. Intracellular staining was carried out using the BD Cytofix/Cytoperm kit according to the manufacturer’s instructions (BD). Intracellular staining was performed using NOS2 antibody (clone CXNFT). All flow cytometry data acquisition was performed on a LSRII using FACSDiva software (BD Biosciences) and all analysis was performed using FlowJo X v0. 7 (TreeStar). Following perfusion, mouse lung tissue was collected and submerged in RNAlater (Ambion) for 24 hours prior to long term storage at -80°C. RNA was prepared from mouse lungs using Trisure (Bioline) according to the manufacturer’s instructions (Bioline). Total RNA (2 μg) was reverse transcribed using the Tetro cDNA synthesis Kit with random primers according to the manufacturer’s instructions (Bioline). Data are expressed as fold increases over uninfected controls and were calculated by the ΔΔCT method using 18S as the reference gene. For absolute viral nucleoprotein quantification, RNA was extracted from 1 x 107 PFU PR8 using the ISOLATEII RNA kit according to the manufacturer’s instructions (Bioline) and 100 ng reverse-transcribed with the Tetro cDNA synthesis kit using IAV nucleoprotein specific primers [39]. Following amplification, the 216 bp cDNA product was gel purified using a Gel Extraction kit (Sigma Aldrich) and total copy number determined based on size and yield of product. A standard curve was generated to determine absolute viral nucleoprotein mRNA copy number among sample mRNA. All quantitative reverse-transcriptase PCR (qRT-PCR) was performed using SYBR NoROX master mix (Bioline) on a Roche LightCycler480. Forward and reverse qRT-PCR primers are listed in Table 1. All statistical analyses were performed in Prism 6 (GraphPad Software). Significance was determined using Student’s t-test when comparing two experimental groups or one-way ANOVA followed by Tukey’s post-test correction for more than two groups. Results with p<0. 05 were deemed statistically significant. *<0. 05, **<0. 01, ***<0. 001, ****<0. 0001. | Title: Functional Interplay between Type I and II Interferons Is Essential to Limit Influenza A Virus-Induced Tissue Inflammation Summary: Influenza A virus (IAV) is a leading cause of respiratory infection and induces a strong acute inflammation manifested by the recruitment of monocytes and neutrophils as well as the production of proinflammatory cytokines in infected lungs. The interferons (IFNs) are strongly induced by IAV and are known to mediate host resistance to the infection. However, in contrast to their well-studied inhibitory effect on viral replication, the effects of IFNs on host inflammatory responses are less well understood. In this manuscript, we demonstrate that anti-viral IFN signaling is also required for the orchestration of a tissue response associated with the protection against IAV infection in mice. Importantly, we identify that type I IFNs cross-regulate and cooperate with IFN-γ to inhibit monocyte activation and neutrophil infiltration, respectively. This study also demonstrates that Ly6Clo monocytes/macrophages can potentially mediate influenza virus-induced inflammation, suggesting that IFNs dictate the homeostasis versus inflammatory function of mononuclear phagocytes in viral infection. Our study reveals a novel IFN-dependent regulatory mechanism designed to prevent the excessive immunopathology while preserving its anti-microbial functions. Moreover, these observations have particular relevance for understanding the mechanisms underlying the strong inflammatory response associated with lethal IAV strains and have implications for the development of new immunotherapies to treat influenza. | 9,315 | 344 | lay_plos | en |
Summarize: Federal investigators have determined that a TSA program is an expensive failure. The TSA trains officers to detect certain types of behaviors, searching for those who don't seem to fit in – but there's no evidence behavior detection works. NBC's Tom Costello reports The federal government may have wasted $1 billion on a TSA program called “SPOT” that profiles people who may be “bad guys” at airports by talking to them, the Government Accountability Office reported Wednesday. There is no evidence that it works, it said. The Transportation Security Administration’s Screening of Passengers by Observation Techniques (SPOT) program relies on training personnel to recognize indicators like fear, stress or deceptive behavior that can be used to identify persons who may pose a risk to aviation security. Those who exhibit those indicators are subjected to additional security screening. But the GAO report concludes the training produces results that are “the same as or slightly better than chance.” The program was rolled out in 2007 and now fields an estimated 3,000 “behavior detection officers” at 176 of the more than 450 TSA-regulated airports in the U.S., the GAO report said. Four “meta analyses” of more than 400 studies from the past 60 years reviewed by the GAO found that such training produced results that were either equal to or slightly better than those of non-trained observers. The GAO also analyzed data from fiscal 2011 and 2012 and found that the rate at which TSA officers referred passengers for additional screening based on the indicators varied significantly across airports. That raises questions about whether the indicators are subjective or were being unevenly applied, the report said. Rick Wilking / Reuters file Transportation Security Agency officers workers perform security checks at Denver International Airport on Nov. 24, 2010. Furthermore, a Department of Homeland Security study in April 2011 conducted to evaluate the effectiveness of SPOT in response to a previous GAO report critical of the program produced unreliable data, it found. “Available evidence does not support whether behavioral indicators … can be used to identify persons who may pose a risk to aviation security,” the GAO concluded. The program does have its defenders. Rafi Ron, CEO of New Age Security Solutions and former director of security at Israel's Ben Gurion airport, said the observational training supplements other screening systems and procedures. “I think that it is an extremely important layer because otherwise we will go back to the so-called dark ages of believing that... this is all about detecting weapons or items,” he told NBC News. “What we are doing is not enough.... If we are facing somebody who presents a high level of risk, then we need to search him beyond what we are doing at the airport level, the checkpoint level." Rep. Mike McCaul, R-Texas, the chairman of House Homeland Security Committee, said in a statement to NBC News that the GAO report is “concerning, particularly in light of the fact that TSA has spent almost $1 billion on the program.” “While I believe that there is value in utilizing behavioral detection and analysis in the aviation environment, we can only support programs that are proven effective,” he said. “The terrorist threats to our aviation system require us to constantly re-evaluate and evolve our security procedure, and if this program isn't working, we need to find something that will." Rep. Bennie Thompson of Mississippi, the ranking Democrat on the committee, said he intended to question TSA Administrator John S. Pistole about the GAO report at a hearing on Thursday. "I look forward to hearing the administrator explain how the over $200 million per year currently spent on TSA’s failed behavior detection program could be put to use on proven and effective measures to enhance aviation security,” he said. Representatives of the TSA and its parent agency, the Department of Homeland Security, had no immediate comment on the report. But within the report, TSA officials agreed that some of the behavioral indicators need to be better defined and said they are working on that. They also said the agency plans to collect additional performance data to better evaluate SPOT’s effectiveness. But DHS disagreed with the GAO’s recommendation that the TSA administrator “limit future funding support for the agency’s behavior detection activities until TSA can provide scientifically validated evidence.” In its response within the report, DHS faulted both the GAO’s findings related to the 2011 SPOT validation study, saying its use of different statistical techniques resulted in “misleading” conclusions, and that its review of the research literature omitted some studies that supported the use of behavior detection. NBC News Correspondent Tom Costello contributed to this report. More from NBC News Investigations: Follow NBC News Investigations on Twitter and Facebook A TSA security officer watches as passengers go through security at the Salt Lake City International Airport, Nov. 21, 2012. (GEORGE FREY/REUTERS) A federal review concludes there’s no solid evidence that airport checkpoint personnel have a clue when they scan the approaching line for suspicious passengers. In a report to be presented to a House subcommittee Thursday, the Government Accountability Office says there is no evidence that it’s effective for Transportation Security Administration officers to scan crowds for telltale signs someone might be a terrorist. Critics have suggested that the stress and exhaustion that often accompany air travel are too easily misread as suspicious behavior. The GAO report recommends that Congress stop funding for the program, which has cost more than $878 million since its launch in 2007. TSA Administrator John S. Pistole is scheduled to join the GAO’s Stephen M. Lord in testimony before the committee Thursday. While the program predates Pistole’s appointment to head the agency, its mission is consistent with his drive toward a risk-based system rather than one in which all passengers receive the same treatment, regardless of the risk they appear to pose. Rep. Richard Hudson (R-N.C.), chairman of the subcommittee on transportation security, called the hearing “a timely opportunity to review whether this program and others are an effective and efficient use of resources.” Rep. Bennie Thompson (Miss.), the top-ranking Democrat on the Committee on Homeland Security, said the GAO report confirmed that the program “is fundamentally flawed, cannot be proven effective, and should no longer be funded with taxpayer dollars.” The TSA defended the program Wednesday. “Behavior detection is vital to TSA’s layered approach to deter, detect, and disrupt individuals who pose a threat to aviation,” the TSA said in statement responding to the report. “Looking for suspicious behavior is a common sense approach used by law enforcement and security personnel across the country and the world.” The Screening of Passengers by Observation Techniques (SPOT) program employs 2,800 TSA personnel. “TSA has not demonstrated that [behavior-detection officers] can consistently interpret the SPOT behavioral indicators,” the GAO report says. “The subjectivity of the SPOT behavioral indicators and variation in BDO referral rates raise questions about the continued use of behavior indicators for detecting passengers who might pose a risk to aviation security.” The GAO recommends that funding be “directed to programs that have demonstrated their effectiveness.” “We completely support defunding it,” said Maya Berry, executive director of the Arab American Institute, who wrote to Homeland Security Secretary Janet Napolitano in June urging an end to SPOT. “It’s discriminatory in nature and terribly ineffective,” Berry said. “It’s used to target people who are perceived to be Arab Americans. We have a deep history and understanding of how this program works, and that is related to experience that Americans of Arab descent have when they travel to Israel.” The watchdog group Judicial Watch, which has criticized the TSA and Department of Homeland Security as virtually dysfunctional, agreed with the GAO recommendation. “The TSA continues to treat all fliers as a potential threat,” said Tom Fitton, president of Judicial Watch. “They’re just looking at behavior and not looking into other things, like travel patterns. They’re not focused on what they ought to be focused on.” Behavior-detection officers work in pairs at airport checkpoints, using an evaluation system of behaviors that suggest that someone should be scrutinized. The TSA workers may ask a police officer to talk with the passenger. If that doesn’t resolve the concerns, the person may not be permitted to pass through to the boarding area. During a one-year period ending in September 2012, TSA records show that 37,370 passengers were targeted under the SPOT program, 2,214 were referred to a police officer and 199 were arrested. The TSA screens about 1.8 million passengers a day at 450 U.S. airports. Rep. Cedric L. Richmond (La.), the top-ranking Democrat on the subcommittee, called the GAO report “a serious indictment” of the SPOT program. “With a single report, GAO has displayed that the science behind the program is nonexistent and that the study TSA cites in defending the program was fundamentally flawed,” Richmond said. “Given TSA’s unwillingness to concur with GAO’s recommendation that the agency limit funding for the program until it could be proven, it is now up to Congress to take a hard look at reprioritizing the funding for this program.” $900M TSA program to spot bad guys isn't working, gov't report says Ta'u Pupu'a: Off the NFL field and onto the opera stage (CBS News) WASHINGTON -- At Washington's Union Station, CBS News watched two men with backpacks as they watched everyone else. They are undercover behavior detection officers, trained to pick out bad guys by looking for expressions of fear, anxiety or deception. Undercover behavior detection officers are trained to pick out bad guys by looking for expressions of fear, anxiety or deception. / CBS News Since 2007, the Transportation Security Administration has spent $900 million training and deploying 3,000 behavior detection officers. Those so-called BDOs are now stationed at major transit hubs, primarily at 176 of the nation's busiest airports. But a new report from the Government Accountability Office questions whether BDOs are effective, concluding: "Available evidence does not support whether behavioral indicators... can be used to identify persons who may pose a risk to aviation security." The TSA argues the BDOs provide a critical layer of defense by looking for signals which can't be picked up by metal detectors or explosives scanners. Questions remain over pre-checkpoint airport security After LAX shooting, should TSA officers carry weapons? TSA employees handing out preferential treatment, GAO report reveals In a statement, the TSA said: "Looking for suspicious behavior is a common sense approach... and when combined with other security layers helps mitigate a variety of threats." A 2011 Homeland Security analysis found the BDOs to be highly effective, identifying high-risk passengers far more often than random screening. But the GAO study rejected that Homeland study, saying the findings were based on bad science. And the GAO questions the whole premise of behavior-based detection, concluding it "is the same or slightly better than chance." The GAO, with some support in Congress, now is calling on Homeland Security to cut funding for the behavioral program until it can be proven effective. But TSA is promising to fight to keep the BDOs at their posts. | Summary: Nearly $1 billion spent on a TSA behavioral screening program may have been better spent in Vegas. Started in 2007 at a cost of $200 million a year, the Screening of Passengers by Observation Techniques (SPOT) program trains officers to scan crowded airports for suspicious-looking people. There's just one problem: There's "no evidence behavior detention works," a GAO report has found, noting the results of identification from SPOT, which employs 3,000 officers across the country, are "the same as or slightly better than chance," reports NBC News. The report, which looked at 400 studies over 60 years, has called for a slash in funding until the TSA "can provide scientifically validated evidence"-but Homeland Security says there's plenty out there. In a response, it said studies supporting behavior detection were left out of the GAO's report and the program's different techniques result in "misleading" conclusions. The TSA calls the program "a common sense approach," CBS News reports, but Rep. Bennie Thompson tells the Washington Post it "is fundamentally flawed, cannot be proven effective, and should no longer be funded with taxpayer dollars." | 2,583 | 274 | multi_news | en |
Summarize: At least six people were killed in an early morning suicide attack Wednesday in the Afghan capital, hours after a surprise visit to Afghanistan by President Barack Obama, government officials said. The Taliban claimed responsibility for the attack and said it was a response to Obama's visit. A series of explosions and gunfire rang out in eastern Kabul at around 6 a.m. near a private armed compound that houses hundreds of international workers. Shooting continued for hours and it was not clear later whether the attack was finished, as another large explosion sounded around 8 a.m. from inside the complex _ known as Green Village. An Afghan police official said two suicide attackers were still inside Green Village and were "resisting." The official spoke on condition of anonymity because he was not authorized to release the information. One of the first blasts was a suicide car bomb that exploded near Jalalabad road _ one of the main thoroughfares out of the city, said Interior Ministry spokesman Sediq Sediqi. A station wagon that was driving past was caught up in the explosion and four people inside were killed, Sediqi said. A passer-by and a security guard for a nearby building also were killed. The explosions happened hours after Obama left Afghanistan after a quick visit to mark the first anniversary of Osama bin Laden's death. He spoke to troops and signed a pact with Afghan President Hamid Karzai to govern the U.S. presence in Afghanistan through 2024. Taliban spokesman Zabiullah Mujahid claimed responsibility for the attack and said it was planned Tuesday night as a response to Obama's trip. "This is a reaction to Obama's visit to Afghanistan," Mujahid said, without elaborating. He said the target was a "foreign military base." NATO forces spokesman Capt. Justin Brockhoff said there were no indications that any NATO bases were under attack. The Green Village complex, with its towering blast walls and heavily armed security force, is very similar in appearance to NATO bases in the city. An Associated Press reporter at the scene saw a group of Afghan soldiers enter the Green Village compound, after which heavy shooting could be heard coming from inside. Outside the complex, men could be seen carrying a wounded man covered with blood, apparently pulled out of the flames engulfing a nearby car. "These people evacuated a man from the burning car, two bodies are laying there now and three or four other victims were evacuated from the school," said Ahmad Zia, a resident who saw the explosion. Green Village was also the target of anti-foreigner protests following the burning of Qurans at a U.S. base in February. At that time, violent protests raged outside, but the angry crowds did not breach the compound's defenses. ___ Associated Press writers Heidi Vogt and Rahim Faiez contributed to this report. KABUL Suicide bombers attacked a compound housing Westerners in Kabul on Wednesday hours after U.S. President Barack Obama signed a security pact during a short visit to a city that remains vulnerable to a resilient insurgency. The Taliban claimed responsibility for the attack which involved a car bomb and insurgents disguised as women on the eastern outskirts of the capital, killing seven people, a Gurkha guard and six passers-by, and wounding 17. The Taliban said it was in response to Obama's visit and to the strategic partnership deal he signed with Afghan President Hamid Karzai, a pact that sets out a long-term U.S. role after most foreign combat troops leave by the end of 2014. The insurgency also claimed their spring offensive, which began two weeks ago with attacks in Kabul, would be renewed on Thursday, despite a security clamp-down in the capital. Obama's visit came a year after U.S. special forces troops killed al Qaeda leader Osama bin Laden, the architect of the September 11, 2001, attacks, in a raid in neighboring Pakistan. In a televised address to the American people from a base north of Kabul, he said the war in Afghanistan was winding down. "As we emerge from a decade of conflict abroad and economic crisis at home, it's time to renew America," Obama said, speaking against a backdrop of armored vehicles and a U.S. flag. "This time of war began in Afghanistan, and this is where it will end. Nearly 3,000 U.S. and NATO soldiers have been killed in Afghanistan since the Taliban rulers were ousted in 2001. The Taliban, overthrown by U.S.-backed Afghan forces for harboring bin Laden and other militants, were quick to take credit for Wednesday's attack at Green Village, one of several compounds for Westerners on a main road out of the capital. "This attack was to make clear our reaction to Obama's trip to Afghanistan. The message was that instead of signing a strategic partnership deal with Afghanistan, he should think about taking his troops out from Afghanistan and leave it to Afghans to rebuild their country," Taliban spokesman Zabihullah Mujahid told Reuters by telephone from an undisclosed location. But America's Kabul ambassador, Ryan Crocker, said involvement of the Haqqani network - which Washington believes is based in Pakistan's North Waziristan region and which it blames for high-profile attacks in Kabul in April - could not be ruled out. On the anniversary of bin Laden's killing, Crocker said he did not believe there would be a sole turning point in the war. "Al Qaeda is still there. We do feel we are prevailing in this with our Afghan partners," he said. "We cannot be in a position of taking on ourselves bringing perfection to Afghanistan. That has to be left to Afghans." But Crocker said there would be no repeat of the 1990s when a withdrawal of Western backers in the wake of the Soviet withdrawal unleashed a vicious civil war out of which the Taliban and al Qaeda support bases arose. BLOOD STAINS Hundreds of police and intelligence agency troops surrounded the area around Green Village after the attack. Ruined cars were seen in front of the compound gates but officials said no attackers made it inside the heavily-guarded complex. "I was going to the office when the car in front of me blew up. I got on my bicycle and fled," 40-year-old Farid Ahmad Mohammad told Reuters near the scene of the explosion. A worker at the compound, Jamrod, said at a hospital where the wounded had been taken that he had been showing his identity card at the compound's main gate when the vehicle exploded. "I heard a bang and then I slammed into the wall," Jamrod, still clad in blood-stained jeans, told Reuters. Wednesday's attack was the latest in a recent surge of violence after the Taliban announced they had begun their usual "spring offensive", and since they suspended tentative steps towards peace talks with the United States. Such incidents raise troubling questions about the readiness of Afghan forces to take over when militants remain able to stage high-profile attacks, even when already tight security had been beefed up even further for Obama's visit. Insurgents staged coordinated attacks in Kabul last month, paralyzing the city's centre and diplomatic area for 18 hours. The Taliban also claimed responsibility for those attacks, but U.S. and Afghan officials blamed the militant, al Qaeda-linked Haqqani network. ELECTION YEAR Obama's visit was clearly an election-year event. He spoke to U.S. troops during a stay in Afghanistan of roughly six hours and emphasized bin Laden's demise, an event his re-election campaign has touted as one of his most important achievements in office. "Not only were we able to drive al Qaeda out of Afghanistan, but slowly and systematically we have been able to decimate the ranks of al Qaeda, and a year ago we were able to finally bring Osama bin Laden to justice," Obama said to cheers. But even as he asserted in his speech that there was a "clear path" to fulfilling the U.S. mission in Afghanistan and made his strongest claim yet that the defeat of al Qaeda was "within reach", he warned of further hardship ahead. "I recognize that many Americans are tired of war... But we must finish the job we started in Afghanistan and end this war responsibly," he said at Bagram airbase, where only months ago thousands of Afghans rioted after U.S. troops accidentally burned copies of the Koran, the Muslim holy book. That incident, and the killing of 17 Afghan civilians by a rogue U.S. soldier weeks later, plunged already tense relations to their lowest point in years. While speaking in broad terms of "difficult days ahead", Obama did not address some of the thorniest challenges. These include corruption in Karzai's government, the unsteadiness of Afghan forces in the face of a resilient Taliban insurgency, and Washington's strained ties with Pakistan, where U.S. officials see selective cooperation in cracking down on militants fuelling cross-border violence. Earlier, Obama met Karzai at his walled garden palace in Kabul, where they signed the Strategic Partnership Agreement. "By signing this document, we close the last 10 years and open a new season of equal relations," Karzai said after the meeting. The agreement does not specify whether a reduced number of U.S. troops, possibly special forces, and advisers will remain after NATO's 2014 withdrawal deadline. That will be dealt with in a separate status-of-forces agreement still being worked out. (Additional reporting by Rob Taylor, Hamid Shalizi and Caren Bohan; Writing by Raju Gopalakrishnan and Rob Taylor; Editing by Nick Macfie) | Summary: At least seven people were killed as suicide bombers hit targets in Kabul just hours after the departure of President Obama. A suicide car bomber killed a guard and several passers-by at the gates of the "Green Village" compound that houses hundreds of international workers, Reuters reports. Other attackers then stormed the compound and fought security forces, Afghan officials tell the AP. At least 17 people were injured, mostly children on their way to school. A Taliban spokesman claimed responsibility for the attack, saying it was a response to Obama's visit to Afghanistan and signing of a security accord with Hamid Karzai. "This was a message to Obama that those are not real Afghans that are signing documents about this country," he said. "The real Afghan nation are those people that are not letting foreign invaders stay in this country or disrespect the dignity of our country." | 2,163 | 185 | multi_news | en |
Summarize: About HHS The mission of the U.S. Department of Health and Human Services (HHS) is to "enhance the health and well-being of Americans by providing for effective health and human services and by fostering sound, sustained advances in the sciences underlying medicine, public health, and social services." HHS is currently organized into 11 main agencies, called "operating divisions," which are responsible for a wide variety of health and human services and related research (see a list of these agencies in the G lossary below). In addition, HHS has a number of "staff divisions" within the Office of the Secretary (OS). These staff divisions fulfill a broad array of management, research, oversight, and emergency preparedness functions in support of the entire department. Eight of the HHS operating divisions are part of the U.S. Public Health Service (PHS). PHS agencies have diverse missions in support of public health, ranging from the provision of health care services and supports (e.g., IHS, HRSA, SAMHSA), to the advancement of health care quality and medical research (e.g., AHRQ, NIH), to the prevention and control of infectious and chronic diseases and environmental health hazards (e.g., CDC, ATSDR), and the regulation of food and drugs (e.g., FDA). The three remaining HHS operating divisions are not PHS agencies: ACF, ACL, and CMS. ACF and ACL largely administer human services programs focused on the well-being of vulnerable children, families, older Americans, and individuals with disabilities. CMS—which accounts for the largest share of the HHS budget by far—is responsible for administering the Medicare and Medicaid programs, and some aspects of the private health insurance market. Overview of the FY2018 HHS Budget Request The HHS budget request for FY2018 was affected by two notable circumstances. The first was a presidential transition, from the Administration of President Barack H. Obama to the Administration of President Donald J. Trump, occurring in late January 2017. As a result of this transition, the full FY2018 budget submission was delayed until May 22, 2017. The second notable circumstance affecting the FY2018 HHS budget request is that final FY2017 appropriations ( P.L. 115-31 ) were not enacted until May 5, 2017, about two weeks before the FY2018 budget was submitted. Consequently, final appropriations levels for FY2017 were largely unknown during the formulation of the FY2018 budget proposal, and the HHS budget does not include a display of FY2017-enacted levels. The HHS budget instead displays FY2017 estimates derived from two sources: For discretionary spending programs, the HHS budget displays annualized estimates of funding provided under the second FY2017 continuing resolution (CR, P.L. 114-254 ). Generally, this CR was a formulaic extension of FY2016 funding levels with an across-the-board adjustment and exceptions for particular accounts and activities. For mandatory spend ing programs, the HHS budget displays estimates of the amounts expected to be needed for FY2017 based on criteria outlined in authorizing law. (For related discussion, see " Budgetary Resources versus Appropriations.") While the estimates of annualized spending under the FY2017 CR may have informed FY2018 budget negotiations within the Administration, these estimates (in particular) should not be treated as FY2017 "final" or enacted levels for the purposes of comparison to prior years or the FY2018 proposal. Under the budget request, HHS would spend an estimated $1.131 trillion in outlays in FY2018 (see Table 1 ). This is $422 million (+0.04%) more than the FY2017 estimate (based on the annualized CR and current services mandatory spending), and about $28 billion (+2.55%) more than FY2016 actual. The Office of Management and Budget (OMB) estimates that HHS will account for more than a quarter of all federal outlays (nearly 28%) in FY2018. HHS has accounted for at least 20% of all federal outlays in each year since FY1995. Figure 1 displays proposed FY2018 HHS outlays by major program or spending category in the President's request. As this figure shows, mandatory spending typically accounts for the vast majority of the HHS budget. In fact, two programs—Medicare and Medicaid—are expected to account for 88% of all estimated HHS spending in FY2018. Medicare and Medicaid are "entitlement" programs, meaning the federal government is required to make mandatory payments to individuals, states, or other entities based on criteria established in authorizing law. This figure also shows that discretionary spending accounts for only about 7% of FY2018 HHS outlays in the President's request. Although discretionary spending represents a relatively small share of total HHS spending, the department nevertheless receives more discretionary money than most federal departments. According to OMB data, more than half of the President's request for discretionary budget authority in FY2018 would go to the Department of Defense (56%), with the second largest share going to the Department of Veterans Affairs (7%). HHS would receive the third largest share (nearly 6%) of all discretionary budget authority requested by the President, followed by the Department of Education (5%). Budgetary Resources versus Appropriations Readers should be aware that the HHS budget includes a broader set of budgetary resources than the amounts provided to HHS through the annual appropriations process. As a result, certain amounts shown in FY2018 HHS budget materials (including amounts for prior years) will not match amounts provided to HHS by annual appropriations acts and displayed in accompanying congressional documents. There are several reasons for this, described throughout this section. First, mandatory spending makes up a large portion of the HHS budget and much of that spending is provided directly by authorizing laws, not through appropriations acts. All discretionary spending is controlled and provided through the annual appropriations process. By contrast, all mandatory spending is controlled by the program's authorizing statute. In most cases, that authorizing statute also provides the funds for the program. However, the budget authority for some mandatory programs, including Medicaid, while controlled by criteria in the authorizing statute, must still be provided through the annual appropriations process; such programs are commonly referred to as "appropriated entitlements" or "appropriated mandatories." In addition, the HHS budget request takes into account the department as a whole, while the appropriations process divides HHS funding across three different appropriations bills. While most of the discretionary spending for the department is provided through the Departments of Labor, Health and Human Services, and Education, and Related Agencies (LHHS) Appropriations Act, funding for certain HHS agencies and activities is appropriated in two other bills—the Departments of the Interior, Environment, and Related Agencies Appropriations Act (INT) and the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act (AG). Table 2 lists HHS agencies by appropriations bill. Moreover, the Administration's estimates for HHS programs may follow different conventions than congressional scorekeepers. For example, certain transfers of funding between HHS agencies (or from HHS to other federal agencies) that occurred in prior fiscal years, or are expected to occur in this fiscal year, may be accounted for in the Administration estimates but not necessarily in the congressional documents. In addition, HHS budget materials may include two different estimates for mandatory spending programs in FY2018: proposed law and current law. Proposed law estimates take into account changes in mandatory spending proposed in the FY2018 HHS budget request. Such proposals would need to be enacted into law to affect the budgetary resources ultimately available to the mandatory spending program. HHS materials may also show a current law or current services estimate for mandatory spending programs. These estimates assume that no changes will be made to existing policies, and instead estimate mandatory spending for programs based on criteria established in current authorizing law. The HHS budget estimates in this report reflect the proposed law estimates for mandatory spending programs, but readers should be aware that other HHS, OMB, or congressional estimates might reflect current law instead. Finally, the amounts of discretionary spending provided in the appropriations bills do not necessarily account for all of the budgetary resources that are available to those agencies. This is because agencies within HHS may have the authority to expend user fees and other types of collections that effectively supplement those appropriations. In addition, agencies may receive transfers of budgetary resources from other sources, such as from the Public Health Service Evaluation Set-Aside (also referred to as the PHS Tap) or one of the mandatory trust funds established by the Patient Protection and Affordable Care Act (ACA, P.L. 111-148 ). Budgetary totals that account for these sorts of resources in the Administration estimates are referred to as being at the "program level." HHS agencies that have historically had notable differences between the amounts in the appropriations bills and their program level include the Food and Drug Administration (due to user fees) and the Agency for Healthcare Research and Quality (due to transfers). The program level for each agency is listed in the table entitled, "Composition of the HHS Budget Discretionary Programs" in the HHS FY2018 Budget in Brief (BIB). HHS Budget by Operating Division Table 3 displays budgetary totals for each HHS operating division. These totals are inclusive of both mandatory and discretionary spending. The FY2016 actual, FY2017 estimate (based on the annualized CR and current services mandatory spending), and FY2018 request figures are taken from the HHS BIB for FY2018; the FY2015 actual figures are taken from the FY2017 BIB. The remainder of this section provides a brief summary of the mission of each operating division, the FY2018 budget request, and links to additional resources related to that request. (Links are also provided to resources on amounts enacted for FY2017 in the Consolidated Appropriations Act, 2017.) A table of Key Policy Staff is included at the end of the report. The figures in this section are provided in terms of budget authority and outlays. Budget authority (BA) is the authority provided by federal law to enter into contracts or other financial obligations that will result in immediate or future expenditures involving federal government funds. Outlays occur when funds are actually expended from the Treasury and could be the result of either new budget authority enacted in the current fiscal year or unexpended budget authority that was enacted in previous fiscal years. As a consequence, the BA and outlays in this table represent two different ways of accounting for the funding that is provided to each HHS agency through the federal budget process. Administration for Children and Families (ACF) The ACF mission is focused on promoting the "economic and social well-being of children, youth, families, and communities." ACF administers a wide array of human services programs, including Temporary Assistance for Needy Families (TANF), Head Start, child care, the Social Services Block Grant (SSBG), and various child welfare programs. Relevant Appropriations Bill: LHHS FY201 8 Request: BA: $46.535 billion Outlays: $48.289 billion Additional Resources Related to the FY201 8 Request: Congressional Justification, available at https://www.acf.hhs.gov/sites/default/files/olab/acf_master_cj_508_compmay_21_2017.pdf. All-Purpose Table (p. 6), available at https://www.acf.hhs.gov/sites/default/files/olab/acf_master_cj_508_compmay_21_2017.pdf#page=11. BIB Chapter (p. 74), available at https://www.hhs.gov/sites/default/files/Consolidated%20BIB_ONLINE_remediated.pdf#page=78. Additional Resources Related to FY2017 Appropriations: Appropriations language ( P.L. 115-31 ), available at https://www.congress.gov/115/bills/hr244/BILLS-115hr244enr.pdf#page=397. Appropriations funding table (explanatory statement), available at https://www.congress.gov/crec/2017/05/03/CREC-2017-05-03-bk3.pdf#page=43. Administration for Community Living (ACL) The ACL mission is focused on maximizing the "independence, well-being, and health of older adults, people with disabilities across the lifespan, and their families and caregivers." ACL administers a number of programs targeted at older Americans and the disabled, including Home and Community-Based Supportive Services and State Councils on Developmental Disabilities. Relevant Appropriations Bill: LHHS FY2018 Request: BA: $1.851 billion Outlays: $1.935 billion Additional Resources Related to the FY2018 Request: Congressional Justification, https://www.acl.gov/sites/default/files/about-acl/2017-05/FY%202018%20ACL%20Budget%20Congressional%20Justification%20v2.pdf. All-Purpose Table (p. 13), available at https://www.acl.gov/sites/default/files/about-acl/2017-05/FY%202018%20ACL%20Budget%20Congressional%20Justification%20v2.pdf#page=18. BIB Chapter (p. 85), available at https://www.hhs.gov/sites/default/files/Consolidated%20BIB_ONLINE_remediated.pdf#page=89. Additional Resources Related to FY2017 Appropriations: Appropriations language ( P.L. 115-31 ), available at https://www.congress.gov/115/bills/hr244/BILLS-115hr244enr.pdf#page=400. Appropriations funding table (explanatory statement), available at https://www.congress.gov/crec/2017/05/03/CREC-2017-05-03-bk3.pdf#page=49. Agency for Healthcare Research and Quality (AHRQ) The AHRQ mission is focused on research to make health care "safer, higher quality, more accessible, equitable, and affordable." Specific AHRQ research efforts are aimed at reducing the costs of care, promoting patient safety, measuring the quality of health care, and improving health care services, organization, and financing. The FY2018 President's budget proposes consolidating AHRQ's functions within NIH, in the new National Institute for Research on Safety and Quality (NIRSQ). Consequently, the FY2018 budget documents provided below reference the NIRSQ, and not AHRQ. Relevant Appropriations Bill: LHHS FY2018 Request: BA: $0 million Outlays: $288 million Additional Resources Related to the FY2018 Request: Congressional Justification, available at https://www.ahrq.gov/sites/default/files/wysiwyg/cpi/about/mission/budget/2018/NIRSQ.pdf. All-Purpose Table (p. 4), available at https://www.ahrq.gov/sites/default/files/wysiwyg/cpi/about/mission/budget/2018/NIRSQ.pdf#page=4. BIB Chapter: There is no FY2018 BIB chapter for AHRQ. Additional Resources Related to FY2017 Appropriations: Appropriations language ( P.L. 115-31 ), available at https://www.congress.gov/115/bills/hr244/BILLS-115hr244enr.pdf#page=395. Appropriations funding table (explanatory statement), available at https://www.congress.gov/crec/2017/05/03/CREC-2017-05-03-bk3.pdf#page=40. Centers for Disease Control and Prevention (CDC) and Agency for Toxic Substances and Disease Registry (ATSDR)19 The CDC mission is focused on "disease prevention and control, environmental health, and health promotion and health education." CDC is organized into a number of centers, institutes, and offices, some focused on specific public health challenges (e.g., injury prevention), and others focused on general public health capabilities (e.g., surveillance and laboratory services). In addition, the Agency for Toxic Substances and Disease Registry (ATSDR) is headed by the CDC director. For that reason, the ATSDR budget is often shown within CDC. Following the conventions of the FY2018 HHS Budget in Brief, ATSDR's budget request is included in the CDC totals shown in this report. ATSDR's work is focused on preventing or mitigating the adverse effects resulting from exposure to hazardous substances in the environment. Relevant Appropriations Bills: LHHS (CDC) INT (ATSDR) FY2018 Request (CDC and ATSDR combined): BA: $6.374 billion Outlays: $7.275 billion Additional Resources Related to the FY2018 Request: CDC Congressional Justification, available at https://www.cdc.gov/budget/documents/fy2018/fy-2018-cdc-congressional-justification.pdf. All-Purpose Table (p. 18), available at https://www.cdc.gov/budget/documents/fy2018/fy-2018-cdc-congressional-justification.pdf#page=18. ATSDR Congressional Justification, available at https://www.cdc.gov/budget/documents/fy2018/fy-2018-atsdr.pdf. BIB Chapter (p. 28), available at https://www.hhs.gov/sites/default/files/Consolidated%20BIB_ONLINE_remediated.pdf#page=32. Additional Resources Related to FY2017 Appropriations: CDC appropriations language ( P.L. 115-31 ), available at https://www.congress.gov/115/bills/hr244/BILLS-115hr244enr.pdf#page=387. CDC appropriations funding table (explanatory statement), available at https://www.congress.gov/crec/2017/05/03/CREC-2017-05-03-bk3.pdf#page=31. ATSDR appropriations language ( P.L. 115-31 ), available at https://www.congress.gov/115/bills/hr244/BILLS-115hr244enr.pdf#page=353. ATSDR appropriations funding table (explanatory statement), available at https://www.congress.gov/crec/2017/05/03/CREC-2017-05-03-bk2.pdf#page=611. Centers for Medicare & Medicaid Services (CMS) The CMS mission is focused on ensuring "effective, up-to-date health care coverage and promot[ing] quality care for beneficiaries" of Medicare, Medicaid, the State Children's Health Insurance Program (CHIP), and new private insurance and private insurance market reform programs. The President's budget estimates that in FY2018, "over 143 million Americans will rely on programs CMS administers including Medicare, Medicaid, the Children's Health Insurance Program (CHIP), and the Health Insurance Exchanges." Relevant Appropriations Bill: LHHS FY201 8 Request: BA: $1,009.626 billion Outlays: $1,019.633 billion Additional Resources Related to the FY201 8 Request: Congressional Justification, available at https://www.cms.gov/About-CMS/Agency-Information/PerformanceBudget/Downloads/FY2018-CJ-Final.pdf. All-Purpose Table (p. 10), available at https://www.cms.gov/About-CMS/Agency-Information/PerformanceBudget/Downloads/FY2018-CJ-Final.pdf#page=16. BIB Chapter (p. 49), available at https://www.hhs.gov/sites/default/files/Consolidated%20BIB_ONLINE_remediated.pdf#page=53. Additional Resources Related to FY2017 Appropriations: Appropriations language ( P.L. 115-31 ), available at https://www.congress.gov/115/bills/hr244/BILLS-115hr244enr.pdf#page=395. Appropriations funding table (explanatory statement), available at https://www.congress.gov/crec/2017/05/03/CREC-2017-05-03-bk3.pdf#page=41. Food and Drug Administration (FDA) The FDA mission is focused on regulating the safety of human foods, dietary supplements, cosmetics, and animal foods; and the safety and effectiveness of human drugs, biological products (e.g., vaccines), medical devices, radiation-emitting products, and animal drugs. It also regulates the manufacture, marketing, and sale of tobacco products. Relevant Appropriations Bill: AG FY2018 Request: BA: $1.891 billion Outlays: $2.080 billion Additional Resources Related to the FY2018 Request: Congressional Justification, available at https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/BudgetReports/UCM559923.pdf. All-Purpose Table (p. 9), available at https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/BudgetReports/UCM559923.pdf#page=17. BIB Chapter (p. 14), available at https://www.hhs.gov/sites/default/files/Consolidated%20BIB_ONLINE_remediated.pdf#page=18. Additional Resources Related to FY2017 Appropriations: Appropriations language ( P.L. 115-31 ), available at https://www.congress.gov/115/bills/hr244/BILLS-115hr244enr.pdf#page=29. Appropriations funding table (explanatory statement), available at https://www.congress.gov/crec/2017/05/03/CREC-2017-05-03-bk2.pdf#page=32. Health Resources and Services Administration (HRSA) The HRSA mission is focused on "improving access to health care for those who are uninsured, isolated, or medically vulnerable." Among its many programs and activities, HRSA supports health care workforce training, the National Health Service Corps, and the federal health centers program, which provides grants to nonprofit entities that provide primary care services to people who experience financial, geographic, cultural, or other barriers to health care. Relevant Appropriations Bill: LHHS FY2018 Request: BA: $10.205 billion Outlays: $10.828 billion Additional Resources Related to the FY2018 Request: Congressional Justification, available at https://www.hrsa.gov/about/budget/budgetjustification2018.pdf. All-Purpose Table (p. 15), available at https://www.hrsa.gov/about/budget/budgetjustification2018.pdf#page=16. BIB Chapter (p. 19), available at https://www.hhs.gov/sites/default/files/Consolidated%20BIB_ONLINE_remediated.pdf#page=23. Additional Resources Related to FY2017 Appropriations: Appropriations language ( P.L. 115-31 ), available at https://www.congress.gov/115/bills/hr244/BILLS-115hr244enr.pdf#page=385. Appropriations funding table (explanatory statement), available at https://www.congress.gov/crec/2017/05/03/CREC-2017-05-03-bk3.pdf#page=26. Indian Health Service (IHS) The IHS mission is focused on providing "comprehensive health services for American Indians and Alaska Natives... to improve their health status and overall quality of life." IHS provides health care for approximately 2.2 million eligible American Indians/Alaska Natives through a system of programs and facilities located on or near Indian reservations, and through contractors in certain urban areas. Relevant Appropriations Bill: INT FY2018 Request: BA: $4.898 billion Outlays: $4.939 billion Additional Resources Related to the FY2018 Request: Congressional Justification, available at https://www.ihs.gov/budgetformulation/includes/themes/newihstheme/display_objects/documents/FY2018CongressionalJustification.pdf. All-Purpose Table (p. 7), available at https://www.ihs.gov/budgetformulation/includes/themes/newihstheme/display_objects/documents/FY2018CongressionalJustification.pdf#page=17. BIB Chapter (p. 25), available at https://www.hhs.gov/sites/default/files/Consolidated%20BIB_ONLINE_remediated.pdf#page=29. Additional Resources Related to FY2017 Appropriations: Appropriations language ( P.L. 115-31 ), available at https://www.congress.gov/115/bills/hr244/BILLS-115hr244enr.pdf#page=350. Appropriations funding table (explanatory statement), available at https://www.congress.gov/crec/2017/05/03/CREC-2017-05-03-bk2.pdf#page=609. National Institutes of Health (NIH) The NIH mission is focused on supporting and conducting research "into the causes, diagnosis, treatment, control, and prevention of diseases" and promoting the "acquisition and dissemination of medical knowledge to health professionals and the public." NIH is organized into 27 research institutes and centers, headed by the NIH Director. In FY2018, the majority of the NIH budget (over 80%) will support research performed by more than 300,000 researchers who work at more than 2,500 universities, medical schools, and other research institutions. Relevant Appropriations Bill: LHHS FY2018 Request: BA: $26.049 billion Outlays: $30.195 billion Additional Resources Related to the FY2018 Request: Congressional Justification, available at https://officeofbudget.od.nih.gov/pdfs/FY18/NIH%20Overview%20Volume%20Final.pdf. All-Purpose Table (p. 16), https://officeofbudget.od.nih.gov/pdfs/FY18/NIH%20Overview%20Volume%20Final.pdf#page=20. BIB Chapter (p. 36), available at https://www.hhs.gov/sites/default/files/Consolidated%20BIB_ONLINE_remediated.pdf#page=40. Additional Resources Related to FY2017 Appropriations: Appropriations language ( P.L. 115-31 ), available at https://www.congress.gov/115/bills/hr244/BILLS-115hr244enr.pdf#page=390. Appropriations funding table (explanatory statement), available at https://www.congress.gov/crec/2017/05/03/CREC-2017-05-03-bk3.pdf#page=34. Substance Abuse and Mental Health Services Administration (SAMHSA) The SAMHSA mission is focused on reducing the "impact of substance abuse and mental illness on America's communities." SAMHSA coordinates behavioral health surveillance to better understand the impact of substance abuse and mental illness on children, individuals, and families, and the costs associated with treatment. Relevant Appropriations Bill: LHHS FY2018 Request: BA: $3.771 billion Outlays: $3.688 billion Additional Resources Related to the FY2018 Request: Congressional Justification, available at https://www.samhsa.gov/sites/default/files/samhsa-fy-2018-congressional-justification.pdf. All-Purpose Table (p. 6), available at https://www.samhsa.gov/sites/default/files/samhsa-fy-2018-congressional-justification.pdf#page=14. BIB Chapter (p. 48), available at https://www.hhs.gov/sites/default/files/Consolidated%20BIB_ONLINE_remediated.pdf#page=44. Additional Resources Related to FY2017 Appropriations: Appropriations language ( P.L. 115-31 ), available at https://www.congress.gov/115/bills/hr244/BILLS-115hr244enr.pdf#page=393. Appropriations funding table (explanatory statement), available at https://www.congress.gov/crec/2017/05/03/CREC-2017-05-03-bk3.pdf#page=37. | Summary: This report provides information about the FY2018 budget request for the Department of Health and Human Services (HHS). It begins by reviewing the department's mission and structure. This is followed by an overview of the total FY2018 request for the department. Next, the report discusses the concept of the HHS budget as a whole, compared to funding provided to HHS through the annual appropriations process. This distinction is important because certain amounts shown in FY2018 HHS budget materials (including amounts for prior years) will not match amounts provided to HHS by annual appropriations acts (and displayed in accompanying congressional documents), because they take into account a broader set of budgetary resources. The report concludes with a breakdown of the HHS request by agency, along with additional HHS resources that provide further information on the request. A table of key policy staff is included at the end of the report. | 7,216 | 199 | gov_report | en |
Summarize: Introduction Congress, the President, and executive branch agencies use federal advisory committees to gain expertise and policy advice from individuals within and outside the federal government. Federal advisory committees are created to bring together various experts—often with divergent opinions and political backgrounds—to examine an issue and recommend statutory, regulatory, grantmaking, or other policy actions. Federal advisory committees are one of only a few formalized mechanisms for private-sector citizens to participate in the federal policymaking process. Federal advisory committees, however, are prohibited from creating policy or issuing regulations. Their role is to remain strictly advisory. Federal advisory committees can be called task forces, panels, commissions, working groups, boards, councils, conferences, or other titles. As noted above, federal advisory committees can be established either by Congress, the President, or an agency head. Congress has the power to establish a committee in two ways. First, Congress can specifically mandate that the committee be established by law. Second, Congress can authorize the establishment of a committee, but leaves the decision on whether to actually create the entity to a designated agency. Congress may decide to establish a federal advisory committee for a variety of reasons, among them to allow the federal government to collect the experts on a particularly technical or scientific topic in one location to debate the potential policy outcomes; to ensure that appropriate stakeholders of a particular policy arena have the opportunity to voice their opinions to policymakers; to attempt to remove a controversial policy option or funding decision from a highly charged political arena; or to reduce congressional or executive branch workloads. When Congress chooses to establish an advisory committee, it may also determine whether the committee should be governed by or be exempted from the transparency, access, and reporting requirements of the Federal Advisory Committee Act (FACA). For example, FACA requires all applicable advisory committees to file a charter prior to operation. The charter is required to include the committee's objectives, the committee's affiliated agency, the committee's duties, the estimated operating costs, the estimated number of committee meetings, and the anticipated termination date, among other information. Additionally, all advisory committee meetings that are subject to FACA are presumed to be open to the public, with certain specified exceptions. Adequate notice of advisory committee meetings must therefore be published in advance in the Federal Register. Subject to certain records protections provided in the Freedom of Information Act, all papers, records, and minutes of meetings must be made available for public inspection. Membership must be "fairly balanced in terms of the points of view represented and the functions to be performed," and the committee should "not be inappropriately influenced by the appointing authority or by any special interest." This report assists Members and staff when they are deciding whether a federal advisory committee is the appropriate mechanism to assist policymaking, grantmaking, or other questions. This report provides analysis of some primary components of federal advisory committee design, including examples of federal advisory committee structure and operations. The report examines some reasons Congress may choose to establish an advisory committee, and provides context to understand when applying the provisions of FACA to a committee could assist or hinder a committee's operations. This report uses the provisions of FACA and information within the FACA Database to shape its analysis of federal advisory committee creation. As part of FACA's statutory and regulatory requirements, agency officials report operating practices and committee costs into the FACA Database, an online data collection tool the General Services Administration (GSA) created and manages. The database is the only publicly available source that includes aggregated and historical information on FACA committee membership, operations, and costs. The collection of data on federal advisory committees and their operations provides around 1,000 examples of operating advisory committees in any year, more than half of which were created by statute. Why Establish a Federal Advisory Committee? Federal advisory committees can be established for a variety of reasons. According to a 1972 Senate Government Operations Committee report, advisory committees were intended to provide an "opportunity for the public to learn either about [advisory committee] deliberations and recommendations or about the information on which [advisory committees] base those recommendations." Federal advisory committees, therefore, can be especially helpful in policy arenas where public access to and participation in debates and discussions are as important as (or, possibly more important than) the policy recommendations that emerge from those discussions. In an examination of advisory commissions established by presidential directive, one scholar stated that these advisory commissions have traditionally allowed a President to deflect blame, buy time, and give the appearance of action on issues that are too politically charged, too difficult, to solve. The same study noted that commissions are used by presidents to garner greater public support for a policy to which the president is already committed; show symbolic concern over a situation at the highest level of government; establish a fact base for others to use; respond to crises; deflect political heat from the president and allow passions to cool when issues become explosive; overcome the "stovepipes" and parochial thinking of the permanent bureaucracy; gather more information about a problem and its policy alternatives; forge consensus among the interests represented on the commission itself; and change the hearts and minds of men. The study attempted to group commissions into three categories: agenda commissions, which aim to attract support and attention to presidential policy initiatives; information commissions, which are designed to give "new ideas, new facts, and new analysis to policymakers"; and political constellation commissions, which seek to "foster consensus, compromise, and cooperation in a policy domain." Another researcher who examined the impetus for committee creation found that some committees are created to acquire new ideas from outside experts. He added, however, that committees may be created to allow politicians to avoid blame for issues that are too cumbersome or too politically charged. Moreover, he stated that Members of Congress may create committees because of the immense workload of legislators. Creating an advisory committee can "pare down Congress's workload to more manageable dimensions or to handle and manage a problem in a timely manner." Scholars and practitioners of government have debated whether advisory bodies, in fact, increase public interaction with the federal government. Other debates continue over whether advisory committees have a positive effect on the federal government, or if they are a symptom of a federal government that is not performing properly. In 2011, two scholars found evidence that advisory committees can be useful to federal agencies, especially those that have a technical or scientific focus. Agencies like the Food and Drug Administration (FDA) consult "advisory committees when in-house information processing is relatively costly and the political stakes of its decisions are high." The highly valued information and expertise from advisory committees can be influential when agencies decide whether to approve a drug, device, or other committee recommendation. Also in 2011, another scholar examining the utility of advisory committees in a national security context found that "national security commissions are much more likely to influence policy when they are formed in response to a crisis, established by the executive branch, or given a narrow mandate." According to the author, Congress's fragmented decisionmaking makes it relatively hard for Congress to act with alacrity.... The president or an agency head can form a commission and appoint its members quite quickly—often within weeks. But when members of Congress seek to establish a commission, the slow pace of the legislative process frequently allows the passage of many months, or even years, before its authorizing statute is enacted, and additional months typically go by before its members are appointed. In 2012, the Government Accountability Office (GAO) released a report that noted four practices that may influence the utility of an advisory body. The four practices are 1. securing clear agency commitment; 2. finding a balance between responsiveness to the agency and independence; 3. leveraging resources through collaboration with similar groups; and 4. evaluating the group's usefulness to identify future directions or improvements. Building on this examination of the FDA drug approval process, another scholar found that the FDA is less likely to require warning labels on pharmaceutical drugs and is less likely to withdraw a drug from the market if the drug was reviewed and recommended for approval by an advisory committee. This finding may demonstrate that decisions that rely on the recommendations or advice of an advisory committee are more reliable or scientifically sound than those that are not. A Congressional Research Service (CRS) review of FY2014 committee-reported information in the FACA Database found that statutorily established FACA committees tended to report lower percentages of their recommendations being fully implemented by their affiliated agencies when compared to the recommendation implementation rates reported by committees established by the agencies. In the analysis, 123 advisory committees established by agency authority reported an average of 65.6% of their recommendations were fully implemented by their affiliated agencies. The median reported percentage of full recommendation implementation was 76%. By contrast, the 250 advisory committees required to be established by statute that reported implementation data had an average of 45.9% of their recommendations fully implemented, and a median of 50% full recommendation implementation. The finding suggests that agencies' officials may be more likely to implement recommendations from advisory bodies that they established, rather than the advisory bodies that Congress established within the agency. CRS's analysis also found that scientific technical program advisory board committees and national policy issue advisory board committees reported higher rates of full implementation of their recommendations than committees that were non-scientific program advisory board committees or were committees involved in grantmaking. For example, the 136 scientific technical program advisory boards that provided data on the implementation of their recommendations found, on average, that 60.2% of their recommendations were fully implemented. The median percentage of full implementation of recommendations was 77%. The 66 national policy issue advisory board committees that reported on their full recommendation implementation had, on average, 52.0% of their recommendations fully implemented. The median percentage of full implementation was 58%. In contrast, the 75 grant review committees reported, on average 41.9%, of their recommendations were fully implemented, but the median reported full implementation of recommendations was 0%. Overall, the literature on federal advisory committees has shown that they can have influence on an agency's decisionmaking process. The range and depth of that influence, however, is unclear because the scope of scholarly research on federal advisory committees is limited and the design and purposes of the 1,000 federal advisory committees are vast. Scholars have tended to focus analyses on national security-related or FDA drug approval-related advisory committees, making it more difficult to understand the utility of advisory committees governmentwide. More recent research indicates that establishing advisory committees that focus on scientific technical programs or national policy issues might lead to higher percentages of full implementation of advisory committee recommendations than creating advisory committees that focus on non-scientific programs or grantmaking issues. Congress's Role in Establishing FACA Committees This section explores available data on the creation of advisory committees, using data from the FACA Database. Advisory committees that are exempted from FACA, therefore, are not included in this analysis. In any given fiscal year, Congress establishes a majority of FACA committees. Of the 1,009 active federal advisory committees in FY2015, Congress statutorily required the establishment of 539 (53.4%). Additionally, 183 (18.1%) of the active FACA committees were authorized, but not required, by statute. Figure 1 shows the percentage of total active committees in FY2015 by establishment authority. Of the 1,009 active advisory committees, 42 were newly established in FY2015. Twenty (47.6%) of the 42 new committees were required by statute. Members and staff contemplating the establishment of a new advisory committee may seek examples of statutory language establishing advisory committees. Table 1 below includes the statutory authority for each of the 20 new statutorily required committees established in FY2015. Table 1 includes the name of the committee, its affiliated federal agency or department, and its statutory authority. In most cases, the table includes the authorizing language's U.S. Code citation. In some cases, when an advisory body's authority isn't codified, the most recent statutory authority for the committee is provided. As shown above, Congress plays an important role in the establishment of FACA committees. Currently, 71.5% of all active committees were required to be or authorized to be established by Congress. Of the 20 new statutorily required committees that began operations in FY2015, the Department of the Interior houses the most (5). Three of the committees were required by statute eight or more years before their operations began. In one case, the affiliated department's policies and operations led to operational delays. In another case, two previously operating committees were merged to form a single, new committee. In the final case, the affiliated agency determined that a committee that previously operated outside of FACA's provisions should being operating pursuant to FACA. Considerations When Creating an Advisory Committee As Congress deliberates the establishment of an advisory committee, Members and staff may take into consideration its goals and potential structure. Among the considerations pertinent to the establishment of an advisory committee and to its composition, operation, and effectiveness are the following: defining the committee's mandate; whether FACA's transparency and access provisions should apply; establishing committee membership; defining committee duties; setting the committee's mission; allocating proper funding, support staff, and office space; mandating the committee's reporting requirements; and determining a committee sunset date. Below are a series of possible considerations of the various elements of advisory committees for Members or staff who seek to establish an advisory committee by statute. Establishment and Charter For committees created by statute, the legislative language provides the building blocks, and sometimes the details, that the agency administering the advisory committee must put in the committee's charter. Statutory language establishing an advisory committee can detail the name, purpose, authorities, and membership of an advisory committee—and these requirements likely would be placed in the committee's charter. In contrast, statutory language can direct an agency to establish a committee that examines a particular area of interest, and provide few details on operations and bylaws—all of which need to be detailed in the charter. Statutory language may be included in the charter, but the statute itself would not qualify as the charter. Federal advisory committee charters must contain at least 15 elements, including the federal advisory committee's name, its establishment authority, information on its objectives and scope, and a list of its duties. Statutes establishing committees have no such requirements. Establishing statutes and charters may include language that highlights agency, presidential, or congressional findings that prompted the committee's creation—but such findings are not required. Once committee authority is established, the charter includes a section on "duties" and objectives and scope, specifying the committee's mandate or responsibilities. A committee's objectives may be stated in specific terms—in statutory language or in the charter—to guide the federal advisory committee's members and staff in carrying out their responsibilities. Pursuant to FACA, charters should authorize enough autonomy to ensure that the advisory body provides independent advice that is not "inappropriately influenced by the appointing authority or by any special interest." FACA's Application Congress may choose to require an advisory committee to operate pursuant to FACA's transparency, access, and reporting provisions. On the other hand, Congress may choose to exempt the advisory committee from these provisions. Congress also has the option to select particular provisions from FACA and apply them to an advisory committee without requiring the advisory committee to follow all of FACA's requirements (see "Applying Selected FACA Provisions" text box for an example). As noted above, FACA established the first statutory requirements for management of, access to, and oversight of federal committees. FACA places certain requirements on the formation and oversight of federal advisory committees. For example, FACA requires advisory committee meetings to be open to the public and requires agencies to publish advance notice of their meetings so the public may attend. Additionally, all advisory committee records are to be made available to the public, unless such release is otherwise protected by law. Congress is also to determine if the committees are "fairly balanced in terms of the points of view represented and the functions to be performed." FACA committees established legislatively are to be created with enough autonomy from the appointing power (Congress, the President, or an agency head) so as to not be unduly influenced. Each committee's reporting requirements are to be clearly stipulated, and proper funding and staffing are to be provided. While FACA may improve both the reality and perception of transparent governmental operation and accessibility, its requirements may also place a number of additional chartering, record-keeping, notification, and oversight requirements on the entity. In particular, agencies have claimed that compliance with the various FACA requirements are cumbersome and resource intensive, thereby reducing the ability of committees to focus on substantive issues in a spontaneous and timely fashion. Moreover, some scholars have argued that the scope of the openness requirements could have the practical effect of stifling candid advice and discussion within a committee. Congress may choose to exempt a statutorily established advisory committee from FACA to allow it potentially to operate more quickly and less expensively than FACA might permit. For example, the requirement that all meetings be posted "with timely notice" in the Federal Register may slow down the daily operations of an advisory committee, which will typically not hold meetings until 15 days after the notice is published. On the other hand, exempting an advisory committee from FACA's requirements could make congressional and public oversight of the entity more difficult. As noted above, when Congress is creating an advisory committee in statute it may choose to select certain provisions of FACA and apply them. For example, Congress may choose to exempt an advisory committee from FACA, yet require it to hold open meetings and advertise those meetings online or in the Federal Register at least 15 days prior to any meeting. Congress may also choose to exempt an advisory committee from FACA, yet require it to report annually on its membership, operations, recommendations, and operating costs—putting such information online or providing the information in a report to Congress. The North American Wetlands Conservation Council, within the U.S. Fish and Wildlife Service, is exempted from FACA, but required by statute to "be open to the public." Additionally, the chairman of the council is required to "take appropriate steps to provide adequate notice to the pubic of the time and place of... meetings." Exempting a committee from FACA, however, can affect congressional and public oversight efforts of a federal advisory committee. When FACA's reporting requirements are removed from an advisory committee's operations, it may be more difficult for Congress and the public to track a committee's operations and costs. Applying FACA's provisions, on the other hand, requires agency officials to report operations and costs into the FACA Database, providing a one-stop online text-searchable portal for information on FACA committee operations governmentwide. Membership There are few restrictions on the membership of advisory committees. Pursuant to the FACA, each federal advisory committee must have at least one member who is not a "full-time, or permanent part-time" officer or employee of the federal government. Membership must also "be fairly balanced in terms of the points of view represented and the functions to be performed by the advisory committee." Federal ethics statutes and regulations also may affect committee membership. FACA committee charters must address membership structure. A statute establishing a federal advisory committee, however, may or may not address the committee's membership. If Congress determined it would like greater control over the membership structure of an advisory committee, Congress may want to provide guidelines for membership appointments to executive branch officials in advisory committee establishing language. Congress may also choose to provide direct membership appointments to particular officials or organizations. Table 2 includes selected statutory examples of FACA committee membership design. In many cases, the statutory language used to establish the committee membership requirements will be similar or identical to the language the agency uses in the charter. The text box "Membership: An Example of Statutory Language" provides one example of statutory language that is nearly identical to the language then written into the charter establishing the membership requirements of the Advisory Committee for Trade Policy and Negotiations. The size and structure of an advisory committee can affect the intended mission. For example, the size of the committee may be small enough to allow all members a chance to communicate their expertise and opinion, but large enough to include the appropriate stakeholders and maintain a quorum even when members are absent. Size and member appointment, therefore, largely depend on the committee's functions and mission. Additionally, members can be appointed on a staggered schedule to ensure that there are always a few continuing committee members serving at any given time—allowing for greater continuity in operations over time. Some committees are designed to include specific members of the federal government or their designees. Compensation and Travel Advisory committee members who are not employees or officers of the federal government may or may not receive compensation for their work on a committee. The authority that establishes the committee determines whether committee members are to receive pay, and—if they are paid—their pay level. Pursuant to FACA, neither committee members nor staff may be paid more than the equivalent of Executive Level IV pay ($160,300 for 2016), unless otherwise directed by statute. In addition to compensation for their service, committee members and staff may also be provided compensation to cover travel expenses as well as a per diem. Congress may choose to maintain the pay caps set by FACA or establish unique pay rates for a particular advisory committee. Congress may also choose to prohibit advisory committee members from receiving a salary for their service. These members could still receive payment for travel expenses and a per diem. Committee Staff Generally speaking, committees are comprised of members and staff, and may also include consultants. Pursuant to FACA, agencies must assign a committee management officer (CMO) to "oversee the administration" of FACA and a designated federal officer (DFO), whose duties are as follows: ensure compliance with FACA, and any other applicable laws and regulations; call, attend, and adjourn committee meetings; approve agendas; maintain required records on costs and membership; ensure efficient operations; maintain records for availability to the public; and provide copies of committee report to the CMO for forwarding to the Library of Congress. Staff may include additional agency support staff and an executive director (who may also serve as the DFO). Committee Reports and Recommendations Most committees are required to generate a report or recommendations to the President, Congress, or an agency head. Some committees may also be required to make interim or annual reports. FACA includes no provisions that control or direct the creation or dissemination of a report or recommendations. Statutory language, however, often articulates an advisory committee's reporting requirements, and these reporting requirements must be included in the committee's charter. For example, the Founding Fathers Advisory Committee within the National Archives and Records Administration is statutorily required to "report to the Archivist on the progress of the various projects" it is required to review. Statutory language establishing an advisory committee may require various reporting requirements. The statutorily required Nanotechnology Advisory Panel, for example, is required to report its "assessments" and "recommendations" to the President once every two years. The statute then requires the Director of the Office of Science and Technology Policy to transmit copies of the panel's reports to the Senate Committee on Commerce, Science and Technology Policy and the House Committee on Science—as well as any other appropriate committees of jurisdiction. A statute that establishes an advisory committee may include additional provisions or requirements for executive branch action or response to those recommendations. For example, the National Agricultural Research, Extension, Education, and Economic Advisory Board requires the Secretary of Agriculture to "solicit the written opinions and recommendations of the Advisory Board" and "provide a written response to the Advisory Board regarding the manner and extent to which the Secretary will implement recommendations submitted by the Advisory Board." The effort the Secretary of Agriculture might put into creation of that response, however, may largely correspond to the Administration's interest in the advisory board and its findings. A federal advisory committee's recommendations are strictly advisory and cannot mandate policy action by recipients of the report. In the case of a presidential advisory committee, however, the President must submit to Congress—within a year of receiving a committee's public report—proposals for action or reasons for inaction on the recommendations in the public report. Advisory committees established by agency heads do not appear to have similar requirements to report their actions or inactions to Congress. Committee Authorities Explicit authority may be needed to accomplish certain special duties for which an advisory committee may be responsible. For example, committees would need specific statutory authority to hold hearings, use the franking privilege, accept certain donations, and permit volunteers to work on the staff. If a committee is created by statute and exempted from FACA, Congress may also choose to vest the committee with hiring and pay authorities. Without such authorities, a federal advisory committee would work with the affiliated agency to hire staff and appoint members to the committee, which could lead to delays in starting committee operations. Vesting a committee with subpoena power is done on a very selective basis—and is largely dependent upon the mission of the panel. In the late 1990s, for example, Congress vested the National Gambling Impact Study Commission, a FACA committee, with subpoena authority. One advisory committee's statutory authority and charter, in contrast, explicitly denied the entity subpoena authority. No FACA committees currently appear to have subpoena authority. Bylaws and Procedures Specific procedural requirements—like quorum qualifications—can often be found in committee charters. Other bylaws, including election procedures to determine a chairperson, vote tallying, filling membership vacancies, and reporting procedures also may be included in the charter. In other cases, committee procedures may be included in the legislation that establishes an advisory body. If committee procedures are provided by statute, Congress may have greater control over the body's operations, procedures, and outcomes. On the other hand, if procedures are in statute, the advisory body may not have the autonomy to conduct meetings that provide the optimal opportunity to share candid advice and present new ideas. For FACA committees, the DFO from the sponsoring agency is responsible for approving or calling the meeting of the committee, approving the committee agenda (except for presidential advisory committees), adjourning meetings when it is determined to be in the public interest, and certifying minutes. Funding68 FACA includes no provisions related to the funding of the federal advisory committee. Congress may directly fund a committee through the appropriations process, or it may instruct an agency to use its existing annual appropriation. If provided the authority to do so in statute, an advisory committee may also be funded through private donations. A committee charter may include a determination, within a committee's provided authorities and requirements, as to whether an entity may accept such private financial gifts. If a committee is permitted to accept donations or other, in kind, gifts, the authority that created the advisory body may require detailed recordkeeping of such donations to maintain transparency and to avoid the perception of undue influence. Committee Termination Unless statutorily mandated or otherwise extended by the President or a federal officer, a FACA committee will automatically terminate two years after its establishment. Consequently, most advisory committees must renew their charters every two years. Some committees that are created by statute include provisions to terminate on specific dates or a particular number of years after their establishment. When establishing a committee by statute, a Member or staff may take into account the time and costs for administrative actions. The agency, for example, will need time to assign staff, find suitable office space, and address other logistical concerns. Upon completion of these objectives, the committee also will need additional time to create a final report, file any required records, and vacate the office space. Advisory Committee Establishment in the 114th Congress Table 3 provides a selected list of the advisory committees proposed for establishment by statute in the 114 th Congress. These federal advisory committees are proposed in a variety of subjects and substantive policy arenas. For Members and staff interested in establishing an advisory body, these bills may provide ideas or context for how to design draft language. | Summary: Federal advisory committees provide a formal forum for members of the public to provide advice and recommendations to the federal government on issues ranging from how to support trade goals of small and minority-owned businesses to which drugs best treat arthritis pain. Many of the roughly 1,000 federal advisory committees that operate at any given time are required to operate pursuant to the open meetings, records access, and reporting requirements of the Federal Advisory Committee Act (FACA). Advisory committees are established for a number of reasons. These reasons often include acquiring new ideas from non-governmental experts, removing certain controversial topics from politically charged arenas, and reducing the workload of executive branch employees and Members of Congress. Historically, Congress has established the majority of federal advisory committees. Of more than 1,000 federal advisory committees operating pursuant to FACA (FACA committees) in FY2015, for example, 722 (71.6%) were mandated or authorized by Congress-539 (53.4%) of which were required by statute while 183 (18.1%) were authorized, but not required, by statute. Other FACA committees were established by executive branch agencies or the President. In FY2015, 20 new FACA committees that were required to be created by statute began operations. Five of these 20 new FACA committees were required to be established within the Department of the Interior-more than any other federal agency. Legislative provisions seeking to establish 11 additional FACA committees have been introduced but not enacted in the 114th Congress. Should Congress want to authorize a new federal advisory committee, there are several statutory choices that might be considered. These considerations include a committee's mandate, membership requirements, powers, funding, and termination. This report provides a brief overview on how Congress can establish federal advisory committees, and provides some considerations as to why a federal advisory committee may or may not be an appropriate mechanism to assist a particular policy or funding question. The report also explores why FACA may or may not be appropriate for application to particular advisory committees. It presents data on the number of active FACA committees established by Congress with special emphasis on the committees established in FY2015. This report concludes by presenting a list of the federal advisory committees currently proposed for statutory establishment in the 114th Congress. | 6,363 | 540 | gov_report | en |
Write a title and summarize: SECTION 1. SHORT TITLE. This Act may be cited as the ``Iran Missile Proliferation Sanctions Act of 1997''. SEC. 2. REPORTS ON MISSILE PROLIFERATION TO IRAN. (a) Reports.--Except as provided in subsection (c), the President shall, at the times specified in subsection (b), submit to the Committee on International Relations of the House of Representatives and the Committee on Foreign Relations of the Senate a report identifying every foreign person with respect to whom there is credible information indicating that that person, on or after August 8, 1995-- (1)(A) transferred items on the MTCR Annex, or items that the United States proposes for addition to the MTCR Annex, that contributed to Iran's efforts to acquire, develop, or produce ballistic missiles, or (B) provided technical assistance or facilities which the President deems to be of concern because of their direct contribution to Iran's efforts to acquire, develop, or produce ballistic missiles; or (2)(A) attempted to transfer items on the MTCR Annex, or items that the United States proposes for addition to the MTCR Annex, that would have contributed to Iran's efforts to acquire, develop, or produce ballistic missiles, or (B) attempted to provide technical assistance or facilities which the President deems to be of concern because of their direct contribution to Iran's efforts to acquire, develop, or produce ballistic missiles. (b) Timing of Reports.--The reports under subsection (a) shall be submitted not later than 30 days after the date of the enactment of this Act, not later than 180 days after such date of enactment, not later than 1 year after such date of enactment, and not later than the end of each 1-year period thereafter. (c) Exceptions.--Any foreign person who-- (1) was identified in a previous report submitted under subsection (a) on account of a particular transfer, transaction, or attempt, (2) has engaged in a transfer or transaction that was the basis for the imposition of sanctions with respect to that person under section 73 of the Arms Export Control Act or section 1604 of the Iran-Iraq Arms Non-Proliferation Act of 1992, (3) may have engaged in a transfer or transaction, or made an attempt, that was the subject of a waiver under section 4, or (4) has engaged in a transfer or transaction, or made an attempt, on behalf of, or in concert with, the Government of the United States, is not required to be identified on account of that same transfer, transaction, or attempt in any report submitted thereafter under this section. (d) Submission in Classified Form.--When the President considers it appropriate, reports submitted under subsection (a), or appropriate parts thereof, may be submitted in classified form. SEC. 3. IMPOSITION OF SANCTIONS. (a) Requirement To Impose Sanctions.-- (1) Requirement to impose sanctions.--The sanctions described in subsection (b) shall be imposed on-- (A) any foreign person identified under subsection (a)(1) of section 2 in a report submitted under that section, and (B) any foreign person identified under subsection (a)(2) of section 2 in a report submitted under that section, if that person has been identified in that report or a previous report as having made at least 1 other attempt described in subsection (a)(2) of that section. (2) Effective date of sanctions.--The sanctions shall be effective-- (A) 30 days after the report triggering the sanction is submitted, if the report is submitted on or before the date required by section 2(b); (B) 30 days after the date required by section 2(b) for submitting the report, if the report triggering the sanction is submitted within 30 days after that date; and (C) on the date that the report triggering the sanction is submitted, if that report is submitted more than 30 days after the date required by section 2(b). (b) Description of Sanctions.--The sanctions referred to in subsection (a) that are to be imposed on a foreign person described in that subsection are the following: (1) Arms export sanction.--For a period of not less than 2 years, the United States Government shall not sell to that person any item on the United States Munitions List as in effect on August 8, 1995, and shall terminate sales to that person of any defense articles, defense services, or design and construction services under the Arms Export Control Act. (2) Dual use sanction.--For a period of not less than 2 years, the authorities of section 6 of the Export Administration Act of 1979 shall be used to prohibit the export to that person of any goods or technology on the control list established under section 5(c)(1) of that Act. (3) United states assistance.--For a period of not less than 2 years, the United States Government shall not provide any assistance in the form of grants, loans, credits, guarantees, or otherwise, to that person. SEC. 4. WAIVER ON BASIS OF ADDITIONAL INFORMATION. (a) In General.--The President may waive the imposition of any sanction that would otherwise be required under section 3 on any foreign person 15 days after the President determines and reports to the Committee on International Relations of the House of Representatives and the Committee on Foreign Relations of the Senate that, on the basis of information provided by that person, or otherwise obtained by the President, the President is persuaded that the person did not, on or after August 8, 1995-- (1)(A) transfer items on the MTCR Annex, or items that the United States proposes for addition to the MTCR Annex, that contributed to Iran's efforts to acquire, develop, or produce ballistic missiles, or (B) provide technical assistance or facilities which the President deems to be of concern because of their direct contribution to Iran's efforts to acquire, develop, or produce ballistic missiles; or (2) attempt on more than one occasion-- (A) to transfer items on the MTCR Annex, or items that the United States proposes for addition to the MTCR Annex, that would have contributed to Iran's efforts to acquire, develop, or produce ballistic missiles, or (B) to provide technical assistance or facilities described in paragraph (1)(B). (b) Written Justification.--The determination and report of the President under subsection (a) shall include a written justification describing in detail-- (1) the credible information indicating that the person-- (A) transferred items described in section 2(a)(1)(A), or provided technical assistance or facilities described in section 2(a)(1)(B); or (B) attempted to transfer items described in section 2(a)(1)(A), or attempted to provide technical assistance or facilities described in section 2(a)(1)(B); (2) the additional information which persuaded the President that the person did not-- (A) transfer items described in section 2(a)(1)(A), or provide technical assistance or facilities described in section 2(a)(1)(B); or (B) attempt to transfer items described in section 2(a)(1)(A), or attempt to provide technical assistance or facilities described in section 2(a)(1)(B); and (3) the analysis of the information supporting the President's conclusion. (c) Submission in Classified Form.--When the President considers it appropriate, the determination and report of the President under subsection (a) and the written justification under subsection (b), or appropriate parts thereof, may be submitted in classified form. SEC. 5. WAIVER ON BASIS OF NATIONAL SECURITY. (a) In General.--The President may waive the imposition of any sanction that would otherwise be required under section 3 on any foreign person 15 days after the President determines and reports to the Committee on International Relations of the House of Representatives and the Committee on Foreign Relations of the Senate that such waiver is essential to the national security of the United States. (b) Written Justification.--The determination and report of the President under subsection (a) shall include a written justification describing in detail the facts and circumstances supporting the President's conclusion. (c) Submission in Classified Form.--When the President considers it appropriate, the determination and report of the President under subsection (a) and the written justification under subsection (b), or appropriate parts thereof, may be submitted in classified form. SEC. 6. ADDITIONAL INFORMATION REGARDING ACTIONS BY GOVERNMENT OF PRIMARY JURISDICTION. As part of each report submitted under section 2, the President shall include the following information with respect to each foreign person identified in that report: (1) A statement regarding whether the government of primary jurisdiction over that person was aware of the activities that were the basis for the identification of that person in the report. (2) If the government of primary jurisdiction was not aware of the activities that were the basis for the identification of that person in the report, an explanation of the reasons why the United States Government did not inform that government of those activities. (3) If the government of primary jurisdiction was aware of the activities that were the basis for the identification of that person in the report, a description of the efforts, if any, undertaken by that government to prevent those activities, and an assessment of the effectiveness of those efforts, including an explanation of why those efforts failed. (4) If the government of primary jurisdiction was aware of the activities that were the basis for the identification of that person in the report and failed to undertake effective efforts to prevent those activities, a description of any sanctions that have been imposed on that government by the United States Government because of such failure. SEC. 7. PURCHASE OF WEAPONS TECHNOLOGY. (a) Sense of the Congress.--It is the sense of the Congress that the President should exercise the authority granted to him under section 504 of the Freedom for Russia and Emerging Eurasian Democracies and Open Markets Support Act of 1992 (22 U.S.C. 5854)-- (1) to prevent the transfer of weapons-related material and delivery systems to Iran through the purchase, barter, or other acquisition of such material and delivery systems; and (2) to prevent the transfer to Iran of scientific and technical expertise with respect to such weapons-related material and delivery systems. (b) Availability of Amounts.--Amounts hereafter made available, subject to the availability of appropriations, to carry out chapter 11 of part I of the Foreign Assistance Act of 1961 (22 U.S.C. 2295 et seq.; relating to assistance for the independent states of the former Soviet Union) may be used to carry out subsection (a). SEC. 8. DEFINITIONS. For the purposes of this Act-- (1) the terms ``foreign person'' and ``person'' mean-- (A) a natural person that is an alien; (B) a corporation, business association, partnership, society, trust, or any other nongovernmental entity, organization, or group, that is organized under the laws of a foreign country or has its principal place of business in a foreign country; (C) any foreign governmental entity operating as a business enterprise; and (D) any successor or subsidiary of any entity described in subparagraph (B) or (C); (2) the term ``government of primary jurisdiction'' means-- (A) in the case of a natural person, the foreign government of the country of which the person is a citizen or national; (B) in the case of an entity described in subparagraph (B) of paragraph (1), the foreign government of the country in which the entity has its principal place of business, or the foreign government under whose laws that entity is organized; and (C) in the case of a foreign governmental entity described in subparagraph (C) of paragraph (1), the foreign government of which that entity is a part; and (3) the term ``MTCR Annex'' has the meaning given that term in section 11B(c)(4) of the Export Administration Act of 1979 (50 U.S.C. 2410b(c)(4)). | Title: Iran Missile Proliferation Sanctions Act of 1997 Summary: Iran Missile Proliferation Sanctions Act of 1997 - Directs the President to report periodically to specified congressional committees on foreign persons who, on or after August 8, 1995, have transferred, or attempted to transfer, controlled goods or technology, or provided, or attempted to provide, technical assistance or facilities that contributed, or would have contributed, to Iran's efforts to acquire, develop, or produce ballistic missiles. Excludes from identification in such reports any such persons who were previously identified or sanctioned, who are subject to a waiver, or who have acted on behalf of, or in concert with, the United States. Requires imposition on such persons of minimum two-year sanctions prohibiting: (1) sales to such persons of items on the United States Munitions List (and terminating sales of any controlled U.S. arms); (2) the export to such persons of dual use goods and technology; and (3) the provision of U.S. financial assistance. Authorizes the President to waive such sanctions on the basis of U.S. national security or additional information demonstrating that the sanctioned person did not commit the acts alleged. Expresses the sense of the Congress that the President should exercise the authority granted to him under the Freedom for Russia and Emerging Eurasian Democracies and Open Markets Support Act of 1992 to prevent: (1) the transfer through purchase, barter, or other acquisition of weapons-related material and delivery systems to Iran; and (2) the transfer to Iran of scientific and technical expertise with respect to such material and systems. Authorizes the use of certain assistance, otherwise available for the independent states of the former Soviet Union under the Foreign Assistance Act of 1961, to prevent such transfers. | 2,805 | 401 | billsum | en |
Write a title and summarize: Buruli Ulcer (BU) is a tropical infectious skin disease that is currently treated with 8 weeks of intramuscular streptomycin and oral rifampicin. As prolonged streptomycin administration can cause both oto- and nephrotoxicity, we evaluated its long term toxicity by following-up former BU patients that had received either 4 or 8 weeks of streptomycin in addition to other drugs between 2006 and 2008, in the context of a randomized controlled trial. Former patients were retrieved in 2012, and oto- and nephrotoxicity were determined by audiometry and serum creatinine levels. Data were compared with baseline and week 8 measurements during the drug trial. Of the total of 151 former patients, 127 (84%) were retrieved. Ototoxicity was present in 29% of adults and 25% of children. Adults in the 8 week streptomycin group had significantly higher hearing thresholds in all frequencies at long term follow-up, and these differences were most prominent in the high frequencies. In children, no differences between the two treatment arms were found. Nephrotoxicity that had been detected in 14% of adults and in 13% of children during treatment, was present in only 2. 4% of patients at long term follow-up. Prolonged streptomycin administration in the adult study subjects caused significant persistent hearing loss, especially in the high frequency range. Nephrotoxicity was also present in both adults and children but appeared to be transient. Streptomycin should be given with caution especially in patients aged 16 or older, and in individuals with concurrent risks for renal dysfunction or hearing loss. Buruli ulcer (BU) is a Neglected Tropical Disease caused by infection with Mycobacterium ulcerans. Necrotic skin lesions characterize the disease, often with typical undermined edges. Treatment delay may result in disfigurement and functional limitations [1]. Though isolated cases or small outbreaks have been reported in over 30 countries, the disease is mainly found in endemic areas in rural West- and Central-Africa, with around 6. 000 cases occurring annually [2]–[4]. Over the past decade the main mode of treatment has shifted from surgery to antimicrobial therapy. Several antibiotic regimens have been proposed and studied, and the current regimen advised by the World Health Organization consists of 8 weeks of oral rifampicin and intramuscular streptomycin [5]–[8]. Although surgery can be problematic in under-resourced developing countries due to high costs and low availability, prolonged streptomycin administration has complications of its own. These complications are partly related to the parenteral mode of administration of streptomycin, but also to its intrinsic toxicity, notably, ototoxicity and nephrotoxicity [9]. Streptomycin induced ototoxicity encompasses damage to both the cochlea and vestibulum [10], although the effects of vestibular damage can to some extent be compensated for by the brain, and so are clinically less prominent [11]. The damage is caused by reactive oxygen species that are formed by a redox-active complex of parts of the aminoglycoside and biologically available iron ions [12]. The most frequently reported manifestations of ototoxicity are high-frequency sensorineural hearing loss, and vestibular dysfunction resulting in disequilibrium and loss of the vestibular ocular-reflex [12]. These side-effects are often transient, but chronic effects, especially hearing loss, have also been reported. The wide range in incidence varies between 5% and 25%, depending on the specific aminoglycoside drug, patient group (older age groups are probably more vulnerable), and definition of ototoxicity including the method of detection [13], [14]. The occurrence of ototoxicity does not appear to be related to the individual dosages or the frequency of administration per se, but rather to the cumulative dose, and the age of the patient [15]. Also, there appears to be a modest genetic susceptibility, caused by a point mutation in mitochondrial DNA [16]. The nephrotoxic effects of streptomycin are most prominent in the proximal tubule, and transient nephropathy, manifested by a slow rise in serum creatinine and a decreased glomerular filtration rate, is observed in 10–20% of therapeutic courses [17]. Unlike aminoglycoside-induced ototoxicity, long-term kidney damage is uncommon. It has long been hypothesized that aminoglycoside-induced nephrotoxicity would lead to increased serum concentrations of the drug, resulting in ototoxicity, or that some other link between aminoglycoside induced oto- and nephrotoxicity existed. Several studies have however been unable to demonstrate such a relationship, and it is believed that the two are largely independent [15], [18], [19]. With a total cumulative dose of up to 56 g (15 mg/kg daily with a 1 g daily maximum, 56 doses), the amount of streptomycin that is administered to treat BU is higher than in the treatment of brucellosis, endocarditis, and urinary tract infections, but similar to the treatment of Mycobacterium avium complex and second line treatment for tuberculosis. However, no data exist on the long-term toxicity of the currently recommended regimen of antimicrobial therapy in BU. Therefore, we chose to study former BU patients that participated earlier in a randomized controlled trial conducted between 2006 and 2008 [20]. In that trial patients were randomized to receive either 8 or 4 weeks of streptomycin, allowing a direct comparison between the two groups in terms of long-term streptomycin toxicity. The study protocol was approved by the Committee on Human Research, Publication, and Ethics of the Kwame Nkrumah University of Science and Technology and the Komfo Anokye Teaching Hospital, Kumasi (reference number CHRPE/AP/133/12). Written informed consent was obtained from all participants aged ≥12 years, and consent from parents, or legal representatives of participants aged ≤18 years. We retrieved our study subjects among individuals that had earlier participated in the Burulico trial, conducted between 2006 and 2009 in Ghana, registered with number NCT00321178 at clinicaltrials. gov. For that trial, patients aged 5 years or older, clinically diagnosed with early (duration <6 months), limited (cross-sectional diameter <10 cm) M ulcerans infection were included, and randomized to receive either 8 weeks of streptomycin at 15 mg/kg daily (max 1000 mg daily) and 8 weeks of rifampicin at 10 mg/kg daily (max 600 mg daily), or 4 weeks of streptomycin and rifampicin, followed by 4 weeks of rifampicin and clarithromycin at 7. 5 mg/kg daily. Pregnancy, drug intolerance, and renal, hepatic, and acoustic impairment were among the exclusion criteria, and co-medication with drugs other than the study drugs occurred in less than 5% of patients, and mainly consisted of NSAIDs. Patients had a median age of 12 and 30% were male. Patient characteristics are described in more detail in Nienhuis et al. [20]. For the present follow-up study, participants were retrieved between June and November 2012 by visiting their last known village or through telephone contact if available. If the former patient was no longer living at the last known village, neighbors, relatives, and community leaders were asked for additional information. When a former patient was located, he or she was informed about the study, given time to consider participation, and was asked for consent. The equipment and procedure followed for audiometry at follow-up were identical to those during the drug trial. Audiometry was performed in a quiet room in one of the two study hospitals of the BURULICO drug trial with portable Interacoustics AS208 audiometers, with circumaural earphones with noise reducing Peltor mute cushions. The audiometers were calibrated to ISO64, both before the drug trial and again before the follow-up. Biological calibration performed weekly. During a biological calibration session, a person with known, stable hearing thresholds was tested. A persistent deviation of 10 dB or more would prompt acoustic calibration of the audiometer. However, both during the drug trial and the follow-up study, no acoustic calibration was necessary. As soundproof rooms were not available at the study sites, ambient noise (AN) levels were measured with a voltcraft SL-100 ambient noise meter in dBA filter weighting during each audiometry session. The person performing the follow-up audiometry was blinded to the treatment allocation during the Burulico study, and was therefore unaware of earlier streptomycin treatment duration. Both ears were tested, the right ear first. Frequencies were tested in the following order: 1,2, 4,6, 8,0. 5 and 0. 25 kHz. Testing started with presenting a loud tone. Then the intensity was decreased in steps of 5 dB until the tone was not heard anymore. The last tone still heard was the level of audibility of the first test run. Then the intensity was increased with 10 dB before being decreased again in steps of 5 dB, until the tone was no longer heard (the second test run). If the results of the two test runs were not identical, the process was repeated until two identical levels of audibility were found. This level was considered the hearing threshold. The same procedure was followed during the drug trial, and so, audiograms were available for baseline, after 8 weeks of treatment, and at long-term follow-up. In addition to audiometry, each subject was asked at follow-up about complaints of hearing loss and dizziness after completion of treatment. To detect late nephrotoxic effects of the streptomycin administration 4–6 years earlier, serum creatinine was measured in a sample of venous blood (approximately 2 ml) at the same laboratory, where serum creatinine was measured during the drug trial, using the same analytic technique. The results were compared with the measurements at baseline, after 2,4, 6, and 8 weeks of treatment during the BURULICO study. Patients with suspected long-term nephrotoxicity were referred to the hospital for further management. The total cumulative dose of streptomycin administered was estimated to be 56 times the daily dose. Individual records of compliance were not available, but during the drug trial, streptomycin administration was only performed in participating hospitals and health centers and was recorded on tally sheets with compliance approaching 100%. As aminoglycoside toxicity is reported to occur less frequently in children [21], [22], we analyzed the results separately for those ≤16 and >16 years of age at the time of receiving streptomycin treatment during the Burulico trial. For each frequency, the mean of measurement results of audiometry of both ears was recorded. As the distribution of hearing thresholds is usually skewed to the left, differences between the two treatment arms were assessed with nonparametric Mann-Whitney-U tests. According to the criteria of the American Speech-Language-Hearing Association [23], an increased threshold of 20 dB at any one frequency or an increase of 15 dB at two consecutive frequencies was classified as hearing loss. Nephrotoxicity was defined as a rise in serum creatinine at two consecutive assessments during treatment compared to baseline of ≥44 µmol/L (0. 5 mg/dL) or 50% [17], [24]. As serum creatinine levels increase with age and body weight, especially muscle mass, it was not possible to make a meaningful direct comparison between the serum creatinine concentrations in the present study with those obtained 4–6 years earlier during the drug trial. Instead, a decrease of the estimated Glomerular Filtration Rate (eGFR) of >25% in this follow-up study compared to baseline was defined as long term nephrotoxicity [25]. In adults, the eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [26], as this was earlier shown to be superior to other equations in a Ghanaian population [27]. In children the eGFR was computed using the revised Schwartz formula [28]. Of the 151 former participants of the Burulico trial 127 individuals (84%) were retrieved for follow up. Although the trial had taken place in the Ashanti region of Ghana, many former patients were not ethnically Ashanti, and had moved away from the study site, and patients were retrieved in 9 of Ghanas 11 regions, including the three Northern regions more than 700 kilometers and approximately 10 hours by road from the original study site. 68% of the retrieved former patients were female, and the median age at follow-up was 18 years. Sixty-eight percent of our study participants had been 16 or younger at the time they received treatment during the Burulico trial. Of the 24 former patients not retrieved, 4 were already lost to follow-up during the Burulico trial, 3 had moved abroad, 2 had deceased, and the fate of the remaining 15 was unknown. The patients that were lost to follow-up did not differ significantly from the patients that were retrieved in terms of baseline and 8 week audiometry and serum creatinine, age, sex or treatment arm. The median duration between drug administration and follow-up was 5 years. Overall, the patients reported to be doing well. 28% reported to have experienced another disease since their BU was cured, with most patients reporting malaria, headache, and stomach ache. One retrieved patient was HIV-positive. Three patients reported currently taking analgesics, and 2 patients reported currently taking anti-hypertensives. Twenty-nine percent of adults, and 25% of children were classified as having hearing loss compared to baseline audiometry after 8 weeks of treatment, and 31% of adults, and 27% of children were classified as having hearing loss at long term follow-up compared to baseline audiometry. Hearing loss after 8 weeks was significantly associated with hearing loss at long term follow-up in (p = 0. 017 by Χ2), but not in children (p = 0. 102 by Χ2). The average hearing thresholds at long-term follow up for both treatment arms for adults are shown in Figure 1, and for children in Figure 2. For adults, no differences between the two treatment arms existed in any of the frequencies at baseline, and after 8 weeks of treatment, there was a significant difference in hearing threshold between treatment arms at 6000 Hz (p = 0. 03) in adults, while those at 500 (p = 0. 07), 1000 (p = 0. 09), and 8000 Hz (p = 0. 09) approached significance by Mann-Whitney U test. For children, there were no significant differences between the treatment arms at any frequency at baseline or after 8 weeks of treatment. For both adults and children, univariate associations between long term ototoxicity and treatment arm, age, sex, total cumulative dose of streptomycin and complaints of hearing loss were determined. The results are shown in table 1. The average (SD) level of ambient noise (AN) was 45. 6 (6. 5) dB. From self-report, 10% of adults reported experiencing hearing loss (5% in the 8 week streptomycin group vs 16% in the 4 week streptomycin group; p>0. 3 by Χ2) and 12% of children reported experiencing hearing loss (9% in the 8 week streptomycin group vs 15% in the 4 week streptomycin group; p>0. 3 by Χ2) after treatment was completed. Ten percent of adults reported experiencing dizzyness (5% in the 8 week streptomycin group vs 16% in the 4 week streptomycin group; p>0. 3 by Χ2) and 12% of children reported experiencing dizzyness (9% in the 8 week streptomycin group vs 15% in the 4 week streptomycin group; p>0. 3 by Χ2) after treatment was completed. There appeared to be no association between audiometrically classified and self-reported hearing loss, as 14% of the patients that were audiometrically classified as having hearing loss at long term follow-up also complained of hearing loss vs 9% of patients that were not audiometrically classified as having hearing loss (p>0. 3 by Χ2). During treatment, 14% of adults, and 13% of children were classified as having nephrotoxicity. At long term follow-up 1 adult (2. 4%) and 2 children (2. 4%) were classified as having long-term nephrotoxicity. All 3 of these patients had received streptomycin for 8 weeks (p<0. 1 by Χ2), but only 1 was also classified as having nephrotoxicity during treatment. The average serum creatinine concentrations for both treatment arms for adults are shown in Figure 3, and for children in Figure 4. For both adults and children, univariate associations between nephrotoxicity and treatment arm, age, weight, sex, and total cumulative dose of streptomycin were determined. The results are shown in table 2. In this study we followed-up individuals that were randomly assigned to either 4 or 8 weeks of streptomycin injections 4 to 6 years earlier, and that had similar results in audiometry at baseline. This provided a unique model to compare long-term toxicity incurred by doubling the cumulative dosage of streptomycin. In adults, we found an important and clinically relevant increase in hearing loss in the high frequencies in individuals that had received 8 weeks of streptomycin, in comparison to those that had received only 4 weeks of this aminoglycoside. In children, no differences between the two treatment arms were detectable. Although macrolides, especially, azithromycin have also been connected to hearing loss [29], the ototoxicity associated with prolonged streptomycin use was significantly more pronounced than in individuals that had received clarithromycin instead. The ototoxic effects of prolonged duration of streptomycin therapy appeared to differ between adults and children. To our knowledge, no studies have evaluated the ototoxicity of an aminoglycoside in a study population consisting of both children and adults suffering from the same illness, exposed to the same treatment schedule. Low levels of ototoxicity in children have been reported before [21], [22], but the exact mechanisms for this interaction with age are not well understood [21]. The incidence of hearing loss in our study was slightly higher than in earlier reports, which may be due to the fact that we used the formal ASHA criteria that are designed to detect early changes, so as to avoid more severe damage with ongoing aminoglycoside administration. In children, there was only a weak relationship between hearing loss detected by audiometry and complaints of hearing loss by the patient, and in adults there was no relationship at all. Audiometric and subjective ototoxicity often correlate poorly [15], [30], [31], because audiometric toxicity is usually – as in our study – present in the high frequencies. High frequency hearing loss does not affect primary speech hearing, but rather affects the ability to follow group conversations, and causes people to hear the wrong words without noticing it [32]. This may explain why many clinicians are not very concerned about ototoxicity in the treatment of BU, as their patients usually do not report hearing loss spontaneously. In our study, nephrotoxicity was present in both children and adults, occurred more often in the 8 week streptomycin group and appeared to be related to the total cumulative dose of streptomycin. However, long term nephrotoxicity was only detected in 3 study subjects. The occurrence of both transient and long-term streptomycin nephrotoxicity in our study might be a low estimate for the population at risk in general, as BU is a local infection, usually without systemic involvement, and most patients were young and did not have any significant comorbidities, medical history or co-medication, contrary to other patient categories that are administered aminoglycosides, e. g. ICU patients or those with cystic fibrosis. In addition, streptomycin was administered once daily, which is known to reduce the incidence of nephrotoxicity [33]. Our study had several limitations. First, after an intensive search, we only retrieved 127 (84%) of the population that we intended to study. Of the 24 subjects that were lost to follow-up, we could not detect features that might have introduced bias, but we cannot completely rule out that some bias was introduced. Next, although the group that was earlier exposed to 4 weeks of streptomycin had (near) normal audiograms, we did not attempt to enroll a matched control group that had not had streptomycin injections. Also, variability between measurements is likely to be higher than desirable, due to high levels of AN, although average levels of AN were only slightly higher compared to accepted bedside testing levels in the USA [34], [35]. This implies that the absolute numbers of hearing loss should be interpreted with caution, but as AN levels were similar for all measurements, it is not likely to have influenced the differences found between the two treatment arms. The strength of our findings is that we could detect a difference between groups that appeared well matched. With known baseline characteristics, with a well-documented increased exposure to streptomycin, we conclude that prolonged streptomycin administration in the adult study subjects caused significant hearing loss, especially in the high frequency range. In addition, we obtained ototoxicity data from a patient sample that included both adults and children suffering from the same illness and receiving the same treatment, with differential effects in terms of toxicity. Our study results support ongoing attempts to try replacing injected streptomycin by an alternative, e. g. clarithromycin. Currently a trial to compare standard care (streptomycin plus rifampicin) with oral treatment consisting of clarithromycin in extended release formulation combined with rifampicin is ongoing [36]. We conclude that streptomycin with cumulative dosages, especially in patients aged 16 or older should be given with caution, especially in individuals with concurrent risks for renal dysfunction or hearing loss. | Title: Long Term Streptomycin Toxicity in the Treatment of Buruli Ulcer: Follow-up of Participants in the BURULICO Drug Trial Summary: Buruli Ulcer is an infectious skin disease, mainly occurring in West Africa. Previously, the disease was treated exclusively by surgery, but in the last decade, effective treatment with antibiotics has been established. The WHO recommended regimen consists of 8 weeks of oral rifampicin combined with intramuscular streptomycin. However, prolonged use of streptomycin is known to cause permanent ototoxicity and transient nephrotoxicity. To study this, we performed audiometry and measured the serum creatinine in 127 former Buruli ulcer patients who received either 4 or 8 weeks of streptomycin 4 to 6 years ago. Ototoxicity was present in 29% of adults and 25% of children. Adults who received 8 weeks of streptomycin had significantly worse hearing at long term follow-up, and this was most prominent in the high frequencies. In children, no differences between the two groups were found. Nephrotoxicity that had been detected in 14% of adults and in 13% of children during treatment, was present in only 2. 4% of patients at long term follow-up. The findings indicate that caution should be exercised when prescribing streptomycin to adults for prolonged periods of time. Treatment regimens for Buruli ulcer that do not contain streptomycin are desirable and should be investigated. | 5,098 | 327 | lay_plos | en |
Write a title and summarize: One of the major breakthroughs in oncogenesis research in recent years is the discovery that, in most patients, oncogenic mutations are concentrated in a few core biological functional pathways. This discovery indicates that oncogenic mechanisms are highly related to the dynamics of biologic regulatory networks, which govern the behaviour of functional pathways. Here, we propose that oncogenic mutations found in different biological functional pathways are closely related to parameter sensitivity of the corresponding networks. To test this hypothesis, we focus on the DNA damage-induced apoptotic pathway—the most important safeguard against oncogenesis. We first built the regulatory network that governs the apoptosis pathway, and then translated the network into dynamics equations. Using sensitivity analysis of the network parameters and comparing the results with cancer gene mutation spectra, we found that parameters that significantly affect the bifurcation point correspond to high-frequency oncogenic mutations. This result shows that the position of the bifurcation point is a better measure of the functionality of a biological network than gene expression levels of certain key proteins. It further demonstrates the suitability of applying systems-level analysis to biological networks as opposed to studying genes or proteins in isolation. Cancer is one of the most important diseases affecting human health today [1]. Although cancer is considered a genetic disease [2], with a variety of oncogenes and tumour suppressor genes identified, the specific genomic alterations vary wildly between and within cancer types. In 2008, three high-throughput cancer genomic studies reported that cancer gene mutations are concentrated in a limited number of core cellular pathways and regulatory processes [3]–[5]. This discovery suggests that oncogenesis is highly related to the dynamics of biologic regulatory networks, which govern the behaviour of functional pathways. Clearly, to understand the mechanisms underlying oncogenesis, we need to take a systems and dynamics approach. A number of studies have proposed a network-based approach to investigate oncogenesis. For example, Torkamani and Schork identified functionally related gene modules targeted by somatic mutation in cancer [6]; Cerami et al. proposed an automated network analysis approach to identify candidate oncogenic processes [7]. A more recent approach by Stites et al. sought to explain mutations in Ras pathway, which are commonly found in cancer, by investigating the steady state concentrations of cellular proteins in parameters changes [8]. In this paper, we propose a new way to identify high-frequency gene mutations in cancer cells. We reason that because gene mutations may affect the activities of their corresponding proteins in a biological regulatory network, they can be considered as perturbations of the system' s dynamics. Therefore, those mutations that qualitatively affect biological network function should correspond to mutation hot spots in cancer. From a dynamics point of view, a qualitative change in a system relates to bifurcations—oncogenic mutations should therefore significantly affect certain bifurcation points. One of the hallmarks of cancer is evasion of apoptosis; in fact p53 mutations are found in most human cancers [9]. We therefore chose the DNA damage-induced p53-centered apoptosis pathway, as an example, to evaluate our hypothesis. We evaluated the sensitivity of bifurcation points to different network parameters, and compared the results with the cancer gene mutation spectrum. We found that parameters that significantly affect the bifurcation points corresponded to high-frequency oncogenic mutations. This study investigates the mutation spectrum found in cancer cells and provides a useful tool for predicting oncogenic mutations. We focused on the apoptotic pathway that responds to sustained DNA damage, induced by the chemotherapeutic compound, etoposide [10], [11]. A recent study showed that while low-dose etoposide induces oscillations in p53 levels, caspase3 levels remain low, and most cells survive; in contrast, high-dose etoposide induces a monotonic increase in p53 concentration, followed by a rapid increase in caspase3 with most cells undergoing apoptosis [11]. This experiment further justifies the use of p53 in our model. A schematic of the corresponding regulatory network, which is a modification of the p53 DNA damage response network established and analysed by Li et al. [12], is shown in Figure 1. Nuclear p53 induces mdm2 transcription, while MDM2 antagonizes p53 by promoting multistep ubiquitination and proteasome-dependent degradation of p53 [13], [14]. In unstressed cells, p53 is kept at a low concentration by its negative regulator MDM2. DNA damage reduces the binding affinity between p53 and MDM2 by inducing phosphorylation of p53 and MDM2 [15] — phosphorylated MDM2 undergoes rapid degradation [16] and p53 is subsequently activated by phosphorylation to a “response state”, triggering downstream events, such as apoptosis and cell-cycle arrest [17]. As shown in Figure 1, mono-ubiquitinated p53 is exported to the cytoplasm, while poly-ubiquitinated p53 undergoes degradation [18]. At elevated p53 levels, apoptosis can be initiated by both nuclear and cytoplasmic (or mitochondrial) p53 [19]. While nuclear p53 regulates the transcription of pro-apoptotic proteins such as Puma, Noxa, Bax and Bak [20], mitochondrial p53 exerts a direct pro-apoptotic effect by interacting with Bax and Bak to form a positive feedback loop that activates caspase3 [20]–[24]. In the experiments conducted by Chipuk et al. [21] and Chen et al. [11], p53 appears to regulate apoptosis through its cytoplasmic pro-death activity and not its nuclear activity. Many previous studies of p53 dynamics have focused on the response to transient DNA damage induced by ionising radiation or UV; following cell-cycle arrest, cell proliferation resumes once the DNA damage is repaired [25], [26]. In our model, we consider sustained DNA damage, which is maintained at a constant damage level until the cell initiates apoptosis [12]. In this way, we can ignore the cell-cycle arrest pathway, and instead concentrate on the apoptosis pathway. We first present an overview of network dynamics in response to DNA damage at two typical doses of etoposide. As shown in Figure 2, at 1 µM etoposide (low DNA damage), the concentration of nuclear p53 (including inactivated- and activated-p53) oscillates around basal levels (blue line), while the concentration of caspase3 remains low (green line), indicating that apoptosis has not been trigged. At 100 µM etoposide (high DNA damage), nuclear p53 increases monotonically (black line), which is followed by a rapid increase in caspase3 (red line), which in turn triggers downstream apoptotic processes. These results are consistent with the experimental observations of Chen et al. [11], indicating that our model qualitatively reflects the real system. Having created a suitable model, we next conducted bifurcation analysis to identify potential qualitative changes in the system. Using the level of DNA damage as the control parameter, two types of bifurcations were found in this analysis: two Hopf bifurcations and one saddle-node bifurcation. The transition diagrams of these bifurcations are presented in Figure 3. In Figure 3A, as the level of DNA damage increases, nuclear p53 undergoes two Hopf bifurcations. In the first bifurcation, with increasing DNA damage, the system changes from a low steady state to an oscillatory state; in the second bifurcation, with further DNA damage, the oscillatory state changes to a high steady state. This result is consistent with previously published observations [10], [12], [27]–[29]. In the case of caspase3, there exists a saddle-node bifurcation as a function of the level of DNA damage, where a stable node collides with an unstable saddle at the bifurcation point, as shown in Figure 3B. This bifurcation separates the system into two dynamic regimes: a mono-stable steady state regime and a bistable regime. In the bistable regime, one steady state corresponds to a low caspase3 concentration and the other to a high caspase3 concentration. In a wild-type cell, the caspase3 concentration remains low. Once the DNA damage level increases beyond the bifurcation point (about 26 µM etoposide in Figure 3B), the system will switch to a high caspase3 concentration that turns on the apoptosis pathway. Notice that this switch is irreversible—once the apoptosis pathway is turned on, caspase3 can maintain the high level state even when the level of DNA damage falls below the initial threshold. Our model is based on biological facts, together with certain assumptions and simplifications. The details of our model are presented in the Supporting Information (Text S1). Notice that in our model, ac-p53 refers to phosphorylated p53. In biological systems, many biological functions are controlled through dynamic bifurcations. A good example is the saddle-node bifurcation in G1/S transition of the cell cycle [30]–[33], where the qualitative behaviour of the system is significantly affected by changes in control parameters, which may dramatically affect the location of the critical point. Figure 3C represents such an example in the apoptosis pathway, where increasing the control parameter kf5 (which corresponds to the rate of association of mono-ub-p53 and MDM2 in the regulatory network of Figure 1) 1. 9-fold, shifts the critical point to the right. If kf5 is increased 4. 2-fold, the high caspase3 state can never be reached under medium or high drug dose. This indicates that if the parameter kf5 is increased due to certain mutations, apoptosis will not be initiated properly, or will not initiate at all, even when the DNA is seriously damaged. The damaged cells therefore have a chance to bypass apoptosis, which may facilitate oncogenesis. The effect of parameter changes on the location of the bifurcation point is not evenly distributed: some parameters significantly impact the bifurcation points, while others do not. We believe that genes that fall in the former category play important roles in oncogenesis. To identify which parameters have a major impact on the location of the bifurcation point, we conducted parameter sensitivity analysis by increasing and decreasing each of the 54 parameters in our model 1. 2-fold and recording the percentage change of the bifurcation points. In this way, we established a spectrum of parameter sensitivity, which allowed us to compare the result with the oncogenic mutation spectrum. High-throughput cancer genomic projects, such as the Cancer Genome Atlas (TCGA) and the Catalogue of Somatic Mutations in Cancers (COSMIC) [34], are major resources to obtain the spectrum of genetic variants in different cancer types [35]. To investigate the relationship between parameter changes and the spectrum of cancer gene mutations, we chose skin cancer mutated genes from the Catalogue of Somatic Mutations in Cancers (COSMIC) and glioblastoma multiforme mutated genes from the “CAN-genes” by Parsons et al. [4], and TCGA [5]. Based on the knowledge of biochemical reactions and gene expression [3]–[5], we concentrated on three types of gene mutations: somatic mutations, amplifications, and deletions. Each mutation corresponds to specific parameters in ordinary differential equations (ODEs) in our model, the basis and details of which are given in the Supporting Information (Text S1). The main result of our calculation is summarized in Figure 4. Parameter sensitivities of the saddle-node bifurcation point of each parameter of the apoptosis pathway are shown in Figure 4A (see also Supporting Information Table S2); parameters that cause large or small changes in bifurcation points are marked in yellow, and green, respectively. For the apoptosis pathway about 70% of the parameters are non-influential: the bifurcation point varies very little when changing those parameters. This suggests that the apoptosis pathway is robust, a hallmark of biological networks. However, about 26% of parameters have significant effects on the critical bifurcation points, such as gc_Bax (the basal generation rate of Bax) and kex (nuclear-export rate of mono-ubiquitinated p53), see Figure 4A. A small change in these parameters will induce large changes in the bifurcation points, as shown in Figure 3B. Increasing gc_Bax causes the critical bifurcation point to shift to the left. Therefore, in a biological experiment, to achieve a given rate of apoptosis, increasing the basal generation rate of Bax will require a lower dose of the DNA damaging drug compared with the unaltered basal generation rate of Bax. Similarly, increasing kex will cause the critical bifurcation point to shift to the left, so that for a given rate of apoptosis, increasing the nuclear-export rate of mono-ubiquitinated p53 will require a lower dose of the DNA damaging drug compared with the unaltered nuclear-export rate. Our parameter sensitivity analysis of critical bifurcation points is in agreement with the literature. For example, overexpression of Bax significantly increases the rate of radiation-induced apoptosis in human breast cancer cells [36], indicating that a perturbation of the basal generation rate of Bax (in our model the corresponding parameter is gc_Bax) would significantly affect the rate of apoptosis—as is indeed predicted by our model. Furthermore, mitochondrial p53-translocation and -accumulation may be induced by a variety of apoptotic stimuli, [37], [38]. In fact Marchenko et al. found that the rate of apoptosis is significantly increased after redirecting p53 from the nucleus to the mitochondria by using mitochondrial import leader peptides [37]. This means that a perturbation in the nuclear-export rate of p53 (in our model the corresponding parameter is kex) could greatly alter the rate of apoptosis. Again, we confirmed this effect in our model. Moreover, Dewson et al. recently reported that following apoptotic signalling in cells and mitochondrial fractions, Bax homodimerises via a BH3: groove interface interaction [39], a necessary step in the apoptotic pathway. The key interaction domains that affect apoptotic function are located in the α2–α5 regions (54–126A) of Bax; mutations in one of these key residues disrupt apoptotic function, thereby reducing the rate of cell death following treatment with etoposide [39]. According to the COSMIC database, cancer mutation hot spots do exist in the α2–α5 helices of Bax. These loss-of-function mutations in the Bax BH3 domain decrease the dimerization rate of activated Bax (in our model the corresponding parameter is kf10). Our model showed that kf10 is indeed a sensitive parameter and a slight decrease in kf10 shifts the critical bifurcation point to the right. We next sought to compare our results to those of Stites et al. who investigated mutations in Ras pathway by measuring the steady state concentrations of cellular proteins in parameter changes [8]. In addition to parameter sensitivity analysis of the bifurcation points, we therefore used the steady-state concentration of caspase3 as a measure of oncogenesis. To achieve this, we increased and decreased each of the 54 parameters 1. 2-fold and recorded the percentage change in the steady-state concentration of caspase3. The results are presented in Figure 4B (See also Supporting Information Table S3). The parameters that cause a large or small percentage change in the steady-state concentration of caspase3 are marked in magenta and blue, respectively. Overall, we found that the bifurcation point and the steady-state concentration of caspase3 are sensitive to mutually exclusive sets of parameters. As shown in Figure 4A, the critical points of bifurcation are largely affected by 15 parameters (yellow in Figure 4A), which we then selected to compare with the skin cancer and glioblastoma multiforme gene mutation spectrum, as shown in Figure 5A. Changes in the bifurcation point (yellow bar) and in the steady-state concentration of caspase3 (blue bar) are displayed alongside mutation frequencies in skin cancer and glioblastoma multiforme. Almost all influential parameters correspond to mutation hot spots in skin cancer and glioblastoma multiforme. This result supports our hypothesis that bifurcation points are sensitive to parameters corresponding to mutations that are most likely oncogenic. Here, we note that the definition of “mutation hot spot” is not quantitative; we will discuss this issue in the last section of the paper. For the sake of comparison, we also selected the parameters to which the bifurcation point was insensitive; the result is presented in Figures 5B and 5C. We found that a part of the insensitive parameters correspond to very small number of mutation hot spots (Figure 5B), but the other part correspond to a large number of mutation hot spots (Figure 5C). Several factors may contribute to the inconsistency. It is well established that alteration of a single gene may not be oncogenic in itself [40]—in most cases, multiple hits are necessary [41]. We therefore suggest a synergistic effect for these parameters (Figure 5C), where two or more parameter changes, which are non-influential in isolation, may induce sensitivity in the bifurcation point when they co-occur. Indeed, we found that by decreasing kf3 (association rate of p53 and MDM2) and increasing kr3 (dissociation rate of p53/MDM2 complex) at the same time by 1. 2-fold, the bifurcation point changes by about 22%. However, when changing these two parameters in isolation, the bifurcation point only changes by 5% and 2%. This may partially explain the observed inconsistency. Furthermore, one gene mutation may affect several parameters in our model, and one model parameter may involve several genes. In our analysis, the one-to-one mapping between the model parameters and the genes involved in the network is certainly an oversimplification. Fully understanding this behaviour requires detailed knowledge of the effect of mutations on the parameters, which is not available except in a few special cases. Similarly, we investigated the effect of different parameters on the steady state concentration of caspase3 as a measure of oncogenesis. We identified two parameters (magenta in Figure 4B), which led to the largest changes in the steady-state concentration of caspase3. We also calculated changes in the critical point when changing the parameters (Figure 6). According to the results in Figures 5A and 6, and compared with the results of bifurcation points, the relationship between the protein steady-state concentration and the cancer mutation spectrum is very weak. Our work is based on the hypothesis that key regulators in physiological networks and oncogenesis are closely correlated and that the critical point of bifurcation is a good measure of network functionality. Therefore, mutations that cause variations in parameters that affect the bifurcation point are more likely to be oncogenic. In our apoptosis model, the location of the saddle-node bifurcation point reflects the DNA damage threshold where apoptosis is activated; when this threshold is exceeded, the system will switch from the low to the high state, which is accompanied by a rapid increase in caspase3 levels. A mutation may increase the apoptotic threshold, thereby allowing cells to evade apoptosis even at high levels of DNA damage, which may facilitate oncogenesis—a hypothesis that was confirmed by our analysis. Distinguishing driver- from passenger-mutations is a central challenge in cancer research [42]–[44], and recently a network-based approach to identify cancer driver mutations has been proposed [6], [7]. Similarly, our strategy may be applied to identify driver mutations by identifying parameters with the greatest impact on the bifurcation point. Several issues need to be addressed in this analysis: First, what is the impact of the Hopf bifurcation of nuclear p53 on oncogenesis? Although a number of studies have investigated the oscillatory behaviour of p53 in response to stress [25], [45]–[47], the functional role of these oscillations in DNA damage response remains unclear. We also conducted parameter sensitivity analysis of the Hopf bifurcation of nuclear p53 as a function of the level of DNA damage [12], and found a strong correlation between the spectrum of parameter sensitivities and the oncogenic mutation spectrum (see Figure S1). This may indicate that nuclear p53 oscillation plays a crucial role in protecting the cell against malignant transformation [11]. Second, as previously stated, our model parameters do not have one-to-one correspondence with gene mutations: changing one parameter may correspond to mutations in different genes or different types of mutations in the same gene. For example, the association and dissociation constants of two proteins may relate to mutations in either of the associated genes; an increase in a given protein may be caused by an increase in gene copy number, or by an increase in the catalytic efficiency of the relevant transcription factor (corresponding to the mutation). Moreover, different mutations in a single gene may correspond to different parameters: a gene mutation may change the functionality of the protein, reduce the binding capacity of the protein with another protein, or alter its phosphorylation efficiency. As molecular biology advances, information regarding the function of different mutations in regulatory networks will become more quantitative, which will allow for more precise analysis using our model. The third concern relates to the definition of an oncogenic mutation hot spot. Different genes may be involved in different regulatory pathways, and have very large differences in mutation frequency. For example, p53 is involved in several regulatory pathways and has hundreds of known mutations, while Puma (BBC3) is involved in the apoptosis pathway, with only four or five known mutations. A method for normalising mutation frequency is necessary to allow quantitative analysis using our model. However, due to the lack of detailed information on the impact of each mutation on different regulatory pathways and on the model parameters, our analysis can only be qualitative. In this work, we used arbitrary thresholds to define a “mutation hot spot”, that were determined by our knowledge of the specific gene. As such, for genes involved in several regulatory pathways and with a high mutation frequency (like p53), we set a high threshold value (>10) for mutation hot spots. For genes involved in only one or two pathways, and which have very low mutation frequencies (like Puma), we believe that in spite of the low mutation frequency, they are still mutation hot spots. Because of the lack of detailed information on the impact of each mutation on the model parameters, our analysis can only achieve qualitative conclusions. The fourth issue relates to the simplicity of our model network: although the apoptosis pathway involves both the extrinsic and intrinsic pathways [48], we used a simplified, qualitative network model to conduct our research. To prove the validity of our model, we extended the current apoptosis pathway and repeated our analysis. Compared with the original model, the extended model consisted of 10 additional nodes including Noxa, Mcl-1, Bcl-xL and the complexes that they formed. Puma, Noxa, Bcl-2, Mcl-1 and Bcl-xL are all proteins of the Bcl-2 family. Like Puma, Noxa is a pro-apoptotic protein, which is regulated by nuclear p53 at the transcriptional level. Bcl-2, Mcl-1 and Bcl-xL are pro-survival proteins that inhibit cell apoptosis [48]. Puma binds Bcl-2, Bcl-xL and Mcl-1, whereas Noxa binds only Mcl-1 [49]. The corresponding extended regulatory network is shown in Figure 7. The details of the extended model are presented in the Supporting Information (Text S1, Figure S2and Figure S3). The results of the parameter sensitivity analysis and the correspondence between parameter sensitivity and mutations are shown in Figure 8. Notably, sensitive parameters in the extended pathway are very similar to those of the simplified pathway, with the 15 most influential parameters shared between the simplified (Figure 4A) and the extended pathways (Figure 8A). However, in the extended pathway, we found three additional sensitive parameters. Similar to the results of the simplified model (Figure 5A), we found that all sensitive parameters in the extended pathway correspond to mutation hot spots found in skin cancer and glioblastoma multiforme (Figure 8C). The analysis of the extended version of the network produces almost the same results as the simplified network, which supports the applicability and validity of our method. Finally, in our analysis, the change of each mutated property (parameter in ODE) was counted only once within our model, despite the general consensus that more than one mutation is needed for oncogenesis to occur [50]. Our primary goal is to study the role of mutated genes in cancer-related biological functions. In future, we will analyse the role of multiple mutations on network functionality. We compiled a set of ordinary differential equations (ODEs) (Text S1.) to model the apoptotic pathway in response to DNA damage. Model parameters were chosen based on the literature and biochemical constraints [51]. The skin cancer mutated genes database was obtained from COSMIC (http: //www. sanger. ac. uk/genetics/CGP/cosmic), glioblastoma multiforme mutated genes from the “CAN-genes” by Parsons et al. [4], and TCGA [5]. The “CAN-genes” by Parsons et al. [4] included genes frequently mutated in 22 glioblastoma multiforme samples. The TCGA project has catalogued somatic mutations and recurrent copy number alterations in 91 glioblastoma multiforme cases [5]. The basis and details of the correspondence of three forms of gene mutations and specific parameters in ordinary differential equations (ODEs) in our model are given in Text S1. | Title: Correlation between Oncogenic Mutations and Parameter Sensitivity of the Apoptosis Pathway Model Summary: Among complex genetic diseases affecting humans, cancer is a major cause of death. In 2008, a genome-wide analysis of hundreds of tumour samples showed that oncogenic mutations are concentrated in a few core functional pathways, revealing a new conceptual framework for cancer biology research, where the role of oncogenic mutations and oncogenic mechanisms are addressed from a network perspective. We therefore propose a new way of identifying high-frequency gene mutations in cancer: gene mutations may affect their corresponding proteins' activity in the biological regulatory network and can be considered as perturbations of the dynamical system. Therefore, mutations that induce qualitative changes in biological networks should correspond to high-frequency mutations in cancer. This concept can help us identify and understand the function of genes that play an important role in oncogenesis, thereby allowing targeted and effective design of gene-based therapy in cancer. | 5,921 | 218 | lay_plos | en |
Summarize: An 80-year-old man was Tasered, handcuffed and finally restrained on a stretcher after allegedly firing nine shots at police over a dispute with his daily newspaper. Joseph Smith reportedly called 911 and threatened to kill himself and the dispatcher because he had'some beef' with The Philadelphia Inquirer following the loss of his money in stocks. When around 50 police and SWAT officers arrived at his apartment in Upper Darby, Philadelphia, the OAP screamed from his third-floor window: 'I'm not leaving without shooting!', it is claimed. Restrained: Joseph Smith, 80, was Tasered, handcuffed and finally restrained on a stretcher after allegedly firing nine shots at police on Wednesday evening. Above, Smith is placed an ambulance via stretcher. Over the next three hours, he allegedly fired nine rounds toward police in the building's courtyard, before threatening to shoot down a news helicopter flying over the scene in Providence Road. Minutes later, police launched tear gas into Smith's window, before throwing a stun grenade into his apartment and storming the room, Police Superintendent Michael Chitwood told The Inquirer. There, they reportedly discovered the pensioner crouched on all fours with a 9mm gun in his head. Despite dropping the pistol, Smith allegedly lashed out at six officers who tried to detain him, persisting even when he was struck twice with a Taser. Angry reader: Smith (pictured in his mugshot) reportedly called 911 and threatened to kill himself and the dispatcher because he had a 'beef' with The Philadelphia Inquirer following the loss of his money in stocks. Scene: When around 50 police officers arrived at the Lansdowne Towers Apartment Complex (pictured) in Philadelphia, the OAP allegedly screamed from his third-floor window: 'I'm not leaving without shooting!' But two sets of handcuffs and a stretcher later, he was eventually transported out of the property at the Lansdowne Towers Apartment Complex, situated near Industrial Park Drive. 'He's one nasty senior citizen,' Supt Chitwood said following the incident at 7.45pm on Wednesday. 'When we tried to negotiate with him, he would scream all types of things.' Supt Chitwood added that none of his officers had been struck by the fired bullets. Following the alleged attack, police reportedly recovered hundreds of rounds of ammunition - along with the 9mm gun and a.22-caliber rifle - from Smith's apartment. Motivation: Following the alleged attack, police recovered hundreds of rounds of ammunition - along with two guns - from Smith's apartment. Above, the suspect was apparently angry with The Philadelphia Inquirer. During an interview with officers, the pensioner's family claimed that he had not slept for four days, Supt Chitwood said. It remains unclear whether Smith was intoxicated at the time. 'Let me tell you something: The way he was acting and how strong he was, he had to be on something, but I don't know for sure,' Supt Chitwood said. Smith is currently in custody at Delaware County Prison, according to the Delaware County Daily Times. He is likely to be charged with aggravated assault, firearms crimes and other charges | Summary: Joseph Smith, 80, 'fired nine shots at police from his apartment window' When officers tried to arrest him, he then reportedly lashed out at them. Finally detained after being Tasered, handcuffed and fixed to a stretcher. 'He's a nasty senior citizen,' police said following Wednesday's incident. Smith allegedly had 'beef' with The Philadelphia Inquirer following the loss of his money in stocks; he remains in custody at Delaware County Prison. | 777 | 110 | cnn_dailymail | en |
Summarize: These shocking pictures show the moment two firemen were swept off a 13th floor balcony in China before falling hand-in-hand to their death. Qian Lingyun, 23, and Liu Jie, 20, were trying to extinguish a blaze sweeping through an apartment block in Shanghai yesterday when the tragedy happened. According to passers-by, Liu apparently fell from the balcony first after being pushed back by a wall of flame, and Qian had grabbed his hand to try and save him. Scroll down for video. These shocking pictures capture the moment two firefighters plunged 13 storeys to their deaths in Shanghai. However, the weight proved too much, and the pair plunged from the block of flats, falling hand in hand on to the pavement below. Fire brigade spokesman Jian Ku said: 'Firemen always watch each other's backs, they look after each other, this tragic death shows the strength of that bond between colleagues. 'Guarding one another in life, inseparable in death.' The tragedy happened when emergency services were called to tackle a blaze on floor 13 of a residential block. The fire had broken out in an apartment kitchen and had spread rapidly through the property, threatening to engulf the entire building. The men had been trying to put out a blaze on the 13th floor of this apartment block when tragedy struck. An explosion threw Liu from this balcony, and Qian tried to grab him but wasn't strong enough. According to officials, the apartment's owners had been using a large amount of electrical equipment, which may have started the fire. Jian Ku added: 'Firefighters were engaged in rescue efforts at the scene that involved seeing if people were trapped inside and putting out the blaze when an explosion caused them to be thrown from the building. 'One managed to grab a handhold and grabbed his colleague, with the result they both plunged to their deaths. 'All their colleagues and friends are mourning for them and send condolences to their families.' The fire is thought to have started in a kitchen before gutting the flat and threatening the whole block. Police are investigating. Firefighters say flat's owners were using a large amount of electrical equipment. Qian and Liu had joined the city's fire service in December 2012. The tragic video of their deaths was taken by a passer by, Ken Lo, on his mobile phone. He said: 'It looked like one fell first and the other reached over to grab him. 'The falling one managed to grasp the hand of his comrade but his weight was too great. His would-be rescuer was pulled over into the void. It was a terrible thing to witness.' A police probe into the blaze is under way | Summary: Firefighters called to kitchen fire in apartment block in Shanghai yesterday. Qian Lingyun, 23, and Liu Jie, 20, were trying to extinguish 13th floor blaze. Explosion threw Liu over balcony, but Qian managed to grab his arm. Qian tried to pull Liu to safety, but weight proved too much for him. Pair plunged hand-in-hand to their deaths on the pavement below. Spokesman praised men 'guarding one another in life, inseparable in death' | 622 | 120 | cnn_dailymail | en |
Write a title and summarize: SECTION 1. SHORT TITLE. This Act may be cited as the ``Comprehensive Learning Assessment for Students and Schools (CLASS) Act''. SEC. 2. AMENDMENTS REGARDING ADEQUATE YEARLY PROGRESS AND ASSESSMENTS. (a) Continuous Growth Models.--Clause (iii) of section 1111(b)(2)(C) of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6311(b)(2)(C)) is amended by striking ``for all students'' and inserting ``for all students, as demonstrated by measures of students' progress toward proficiency, including longitudinal growth''. (b) Averaging Procedure.--Subparagraph (J) of section 1111(b)(2) of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6311(b)(2)) is amended by adding at the end the following: ``(iv) The State may average data by other means that are designed to increase the stability of school-building results from year to year.''. (c) Adequate Yearly Progress by Group and Subject.--Section 1116(b) of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6316(b)) is amended-- (1) in subparagraph (A) of paragraph (1), by inserting ``with respect to the performance of a particular group of students described in section 1111(b)(2)(C)(v) in the same academic subject,'' after ``that fails, for 2 consecutive years,''; (2) in paragraph (5), by inserting ``with respect to the performance of a particular group of students described in section 1111(b)(2)(C)(v) in the same academic subject,'' after ``that fails to make adequate yearly progress,''; (3) in subparagraph (C) of paragraph (7), by inserting ``with respect to the performance of a particular group of students described in section 1111(b)(2)(C)(v) in the same academic subject,'' after ``that fails to make adequate yearly progress,''; and (4) in subparagraph (A) of paragraph (8), by inserting ``with respect to the performance of a particular group of students described in section 1111(b)(2)(C)(v) in the same academic subject,'' after ``continues to fail to make adequate yearly progress,''. (d) Multiple Measures.--Subparagraph (A) of section 1111(b)(2) of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6311(b)(2)) is amended-- (1) at the end of clause (ii), by striking ``and''; (2) at the end of clause (iii), by striking the period and inserting ``; and''; and (3) at the end, by adding the following: ``(iv) include multiple measures of student academic achievement, such as the proportion of State report card indicators met, a performance index score, student drop-out rate, and a measure based on individual student achievement gains over time, disaggregated by each of the groups of students described in subparagraph (C)(v).''. (e) Cut Scores.--Clause (ii) of section 1111(b)(1)(D) of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6311(b)(1)(D)) is amended-- (1) in subclause (II), by striking ``and'' at the end; (2) in subclause (III), by striking the period at the end and inserting ``; and''; and (3) by adding at the end the following: ``(IV) take into consideration the continuum of achievement by children within the advanced, proficient, and basic levels of achievement described in subclauses (II) and (III) and the yearly progress by children within such continuum.''. (f) No First Score Requirement.--Clause (iv) of section 1111(b)(2)(C) of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6311(b)(2)(C)) is amended-- (1) by striking ``(iv) measures'' and inserting ``(iv)(I) measures''; (2) by inserting ``and'' after ``in paragraph (3);''; and (3) by adding at the end the following: ``(II) if a student takes an assessment described in paragraph (3) for a particular subject or grade level more than once, may use, at the State's discretion, the student's results from subsequent administrations of the assessment;''. (g) Limiting Transfer Options and Supplemental Services to Students From Failing Groups.--Section 1116 of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6316) is amended-- (1) in paragraphs (1)(E)(i), (5)(A), (7)(C)(i), and (8)(A)(i) of subsection (b), by striking the term ``all students enrolled in the school'' each place such term appears and inserting ``all students enrolled in the school, who are members of a group described in section 1111(b)(2)(C)(v) that fails to make adequate yearly progress as defined in the State's plan under section 1111(b)(2),''; (2) in clause (vii) of subsection (c)(10)(C), by inserting ``, who are members of a group described in section 1111(b)(2)(C)(v) that fails to make adequate yearly progress as defined in the State's plan under section 1111(b)(2),'' after ``Authorizing students''; and (3) in subparagraph (A) of subsection (e)(12), by inserting ``, who is a member of a group described in section 1111(b)(2)(C)(v) that fails to make adequate yearly progress as defined in the State's plan under section 1111(b)(2)'' after ``under section 1113(c)(1)''. (h) Assessments.--Clause (ii) of section 1111(b)(3)(C) of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6311(b)(3)(C)) is amended to read as follows: ``(ii) be fully aligned with the State's challenging academic content and student academic achievement standards, be aligned with curriculum and instruction to adequately assess the effect of curriculum and instruction on each such challenging academic content standard, include individual test items (based on technical criteria) that enable students to achieve the items if the students received appropriate instruction, and provide coherent information about student attainment of the State's challenging academic content and student academic achievement standards;''. (i) Assessing Students With Disabilities.-- (1) In general.--Subsection (b) of section 1111 of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6311) is amended by adding at the end the following: ``(11) Children with disabilities.-- ``(A) Modification of standards, assessments.--With respect to a child with a disability, a State plan shall provide for alternate challenging academic content standards and challenging student academic achievement standards under paragraph (1)(A), alternate high standards of academic achievement described in paragraph (2)(C)(i), and alternate yearly student academic assessments described in paragraph (3), to align such standards and assessments with the child's individualized education program. ``(B) Determination of applicable assessment.--In carrying out this paragraph, consistent with the Individuals with Disabilities Education Act, the State-- ``(i) shall allow the individualized education program team of each child with a disability in the State to determine whether an alternate academic assessment should be administered to the child in lieu of the academic assessment otherwise required by paragraph (3); ``(ii) shall require the individualized education program team of the child to select any such alternate academic assessment from among the alternate assessments included in the State's plan pursuant to subparagraph (C); and ``(iii) shall require that any alternate academic assessment administered to a child under this paragraph be more advanced than any such assessment administered to the child in a previous school year under this paragraph. ``(C) Alternative assessments.--Each State plan shall include alternate academic assessments that may be administered to children with disabilities for purposes of complying with this paragraph. ``(D) Definition.--In this paragraph, the term `individualized education program' has the meaning given to that term in section 602 of the Individuals with Disabilities Education Act.''. (2) Rule of construction.--The amendment made by paragraph (1) shall be construed as superseding the 2.0 percent cap at section 200.13(c)(1) of title 34, Code of Federal Regulations (imposing a cap on the number of children with disabilities whose proficient and advanced scores, although based on alternate achievement standards, may be included in calculating adequate yearly progress). (j) Students With Limited English Proficiency.--Paragraph (2) of section 1111(b) of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6311(b)) is amended by adding at the end the following: ``(L) Students with limited english proficiency.-- Notwithstanding subparagraph (C)(v), a State may define adequate yearly progress under subparagraph (C) in a manner that measures the progress of students with limited English proficiency-- ``(i) by continuing to include in a group of students described in subparagraph (C)(v) students who attain proficiency in English; and ``(ii) by excluding the performance of students with limited English proficiency who have resided in the United States for less than 3 years and for whom native language assessments in math and reading or language arts are not available, so as to avoid any distortion in measurement resulting from the new arrivals of such students.''. (k) Separate Starting Points.--Subparagraph (E) of section 1111(b)(2) (20 U.S.C. 6311(b)(2)) is amended by striking ``, using data for the 2001-2002 school year,'' and inserting ``, for each group of students described in subparagraph (C)(v),''. | Title: To amend part A of title I of the Elementary and Secondary Education Act of 1965 regarding adequate yearly progress and assessments Summary: Comprehensive Learning Assessment for Students and Schools (CLASS) Act - Amends the Elementary and Secondary Education Act of 1965 to revise requirements affecting adequate yearly progress (AYP) assessments of students against state academic performance standards. Allows AYP longitudinal growth calculations and the averaging of school data in a manner designed to stabilize school-building results from year to year. Identifies a school as needing improvement, corrective action, or restructuring only on the basis of the unsatisfactory AYP of a particular group of students in the same academic subject for the requisite period of time. Requires multiple measures of student academic achievement. Requires academic achievement standards to calculate AYP within a continuum of achievement by children within advanced, proficient, and basic achievement levels. Allows states to use the results of subsequent assessments of students who take more than one assessment for the same grade and subject. Limits the provision of supplemental services and transfers to those students who fall within a group whose underperformance results in the school's failure to make AYP. Requires state assessments to be aligned with curriculum and instruction so their effectiveness may be assessed. Requires alternate standards and assessments for disabled children aligned with the child's individualized education program. Allows states to measure the AYP of limited English proficient (LEP) children by including children that have attained English proficiency and excluding LEP children who have resided in the country for less than three years. Allows states to set separate starting points for measuring the AYP of each student group. | 2,570 | 367 | billsum | en |
Write a title and summarize: By Kate ScotterBBC News The eponymous hero of this 3,182-line poem battles fierce monsters, rips off his enemy's arm, fights a fire-breathing dragon and defends a nation. It could be the plot of Hollywood's latest blockbuster movie. But this is the story of Beowulf, a poem once told in timber-framed barns in Anglo-Saxon England, to the raucous noise of the mead-swilling crowd. Described by historian and broadcaster Michael Wood as "being at the very root of English literature", the author and the exact date of composition remain a mystery. There is only one surviving manuscript, and even that was nearly destroyed in an 18th Century library fire. Some 1,300 years on from when most historians believe it was written, Beowulf continues to be shared, adapted and revised, whether on screen, in print or in song. JRR Tolkien, who was a noted expert on the poem, is widely thought to have taken inspiration from Beowulf for his Lord of the Rings trilogy. According to Prof Andrew Burn, from University College London (UCL), the roots of popular medieval-themed video games and TV shows can also be found in this epic saga. "Look at Lord of the Rings, Dungeons & Dragons, Game of Thrones, any of those big TV franchises, and you realise what the perennial source of interest there is in the same themes: bravery, mortality, power struggles, social hierarchy," he says. Tolkien, who was a professor of Anglo-Saxon English, completed his own translation of Beowulf in 1926. Irish poet Seamus Heaney's 1999 translation became a bestseller, and children's author Michael Morpurgo has retold the story for younger readers. There have also been comic books, films, TV series and documentaries. Explaining the enduring allure of the poem, Mr Wood says: "Before there was Shakespeare, there was this. It's all great stuff: you have a monster, a hero, the final battle with the dragon. "It's a great story; people have recreated it and remade it. "It's been reworked because it's got that power to it. There's a tragic dimension; people really respond to that. "There are only a few great stories, after all. We always come back to the same themes: monsters, heroes - and Beowulf has those." Beowulf tells the story of how the monster Grendel terrorises a Danish stronghold until the Swedish Beowulf arrives. The young Beowulf kills Grendel, ripping off his arm in the process, and then slays Grendel's avenging mother. Beowulf becomes King of the Geats and reigns for 50 years - until he challenges a dragon that ravages his kingdom. Both Beowulf and the dragon die in this final battle. Author and poet Kevin Crossley-Holland, who has translated the poem into modern English, says it is likely to have been written in about 650. There is only one surviving copy from the whole of the medieval period, the manuscript now known as British Library Cotton MS Vitellius A XV, which will go on display in the library's Anglo-Saxon Kingdoms exhibition in the autumn. Mr Crossley-Holland - for whom the monsters are like "humans gone wrong" and "terrifying because of that" - says that the poem has a very deliberate pace. "It's bit like an old-fashioned dance step; like a quickstep, it advances quite slowly, one step forward, one step sideways. "It doesn't hurry, I suspect because people were coughing and have got sore throats, and groaning because they had arthritis. "And that slow step forward, step sideways, enabled everyone to keep up," he says. He believes it was probably told in three sessions, and there "must've been laughter and filling of mead beakers", during what would have been a "social occasion". Beowulf isn't just significant in English literary history - it is set in Denmark and was actually first translated from the Anglo-Saxon into Danish. As Prof Burn says, the Danes "see it as their poem as well". The professor of English, media and drama was involved in a 2015 project, Playing Beowulf, as part of which workshops were held, challenging students of all ages to transform the story of Beowulf into a video game. Digital Arts Research Education - a partnership between organisations including University College London, the British Library and Game City - worked with five schools in London, primary school pupils in Nottingham, a drama group in Sydney, Australia, and PhD students at UCL. You might also be interested in: As Prof Burn points out, Beowulf lends itself readily to modern interpretations. "You can read the poem as coding; the language is formulaic in its narrative," he says. He argues that Beowulf has "general appeal" due to its themes of "perennial importance". "It's really another superhero story." The festival is being staged in the Suffolk town of Woodbridge, and Mr Crossley-Holland is among those who believe Beowulf might have been written in the area. The town is close to the world famous Anglo-Saxon burial site of Sutton Hoo, where a ship filled with treasures was unearthed in 1939. Believed to be the final resting place of the 7th Century King Raedwald of East Anglia, it is one of the most spectacular and important discoveries in British archaeology. Woodbridge's outgoing mayor Clare Perkins sees the festival as her parting gift. "So many people don't realise the basis of so many epic tales, games and films comes back to Beowulf," she says. "It's the forerunner of George and the Dragon, of Lord of the Rings. "There's so much energy here in Woodbridge; you can feel that energy and, if you are imaginative, you can imagine all the warriors coming across the river." And so even though Beowulf might have been written more than a millennium ago, in the words of Mr Wood, it "still speaks to us". For Mr Crossley-Holland, the poem has lasted the course because of its "huge appetite for life". "We all know time has us beat, but we're all interested in making the most of who we are," he says. "On the whole, life's to be relished, lived to the full, laughed with and at." Beowulf Festival runs from Thursday 3 May to Monday 7 May | Title: Beowulf: The enduring appeal of an Anglo-Saxon "superhero story Summary: As the cold sting of winter finally starts to fade, so the literary festival season edges closer. An addition to the line-up this year is a five-day celebration of the legendary saga of Beowulf. How is it that a story written by an unknown author more than 1,000 years ago still captures the imagination? | 1,492 | 96 | xlsum_en | en |
Summarize: BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] The invention relates to a thermotherapy device, especially for infants, with a horizontal surface which is bordered by lengthwise sides, a head side and a foot side. Furthermore, this invention relates to a process for thermotherapy using such a thermotherapy device. [0003] 2. Description of Related Art [0004] Thermotherapy devices of the initially mentioned type are generally used in the gynecological departments of hospitals for newborns. Existing thermotherapy devices (incubators) have closed, climate-controlled compartments in which a hatch must be opened first to reach the newborn. When a newborn is removed from such a thermotherapy device, it is always necessary to proceed very carefully to avoid injuring the newborn. Another disadvantage of existing incubators is the psychological effect these compartments have on the parents of the newborn. SUMMARY OF THE INVENTION [0005] The object of this invention is therefore to make available a thermotherapy device of the initially mentioned type in which the above described disadvantages do not occur. [0006] This object is achieved in a thermotherapy device of the initially named type in which there is a, preferably, three-sided supply means for an upwardly directed supply of warm moist air with one side supply being in the area of each of the lengthwise sides and/or a foot supply in the area of the foot side, in which there is an exhaust means for exhausting the supplied air in the horizontal surface, the exhaust means being located above the head side, especially above the head area of the horizontal surface which borders the head side, and the supplied air being exhausted simply above the head side and/or the head area. [0007] According to the process intended to achieve this object, warm moist air is blown out and up, preferably solely from the lengthwise sides and/or the foot side, wherein the supplied air is taken from the top, wherein a given microclimate is formed in the area above the horizontal surface and wherein the air is exhausted simply above the head side and/or a head area which borders the head side. [0008] The configuration in accordance with the invention yields a thermotherapy device in a so-called open version. The microclimate prevailing in the incubator with parameters which are defined, for example, in DIN EN 60601-2-19, is stabilized and bounded by air flows, in contrast to the prior art. The desired microclimate forms within the space bordered by the supplied air jets which are directed upward. The configuration in accordance with the invention has the major advantage that the infant located on a horizontal surface can be quickly and easily accessed. Furthermore, it is possible for the parents of the newborn to directly view and touch him without first having to open a hatch, as is the case in the thermotherapy devices known from the prior art. The adverse psychological effect on the parents of the newborn, as occurs in closed incubators, does not arise in the invention. [0009] Moreover, in conjunction with this invention, it has been established that a microclimate which has been stabilized by flow engineering can be implemented above the horizontal surface by there being simply a three-sided air flow with simultaneous intake above the head side. Therefore, in the region of the head side, air is not supplied; this ultimately reduces the energy demands of the thermotherapy device in accordance with the invention since less inlet air is necessary. However, the lack of air supply in the region of the head side also results in a draft being prevented this region. In any case, it goes without saying that it is also fundamentally possible to provide an air supply on the head side if this is considered necessary, even if the three-sided flow guidance is preferred. [0010] Since there is no inlet air supply on the head side, to prevent the effect of adverse cross flows which can arise due the superimposed room air flows, it is a good idea for there to be a front wall on the head side which extends, preferably, at least essentially over the length of the head side. The front wall thus has a bulkheading action and can, moreover, perform a retaining function for the exhaust means so that the exhaust means is attached to the front wall, and thus, can at least partially extend over the horizontal surface. [0011] In order to obtain a closed air curtain which retains the microclimate, it is advantageous for the side guides to extend at least essentially over the full length of the lengthwise sides. The same also applies to the foot supply. Furthermore, the exhaust means should extend at least essentially over the full length of head side in order to ensure an acquisition region that is as large as possible. [0012] In order to limit access to the horizontal surface by the exhaust means or the base body of the exhaust means as little as possible, it is recommended that the exhaust means extend over the horizontal surface from the head side to over an amount of a maximum ⅔ of the length of the horizontal surface. Here, it goes without saying that, according to this feature, there should fundamentally be an overhang and any value up to an amount of a maximum ⅔ of the length of the horizontal surface is possible, without expressed enumeration of discrete values being necessary. [0013] Research has shown that the outflow direction of the laterally supplied air is dependent on the climatic conditions of the ambient air and the microclimate of the thermotherapy device to be established. Fundamentally, the angle should be larger as the density differences of the out-flowing air to the ambient air become larger. In the extreme case, this can even be 90°. This can lead to different embodiments because, for example, the environment in European hospitals in summer is climate-controlled to roughly 26° C. (78.8° F.), while in the United States, a 20° C. (68° F.) room temperature is maintained. However, basically, it is recommended that the inflow directions of the side supplies and the foot supply have an angle between 10° and 60° with respect to vertical. These slanted inlet air flows yield a type of “flow tent” under which the desired microclimate forms. This “flow tent” can be very small since it is intended for infants. Accordingly, it is recommended that the exhaust means be located a very small distance above the horizontal surface, preferably with a distance which is less than the width of the horizontal surface. This arrangement has the additional advantage that only relative short air curtains need be formed; this is easily and economically possible, with low flow velocities. In any case flow velocities of the supplied air of less than 15 cm/s, preferably of less than 8 to 10 cm/s, can be maintained; here, any flow velocity within a given range being possible without it needing to be specifically mentioned. [0014] In order to be able to easily adapt the thermotherapy device in accordance with the invention to certain conditions of use, it is recommended that the outflow directions of the side and foot supply be adjustable, preferably in two directions which run perpendicular to one another or around two axes of rotation which run perpendicular to one another. Adjustment can be performed, on the one hand, via coupling the individual guides to the bed base body or a peripheral frame so that it is possible to adjust the individual guides relative to the horizontal surface. Furthermore, adjustment can take place alternatively or additionally by adjustable louvers in the area of the outflow openings of the inlet air guides. In order also to be able to match the exhaust means to altered conditions, it is recommended that the exhaust means be vertically adjustable and/or that the exhaust means be adjustable preferably around two axes of rotation which are arranged perpendicular to one another. [0015] Fundamentally, the aforementioned oblique outflow direction can also be implemented by the side supplies and/or the foot supplies being integrated in a frame surrounding the horizontal surface that is inclined relative to the horizontal surface. The inclined frame with supplies then has not only flow engineering importance, but is also used to protect the infant located on the horizontal surface from falling down. Moreover, it goes without saying that, on the side supply and on the foot supply, there can be protective walls regardless of whether the individual supplies are arranged inclined or not. The protective walls should be detachably connectable to the respective feed, preferably should be lockable into corresponding slots. Furthermore, the protective walls can be arranged at an angle relative to vertical so that they can acquire a flow-guiding function. [0016] In order to increase the degree of acquisition of the supplied air by the exhaust means, there can be a flap or guide flap on the exhaust means. Here, it is advantageous if the flap is pivotally mounted. Thus, it can be moved selectively into a lower position in which the flap develops a flow-guiding action or into an upper position in which unhampered access to the horizontal surface is ensured. The flap should extend at least in areas over the length of the head side and at least in areas over the length of the horizontal surface which the base body of the exhaust means overhangs to ensure a favorable flow-guiding action in the lower position. Here, it can be advantageous if the flap, in the lower position, extends both over the entire width of the head side or the foot side as well as over the entire length of the horizontal surfaces overhung by the base body of the exhaust means. In this case, the space requirement for pivoting of the flap is, however, correspondingly greater. In order to preclude accidentally falling down and the associated danger potential, the flap can be supported such that it remains in almost any position between the lower and the upper position without separate manual attachment. In addition to the flow-guiding function, the flap can be used to protect an infant located on the horizontal surface against unwanted effects from the outside. Basically, it is preferred that the flap is made from a transparent plastic at least in areas. It goes without saying that, fundamentally, the flap can also be provided elsewhere on the thermotherapy device. It is also possible to provide a retractable, insertable or comparable device instead of a pivoting flap. [0017] Favorable flow-engineering effects for setting of the desired microclimate can otherwise be achieved in that the supplied air emerges, not parallel, but in different directions, from the exit openings of a supply. In order to produce such a diverging flow profile, the exit openings can be aligned in different directions. In this way, for example, a radial outflow can be achieved. Alternatively or additionally to the aforementioned alignment of the exit openings, there can also be a guide device with which the desired flow profile of the air emerging from the supply can be adjusted. This can be recommended if the guide device has flow-guiding louvers or the like. [0018] As already initially mentioned, in conjunction with a thermotherapy device, it is necessary to make available a certain microclimate. To maintain the microclimate, the supplied air should have a temperature between 37° C. (98.6° F.) and 41° C. (105.8° F.), preferably roughly 39° C. (102.2° F.). The relative humidity should be between 80% and 90%, and preferably, roughly 85%, as is established in DIN EN 60601-2-19. So that energy use is as low as possible, for operation of the device in accordance with the invention, the intake air should be filtered and/or thermodynamically conditioned and supplied again to the supply means. Structurally in this connection, there is a means for conditioning the air which is coupled to the exhaust means and which preferably has a filter means, a humidifying means and a heating means. In this connection, it is recommended that the means for conditioning the air be made such that the temperature and/or the humidity of the air can be adjusted. Furthermore, the feed rate of the air should be adjustable in order to consider the effect of cross flows which can arise by superimposed room air flows. This is especially important in spaces in which climate-control systems have been installed. [0019] Furthermore, there should be at least one connection possibility for feed of other gases. In this way, the invention makes it possible to enrich the inlet air with (medical) gases such as, for example, oxygen in order to advantageously adjust the composition of the respired air in the region of the “flow tent” with respect to medical aspects. [0020] The exhaust or acquisition means used to intake the rising thermal air flow should have a high degree of acquisition in order to be able to capture and re-use portions of the supplied air and the energy contained therein which are as large as possible. Therefore, it is recommended that a swirl hood be used as the exhaust means. Preferably, in this connection, it is otherwise such that the front wall on the head side is part of the swirl hood. The front wall thus passes into the swirl hood and has a flow-guiding action. [0021] Other features of the invention will become apparent from the following description of exemplary embodiments in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS [0022] FIG. 1 shows a perspective view of a first preferred embodiment of the thermotherapy device in accordance with the invention, [0023] FIG. 2 shows a top view of the thermotherapy device from FIG. 1, [0024] FIG. 3 shows a cross-sectional view of the thermotherapy device from FIG. 1 taken along line III-III FIG. 2, [0025] FIG. 4 shows a cross-sectional view of the thermotherapy device from FIG. 1 taken along line IV-IV in FIG. 2, [0026] FIG. 5 is a cross-sectional view of a second preferred embodiment of the thermotherapy device in accordance with the invention in a view corresponding to that of FIG. 3, [0027] FIG. 6 is cross-sectional view of the thermotherapy device of FIG. 5 in a view corresponding to that of FIG. 4, [0028] FIG. 7 is a cross-sectional view of a third preferred embodiment of the thermotherapy device in accordance with the invention in a view corresponding to that of FIG. 4, [0029] FIGS. 8 a & 8 b are cross-sectional views of two preferred side supplies, [0030] FIG. 9 is a schematic cross-sectional view of a fourth preferred embodiment of the thermotherapy device in accordance with the invention in a view corresponding to that of FIG. 3, and [0031] FIG. 10 is a perspective view of another embodiment of a thermotherapy device in accordance with the invention. DETAILED DESCRIPTION OF THE INVENTION [0032] FIGS. 1 to 4 show a thermotherapy device 1 with a horizontal surface 5 bordered by two lengthwise sides 2, a head side 3 and a foot side 4. The head side 3 is bordered by the head area 3 a of the horizontal surface 5, the patient intended for thermal therapy lying preferably on the horizontal surface 5 such that at least the head of the patient rests on the head region 3 a. This is however not critical, the head of the patient also being able to rest basically also underneath the head area; this can be the case especially for newborns. It is important that there is intake of the supplied air only above the head side 3 and/or the head region 3 a. [0033] The thermotherapy device 1 has an upwardly directed supply means 6 for supply of warm, moist air on three sides of the horizontal surface 5, with a side supply 7 in the area of each of the two lengthwise sides 2 and a foot supply 8 in the area of the foot side 4. It is pointed out that this embodiment is simply a schematic representation. A description of supply lines and the like has been omitted. The supply means 6 can be easily integrated into a U-shaped or closed frame which surrounds the horizontal surface 5 ; this is not shown in particular. Furthermore, above the head side 3, there is an exhaust means 9 for exhausting the supplied air. With this, the illustrated thermotherapy device 1 enables thermotherapy in which warm moist air is blown upwardly only from the lengthwise sides 2 and the foot side 4 and is exhausted from above at the head end. In this way, a given microclimate can be formed above the horizontal surface 5. [0034] Furthermore, in the illustrated thermotherapy device 1, there is a front wall 10 which is connected to the exhaust means 9. Here, the front wall 10 extends at least essentially over the length of the head side 3. In this way, in the illustrated thermotherapy device 1, and during thermotherapy, bulkheading of the head side 3 is achieved. [0035] While in the illustrated thermotherapy device 1, the side supplies 7 extend over the full length of the lengthwise sides 2, the foot supply 8 extends over the full length of the foot side 4 and the exhaust means 9 extends over the full length of the head side 3, basically, it is also possible for each of the supplies 7, 8 to extend in exactly the same manner as the exhaust means 9 only over part of the corresponding sides 2, 3, 4, when, in this way, sufficient flow over the horizontal surface 5 is achieved by the supplied air. The exhaust means 9 is, moreover, arranged over the horizontal surface 5 such that the exhaust means 9 overhangs the horizontal surface 5 from the head side 3 so that an advantageous air flow is formed. Thus, it is not established how far the exhaust means 9 overhangs the horizontal surface 5. In order to ensure sufficient accessibility of the horizontal surface 5, the exhaust means 9 should overhang the horizontal surface 5 at most by ⅔ of the length of the horizontal surface 5. [0036] The direction in which the air emerges from the side supplies 7 and the foot supply 8 is at an angle from 0 to 90° to the vertical. In this connection, the two side supplies 7 are inclined relative to one another and the outflow direction of the foot supply 8 is directed obliquely toward the head side 3. This arrangement of the outflow directions and otherwise the induction of individual flows yield a contraction of the supplied air in the upper region. [0037] In the thermotherapy device 1 shown in FIGS. 1 to 4, the exhaust means 9 is located at a distance above the horizontal surface 5 which is smaller than the width of the horizontal surface 5. Moreover, the side supplies 7 and the foot supply 8 are arranged inclined with respect to the horizontal surface 5. Not shown is the fact that the incident flow directions of the side supplies 7 and the foot supply 8 as well as the exhaust means 9 can be moved around two axes of rotation which run perpendicular to one another and thus in different directions. The exhaust means 9 is also vertically adjustable; this is however not shown individually. [0038] FIGS. 5 and 6 show a thermotherapy device 1 in which there are protective walls 11 on the side supplies 7 and the foot supply 8. In this connection, the individual protective walls 11 are detachably connected to the respective supplies 7, 8. So that the protective walls 11 can perform a flow-routing function, the protective walls 11 are arranged here at an angle to the vertical. The protective walls 11 of the side supplies 7 are pointed obliquely at one another, while the protective wall 11 of the foot supply 8 is pointed obliquely in the direction toward the head side 3. It has been pointed out that the representation of the protective walls is simply schematic. It goes without saying that they can, of course, also be mounted in another form on the supplies 7, 8 or on the peripheral frame which is not shown individually. [0039] FIG. 7 shows a thermotherapy device 1 in which there is a flap 16 on the base body of the exhaust means 9 which extends in areas over the length of the head side 3 and which is pivotally supported. The flap 16 is located in the lower position in which it extends over part of the length of the horizontal surface 5. In this lower position, the flap 16, as shown schematically in FIG. 7, performs a flow-routing function. It is not shown in particular that the flap 16 can be swung out of the lower position, in this figure clockwise into an upper position which clears access to the horizontal surface 5. Otherwise, the flap 19 can, if necessary, be pivoted farther down, in this figure counterclockwise, overly low pivoting not being feasible since it not only blocks the intake opening of the exhaust means 9, but also adversely affects the handling of the infant on the horizontal surface 5. [0040] FIG. 8 a & 8 b show preferred embodiments of a side supply 7 which enables a diverging outflow of the supplied air. Here, the exit openings 18 in FIG. 8 a have different openings so that a radial flow profile is obtained. This flow profile, as shown in FIG. 8 b, can also be achieved by a flow-routing guide means 19 which is provided in addition or alternatively. It is not shown in particular that other flow profiles can also be produced by the alignment of the exit openings 18 or the use of a guide means 19. It goes without saying that the versions of the side supplies 7 shown in FIGS. 8 a & 8 b can also be provided in the same way for the foot supply 8. [0041] In the thermotherapy device 1 shown in FIG. 9, the schematically shown air conditioning means 12 is coupled to the exhaust means 9. The air conditioning means 12 is shown here as a separate system. However, integration into the device 1 is also easily possible. Furthermore, not shown is a corresponding fan via which the supplied air is exhausted which is connected to the exhaust means 9. The fan can also be integrated into the device 1. The air conditioning means 12 has a humidification means 13 and a heating means 14 so that in addition to the supply speed via the fan, the temperature and humidity of the air can be set in the desired manner. In order to be able to add other gases to the air before it is supplied in order to establish the desired atmosphere over the horizontal surface 5, the air conditioning means 12 has a corresponding connection 15. Here, it is fundamentally also possible for there to be a connection 15 in the area of the supplies 7, 8 and for other gases to be added, viewed in the air flow direction, between the air conditioning means 12 and the supplies 7, 8. [0042] The thermotherapy devices 1 shown in FIGS. 1 to 7 and 9 are otherwise those in which the exhaust means 9 is a swirl hood, the swirl hood 9 passing into the front wall 10. [0043] FIG. 10 shows another embodiment of a thermotherapy device 1 which corresponds essentially to the thermotherapy device 1 shown in FIG. 1. However, in contrast the device of FIG. 1, in the thermotherapy device 1 shown in FIG. 10, the air intake does not take place over the complete length of the head side 3, but simply over the middle area of the horizontal surface 5 which extends on either side of the lengthwise center axis of the horizontal surface 5. In this way, it is possible for the intake of unwanted air on the two ends of the exhaust means 9, which can likewise be a swirl hood in the embodiment shown in FIG. 10, to be largely prevented and the available air flow to be concentrated in the center of the thermal convection flow. Moreover, the embodiment shown in FIG. 10 has the advantage that at least limited access to the patient from the head side 3 is also possible. [0044] Furthermore, in the embodiment shown in FIG. 10, it is provided that the front wall 10 is an integral component of the exhaust means 9, so that the front wall 10 assumes a flow-guiding function. If the exhaust means 9 is a swirl hood, the front wall 10 can pass into the swirl hood, the front wall 10 deflecting the intake flow in the direction to the jacket of the swirl hood. Here, it is provided that the air is simply taken in above the head side 3 and/or the head area 3 a bordering the head side 3. Accordingly, the exhaust means 9 is located above the head side 3 and the head area 3 a and overhangs the horizontal surface 5. The exhaust means 9 extends in the lengthwise direction over part of the width of the horizontal surface 5. [0045] Moreover, it is provided that, laterally on the exhaust means, there are guide elements 20. The guide elements 20 extend from the side walls of the exhaust means 9 and extend beyond the side supplies 7 as far as the lateral front sides 21 of the front wall 10. The guide elements 20 overhang the horizontal surface 5 above the head area 3 a in the manner of a jacket, and a collar opening of the guide element 20 can be made to taper in the direction toward the lateral front side 21 of the front wall 10. The opening width of the collar opening bordering the exhaust means 9 can correspond essentially to the width of the intake opening of the exhaust means 9 and can continuously decrease in the direction to the side supplies, so that the guide element 20 has a triangular base surface. The front wall 10 can otherwise be aligned in the region of the exhaust means 9 with the upper jacket surface of the exhaust means 9 and can be made beveled in the direction to the lateral front sides 21. The front wall 10 can be an integral component of the guide element 20. As a result, the degree of thermal acquisition of the exhaust means 9 is further improved. [0046] It is not shown in particular that the air flow taken in can be divided into two component flows, preferably, the component flows being supplied with a different temperature and/or with a different speed, especially via different exit areas of the horizontal surface 5. Air supply can take place via the side supplies 7 and/or the foot supply 8 such that, on the one hand, the temperature of the inner region of the horizontal surface 5 decreases to the outside and on the other hand the exit speed also decreases from the inside to the outside. The latter reduces the shear flows between the individual air jets and reduces the induction, and thus, the admixture of ambient air. However, basically, it is also possible to break the air down into several component flows and to supply the air with respect to temperature and exit speed staggered accordingly over different exit surfaces of the horizontal surface 5. The exit surfaces can have honeycomb, directional baffle plates in order to produce a certain flow profile. [0047] The aforementioned features of the embodiments shown in FIGS. 1 to 10 can be combined if necessary, i.e., individually or in any combination, even if this is not mentioned and described specifically. | Summary: A thermotherapy device, in particular for babies, has a lying surface limited by longitudinal sides, a head side and a foot side. The thermotherapy device ensures a simple and safe access of a new-born without producing a detrimental psychological effect on parents. For this purpose, an upwardly oriented feeding device for supplying a hot and humid air is advantageously embodied in three parts, namely, a lateral feed pipe in each longitudinal part and/or a feed pipe in each foot side, a suction device for sucking supplied air is arranged above the lying surface, the suction device is arranged above the head side, in particular above the head area of the lying surface in such a way that the supplied air is sucked only above said head side and/or the head area. | 6,321 | 170 | big_patent | en |
Write a title and summarize: To explore pathogenesis in a young Gerstmann-Sträussler-Scheinker Disease (GSS) patient, the corresponding mutation, an eight-residue duplication in the hydrophobic region (HR), was inserted into the wild type mouse PrP gene. Transgenic (Tg) mouse lines expressing this mutation (Tg. HRdup) developed spontaneous neurologic syndromes and brain extracts hastened disease in low-expressor Tg. HRdup mice, suggesting de novo formation of prions. While Tg. HRdup mice exhibited spongiform change, PrP aggregates and the anticipated GSS hallmark of a proteinase K (PK) -resistant 8 kDa fragment deriving from the center of PrP, the LGGLGGYV insertion also imparted alterations in PrP' s unstructured N-terminus, resulting in a 16 kDa species following thermolysin exposure. This species comprises a plausible precursor to the 8 kDa PK-resistant fragment and its detection in adolescent Tg. HRdup mice suggests that an early start to accumulation could account for early disease of the index case. A 16 kDa thermolysin-resistant signature was also found in GSS patients with P102L, A117V, H187R and F198S alleles and has coordinates similar to GSS stop codon mutations. Our data suggest a novel shared pathway of GSS pathogenesis that is fundamentally distinct from that producing structural alterations in the C-terminus of PrP, as observed in other prion diseases such as Creutzfeldt-Jakob Disease and scrapie. Gerstmann-Sträussler-Scheinker Disease (GSS) is an autosomal dominant multi-systemic neurological syndrome that may evolve to frank dementia and often exhibits a protracted clinical course [1]. This inherited amyloidosis is caused by a number of mutations in the human gene, PRNP, on chromosome 20 that encodes the cellular prion protein (PrPC) [2]. PrPC is a GPI-linked protein displayed on the cell surface; its N-terminus is natively unstructured and contains tandem metal binding octarepeats and a hydrophobic region (HR). PrPC' s C-terminal region folds into a globular three-helix bundle with a small two-stranded β sheet [3]. In infectious prion diseases, PrPC refolds to a pathogenesis-associated form, PrPSc, whose structure is dominated by β sheet [4–6]. GSS is of interest as there is a propensity to form amyloid, sometimes accompanied by formation of neurofibrillary tangles (NFTs) [7,8] and because there is only a limited capacity for the generation of infectious titre and/or ability to transmit to recipient species [9]—these properties thus offering a partial parallel to Alzheimer' s Disease, where Aβ amyloid and NFTs are pathologic hallmarks in idiopathic and genetic disease [10] and where transmissibility of clinical disease to animal recipients is not a hallmark [11]. With poor GSS transmission first shown for experiments using non-human primates [12], transmissions into non-Tg rodents are similarly inefficient and stand in contrast to Creutzfeldt-Jakob Disease (CJD) [13]. This inefficiency may be partly overcome by using mice engineered to match the donor PrP allele [14,15], or by using bank voles [16], which are promiscuous hosts for a number of prion diseases [17–21]. Clinical presentation of GSS can be variable and partially dependent on the causative mutation in the PRNP gene coding region, the most common clinical phenotypes are cerebellar ataxia and pyramidal signs with eventual cognitive decline before death [22]. Multicentric plaques composed of truncated PrP fragments are often found in the brains of these patients and spongiosis may or may not be present [23]. A notable PRNP mutation was recently discovered in a young GSS patient. The index case presented with status epilepticus at age 34, prefaced by night terrors at age 26. While the parasomnias subsided after a 6-year period, memory problems and behavioural changes emerged at this age [24]. PRNP sequencing revealed homozygosity for valine at the polymorphic residue 129 and heterozygosity for a partial internal duplication, resulting in a protein with 8 extra residues. This LGGLGGYV insertion lies at the junction between the HR—the most conserved area of PrP and one reported to adopt alternative membrane topologies that are associated with neurodegeneration [25–28]—and the globular domain, where it is predicted to duplicate some of the residues found in the first β-strand of PrP (residues 128–131 [29]). Prompted by findings that early structural rearrangements in the PrPC to PrPSc transition involve the HR [30] and the possibility of discovering a process underlying an aggressive form of GSS disease, we pursued animal modeling. Our studies define a novel misfolded form of mutant PrPC that prefigures the 8 kDa PrP fragment pathognomonic for end-stage GSS with multicentric amyloid plaques [31] and may be shared by other allelic forms of GSS; they also suggest an explanation for the early disease onset of the index case. In analyses of RK13 cells lacking endogenous PrPC we concluded that glycosylation, endoproteolysis, biotinylation of cell-surface PrP and immunocytochemistry with and without cell permeabilization was similar between WT and HRdup and M128V allelic variants of mouse PrP (S1 Fig). We generated three lines of Tg mice expressing mouse PrP with the 8-residue insertion in the HR between amino acids V128/L129 (mouse numbering scheme, Fig 1A, Table 1), Tg. Prnp. HRdup. M128V-32, Tg. Prnp. HRdup. M128V-26 and Tg. Prnp. HRdup. M128V-10 (for brevity, Tg. HRdup-32, Tg. HRdup-26 and Tg. HRdup-10). We also created two control lines expressing a mouse Prnp allele modified to incorporate the equivalent of the human valine 129 polymorphism, Tg. Prnp. M128V-39 and Tg. Prnp. M128V-25 (Tg. M128V-39 and Tg. M128V-25). Since GSS alleles are dominant in their natural setting, transgenes were expressed on an FVB/N Prnp+/+ genetic background. The Tg lines differed in their net steady-state levels of PrPC, with expression levels ranging from 3. 4–1. 6x endogenous for the mutant lines and 1. 9–2. 0x for the control M128V lines (Table 1). With aging, Tg. HRdup mice, but not Tg. M128V mice, developed a spontaneous neurologic syndrome with accompanying neuropathological changes wherein animals with the highest transgene expression levels succumbed to the syndrome faster than their lower expressing counterparts (Tg. HRdup-32 > Tg. HRdup-26 > Tg. HRdup-10; Table 1, Fig 1, S2 and S3 Figs); while the life expectancy of Tg. HRdup-10 mice was not significantly shorter than that of non-Tg FVB/N littermates in our colony, neurological presentation and a discrete pathological signature (below) distinguished it from age-related death. The most notable clinical feature of Tg. HRdup mice was slowly progressing ataxia. As the disease advanced, weight loss was apparent and the animals were euthanized when showing kyphosis and hypokinesia. Tg. M128V mice with comparable PrP expression levels did not present with any neurologic abnormalities and were used throughout the study as negative controls (Table 1). Since myopathy has been described in GSS mice expressing the P102L allele (P101L in mouse PrP [32]), we sought these pathological changes in Tg. HRdup-26 animals with clinical disease; these studies failed to define necrotizing myopathy or neuropathy (S4 Fig), suggesting that these types of lesions do not contribute to the clinical presentation of Tg. HRdup mice. As attempts to transmit GSS isolates to primate and rodent models have yielded varied successes [16,22,33] we explored the issue of transmissibility using Tg. HRdup-10 animals as recipients for brain homogenate from sick Tg. HRdup-26 animals and observed acceleration of disease course from 662 ± 76 to 270 ±38 days post-inoculation (Table 1). Tg. HRdup-10 animals inoculated with non-transgenic, healthy brain homogenate culled at 399 days post inoculation had no signs of disease (Table 1, S5 Fig) while tga20 mice (which express WT PrPC at ~6-7x endogenous levels and thus higher than the other Tg lines in our study [34]) remained healthy and displayed no pathology when inoculated with the same brain homogenates from Tg. HRdup-26 animals in the clinical phase of disease. These data demonstrate that pathogenic processes in the brains of the Tg. HRdup mice extend to the generation of infectivity and offer a parallel to prior studies of transmission/host-range effects when a GSS P102L mutation is inserted into a mouse Prnp gene [15]. Previously reported neuropathological data on the index case were restricted to a right frontal lobe biopsy. The formalin-fixed tissue obtained at autopsy showed only mild to focal moderate spongiosis, with mild gliosis in the neocortex and cerebellum molecular layer (Fig 1C; Fig 1D I and IV); other areas showed no significant spongiosis. Vacuolation and gliosis of the hippocampus, cortex and cerebellum were present in all three Tg. HRdup lines but these features were most prominent in Tg. HRdup-26 animals (Fig 1E). The index case showed most intense multicentric plaque (MCP) burden, as visualized with α-PrP antibodies and Periodic Acid-Schiff (PAS) stain, in the neocortex and slightly less in the cerebellar molecular layer and hippocampus. Moreover, in the neocortex there was a layer oriented distribution of MPCs. Layer 5 and 6 showed most immunostaining with aggregates of MCPs (Fig 1D; II, III, V and VI), followed by layer 1, and the least MCPs in layer 2 and 3. The cerebellum showed less MCPs at the arachnoidal side of the molecular layer and most at the Purkinje cell side. There was no association between plaques and vacuoles (Fig 1D; I and III). Somewhat less intense PrP deposits were found in other grey matter structures including striatum and thalamus with the most sparse and smallest deposits present in the brainstem with granular synaptic deposits in inferior olivary nucleus and dentate nucleus. Tg. HRdup-26 animals showed a similar distribution of PrP plaques, with other affected areas being the anterior olfactory nucleus, corpus callosum, thalamus, anterior commissure and medulla. Some focal PrP deposits in mice stained with PAS (Fig 1E; II, inset). PrP deposits stained with monoclonal antibodies for C-terminal and N-terminal residues are shown in Fig 1F. In the case of Tg. HRdup-10 animals, the most intense PrP deposition was found in the cerebellum (S2 Fig) whereas, interestingly, analogous deposits were scarce in Tg. HRdup-32 animals which succumbed to disease ~400 days earlier. These data are summarized in S1 Table. Aged-matched Tg. M128V-39 animals were negative for all these histopathological hallmarks (S3 Fig). In the case of disease produced by inoculation of Tg. HRdup-10 mice with Tg. HRdup-26 brain extracts, there was an accentuation of spongiform change and focal PrP deposition in the cerebellum (S5B Fig) versus changes seen in aged un-inoculated Tg. HRdup-10 mice (S2 Fig). In the index case, Aβ, phosphorylated tau and proteasome-targeted proteins or inclusions were not detected. In agreement with this, attempts with AT8 antibody (phospho Ser202, phospho Thr205) to detect hyper-phosphorylated tau in Tg mice with spontaneous disease were unsuccessful. Proteinase K (PK) -resistant fragments from the center of PrP and of a molecular mass estimated to be between 6–8 kDa distinguish GSS from the C-terminal fragments that accumulate in CJD [35–38]. For simplicity, we will refer to this fragment in the context of the index case and Tg mice as being" 8 kDa" (but also noting that its molecular mass is predicted as 0. 735 kDa greater than a PK-resistant fragment generated from the corresponding WT sequence). We investigated this situation using frozen brain tissue obtained at autopsy from the index case (Fig 2A). The deep white matter had a paucity of neuropathological change and comprised an internal control for these analyses; notably, the abundance of the 8 kDa fragment normalized for protein loading was correlated with neuropathology visualized by light microscopy. This 8 kDa signature was abundantly present in aged Tg. HRdup-26 mice with spontaneous disease (Fig 2B and 2C (middle panels) ) and present in brain extracts from Tg. HRdup-10 mice with spontaneous disease (Fig 2D), but not in Tg. HRdup-32 mice (Table 1). It was absent from aged Tg. M128V-39 control mice (Fig 2B, 2C and 2D). Antibody mapping confirmed the 8 kDa species originates from the center of the PrP molecule, with 12B2 (res. 88–92) and Sha31 (res. 145–155) epitopes present, but with PrP248 (res. 55–96) and VRQ61 (res. 165–175) epitopes absent (Fig 2C); thus the fragment minimally consists of residues 88–155, in broad agreement with studies of a GSS-associated 7 kDa amyloid extracted fragments mapped to residues ~90–153 [38]. In terms of spontaneous pathogenic processes, the 8 kDa signature fragment was absent in young (healthy) Tg. HRdup-26 mice but was observed in animals with neurological symptoms of disease (Fig 2B). With respect to pathogenesis produced by inoculation, a paucity of this fragment in young, un-inoculated Tg. HRdup-10 mice was overcome in age-matched animals administered brain samples from sick Tg. HRdup-26 mice, whereas the same inoculum administered to over-expresser tga20 mice did not yield the signature fragment (Fig 2E). Regarding the ability to propagate the 8 kDa fragment, these data are in agreement with GSS inoculations performed using prion-susceptible bank voles and Tg mice [16]. In samples from aged human brain, the action of endogenous proteases upon misfolded PrP (but not WT PrPC) can generate a natural protease-resistant domain. As phosphotungstic acid (PTA) precipitation [39] has been used previously to enrich for abnormal PrP in brain homogenates from P101L mice [40], we applied this procedure to process brain samples from our Tg mice. Subsequent western blot analysis of PrP revealed an 8 kDa signature in sick Tg. HRdup-26 mice, but not in control Tg. M128V-39 mice (Fig 3A). Immunoreactive species migrating between the positions of the 16 and 17 kDa molecular weight size marker were also noted. These data suggest a process wherein misfolded PrP assembles into higher molecular weight aggregates such that a core structure is not digested to completion by endogenous proteolytic processes (Fig 3A). To assess the quaternary state of PrP, we performed ultracentrifugation assays utilizing a linear gradient of 10–45% sucrose in the presence of 1% Sarkosyl; we analyzed brain homogenates from three biological replicates for each allelic type. These velocity centrifugation studies (Fig 3B–3G) revealed that HRdup PrP populates higher molecular weight gradient fractions (highest fraction numbers) in comparison to M128V PrP. Comparing sick Tg animals to their healthy genotypic counterparts (Fig 3C versus 3D, 3E versus 3F) revealed more signal in high molecular weight fractions such as fractions 7 and 8 whereas signal was not detected at all in fraction 4–8 of Tg. M128V animals (Fig 3G). Sick Tg. HRdup-32 mice showed a profile similar to healthy Tg. HRdup-26 mice, which is in line with the absence of PK-resistant PrP in these animals (Fig 3B versus Fig 3C). These analyses suggest that, in the context of the HRdup mutation, the development of PK resistant PrP detected by immunoblotting and focal PrP aggregates revealed by immunostaining is associated with detergent insoluble aggregates that are present in the bottom fractions of the gradient (summarized in Fig 3H). We next turned to secondary and tertiary structure. Recombinant PrPs corresponding to WT, M128V (residues 118–231) and HRdup (residues 118–231 with an extra eight amino acids) were expressed by standard procedures. 1H NMR spectroscopy revealed all proteins were highly enriched and folded into a primarily α-helical structure (S6 Fig). To evaluate the stability of HRdup PrP, we performed a urea denaturation series (Fig 4A and 4B). Using previous chemical shift assignments of WT PrP, five resonances were identified in protons of the following residues: isoleucine181, Hγ2; phenylalanine197, Hα; tyrosine161, Hα; tyrosine217, Hδ; and tyrosine162, Hε. Stacked 1D spectra of samples under different urea concentrations are shown in S7 Fig. As previously performed to determine the stability of hamster, mouse, rabbit and bovine PrP [41], peak area values as a function of added urea were normalized to the largest value during denaturation process and then plotted against urea concentration. Two thermodynamic parameters, [D]1/2, the urea concentration at half point of unfolding and m, the slope of the denaturation curve which reflects the sensitivity of each resonance towards urea were extracted. Denaturing curves and [D]1/2 or m half values (S2 Table) for all five chosen resonances reveal that HRdup PrP had a similar sensitivity towards urea denaturation as WT and M128V PrP. Next, since the insertion in the HRdup allele includes extra residues as found within β-strand 1 in WT PrP, 2D NMR experiments were used to assess the short β-sheet structure in HRdup PrP. Here two characteristics indicate the presence of β-sheet structure: the downfield shift of Hα resonances [42] and presence of nuclear Overhauser effects (NOEs) within the α-H region (4 ppm to 5 ppm), due to the short distance between α-Hs from opposing residues in β-sheets. Within the α-H region of both HRdup and M128V we observed the NOEs from the two spectra as having the same chemical shifts, which indicate identical β-sheet structures formed by the same residues in the two sequences (Fig 4C–4E, S8 Fig). These NOEs are also consistent with those reported for the same region of WT mouse PrP [29]; this spectral information allowed assignments the NOEs in our spectra leading to the conclusion that the eight extra amino acids do not disrupt the short β-sheet structure present in all reported mammalian PrP NMR structures. However, these analyses are not able to determine if β-strand 1 of HRdup is composed of residues 127–130 (Tyr, Val, Leu and Gly) or residues 7–8 of the insertion and residues 129–130, or a mixture of the two. Further analyses used molecular dynamics (MD) to probe PrP structure. Two MD trajectories for molecules with GYVLGGLG inserted between G125 and G126, the preferred model identified by homology modeling, (" HRdup-I" and" HRdup-II" ) and two for molecules without the insert (" M128V-I" and" M128V-II" ) were simulated at a temperature 310 K and pH 4. 5 for 20 ns each, with secondary structure (SS) elements shown in Fig 5A and S9 Fig (see also S3 Table). Both M128V structures retained all major secondary structure elements including β-strands S1 and S2 and three α-helices H1, H2, and H3, with the exception of a small C-terminal part of H2 (Fig 5A and S9A and S9B Fig). In system HRdup-I, the N-terminus of helix H2 and almost the entire helix H3 unfolded (Fig 5A and S9C Fig). Residues insG6 and insL7 replace G123, and L124, forming a new beta strand. In system HRdup-II (S9D Fig) helix H2 and the middle part of helix H3 unfolded. Transient β-content was occasionally observed in N-terminal area of M128V-I, and to a greater extent in the areas of the insert and loop S2-H2 in HRdup-I and HRdup-II (S4 Table). To quantify structural differences between the alleles we averaged the per-residue solvent-accessible areas (SASA) [43] over the last 2 ns from the four MD trajectories (Fig 5B and S5 and S6 Tables). Two trajectories for HRdup and those for M128V exhibit close total SASAs for various groups of residues, as well as for the entire protein (S5 Table), and average per-residue SASAs were also close in HRdup and in M128V. However, the insert caused local effects (Fig 5B). Changes in SASA were evident in extended regions such as P104-K109, V111-V120, V121-G125, A132-D146, P164-Q167, N173-V179, V188-M204. (Fig 5B and S5 Table). Only a few residues with charged side-chains exhibited large differences in SASA suggesting a dominating effect on the hydrophobic residues. Next, PrP dynamics were analyzed by an essential collective dynamics tool (ECD). ECD results supported the aforementioned trends, with main-chain flexibility profiles [44–47] of the PrP constructs shown in Fig 5C. High levels of the flexibility descriptor represent loops, whereas minima indicate rigid areas such as α-helices or β-strands. In both constructs the areas of helices H2 and H3 are characterized by broad minima indicating a relative rigidity whereas helix H1 is less stable, which is not unusual for PrP [44,45]. The insertion caused extended regions of increased rigidity N-terminal to the insert and in the area of L108, where a systematic decrease in SASA was also observed (Fig 5B). The insert also seemed to destabilize the N-terminal part of helices H2 and H3 (Fig 5C) while increasing SASA in the same area (Fig 5B). Overall, data in Fig 5B and 5C indicates that an increase in per-residue SASA is often associated with greater main-chain flexibility, and vice versa. ECD pair correlation maps (S10 Fig) provide complementary information on dynamic correlations of atomic motion within the same statistical-mechanical framework [46,47], with S7 Table listing non-consecutive residues that show the strongest dynamic correlations in this type of analysis; Fig 5D and 5E graph these data and compares them with the 2D NOESY experiments. In summary, for M128V, the strongest correlations were found between β-strands S1 and S2, between β-strand S2 and helix H2, between helices H2 and H3, and between β-strand S2 and helix H3. For HRdup, the correlated elements are similar but the number of strongly correlated residues in H2 and H3 was notably decreased, whereas an additional correlation was observed between residues insG8 and Y127 with N-terminal residue A116. Lastly, given the role of protein assembly effects in prion biology, protein/protein docking was assessed using representative trajectories (S11 Fig and S8 Table). Beyond intermolecular contacts found in top dimer model based on M128V-I and M128V-II, new contacts appeared or became more frequent in the N-terminus (W98, K100, A114, A115) and helix H3 (Y225, D226) of the HRdup-I and HRdup-II constructs. N-terminal contacts involving W98, K100, V111, and A116 were also frequently observed in heterodimers (S8 Table). The protease thermolysin was used as an enzymatic probe of conformation to interrogate PrPC' s natively disordered region [48,49]. Thermolysin will completely degrade PrPC (see below) but produces a signature that includes protease-resistant full-length PrPSc from diseases such as mouse-adapted scrapie, hence providing information about the accessibility of residues in the natively disordered N-terminal region. For samples taken at autopsy, digestion of normalized protein samples from the index case from neuroanatomical areas with notable pathology (cerebellum (Cb); frontal cortex (FC); parietal cortex, PC) ) yielded an intense 16 kDa thermolysin resistant species (Fig 6A) appearing as a doublet in the cerebellar sample, while the 16 kDa signal from an area with less pathological staining (deep white matter (WM) ) was less notable. A 16 kDa species was also present in PTA precipitations from the same four tissue samples processed without any in vitro protease digestion (Fig 6B, Sha 31 antibody, lanes1-4). Here the relative abundance Cb ~FC ~PC > WM was again noted. While an 8 kDa species was not apparent in these analyses of the PTA precipitates of human material (Fig 6B, lanes 1–4), the same samples did yield an 8 kDa PrP fragment after PK digestion (Fig 6B, lanes 5–8) with a similar profile of signal intensity as noted above with thermolysin digestion, namely three robust signals (Cb ~FC, ~PC) versus a smaller signal (WM). A 16 kDa species was also seen with an octarepeat antibody in undigested PTA-precipitates (Fig 6C). Next, to address disease specificity, we sought similar signatures in sporadic CJD material or in normal brain. Two types of sCJD case containing a V129 polymorphism did not yield strong 16 kDa species but instead multiple species closer to the mobility of undigested PrP (Fig 6D). A normal control did not produce any TL-resistant species (Fig 6D) while cerebellar material from the proband yielded a doublet running slightly slower than the 16 kDa marker. To assess generality and the possibility that the 16 kDa signature can co-exist with or prefigure the generally accepted appearance of 7–8 kDa PK resistant species present in different types of GSS [37,50,51], we analyzed other GSS cases; these were pre-selected from samples within the US CJD surveillance system as harboring 7–8 kDa PK-resistant fragments. As shown in Fig 6E, this thermolysin resistant PrP doublet of ~16 kDa is shared by brain material obtained from four other GSS alleles (Fig 6E) As anticipated, a TL-resistant 16 kDa species was also present in the brains of TgHR. dup-10 and Tg. HRdup- 32 mice in clinical phase of disease, but not in the control Tg. M128V-39 line (Fig 7A); electrophoretic mobility of the 16 kDa species was unaffected by the use of PNGase F, suggesting that the C-terminus must lie N-terminal to the glycosylation sites (Asn180 and Asn196); this assumption was validated by four antibodies with epitopes N-terminal to these two positions (Fig 7B). Our data exclude that the 16 kDa species corresponds to an un-glycosylated, thermolysin-resistant form of the C1 fragment produced by physiological endoproteolysis of PrPC—this is because two antibody epitopes (248 and 12B2) lie N-terminal to mouse PrP C1 N-termini at residues 109,100 yet can detect the 16 kDa species and also because VRQ61 antibody that detects a C-terminal epitope present within C1 PrP nonetheless fails to detect the 16 kDa species. As the mouse 16 kDa species appears as a doublet with the PrP248 and 12B2 antibodies but less clearly so with Sha31, there may be raggedness at the C-terminus in the vicinity of the Sha 31 epitope, an effect which can be clearly observed using patient derived material (Figs 6E and 7B). Heterogeneous cleavage of PrP has also been noted in vivo during analysis of A117V, F198S and Q217R cases and following PK digestion of GSS cases harbouring the P102L mutation [52–54]. Levels of this species increased with age (Fig 7C). Sick Tg. HRdup mice could contain some immunoreactivity after thermolysin treatment indicative of full-length glycosylated PrP, but this was not the major species. Most notably, the 16 kDa species was detected at ages as young as 7 days in the brains of Tg. HRdup-26 mice (S12 Fig), underscoring occurrence preceding the 8 kDa fragment and hence a potential role as a precursor. With regards to accumulation, level of this species changed by 5-fold and net thermolysin-resistant PrP signal increased by 13. 7-fold between pre-symptomatic (200d) and end-stage (442d) line 26 animals (Fig 7C). We next used an in vitro double-digest experiment (Fig 7D) to explore the ability of 16 kDa thermolysin resistant PrP species to engender an 8 kDa PK resistant fragment. TL digests of 50 μg of protein from two aged Tg. HRdup-26 animals revealed a 16kDa fragment as the major species, along with two sub-molar species, again consistent with the inference of ragged fragment termini. As anticipated, an additional PK treatment after a TL digest yielded an 8 kDa species as the predominant product; in both cases this was accompanied by two sub-molar species, albeit with slower electrophoretic mobility than the predominant species (Fig 7D). We extended these analyses to three other aged Tg. HRdup-26 animals and quantified the percent signal in the vicinity of the 16 or 8 kDa species versus the complete integrated signal in the Mr range of 34–4 kDa. 16 kDa or 8 kDa species comprised > 80% signal in the TL or TL plus PK digests, respectively, and these percentages were not significantly different (Fig 7E). Thus, in an in vitro situation, the major product of a TL digest is efficiently converted after an additional PK digestion to a major product that has similar mobility to the major product of a PK digest; in short, the novel 16 kDa TL-resistant species can engender the 8 kDa PK-resistant hallmark species. Concerning templated seeding and 16 kDa species, the inoculum from Tg. HRdup-26 mice that produced early clinical disease in Tg. HRdup-10 increased the level of 16 kDa species above genotypic controls treated with inoculum from healthy WT mice. No such species was detected in tga20 mice (i. e. expressing WT mouse PrP) seeded with Tg. HRdup-26 inoculum (Fig 7F), suggesting an allelic barrier to seeding [37,50,51]. Prion diseases can be sporadic, infectious or genetic; GSS, in particular, while caused by germline mutations, can also be infectious in certain lab settings. Mice expressing either WT murine PrP with a stop codon before the GPI anchor signal sequence or a natural I109 allele of WT bank vole PrP are reported to develop a spontaneous GSS-like syndrome [21,55] but, for the most part, the goal of attaining GSS-like neuropathology and plaque deposition has been met by Tg mice that introduce mutations within the framework of mouse Prnp [56–58]. Conversely, P101L knock-in mice with 1x endogenous expression levels remain asymptomatic [59,60], as do mice expressing human PrP with a P102L or A117V mutation [14,61] and neither line are described as having spontaneous accumulation of pathognomonic 7–8 kDa PK-resistant fragment. This work presents a third transgenic model of GSS with spontaneous disease appearance where the human GSS mutation is used in the context of WT mouse PrP (the Prnpa allele) but without synthetic epitope tags [62], thus joining Tg. P101L and Tg. A116V models [56,57]. While PK-resistant PrP has not been observed in the brains of Tg. P101L mice or P101L knock-in mice [15,32,56,59,63], here we were able to detect robust levels of a pathognomonic 8 kDa PK-resistant fragment in two Tg lines with spontaneous disease. A similar low molecular weight PK-resistant PrP fragment present in A117V patients has been detected in the brains of sick Tg. A116V mice, though seemingly less prominent than observed in the HRdup expressing animals analyzed here [57] (Fig 2B–2E). An 8 kDa fragment is seen in transmissions from GSS tissue into bank voles [16], and in spontaneously sick Tg mice expressing bank vole PrP or GPI-anchorless mouse PrP [21,55]. Association between the 8 kDa fragment and transmissibility is also present in our studies based on the HRdup GSS allele, where disease presentation in the lowest-expressor line, Tg. HRdup-10, was accelerated and levels of the 8 kDa PK-resistant fragment were enhanced over age-matched (asymptomatic) mice of the same transgenotype (Fig 2E, Table 1). This finding on species-barrier effects aligns with studies using other GSS models and a β-sheet enriched recombinant peptide approximating to the 8 kDa fragment [15,32,63,64], but noting that transmissions into mice expressing P102L human PRNP can reveal different host-range properties than for mouse Prnp [65]. What might be the cis effects of the 8 amino acid insertion upon folding of HRdup PrP? We failed to see significant distinctions between alleles in urea denaturation studies by monitoring five residues in the C-terminal globular domain of WT, M128V and HRdup PrP (Fig 4A and 4B, S7 Fig), suggesting the HRdup insertion does not affect the allele' s PrPC-like global fold. Sequence inspection of HRdup reveals that the first β-sheet is split by the insertion, creating the potential for a second β strand separated by a short linker region (Fig 4C). As conversion from PrPC to PrPSc involves an increase in β-content, one might speculate that HRdup has intrinsically more β-structure than a WT counterpart that could drive its conversion to a PK resistant form [5,66]; while no additional β-sheets were noted in the ensemble measurements of recombinant protein preparations by NMR (Fig 4D and 4E), transient occupation of additional β-structure versus WT controls was noted in MD modeling following the trajectory of individual molecules (S9 Fig, S4 Table). In the HR of WT PrP there are four conserved glycines within three GxxxG motifs, while HRdup contains 6 equally spaced glycines within 5 of these motifs. GxxxG motifs were first identified as mediators of transmembrane helix-helix association [67]; there are indications from prion infections that these extracellular sequences may feature in uptake of prions in the replicative cycle [68]. In vitro work has shown that interruption of these GxxxG repeats decreases the PK resistance of recombinant PrP folded into a β-rich form. This finding has some parallels in allelic alterations in tandem repeats in Shadoo, a PrP family member with a HR lacking an N-terminal palindrome but instead composed solely of GxxxG repeats [69–71]. Further appraisal of the properties of GxxxG sequence motifs in PrPC’s HR may thus be fruitful. Beyond this, as the HR is only one part of PrPC' s natively disordered region and since perturbations were noted in sequences N-terminal to the insertion in MD simulations of monomers and in a dimer interface in in silico docking studies (S11 Fig), the question arises as to whether a larger region is impacted by the HRdup mutation. As a chemical probe, we employed thermolysin, an enzyme used previously to assess A116V PrP expressed in cell culture [72] and where the authors reported a greater resistance of this GSS associated allele to thermolysin relative to PK. However, to the best of our knowledge, the discrete N-terminal 16 kDa thermolysin-resistant species present at robust levels (and using the enzyme at 70°C [73]) is a previously unreported feature, being in line with the distinct molecular nature of GSS in that it differs from digestions of CJD and scrapie brain material. Multimerization and acquisition of protease-resistance often go hand-in-hand for prion diseases and here we note the HRdup PrP holoprotein has different assembly properties than M128V PrP (Fig 3) and that a self-aggregation determinant [74] lies within the boundaries of the 16 kDa species defined by epitope mapping. Moreover, unlike the natural C1 endoproteolytic fragment of PrP, the boundaries of 16 kDa thermolysin-resistant species do not preclude a precursor relationship to the 8 kDa form (Fig 8). Indeed, there is an interrelationship in the levels of 16 and 8 kDa species in i) different brain areas from the index case (Fig 6B), ii) in time-course analyses of normalized brain protein extracts of aging mice where the 16 kDa species occurs earlier than the 8 kDa fragment (Figs 2B, 7C) and iii) in sequential digest experiments (Fig 7D). Our data support a series of events wherein a fraction of full-length HRdup undergoes misfolding in the N-terminal domain such that it starts to assemble to multimers, becomes precipitable with PTA and yields a 16 kDa signature upon thermolysin digestion (Figs 2,3, 6,7 and 8). Enhanced accumulation of the 16 kDa species in inoculated Tg. HRdup-10 mice (Fig 7F) is also compatible with some templating and self-assembly capacity that may warrant further investigation. Over the course of time this conformationally altered form of PrP may yield 8 kDa PrP through the action of endogenous degradative processes (Figs 3A and 8) [38]. Conversely, the use of distinct proteases and antibody mapping, as well as its earlier appearance, exclude an alternative explanation that the 16 kDa PrP species detected by immunoblot reflect SDS-resistant dimers of 8 kDa PrP species. The presence of the 16 kDa signature in four other GSS alleles and its increased levels in more pathologically affected areas of the brain from the index case (Fig 6A, 6B and 6E) both argue for intimate involvement in the disease process. In addition, the C-terminal boundary of the thermolysin-resistant species adjacent to the end of helix 1 offers an unexpected parallel to pathogenic stop codon mutations such as PrP145X, where structural biology and transmission properties have been studied in depth [75–77]. Finally, Tg. HRdup-32 mice succumb to spontaneous disease earliest of all the Tg lines described here and accumulate 16 kDa thermolysin resistant PrP but not the 8 kDa PK resistant fragment (and, hence, cannot accelerate disease in recipient animals), so a straightforward inference from these net data is that the misfolded form of PrP revealed by thermolysin digestion has neurotoxic activity. Hypothetical toxic forms of PrP (PrPL) have been inferred for prion infections, with clinical disease emerging when levels of PrPL transcend a threshold; in this scheme, autocatalytic propagation of PrPSc (" Phase 1" ) precedes toxicity (" Phase 2" ) [78]. We suggest that a permutation of these concepts may come close to representing the GSS pathogenic process; specifically, the potentially toxic species could start to accumulate early on and be diagnosed in tissue by thermolysin treatment as the 16 kDa species. The later disease process may be characterized by two events. First, noting that the level of the 16 kDa thermolysin-resistant species rises with chronological age in Tg mice, levels of toxic misfolded forms of PrP may transcend a threshold needed for clinical manifestation. Second, the 8 kDa PK-resistant species that is adept at autocatalytic propagation events—" infectivity", as measured in experimental transmissions from human source material in bank voles [16] or from Tg mouse material (Fig 2E) —begins to rise. Delayed occurrence of the 8 kDa species may reflect its derivation from the form of misfolded PrP represented by thermolysin resistance. This scheme of pathogenesis is summarized in Fig 8B. While full-length thermolysin-resistant forms of PrP were present at end-stage in Tg mice (Fig 7A–7C) and might also have toxic potential, levels of full-length thermolysin-resistant forms of PrP were unremarkable in human GSS tissue (Fig 6A, 6D and 6E) and hence were not considered an obligatory item in pathogenesis. Future studies to inventory the levels of abnormally folded full-length PrP by use of PTA (Fig 6B and 6C) or by detergent insolubility, may be useful to probe and refine this new view of pathogenesis. In terms of accumulation of 16 kDa thermolysin-resistant PrP and toxicity thresholds, for the Tg. HRdup-26 line, the 16 kDa signature is apparent at almost the very time PrP transcript levels increase in rodents above the levels present in embryos, this transition correlating with neuronal precursor cells ceasing proliferation and beginning to differentiate [79–82]. Clinical disease is scored 400 days later in Tg. HRdup-26 mice and ~170 days later for Tg. HRdup-32 mice. These data beg the question of whether an early start to the accumulation of abnormal PrP species resulted in a corresponding early transit across a threshold for manifestation of clinical symptoms. Of interest, the index case had psychiatric events in his twenties and is reported to have a son affected with an autism spectrum disorder condition (Asperger' s) [24]. Both WT PrPC and HRdup PrP undergo physical interactions with DPP6 [83,84], a type II membrane protein [85] that controls dendritic morphogenesis and one wherein gene disruptions link to different neurodevelopmental disorders [86–88]. Thus, a number of fascinating possibilities may emerge from further investigation of this kindred. More broadly, the Tg. HRdup mice comprise a new tool for structural biological investigations to investigate changes in PrP' s N-terminal region [6] and links to neurotoxicity. Given that other GSS mutants share this chemical signature, there may an opportunity to understand common disease mechanisms in GSS and, pending the generation of new molecular probes for this form of PrP, perhaps more common CNS disorders as well. DNA was extracted from frozen brain tissues in all cases, and genotypic analysis of the PRNP coding region was performed as described [89–91]. On the basis of diagnostic pathology, immunohistochemistry, and western blot examination of 3 brain regions (including frontal, occipital and cerebellum cortices) with mAb 3F4 and 1E4, the pathogenic PrPSc was classified as described previously [31,92–95]. Coronal sections of human brain tissues were obtained at autopsy and stored at -80°C. Three 200–350 mg cuts of frontal (superior and more posterior middle gyri) cortex were taken from each brain and used for molecular analyses. The other symmetric cerebral hemisphere was fixed in formalin and used for neuropathological classification of prion disease using histological and immunohistochemical analysis of samples from 16 anatomical areas and NPDPSC’s standard protocols [93,96,97]. We based the classification on the molecular characteristics of PrPSc on western blots developed with a panel of antibodies as described previously [93,98,99] to exclude GSS cases with a 21 kDa PK-resistant fragment. This criterion, as well as DNA sequencing, allowed the classification of the included cases with pathognomonic 8 kDa fragments as follows: A117V-129V (age 35, disease duration 60 months), P102L-129M (age 37, disease duration 106 months), H187R-129V (age 42, disease duration 108 months) and F198S-129V (age 59, disease duration 120 months). For the index case, we used frozen postmortem tissue from different brain areas, as described in the Figure legends. Healthy brain tissue as well as MV1 and VV2 CJD samples were similarly classified. Cortical samples were used to make homogenates. Transgenic mice were generated using a modified half-genomic construct and standard procedures [34,100]. Animals were housed in groups of up to five under a 12 h light/dark cycle with food and water ad libitum. Tg. CRND8, Tg. TauP301L and tga20 mice have been described previously [34,101,102]. Inoculations were performed by intracerebral injection of 30 μl of 1% (wt/vol) brain homogenate. Brain hemispheres were homogenized in cold PBS by passage through successively larger gauge needles. Whole brain extract was subjected to 10% Tricine-SDS-PAGE and transferred to PVDF membranes (Millipore) using Tris-gly transfer buffer with 20% methanol in the Mini Trans-Blot Electrophoretic Transfer Cell (BioRad) or the XCell Blot Module (Invitrogen). Primary antibodies used were: Sha31 (α-PrP; Spi-bio), 12B2 (α-PrP; from Dr. J. Langeveld) and PrP248 and VRQ61 (α-PrP; from Dr. H. Rezaei). Secondary antibodies used were horseradish peroxidase conjugated goat α-mouse (Bio-Rad). For enzymatic digestion, 250 μg (PK) or 50 μg (thermolysin) of protein was incubated for 1 h at 37°C (PK) or 70°C (thermolysin) with 10 μg/ml PK (Roche) or 50 μg/ml thermolysin (Sigma) in 250 μl. For sequential digests, samples were methanol precipitated after thermolysin treatment, re-suspended in PBS and then digested with PK. 5 mM PMSF (PK) or 10 mM EDTA pH 8 (thermolysin) was used to stop the reaction and samples were centrifuged at 20,800 x g for 1 h at 4°C. Pellets were resuspended in sample buffer containing 50 mM DTT. For removal of carbohydrates, 20 μg of protein was incubated overnight at 37°C with 100 U PNGase F (New England Biolabs) in a volume of 20 μl according to manufacturer' s instructions. Molecular weight markers are SeeBlue Plus 2 pre-stained standards (Invitrogen). Mice: Sagittal sections were fixed in 10% phosphate buffered formalin and embedded in paraffin. Hematoxylin and Eosin staining was done as previously described [103]. For immunodetection, slices were heated to 121°C in 10 mM citrate buffer and allowed to cool to room temperature. Staining for PrPSc was then accomplished by treatment with formic acid and 4 M guanidine thiocyanate before an overnight incubation with biotinylated SAF83 (Cayman Chemicals) or PrP248. GFAP immunodetection was accomplished by subsequent incubation in 3% peroxide and overnight incubation with a biotinylated primary antibody cocktail (BD Biosciences; 556330). These slices are counterstained with Mayer’s hematoxylin. Index case: Brain tissue was obtained at autopsy 21 hours after death. The tissue was partly frozen at -85°C and partly fixed in buffered formalin. The tissue was processed to blocks and embedded in paraffin 14 days after autopsy. Five micrometer sections were stained with hematoxylin and eosin, Periodic Acid-Schiff, and immunohistochemistry was performed for prion protein (12F10 1: 3000 Cayman), amyloid beta (Anti B-Amyloid 17–24 (4G8) 1: 20000 BioLegend), tau (AT8,1: 2500 Leica), and P62 (Anti-SQSTM1 1: 200 Abcam). An equal volume of 4% Sarkosyl was added to 1 mg of a 20% brain homogenate (PBS) and homogenized by passage through a 25g needle. A stock solution of PTA was added to have a final concentration of 2% PTA and the sample was allowed to incubate at 37°C for 16 h with 1200 rpm shaking [39]. The sample was centrifuged at 16,000 x g for 30 minutes and the supernatant was removed. The pellet was resuspended in 50 μl 0. 2% Sarkosyl and then brought to 1000 μl using 2% Sarkosyl. PTA was again added to a final concentration of 2% and the sample was incubated at 37°C for 1 h. Following a second 16,000 x g spin, the pellet was resuspended in 0. 2% Sarkosyl for downstream analysis. Linear 10–45% sucrose gradients were prepared by layering 375 μl of increasing concentrations (5% steps) of sucrose (in PBS, pH 7. 4 and 1% Sarkosyl) in OptiSeal polypropylene tubes (Beckman Coulter). Gradients were linearized by incubation overnight at 4°C. 250 μg of brain homogenate was brought to 300 μl in PBS (pH 7. 4) containing 2% Sarkosyl and layered on top. Samples were centrifuged at 268,000 x g for 73 minutes at 4°C using a swinging bucket rotor and eight fractions were collected from the bottom of the tube. Equivalent volumes of each fraction were then interrogated for the presence of PrP by western blot. The genes moPrP118-231, moPrP118-231 M128V, and moPrP118-231 HRdup, were synthesized by DNA2. 0 with codon optimization. The N terminus of all three proteins had a 6xhis tag with a TEV cleavage site for removal. Protein sequences are listed below: HHHHHHGASTGGQQGENLYFQGAVVGGLGGYVLGGLGGYVLGSAMSRPMIHFGNDWEDRYYRENMYRYPNQVYYRPVDQYSNQNNFVHRCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCVTQYQKESQAYYDGRRSSG HHHHHHGASTGGQQGENLYFQGAVVGGLGGYVLGSAMSRPMIHFGNDWEDRYYRENMYRYPNQVYYRPVDQYSNQNNFVHRCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCVTQYQKESQAYYDGRRSSG HHHHHHGASTGGQQGENLYFQGAVVGGLGGYMLGSAMSRPMIHFGNDWEDRYYRENMYRYPNQVYYRPVDQYSNQNNFVHRCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCVTQYQKESQAYYDGRRSSG Vectors were transformed into BL21 (DE3) cells. The proteins were expressed and purified based on the methodology previously described for the expression of human PrP [104]. For urea denaturing experiments, the samples were prepared the same as described previously [2]. Whilst for two-dimensional (2D) 1H-H1 NOESY experiment, 2 mg protein was dissolved in 500 μl solution that was made up with D2O (99. 9%, Cambridge Isotope Laboratories), 10 mM sodium acetate, and 0. 3 mM DSS-d6; pD was adjusted to 5. 3 using 2 M DCl. The sample was flash frozen, lyophilized and re-suspended using 500 μl D2O (99. 996%, Cambridge Isotope Laboratories) to minimize the H2O signal within the spectra thereby providing a clear view of β-sheet-correlating signals. NMR experiments were performed on an 800 MHz Varian INOVA NMR spectrometer at 25°C. One-dimensional (1D) proton NMR spectra were acquired for urea denaturing experiments with 256 transients, with a spectral width of 15. 0 ppm and a time delay of 2. 5 s; while two-dimensional (2D) H1-H1 NOESY spectra were acquired with 64 transients, 768 increments, spectral widths of 12. 0 ppm for both proton dimensions. The time delay was 1. 5 s and the mixing time was 100 ms. All NMR spectra were processed with VnmrJ software v4. 0 (Varian Inc.) and line broadening of 0. 5 Hz was applied. Further data processing and analysis for both urea denaturing experiments and 2D experiments are the same as previously described [105]. The insert model HRdup was built using the SWISS-MODEL homology modelling server [106]. The moPrP 23–239 sequences with the M128V polymorphism were modified by insertion of a LGGLGGYV sequence between V128 and L129 and uploaded to SWISS-MODEL. The server template search and alignment with BLAST and HHBlits software [107,108] were performed. Direct insertion of a LGGLGGYV between V128 and L129, or GLGGYVLG between G130 and S131 with target-template alignments were also attempted. Those constructs tended to exhibit similar conformations as in the model we adopted for analysis (S3 Table). Both the global and per-residue model quality were assessed using the QMEAN scoring function [109]. Two scores were evaluated: the global model quality estimation (GMOE; scores closest to one indicate the highest quality) and score composite scoring function to estimate the global and local model quality (QMEAN4; the highest negative scores indicate a higher local per-residue reliability of the model). The homology search for mouse PrP sequence with insert produced 285 templates, from which 10 were chosen to build models. These included PDB ID codes 4MA8,4MA7,2L39, and 2L1H (MoPrP) and 4KML, 1QLZ (HuPrP), see S3 Table. The best matching models chosen based on the range, sequence identity, and coverage, included constructs 2L39 with identity 98. 25%, GMQE score 0. 41 and QMEAN4 score -4. 03; 2L1H with identity 99. 11%, GMQE score 0. 45, and QMEAN4 score -1. 94; and 4MA7 with identity 99. 12%, GMQE score 0. 46 and QMEAN4 score -1. 56. The coordinates of the eight amino acid insert model based on the 2L39. pdb construct were uploaded and prepared for the simulations. The best-matching 3D model of HRdup constructed by the SWISS-MODEL tool initially represented a L124-D226 sequence. The N-terminal fragment G89-G123 was added to this initial model using the Accelrys VS software (Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego: Dassault Systèmes, 2016). The choice of pdb structure and the length of the sequence for the control M128V structure without the insert were based upon the best-matching model 2L39. pdb. C-terminal fragment 227–232 was removed to match the HRdup model, and fragment 89–117 and polymorphic mutation M128V were introduced using the Accelrys VS. In all simulation runs, the C-terminal and N-terminal extremities of the main chains were kept charged (−COO- and −NH3+), whereas all other titratable amino acids were assigned their canonical state at pH 4. 5 with the PropKa server software [110]. The HRdup and M128V constructs were subjected to minimizations, equilibrations and production molecular dynamics (MD) simulations in Gromacs v 4. 5. 3 package with OPLS forcefields [111,112]. Starting models were minimized in vacuo for 10000 steps of steepest descent minimization. Then the models were solvated in single point charge extended (SPC/E) rectangular periodic water box, after which Cl− or Na+ ions were added to neutralize the systems. Subsequent solvent minimizations with decreasing position restraints (Kposre = 1×105,1×104,1000,100,10 and 0 kJ mol−1 nm−2) on non-hydrogen protein atoms have been made to relax solvent and protein. Subsequent heating with the Berendsen thermostats from 0 K to 310 K and NPT equilibration with adjustment of solvent density to 1 g/cm3 followed the minimizations. The last equilibration step and the production simulations were conducted at 310 K temperature and at a pressure of 1 atm with isotropic pressure coupling (NPT ensemble). The bond lengths were restrained with the LINCS algorithm with a fourth order of expansion. The short-range electrostatic and van der Waals interactions cut-off radii were equal to 14 Å each. Long-range electrostatic interactions were treated with the particle-mesh Ewald (PME) summation with grid spacing of 0. 135 nm for the fast Fourier transform and cubic interpolation. The simulations were performed for 20 ns for each system; 1 fs time steps were employed, and snapshots saved every 20 fs in order to analyze the essential collective dynamics. For each of the HRdup and M128V constructs, the MD simulations were duplicated from the same starting coordinates, using different starting velocities of atoms. The corresponding MD trajectories are denoted as “I” and “II” in the discussion. To analyze the PrP constructs from MD trajectories, their secondary structure content, numbers of hydrogen bonds and salt bridges, contact maps, and solvent accessible areas (SASA) have been calculated using scripts implemented in Gromacs [112,113] and VMD [114] packages. Final SASA analysis was made according to solvent exposure level defined in [115]. Snapshots from trajectories and graphical representation of models was done with VMD or Accelrys VS [115]. Protein docking and predictions of residues involved in oligomer contacts for representative snapshots from M128V and HRdup trajectories were made through the InterEVDock server integrated in the RPBS Mobyle portal [116]. To analyze and compare dynamics of PrP alleles in greater depth we employed the novel essential collective dynamics (ECD) method [45,47,117–120]. The method stems from the statistical-mechanical analysis of the generalized Langevin dynamics of proteins [117,119], according to which persistent correlations between atoms’ motion in the protein can be determined from principal eigenvectors of the covariance matrix of a protein’s MD trajectory. A suite of dynamics descriptors has been derived within this framework, including in particular the main-chain flexibility profiles and pair correlation maps [118,120]. Previously the method has undergone an extensive validation against NMR-derived (117,119) and X-ray based structural data [47,118,120], and was demonstrated to predict accurately the main-chain flexibility, pair correlations, and other dynamics trends from short fragments of MD trajectories. In this work, the ECD main chain flexibilities and pair correlation maps are obtained for the HRdup and M128V constructs using the techniques described in detail elsewhere [45,47,120]. Representative conformations from the four production MD trajectories were used as templates for protein docking on the InterEVDock server integrated in the RPBS Mobyle portal [121]. 10,000 decoys were created, scored and clustered resulting in 10 models for each of three scoring methods (InterEVScore, SOAP_PP atom-based statistical potential, and FRODOCK). Conservation of residues was assessed with the rate4site. Procedures for the index case have already been described [24]. All other procedures were performed under protocols approved by the Institutional Review Board at Case Western Reserve University. In all cases, written informed consent for research was obtained from the patient or next of kin and the material used had appropriate ethical approval for use in this project. All patient data and samples were coded and handled according to NIH guidelines to protect patient identities. For animal studies, all protocols were in accordance with the Canadian Council on Animal Care and were approved by the Animal Care and Use Committee at the University of Alberta (AUP00000356). | Title: A novel Gerstmann-Sträussler-Scheinker disease mutation defines a precursor for amyloidogenic 8 kDa PrP fragments and reveals N-terminal structural changes shared by other GSS alleles Summary: Prion diseases can be sporadic, infectious or genetic. The central event of all prion diseases is the structural conversion of the cellular prion protein (PrPC) to its disease associated conformer, PrPSc. Gerstmann-Sträussler-Scheinker Disease (GSS) is a genetic prion disease presenting as a multi-systemic neurological syndrome. A novel mutation, an eight amino acid insertion, was discovered in a young GSS patient. We created transgenic mice expressing this mutation and found that they recapitulate key features of the disease; namely PrP deposition in the brain and a low molecular weight proteinase K (PK) resistant internal PrP fragment. While structural investigations did not reveal a gross alteration in the conformation of this mutant PrP, the insertion lying at the boundary of the globular domain causes alterations in the unstructured amino terminal portion of the protein such that it becomes resistant to digestion by the enzyme thermolysin. We demonstrate by kinetic analysis and sequential digestion that this novel thermolysin resistant species is a precursor to the pathognomonic PK resistant fragment. Analysis of samples from other GSS patients revealed this same signature, suggesting a common molecular pathway. | 15,412 | 314 | lay_plos | en |
Summarize: This is a continuation of U.S. patent application Ser. No. 09/362,364 filed Jul. 28, 1999 now abandoned. The invention relates to dental devices, denture products, kits, systems and methods therefor. The invention provides a dental device such as a denture base, clasp, denture and partial denture. The invention provides kits, systems and methods for molding dentures having clasps. The invention provides a semi-crystalline transparent clasp, and partial dentures having a transparent clasp. This invention provides removable partial denture having clasps composed of a transparent semi-crystalline polyamide formed by an injection molding. BACKGROUND OF THE INVENTION Thermoplastic partial denture clasps have been fabricated with pigmented polyamide/copolymer, polyacetal, which have poor aesthetic properties, and transparent ‘amorphous’ polymer compounds, which results in poor physical properties and require laborious fabrication methods. Amorphous polyamides display a clear and colorless quality however; very high viscosities and poor physical/mechanical properties preclude their use as injection molded dental resins. Removable partial dental prostheses are employed to restore one or more, but not all, of the natural teeth of a patient. The primary objectives of a properly designed dental prosthesis include the preservation of remaining teeth, along with hard and soft oral tissue, the restoration of oral function, and the restoration of dental and facial aesthetics. Removable partial dental prostheses are commonly formed with a base or saddle which rests on the oral mucosa in an edentulous space and is coupled by connector means to one or more abutment teeth, that is, a tooth which abuts or is adjacent to the edentulous space. Perhaps one of the most common forms of partial dental prosthesis is the distal extension removable partial denture which is used to replace posterior teeth with artificial teeth on one or both sides of the mouth. Distal extensions are commonly secured to an abutment tooth by clasps, which are mounted on the abutment tooth to provide for stabilization and retention of the prosthesis, and a connector, which extends between the clasp and the base of the distal extension. The base or saddle of the distal extension rests on the alveolar ridge. Prefabricated clear and tooth colored thermoplastic clasps are described in U.S. Pat. No. 5,102,337. The prefabricated clasps are contoured by applying heat to the area which the technician wishes to shape and bend. Kulwiec et al. In U.S. Pat. No. 4,412,824 discloses removable partial dental prosthesis and method of forming and supporting the same. Prior art dental devices have low impact strength. These problems of the prior art are overcome by the present invention. The prior art does not disclose a dental device including thermoplastic polyamide having a Charpy notched impact strength of at least 3.5, or a dental device including polyamide having at least 10 percent by weight of micro-crystals having a largest dimension less than 750 nanometers, as provided by the present invention. OBJECTS OF THE INVENTION It is an object of the invention to provide a dental device including thermoplastic polyamide having a Charpy notched impact strength of at least 3.5. It is an object of the invention to provide a dental device including polyamide having at least 10 percent by weight of micro-crystals having a largest dimension less than 750 nanometers. It is an object of the invention to provide a metal cartridge container containing particles of thermoplastic polyamide effectively free of pigment. It is an object of the invention to provide a method of making a partial dental prosthesis having a substantially transparent clasp, by injecting substantially transparent thermoplastic into a first portion of a mold cavity of a mold containing an artificial tooth, and injecting substantially opaque thermoplastic into a second portion of the mold cavity. It is an object of the invention to provide a removable partial dental prosthesis including an artificial tooth supported by a base integrally connected to a clasp, wherein the base includes pigment and is substantially opaque, and the clasp is substantially transparent and effectively without pigment. It is an object of the invention to provide a kit for making a denture, including: a package supporting a first cartridge enclosing pigment and first particles of thermoplastic and a second cartridge enclosing second particles of thermoplastic effectively free of pigment. It is an object of the present invention to provide a removable partial dental prosthesis which is capable of restoring oral function and dental and facial aesthetics without destruction of adjacent teeth and soft oral tissue. Another object of the present invention is to provide a method of supporting a removable partial dental prosthesis in the mouth and particularly on the alveolar ridge which greatly reduces stress on the ridge and abutment teeth. Still a further object of the present invention is to provide a method for the manufacture or formation of removable partial dentures which is adaptable to denture manufacturing techniques and yet includes structure providing enhanced performance of the prosthesis. Another object of the present invention is to provide a method for supporting a dental prosthesis which enhances the life of the remaining teeth in the mouth and which does not afford a habitat for decay and infection causing debris. It is also an object of the present invention to provide a dental prosthesis which is compact, relatively easy to manufacture, highly durable, and distributes and redirects localized stress forces. The removable dental prosthesis and method of the present invention have other objects and features of advantage which will become more apparent from and are set forth in the following description of the preferred embodiment and the accompanying drawings. Opacity as used herein refers to the percentage of impinging white light transmitted from a spectrophotometer through a 1 mm thick sample of material being tested. Charpy notched impact strength as used herein refers to Notched impact strength in foot-pounds/inch 2 (ft-lb/in 2 ) measured by ISO 179:1993 SUMMARY OF THE INVENTION The invention provides a metal cartridge container containing particles of thermoplastic polyamide effectively free of pigment. The metal cartridge is used in a method of making a partial dental prosthesis having a substantially transparent clasp. First a substantially transparent thermoplastic is injected into a first portion of a mold cavity of a mold containing an artificial tooth, and then a substantially opaque thermoplastic injecting into a second portion of the mold cavity. The removable partial dental prosthesis formed includes an artificial tooth supported by a base integrally connected to a clasp, wherein the base includes pigment and is substantially opaque, and the clasp is substantially transparent and effectively without pigment. The invention provides a dental device including thermoplastic polyamide having a Charpy notched impact strength of at least 3.5 ft-lb/in 2. Preferably the polyamide comprises at least 10 percent by weight of micro-crystals having a largest dimension less than 750 nanometers, and has an opacity less than 50%. More preferably the polyamide comprises at least 20 percent by weight of micro-crystals having a largest dimension less than 750 nanometers, and has a Charpy notched impact strength of at least 4.5 ft-lb/in 2, and an opacity less than 40%. Most preferably the polyamide comprises at least 30 percent by weight of micro-crystals having a largest dimension less than 750 nanometers, and has a Charpy notched impact strength of at least 5 and an opacity less than 30%. The polyamide beneficially may have a Charpy notched impact strength of at least 6, and more beneficially may have a Charpy notched impact strength of at least 7. Preferably the device is a denture, partial denture, clasp, splint, or night guard. Preferably the polyamide has an opacity of less than 30 percent. DESCRIPTION OF THE DRAWING FIG. 1 is a cross-section side view of a cartridge container tube enclosing polyamide from a kit for making a partial denture in accordance with the present invention. FIG. 2 is an end view of the cartridge container tube shown in FIG. 1 in accordance with the present invention. FIG. 3 is a cross-section side view of a cartridge plug which is inserted into the plug end of the cartridge container tube in accordance with the present invention. FIG. 4 is an end view of the cartridge plug shown in FIG. 3 in accordance with the present invention. FIG. 5 is a cross-section side view of a cartridge container tube enclosing polyamide from a kit for making a partial denture in accordance with the present invention. FIG. 6 is an end view of the cartridge container tube shown in FIG. 5 in accordance with the present invention. FIG. 7 is a cross-section side view of a cartridge plug from a kit for making a partial denture in accordance with the present invention. FIG. 8 is an end view of the cartridge cap shown in FIG. 7 in accordance with the present invention. FIG. 9 is a view of an injection mold with sprues for use in accordance with the present invention. FIG. 10 is a schematic diagram of a system for making molded dental devices from polyamide enclosed in a cartridge container tube in accordance with the present invention. DESCRIPTION OF THE PREFERRED EMBODIMENT The invention is now described with more particular reference to FIGS. 1-10. With more particular reference to FIGS. 1-4 is seen cartridge container 12 and cartridge plug 14 enclosing nylon pellets 16. Plug 14 is inserted into plug end 18 of container 12. During shipping and storage cartridge container 12 with cartridge plug 14 inserted plug end 18 encloses nylon pellets 16. In use cartridge container 12, cartridge plug 14 and nylon pellets 16 are heated to melt the nylon pellets 16 to form liquid nylon. The liquid nylon is pressed through burstable end 19 into a mold from cartridge container 12. With more particular reference to FIGS. 5-8 is seen cartridge container 22 and cartridge plug 24 enclosing nylon pellets 26. Plug 24 is inserted into plug end 28 of container 22. During shipping and storage cartridge container 22 with cartridge plug 24 inserted plug end 28 encloses nylon pellets 26. Cap 30 is supported by threaded nozzle 36. Nozzle inner wall 38 encloses an output channel. In use cartridge container 22, cartridge plug 24 and nylon pellets 26 are heated to melt the nylon pellets 26 to form liquid nylon. The liquid nylon is pressed through the output channel and burstable end 29 into a mold from cartridge container 22. With more particular reference to FIGS. 9-10 is seen a mold 100 and a system 110 for making molded dental devices 200 from polyamide 26 enclosed in a cartridge container tube 22. Polyamide 26 enclosed in a cartridge container tube 22 is heated in heater 112. Cap 30 is removed from threaded nozzle 36. Threaded nozzle 36 is positioned under ram 120 in guide 122 of press 114 to force burstable end 29 to open the output channel of nozzle inner wall 38 into mold 100 when pressure is applied to polyamide 26 enclosed in a cartridge container tube 22. Mold 100 is supported by metal flask 102. Mold 100 has molded artificial teeth 202 A and 202 supported therein and made of an acrylic interpenetrating polymer network (IPN). Ram 120 is moved down pressing cartridge plug 24 down. As Ram 120 moves down pressing cartridge plug 24 down cartridge container tube 22 is crushed and pressure is applied to heated polyamide 26 pushing polyamide 26 through passage 196, 197 and 198 into a mold cavity wall 199 enclosing a mold cavity within mold 100 to form dental device 200 having molded polyamide 26 and artificial teeth 202. The mold cavity within mold 100 has the shape of dental device 200. Mold 100 is removed from press 114 and metal flask 102. From mold 100 is removed dental device 200 having molded polyamide 26. The transparent polymer used in clasps made in accordance with the invention preferably consists of a permanently transparent, chemical and stress crack resistant, high impact strength, UV and visible light stable, low water sorption, dimensionally stable, highly water resistant, steam sterilizable, semi-crystalline polyamide resin. This resin is beneficially maintains excellent physical properties while remaining permanently clear and colorless. The transparent semi-crystalline polyamide is preferably injection molded using dental flask/stone investment, a compact heating oven together with a low pressure injection molding machine (less than 90 psi) to sequentially fabricate a partial denture containing a “clear” aesthetic clasp attached to a tissue shaded base resin. The base material consists of a pigmented version of the transparent semi-crystalline polyamide resulting in a monolithic prosthetic device. Sequential injection molding of ‘clear’ aesthetic clasps allows for precise replication of waxed clasp design with high-strength, durable thermoplastic resin. Preferably acetal resins are used in sequential injection molding to fabricate clasps. Preferably bases are made of an opaque/pigmented semi-crystalline acetal resin. EXAMPLE 1 23 grams of pellets of transparent crystalline nylon, Lucitone FRS crystalline nylon without pigment are poured into an aluminum container having a threaded end and then a cap is pressed onto the threaded end and supported by the threads on the threaded end of the container. The cylindrical container body is 1 inch in diameter and 3.5 inches in length. The cylindrical container body is 0.005 inch thick. The conical container end extends from the cylindrical container body and is 0.4 inch in length and has a cylindrical nozzle which is 0.375 inch in diameter. The burstable end of the nozzle is 0.4 inch thick. Transparent crystalline nylon Lucitone® FRS™ in the container is useful for injection molding to form temporary, flexible, and monomer free denture base. It is useful for the fabrication of complete or partial removable dentures as well as occlusal splints and night guards. EXAMPLE 2 23 grams of pellets of transparent crystalline nylon, Lucitone® FRS™ crystalline nylon are coated with red pigment. The nylon pellets are poured into an aluminum container having a threaded end and then a cap is pressed onto the threaded end and supported by the threads on the threaded end of the container. The cylindrical container body is 1 inch in diameter and 3.5 inches in length. The cylindrical container body is 0.005 inch thick. The conical container end extends from the cylindrical container body and is 0.4 inch in length and has a cylindrical nozzle which is 0.375 inch in diameter. The burstable end of the nozzle is 0.4 inch thick. Table 1 describes typical properties, of transparent crystalline nylon, Lucitone FRS used in EXAMPLES 1 and 2, and molding temperatures, and injection, heating and cooling times used in EXAMPLE 3. TABLE 1 Type and Class (according to ADA Type III, Class 1 Spec. 12) Storage temperature for powder and liquid 60° F.-90° F. (16° C.-32° C.) Dosage: 1 cartridge (23 g) Processing Time /Temp. (To reach 18 minutes @ 575 F. injectable stage) Injection Time <1 minute Material used to invest wax-up Dental Stone Cool time (prior to deflask) 5 minutes EXAMPLE 3 A partial denture with a transparent clasp is prepared by: Investment and Spruing Soak a cast and wax up of a patients mount in water for 25 minutes prior to investing. Mix investment and embed the cast and wax-up in the lower half of a flask. Using wax sticks, D-shaped Success™ Sprue Wax Sticks (7 mm×180 mm, Item # 904584) injection sprues are built. On upper dentures, attach the sprue to the posterior border of the denture and make sure the sprue is sufficiently wide. For lower full dentures, attach the sprue to both lingual extensions as well as in the mid-line. Then embed the upper half of the flask. Wax Elimination and Separator Application The flask is placed in boiling water for a 4 to 6 minutes to soften the wax. The bolts on the flask are loosened and the Metal Flask Brackets are removed. The flask is opened and the Space Maintainer is removed. Then a boil out procedure is completed to form a clasp mold and the wax is discarded. The flask is placed in boiling water for a 4 to 6 minutes to soften the wax. The bolts on the flask are loosened and the Metal Flask Brackets are removed. The flask is opened and the Space Maintainer is removed. Then a boil out procedure is completed to form a partial denture mold and the wax is discarded. The molds are flushed with clean boiling water. Bevel the stone with a lab knife around the mouth of the sprue. The flask margin and cavities are checked to ensure that both flask halves fit together with intimate metal contact. A thin coat of Al-Cote® Separating Agent is applied to the model and the model is allowed to dry completely. Mechanical retention is added by grinding diatorics into the teeth. Thermoplastic Injection Insert is positioned on one side of the flask and the flask halves are placed under an infrared heat source. Clear Clasp Fabrication The clasp is waxed to full contour, slightly over building the body of the clasp. All excess model is trimmed away, leaving a small core with the clasp attached. Two clasps are fabricated. Investment and spruing are completed. Wax is eliminated. Clear transparent Lucitone® FRS™ crystalline nylon is Injected into the mold to form the clasps while heating. Heating and Injection After removing the cap from a cartridge, formed by following the procedure of EXAMPLE 1, the container of transparent Lucitone FRS crystalline nylon is placed in an injection sleeve to form an assembly. When the container of transparent Lucitone FRS crystalline nylon is placed in an injection sleeve the threaded end of the container is positioned in the injection sleeve to face away from the injection sleeve handle. A sleeve plug is placed into the remaining space in the heating sleeve. The assembly is inserted into a cartridge furnace (preheated to 575° F.) and a timer is set for 18 minutes. While heating the assembly in the furnace for 18 minutes, the flask halves are assembled and placed in front of the Success Injection System manufactured and sold by Dentsply. The sleeve assembly is removed from the furnace and positioned on top of the flask such that the threaded end of the container fits into the opening of a thermoplastic injection insert to form a combination. The combination is then slid into the Success Injection System and the piston is engaged to press the transparent Lucitone FRS crystalline nylon from the container into the clasp mold enclosed by the flask. Injection into the mold is complete within one (1) minute. Then the flask and sleeve assembly combination is removed from the Injection system. The heating sleeve is then twisted off of the flask and the used container is expelled from the heating sleeve using a knock out base and knock out rod. The injected flask is deflasked five minutes after injection. The clear clasps are finished to final contour with carbide burrs and the clasps are fitted to denture mold. After removing the cap from a cartridge, formed by following the procedure of EXAMPLE 2, the container of pigmented Lucitone FRS crystalline nylon is placed in an injection sleeve to form an assembly. When the container of pigmented Lucitone FRS crystalline nylon is placed in an injection sleeve the threaded end of the container is positioned in the injection sleeve to face away from the injection sleeve handle. A sleeve plug is placed into the remaining space in the heating sleeve. The assembly is inserted into a cartridge furnace (preheated to 575° F.) and a timer is set for 18 minutes. While heating the assembly in the furnace for 18 minutes, the flask halves are assembled and placed in front of the Success Injection System manufactured and sold by Dentsply. The sleeve assembly is removed from the furnace and positioned on top of the flask such that the threaded end of the container fits into the opening of a thermoplastic injection insert to form a combination. The combination is then slid into the Success Injection System and the piston is engaged to press the pigmented Lucitone FRS crystalline nylon from the container into a partial denture mold enclosed by the flask. Injection into the partial denture mold is complete within one (1) minute. Then the flask and sleeve assembly combination is removed from the Injection system. The heating sleeve is then twisted off of the flask and the used container is expelled from the heating sleeve using a knock out base and knock out rod. The injected flask is deflasked five minutes after injection. Finishing and Polishing The flexible partial denture with a transparent clasp is finished using coarse pumice and polished using Tripoli TM polishing compound and High Shine TM polishing compound. EXAMPLE 4 A full denture is prepared by: Investment and Spruing Soak a cast and wax up of a patients mount in water for 25 minutes prior to investing. Mix investment and embed the cast and wax-up in the lower half of a flask. Using wax sticks, D-shaped Success™ Sprue Wax Sticks (7 mm×180 mm, Item # 904584) injection sprues are built. On upper dentures, attach the sprue to the posterior border of the denture and make sure the sprue is sufficiently wide. For lower full dentures, attach the sprue to both lingual extensions as well as in the mid-line. Then embed the upper half of the flask. Wax Elimination and Separator Application The flask is placed in boiling water for a 4 to 6 minutes to soften the wax. The bolts on the flask are loosened and the Metal Flask Brackets are removed. The flask is opened and the Space Maintainer is removed. Then a boil out procedure is completed to form a clasp mold and the wax is discarded. The flask is placed in boiling water for a 4 to 6 minutes to soften the wax. The bolts on the flask are loosened and the Metal Flask Brackets are removed. The flask is opened and the Space Maintainer is removed. Then a boil out procedure is completed to form a full denture mold and the wax is discarded. The molds are flushed with clean boiling water. Bevel the stone with a lab knife around the mouth of the sprue. The flask margin and cavities are checked to ensure that both flask halves fit together with intimate metal contact. A thin coat of Al-Cote® Separating Agent is applied to the model and the model is allowed to dry completely. Mechanical retention is added by grinding diatorics into the teeth. Thermoplastic Injection Insert is positioned on one side of the flask and the flask halves are placed under an infrared heat source. After removing the cap from a cartridge, formed by following the procedure of EXAMPLE 2, the container of pigmented Lucitone FRS crystalline nylon is placed in an injection sleeve to form an assembly. When the container of pigmented Lucitone FRS crystalline nylon is placed in an injection sleeve the threaded end of the container is positioned in the injection sleeve to face away from the injection sleeve handle. A sleeve plug is placed into the remaining space in the heating sleeve. The assembly is inserted into a cartridge furnace (preheated to 575° F.) and a timer is set for 18 minutes. While heating the assembly in the furnace for 18 minutes, the flask halves are assembled and placed in front of the Success Injection System manufactured and sold by Dentsply. The sleeve assembly is removed from the furnace and positioned on top of the flask such that the threaded end of the container fits into the opening of a thermoplastic injection insert to form a combination. The combination is then slid into the Success Injection System and the piston is engaged to press the pigmented Lucitone FRS crystalline nylon from the container into adenture mold enclosed by the flask. Injection into the denture mold is complete within one (1) minute. Then the flask and sleeve assembly combination is removed from the Injection system. The heating sleeve is then twisted off of the flask and the used container is expelled from the heating sleeve using a knock out base and knock out rod. The injected flask is deflasked five minutes after injection. Finishing and Polishing The flexible denture is finished using coarse pumice and polished using Tripoli TM polishing compound and High Shine TM polishing compound. TABLE 2 shows physical properties of the products of Examples 3 and 4 and. The products of Examples 3 and 4 have more than 50 percent greater Charpy notched impact strength than commercially marketed dental products. TABLE 2 Examples Property 3 and 4 Formulation Microcrytalline polyamide Tensile strength (psi) 9000 Tensile Modulus (psi) 232000 Flexural Strength (psi) 9300 Flexural Modulus (psi) 200000 Charpy notched ft-lb/in 2 7.6 Charpy unnotched No break Specific Gravity 1.06 Melt point C. 248 Glass transition T g C 155 Melt flow (g/10 min) N/A Water Absorption % 24 hrs.45 It should be understood that while the present invention has been described in considerable detail with respect to certain specific embodiments thereof, it should not be considered limited to such embodiments but may be used in other ways without departure from the spirit of the invention and the scope of the appended claims. | Summary: The invention provides a method of making a removable partial dental prosthesis by molding a removable partial dental prosthesis having a base, an artificial tooth and a clasp. The artificial tooth is supported by said base. The base is integrally connected to the clasp. The base includes pigment and is substantially opaque. The clasp is effectively free of pigment and is substantially transparent. The base is formed to mate with oral mucosa for support of the prosthesis thereon. | 5,974 | 100 | big_patent | en |
Write a title and summarize: SECTION 1. SHORT TITLE. This Act may be cited as the ``Water Pollution Program Improvement Act of 2000''. SEC. 2. FINDINGS. Congress finds the following: (1) Pollutant loadings from both public and private point sources have decreased dramatically since the enactment of the Federal Water Pollution Control Act in 1972 and such reductions have greatly contributed to achieving national water quality goals. (2) Appropriate emphasis on the management of nonpoint source pollution through a variety of flexible management practices is necessary to meet water quality standards and the goals of the Federal Water Pollution Control Act. (3) Comprehensive watershed management strategies (including estuary management programs, source water protection programs, and other voluntary or statutory programs) are important tools in coordinating point source and nonpoint source water quality programs. (4) State and local governments, businesses, and landowners are expected to spend billions of dollars over the next 20 years to implement watershed management strategies and other programs to address nonpoint source pollution. (5) In order to complete the total maximum daily load calculations required for currently identified waters, States will be required to develop one total maximum daily load allocation per week per region for each of the next 15 years at an estimated cost to the States ranging from $670,000,000 to $1,200,000,000. (6) States have overwhelmingly cited a lack of credible and reliable data and a lack of the resources necessary to collect and analyze such data, as significant limitations to carrying out their responsibilities under the Federal Water Pollution Control Act, including the identification of impaired waters and the development of total maximum daily loads. (7) The General Accounting Office recently concluded that only 6 States have the majority of data needed to assess the condition of their waters. (8) In cases in which there are no reliable monitoring or other analytical data to support a listing or total maximum daily load allocation, waters of the United States are being identified as impaired and total maximum daily loads are being developed under section 303(d) of the Federal Water Pollution Control Act (33 U.S.C. 1313(d)) on the basis of anecdotal evidence. The data used are frequently not subject to quality assurance or quality control measures. (9) Any Federal regulatory or nonregulatory water quality management program-- (A) must be based on sound science, including credible and reliable monitoring data; (B) must be subject to rigorous cost analysis; (C) must be effectively and efficiently implemented; and (D) must have the strong support of affected stakeholders, including State and local governments, landowners, businesses, environmental organizations, and the general public. (10) Any Federal water quality management program or initiative must recognize and accommodate-- (A) State water rights allocations and management programs; (B) the clear distinction between point and nonpoint sources of pollution provided in the Federal Water Pollution Control Act (33 U.S.C. 1251 et seq.); and (C) the exclusive authority of the States to regulate nonpoint sources of pollution. SEC. 3. NATIONAL ACADEMY OF SCIENCES STUDY. (a) Study Required.--The Administrator of the Environmental Protection Agency shall make arrangements with the National Academy of Sciences to conduct a study on-- (1) the scientific basis underlying the development and implementation of total maximum daily loads for pollutants in waters identified under section 303(d)(1)(A) of the Federal Water Pollution Control Act (33 U.S.C. 1313(d)(1)(A)); (2) the costs of implementing measures to comply with the total maximum daily loads; and (3) the availability of alternative programs or mechanisms to reduce the discharge of pollutants from point sources and to reduce pollution from nonpoint sources to achieve water quality standards. (b) Scope.--The study shall include an evaluation of the following: (1) The scientific methodologies (including water quality monitoring and monitoring plans) that are being used by States to identify waters under section 303(d)(1)(A) of the Federal Water Pollution Control Act (33 U.S.C. 1313(d)(1)(A)) and to develop and implement total maximum daily loads for pollutants in such waters, and the costs associated with the methodologies. (2) Any procedures or programs that are being implemented by States and Federal agencies to coordinate and improve monitoring methodologies and the quality of monitoring data. (3) The availability of alternative programs and other regulatory or nonregulatory mechanisms (including Federal, State, and local programs that operate as a functional equivalent to the total maximum daily load program) that may achieve comparable environmental benefits in an impaired water, watershed, or basin. (4) The results achieved by regulatory and voluntary programs, activities, and practices that are being implemented to reduce nonpoint source pollution and the costs of such programs, activities, and practices to State and local governments and the private sector. (5) The feasibility of implementing a pollutant trading program between point sources and nonpoint sources of pollution. (6) An assessment of the total costs (including the costs to Federal land management agencies, State and local governments, and the private sector) associated with programs to reduce the discharge of pollutants from point sources to meet water quality standards on waters currently identified under section 303(d)(1)(A) of the Federal Water Pollution Control Act (33 U.S.C. 1313(d)(1)(A)) and with programs to reduce pollution from nonpoint sources in such waters under section 319 of such Act (33 U.S.C. 1329). (c) Peer Review.--Before submitting a report under subsection (d), the National Academy of Sciences shall provide appropriate Federal, State, and private sector interests an opportunity to review and submit written comments on the report. (d) Report.--Not later than 18 months after the date of enactment of this Act, the National Academy of Sciences shall submit a report on the study to the Administrator of the Environmental Protection Agency, the Committee on Transportation and Infrastructure of the House of Representatives, and the Committee on Environment and Public Works of the Senate. The report shall include recommendations of the National Academy of Sciences for improving the methodologies evaluated under the study, as well as any recommendations received pursuant to subsection (c) that are not otherwise incorporated into the report. (e) Authorization of Appropriations.--There is authorized to be appropriated to carry out this section $5,000,000. Such sums shall remain available until expended. SEC. 4. RULEMAKING. (a) Proposed Rules Defined.--In this section, the term ``proposed rules'' means the Proposed Revisions to the National Pollutant Discharge Elimination System Program and Federal Antidegradation Policy and the Proposed Revisions to the Water Quality Planning and Management Regulations Concerning Total Maximum Daily Loads, published in the Federal Register on August 23, 1999. (b) Consideration of Study.--Before making a final determination with respect to the proposed rules, the Administrator of the Environmental Protection Agency shall-- (1) review the report submitted by the National Academy of Sciences under section 3(d) and incorporate, as appropriate, into the proposed rules the recommendations contained in the report, including recommendations received pursuant to section 3(c); and (2) publish in the Federal Register and receive public comment on-- (A) the recommendations described in paragraph (1) that were incorporated into the proposed rules; and (B) the recommendations described in paragraph (1) that were not incorporated into the proposed rules, including an explanation of why the recommendations were not incorporated. (c) Effect on Proposed Rules.--The Administrator shall not make a final determination on the proposed rules identified in subsection (a) until the conclusion of the public notice and comment period provided under subsection (b)(2). (d) Prohibited Actions.--Except as specifically provided by an Act enacted after the date of enactment of this Act, to ensure that States continue to have exclusive authority to regulate nonpoint sources of pollution-- (1) the Administrator shall not take any action to affect any definition of, or distinction made between, point sources and nonpoint sources of pollution contained in a rule of the Environmental Protection Agency in effect on June 1, 2000; and (2) the Administrator shall not require approval of any measures set forth by a State to control nonpoint sources of pollution pursuant to the Federal Water Pollution Control Act (33 U.S.C. 1251 et seq.), except as authorized by section 319 of such Act (33 U.S.C. 1329). | Title: Water Pollution Program Improvement Act of 2000 Summary: Requires the Administrator, before making a final determination with respect to the Proposed Revisions to the National Pollutant Discharge Elimination System Program and Federal Antidegradation Policy and the Proposed Revisions to the Water Quality Planning and Management Regulations Concerning Total Maximum Daily Loads of August 1999, to: (1) review the NAS report and incorporate recommendations into the proposed revisions; and (2) publish in the Federal Register and receive public comment on incorporated recommendations and those that weren't incorporated, with an explanation why they were not incorporated. Bars the Administrator from making such final determination until the conclusion of the public notice and comment period. Prohibits the Administrator, for purposes of ensuring that States continue to have exclusive authority to regulate nonpoint sources of pollution, from: (1) taking any action to affect any definition of, or distinction made between, point and nonpoint sources of pollution contained in an EPA rule in effect on June 1, 2000; and (2) requiring approval of any measures set forth by a State to control nonpoint sources of pollution pursuant to the Federal Water Pollution Control Act, except as authorized under specified provisions regarding nonpoint source management programs. | 1,971 | 266 | billsum | en |
Write a title and summarize: SECTION 1. SHORT TITLE. This Act may be cited as the ``Technology Education and Training Act of 2001''. SEC. 2. CREDIT FOR INFORMATION TECHNOLOGY TRAINING PROGRAM EXPENSES. (a) In General.--Subpart B of part IV of subchapter A of chapter 1 of the Internal Revenue Code of 1986 is amended by adding at the end the following: ``SEC. 30B. INFORMATION TECHNOLOGY TRAINING PROGRAM EXPENSES. ``(a) General Rule.--In the case of a taxpayer engaged in a trade or business during the taxable year, there shall be allowed as a credit against the tax imposed by this chapter for such taxable year an amount equal to 100 percent of information technology training program expenses of the taxpayer and any employee of the taxpayer paid or incurred by the taxpayer during such taxable year. ``(b) Limitation.-- ``(1) In general.--The amount of information technology training program expenses with respect to any individual which may be taken into account under subsection (a) for the taxable year shall not exceed $1,500. ``(2) Increase in credit amount for participation in certain programs and for certain individuals.--The dollar amount in paragraph (1) shall be increased (but not above $2,000) by the amount of information technology training program expenses paid or incurred by the taxpayer-- ``(A) with respect to a program operated-- ``(i) in an empowerment zone or enterprise community designated under part I of subchapter U or a renewal community designated under part I of subchapter X, ``(ii) in a school district in which at least 50 percent of the students attending schools in such district are eligible for free or reduced-cost lunches under the school lunch program established under the National School Lunch Act, ``(iii) in an area designated as a disaster area by the Secretary of Agriculture or by the President under the Disaster Relief and Emergency Assistance Act in the taxable year or the 4 preceding taxable years, ``(iv) in a rural enterprise community designated under section 766 of the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act, 1999, ``(v) in an area designated by the Secretary of Agriculture as a Rural Economic Area Partnership Zone, ``(vi) in an area over which an Indian tribal government (as defined in section 7701(a)(40)) has jurisdiction, or ``(vii) by an employer who has 200 or fewer employees for each business day in each of 20 or more calendar weeks in the current or preceding calendar year, or ``(B) in the case of an individual with a disability. ``(c) Information Technology Training Program Expenses.--For purposes of this section-- ``(1) In general.--The term `information technology training program expenses' means expenses paid or incurred by reason of the participation of the taxpayer (or any employee of the taxpayer) in any information technology training program if such expenses lead to an industry-accepted information technology certification for the participant. Such term shall only include includes expenses paid for in connection with course work and certification testing which is essential to assessing skill acquisition. ``(2) Information technology training program.--The term `information technology training program' means a program for an industry-accepted information technology certification-- ``(A) by any information technology trade association or corporation, and ``(B) which-- ``(i) is provided for the employees of such association or corporation, or ``(ii) involves-- ``(I) employers, and ``(II) State training programs, school districts, university systems, higher education institutions (as defined in section 101(b) of the Higher Education Act of 1965), or certified commercial information technology training providers. ``(3) Certified commercial information technology training provider.-- ``(A) In general.--The term `certified commercial information technology training provider' means a private sector organization providing an information technology training program which leads to an approved information technology industry certification for the participants. ``(B) Approved industry certification.--For purposes of paragraph (1), an information technology industry certification shall be considered approved if such certification is approved by the Secretary, in consultation with the Information Technology Training Certification Advisory Board. ``(d) Denial of Double Benefit.--No deduction or credit under any other provision of this chapter shall be allowed with respect to information technology training program expenses taken into account for the credit under this section. ``(e) Certain Rules Made Applicable.--For purposes of this section, rules similar to the rules of section 45A(e)(2) and subsections (c), (d), and (e) of section 52 shall apply. ``(f) Application With Other Credits.--The credit allowed by subsection (a) for any taxable year shall not exceed the excess (if any) of-- ``(1) the regular tax for the taxable year reduced by the sum of the credits allowable under the subpart A and the previous sections of this subpart, over ``(2) the tentative minimum tax for the taxable year.''. (b) Clerical Amendment.--The table of sections for subpart B of part IV of subchapter A of chapter 1 of the Internal Revenue Code of 1986 is amended by adding at the end the following: ``Sec. 30B. Information technology training program expenses.''. (c) Effective Date.--The amendments made by this section shall apply to amounts paid or incurred in taxable years beginning after December 31, 2001. SEC. 3. INFORMATION TECHNOLOGY TRAINING CERTIFICATION ADVISORY BOARD. (a) Establishment.--There is established an Information Technology Training Certification Advisory Board (in this section referred to as the ``Board''). (b) Membership.--The Board shall be composed of not more than 15 members appointed by the Secretary of the Treasury from among individuals-- (1) associated with information technology certification and training associations and businesses; and (2) who are not officers or employees of the Federal Government. (c) Meetings.--The Board shall meet not less often than annually. (d) Chairperson.-- (1) In general.--Subject to paragraph (2), the Board shall elect a Chairperson from among its members. (2) Chairperson.--The chairperson shall be an individual who is a member of an information technology industry trade association. (e) Duties.--The Board shall develop a list of information technology industry certifications, for approval by the Secretary of the Treasury, that qualify the provider of the certification as a certified commercial information technology training provider under section 30B(c)(3) of the Internal Revenue Code of 1986, as added by section (2)(a). (f) Submission of List.--Not later than October 1, 2001, and each year thereafter, the Board shall submit the list required under subsection (e) to the Secretary of the Treasury. (g) Board Personnel Matters.-- (1) Compensation of members.--Each member of the Board shall serve without compensation. (2) Travel expenses.--Each member of the Board shall be allowed travel expenses, including per diem in lieu of subsistence, at rates authorized for employees of agencies under subchapter I of chapter 57 of title 5, United States Code, while away from their homes or regular places of business in the performance of services for the Board. (h) Termination of the Board.--Section 14(b) of the Federal Advisory Committee Act (5 U.S.C. App.) shall not apply to the Board. SEC. 4. HOPE SCHOLARSHIP AND LIFETIME LEARNING CREDITS INCLUDE TECHNOLOGY TRAINING CENTERS. (a) In General.--Section 25A(f)(2) of the Internal Revenue Code of 1986 (relating to eligible educational institution) is amended to read as follows: ``(2) Eligible educational institution.--The term `eligible educational institution' means-- ``(A) an institution-- ``(i) which is described in section 101(b) of the Higher Education Act of 1965, and ``(ii) which is eligible to participate in a program under title IV of such Act, or ``(B) a certified commercial information technology training provider (as defined in section 30B(c)(3)).''. (b) Conforming Amendment.--The second sentence of section 221(e)(2) of the Internal Revenue Code of 1986 is amended by striking ``section 25A(f)(2)'' and inserting ``section 25A(f)(2)(A)''. (c) Effective Date.--The amendments made by this section shall apply to taxable years beginning after December 31, 2001. | Title: A bill to amend the Internal Revenue Code of 1986 to allow a credit against income tax for information technology training expenses and for other purposes Summary: Technology Education and Training Act of 2001 - Amends the Internal Revenue Code to: (1) allow a limited tax credit for information technology training program expenses; and (2) make technology training centers eligible educational institutions for purposes of the Hope scholarship and lifetime learning credits.Establishes an Information Technology Training Certification Advisory Board, which shall develop provider certifications for certified commercial information technology training. | 2,070 | 116 | billsum | en |
Write a title and summarize: SECTION 1. SHORT TITLE. This Act may be cited as the ``Childcare Accountability and Responsibility Act of 2012'' or the ``CARE for Kids Act of 2012''. SEC. 2. REQUIREMENT OF A CRIMINAL BACKGROUND CHECK. The Child Care and Development Block Grant Act of 1990 (42 U.S.C. 9858 et seq.) is amended by inserting after section 658G the following new section: ``SEC. 658H. REQUIREMENT OF A CRIMINAL BACKGROUND CHECK. ``(a) Criminal Background Check.-- ``(1) Requirement of a criminal background check.--A State and national criminal background check for an individual who is a child care staff member, a family child care provider, or an adult who resides in the home of a family child care provider is required in any State that receives funds under this subchapter. The criminal background check of such individual shall include-- ``(A) a search of the National Sex Offender Registry established pursuant to the Adam Walsh Child Protection and Safety Act of 2006 (42 U.S.C. 16901 et seq.); ``(B) a search of the National Crime Information Center; ``(C) a search of the State criminal registry or repository in the State in which the individual resides and each State where such individual previously resided; ``(D) a search of State-based abuse and neglect registries and databases, including the abuse and neglect registries and databases of each State where the individual previously resided; and ``(E) a Federal Bureau of Investigation fingerprint check using the Integrated Automated Fingerprint Identification System. ``(2) Ineligibility.--A child care provider or family child care provider shall be ineligible for funds provided under this subchapter if a criminal background check of a child care staff member, a family child care provider, or an adult permitted to reside in such a family child care provider's private residence reveals an adult felony conviction for-- ``(A) child abuse or neglect; ``(B) spousal abuse; ``(C) a crime against children (including child pornography); ``(D) a violent crime, including-- ``(i) physical assault or battery; ``(ii) rape; ``(iii) sexual assault; or ``(iv) homicide; or ``(E) distribution of, possession with intent to distribute, or importation of a controlled substance committed within 5 years prior to submission to a criminal background check. ``(3) Submittal of requests.--Subject to paragraph (4), a child care provider or a family child care provider shall submit a request for a State and national criminal background check to the appropriate State agency designated by the State-- ``(A) with respect to an individual who became a child care staff member or family child care provider, or an adult who began to reside in the private residence of such a provider, before the date of the enactment of the Child Care Accountability and Responsibility Act of 2012-- ``(i) not later than the date under subsection (b) in which a State implements the requirements of this section; and ``(ii) during each 5-year period following the first submission date under this subparagraph for such staff member, family provider, or adult; and ``(B) with respect to an individual who is a prospective child care staff member or family child care provider, or an adult who begins to reside in the private residence of such a provider, on or after the date of the enactment of such Act-- ``(i) prior to the date the individual becomes a child care staff member, a family child care provider, or such adult begins to reside in such residence; and ``(ii) during each 5-year period following the first submission date under this subparagraph for such staff member, family provider, or adult. ``(4) Limitation on requests.--Not more than 1 request for a State and national criminal background check under paragraph (3) is required for any child care staff member, family child care provider, or adult who resides in the private residence of such provider, for each 5-year period described in such paragraph. ``(5) Results.-- ``(A) In general.--Not later than 10 business days after the date on which a request under this section is made for a State and national criminal background check and is received by the appropriate State agency, such agency shall provide the results of the criminal background check to the individual or entity that made such a request. ``(B) Copy of background check.--A State shall provide to a child care provider or an individual subject to a background check under this section, upon request, a copy of the criminal background check conducted pursuant to this section. ``(6) Accuracy of information.--A State shall reasonably attempt to insure that the information included in the background check conducted pursuant to this section is accurate and complete by-- ``(A) obtaining dispositions of arrests that occurred more than 1 year prior to the date that such background check was requested; ``(B) correcting information included that it knows, or reasonably should know, is inaccurate; ``(C) completing incomplete entries, if possible; and ``(D) taking any other steps that would improve upon the accuracy or such information. ``(7) Appeals.-- ``(A) In general.--Not later than 30 days after receipt of the results of a criminal background check conducted pursuant to this section, a child care provider or an individual subject to a background check under this section may appeal such results to the appropriate State agency designated by the State. ``(B) Final ruling by a state.--Not later than 30 days after an appeal is made under subparagraph (A), a State shall-- ``(i) make a determination on the eligibility or ineligibility of the individual; ``(ii) provide the individual with specific findings with respect to the appeal; ``(iii) if possible, promptly make any changes to the individual's criminal record, if any information was inaccurate or incomplete; and ``(iv) report those changes to the individual who requested such appeal. ``(8) Fees.--To defray the costs of carrying out the duties described in this subsection, a State may collect one fee per criminal background check from a child care provider or family child care provider in an amount not to exceed the actual costs to the State for the administration of all required criminal background checks, and such fee for all required criminal background checks may not exceed a total of $36. ``(b) State Compliance.-- ``(1) Time limitation.--A State shall implement the requirements of this section not later than 3 years after the date of the enactment of the Childcare Accountability and Responsibility Act of 2012. ``(2) Extension of time.--The Secretary may grant an extension to the date described in paragraph (1), not longer than 2 years, to a State that makes a good faith effort to satisfy the requirements of this section. ``(c) Definitions.--In this section: ``(1) Adult.--The term `adult' means a person who has attained 18 years of age. ``(2) Child care provider.--The term `child care provider' means a center-based child care provider, a group home child care provider, or other provider of child care services for compensation and on a regular basis (other than a family child care provider) that-- ``(A) is not an individual who is related to all children for whom child care services are provided; and ``(B) is licensed, regulated, or registered under State law or receives funds provided under this subchapter. ``(3) Child care staff member.--The term `child care staff member' means an individual that provides child care services for compensation and on a regular basis (other than an individual who is related to the child or children for whom services are provided), regardless of whether the services are provided for a child care provider or a family child care provider. ``(4) Family child care provider.--The term `family child care provider' means one individual who-- ``(A) provides child care services for fewer than 24 hours per day, as the sole caregiver, in a private residence; ``(B) is not an individual who is related to all children for whom child care services are provided; and ``(C) is licensed, regulated, or registered under State law or receives funds provided under this subchapter. ``(d) Authorization of Appropriations To Conduct Criminal Background Checks.--There are authorized to be appropriated such sums as necessary to offset the administrative costs to conduct State and national criminal background checks under this section.''. | Title: To require a criminal background check for employees of child care providers, family child care providers, and adults who reside in the private residences of family child care providers in States that receive funds from the Child Care and Development Block Grant Program, and for other purposes Summary: Childcare Accountability and Responsibility Act of 2012 or the CARE for Kids Act of 2012 - Amends the Child Care and Development Block Grant Act of 1990 to require a national criminal background check for an individual who is a child care staff member, a family child care provider, or an adult who resides in the home of a family child care provider in any state that receives funds from the Child Care and Development Block Grant Program. Requires that such background check include: (1) a search of the national Sex Offender Registry, the National Crime Information Center, state criminal registries, and state-based abuse and neglect registries and databases; and (2) a Federal Bureau of Investigation (FBI) fingerprint check. Makes a child care provider ineligible for Program funds if the criminal background check reveals an adult felony conviction of any such individual for: (1) child abuse or neglect; (2) spousal abuse; (3) a crime against children (including child pornography); (4) a violent crime; or (5) distribution, possession with intent to distribute, or importation of a controlled substance committed within the previous five years. Allows: (1) a child care provider or an individual subject to a background check to appeal the results to the appropriate designated state agency, and (2) a state to collect a fee from providers for such background checks to defray costs. | 2,025 | 359 | billsum | en |
Summarize: Police officers pepper sprayed a black teenager in his white foster parents' home after they mistook him for a burglar, authorities have said. Cops responded to the home in Fuquay-Varina, North Carolina after a neighbor saw 18-year-old DeShawn Currie entering his family's home through an unlocked side door. The teenager, who moved in with the Tyler family a year ago, said he was stunned when three police officers entered the home and demanded to know who he was. 'They was like, "Put your hands on the door",' DeShawn told WTVD. 'I was like, "For what? This is my house." I was like, "Why are y'all in here?"' Scroll down for video. Hurt: DeShawn Currie, 18, said police officers profiled him when they thought he was a burglar in his white foster parents' house. He said he became angry when they told him he wasn't part of the family. The police officers demanded his ID - which showed a different address - and refused to believe he was part of the family because he was not in any of the pictures on the mantelpiece in the home. Police said they used pepper spray on the teenager when he 'became profane, threatening and belligerent' and'refused to follow instructions' from officers. Stacy Tyler, DeShawn's foster mother, arrived back home to find the police officers there and told them that the teenager was her foster son. Mrs Tyler and her husband, Ricky Tyler, have three other young children. 'He's my baby boy just as much as my other three children are,' Stacy told WTVD of DeShawn. Saddened: His foster parents, Ricky and Stacy Tyler, said they thought of DeShawn as their own son. Part of the family: Cops demanded to know why DeShawn, who joined the family last year, was not in any photos on the mantelpiece if he claimed to be part of the family. It caused him to get angry, he said. The family moved into their new home in July and don't know all their neighbors, the Tylers said. But they were hurt that someone had assumed DeShawn was up to no good - and the teenager said the incident had made him feel less comfortable. 'I had moved into my room, and I'm feeling like I'm loved,' he said. 'Then when they come in and they just profile me and say that I'm not who I am - and that I do not stay here because there was white kids on the wall. That really made me mad.' Police said there had been a spate of crimes in the area recently, but did not specifically say how many or what kind. Scene: The family moved into this home in July and they do not know all their neighbors yet, they said. One neighbor called 911 after seeing DeShawn enter the home and assumed that he was a burglar. A police spokeswoman did not respond when asked specifically about what instructions Currie did not follow. Police also have not said how many officers entered the home, their length of service with the department or their race. Currie was treated by medical personnel at the scene, police said. No charges were filed. See below for video | Summary: Neighbors in Fuquay Varina, North Carolina called cops after seeing DeShawn Currie, 18, enter his family's home through an unlocked door. When officers entered the home, they refused to believe the teen lived there - and demanded to know why he didn't appear in any family photos. DeShawn has been with the family for about a year; they recently moved to the neighborhood and do not yet know all their neighbors. When the teen became angry, officers pepper sprayed him. | 726 | 115 | cnn_dailymail | en |
Summarize: Background FDA is responsible for the safety and quality of domestic and imported pharmaceutical products under the Federal Food, Drug, and Cosmetic Act. Specifically, FDA’s Center for Drug Evaluation and Research (CDER) establishes standards for the safety, effectiveness, and manufacture of prescription pharmaceutical products and over-the-counter medications. CDER reviews the clinical tests and manufacture of new pharmaceutical products before they can be approved for the U.S. market, and it regulates the manufacture of pharmaceutical products already being sold to ensure that they comply with federal statutes and regulations, including current “good manufacturing practice” (GMP). GMP requirements are federal standards for ensuring that pharmaceutical products are high in quality and produced under sanitary conditions. In addition, CDER enforces the act’s prohibitions against the importation of adulterated, misbranded, and counterfeit pharmaceutical products. CDER regulates the manufacture of pharmaceutical products by requesting that FDA’s Office of Regulatory Affairs (ORA) inspect manufacturers both at home and abroad to ensure that pharmaceuticals are produced in conformance with GMPs. ORA manages investigators located in FDA’s 21 district offices. Approximately 375 investigators and 75 microbiologists and chemists conduct inspections of foreign pharmaceutical manufacturers. ORA’s investigators inspect manufacturers that produce pharmaceuticals in finished form as well as manufacturers that produce the active ingredients used in finished pharmaceutical products. Typically, ORA investigators travel abroad for about 3 weeks at a time during which they inspect approximately three manufacturers. Each inspection ranges from 2 to 5 days in length, depending on the number and types of products inspected. In fiscal year 1996, FDA reviewed the results of 287 inspections of foreign pharmaceutical manufacturers conducted by its investigators in 35 countries (see figure 1). About 70 percent of these inspections were performed in manufacturing facilities that produce the active ingredients used in finished pharmaceutical products. CDER requests that ORA’s investigators conduct inspections for three reasons. First, CDER requests pre-approval inspections to ensure that before a new drug application is approved, the manufacturer of the finished pharmaceutical product as well as each manufacturer supplying a bulk pharmaceutical chemical used in the finished pharmaceutical product comply with GMPs. Each step in the manufacture and processing of a new drug, from the sources of raw materials to final packaging must be approved by FDA. Second, CDER requests postapproval or routine surveillance inspections to periodically assess the quality of marketed pharmaceutical products. During these inspections, investigators verify that manufacturers of finished pharmaceutical products and bulk pharmaceutical chemicals comply with GMPs. Third, CDER requests for-cause inspections when it receives information indicating problems in the manufacture of approved pharmaceutical products. In addition, CDER requests for-cause inspections of manufacturers that were not in compliance with GMPs during previous inspections. In for-cause inspections, FDA investigators determine whether the manufacturer has improved its production processes to comply with GMPs. During an inspection, the ORA investigator examines the pharmaceutical manufacturer’s production processes, product packaging and labeling processes, product contents, warehouse practices, quality control, laboratories, recordkeeping systems, and other manufacturing practices. The investigator reports observations of significant objectionable conditions and practices that do not conform to GMPs on the list-of-observations form, commonly referred to as FDA form 483. At the end of the inspection, the investigator gives a copy of the form 483 to the highest ranking management official present at the manufacturing facility. The investigator also discusses the observations on the form 483 with the firm’s management to ensure that they are aware of any deviations from GMPs that were observed during the inspection and suggests that the manufacturer respond to FDA in writing concerning all actions taken as a result of the observations. Figure 2 shows FDA’s process for managing foreign pharmaceutical inspections. After returning to the district office, the investigator prepares an establishment inspection report that describes the manufacturing operations observed during the inspection and any conditions that may violate federal statutes and regulations. The investigator also recommends whether the manufacturer is acceptable to supply pharmaceutical products to the United States. The investigator’s district office formally endorses the recommendation after reviewing the inspection report to determine if it supports the proposed recommendation. The district office forwards its endorsement along with the investigator’s establishment inspection report and the form 483 to CDER. The foreign inspection team within CDER’s Office of Compliance reviews the documentation and the manufacturer’s written response to FDA about any corrective actions taken. CDER then decides whether the manufacturer complies with GMPs. Inspections of pharmaceutical manufacturers are classified in one of three categories. As table 1 shows, during fiscal year 1996, 238 inspections (or 83 percent) revealed deviations from GMPs. Of these, CDER determined that 46 inspections revealed deviations from GMPs that ranked in the most serious (or “official action indicated”) category. When CDER classifies a foreign pharmaceutical inspection as “official action indicated” (OAI), it sends the manufacturer an enforcement letter. CDER issues two types of enforcement letters: untitled letters and warning letters. CDER issues an untitled letter to a foreign manufacturer when the inspection was conducted as part of its review of a new drug application and the manufacturer has not previously been inspected and accepted to supply approved pharmaceutical products to the United States. The untitled letter notifies the manufacturer that its manufacturing process does not comply with federal statutes and regulations and that failure to take corrective action may result in the disapproval of any new drug application on which the manufacturer is listed. CDER issues a warning letter to a foreign manufacturer when a subsequent inspection of its facility is classified as OAI. Warning letters are issued to manufacturers that are already supplying approved pharmaceutical products to the United States. Warning letters indicate that serious manufacturing deficiencies can and are affecting commercially marketed products. The warning letter notifies the manufacturer of its violation of federal statutes and regulations and that failure to take corrective action may result in further FDA enforcement action. CDER issued 17 untitled letters and 19 warning letters to foreign pharmaceutical manufacturers in fiscal year 1996. If CDER classifies an inspection as OAI and believes the manufacturer’s product is adulterated because it was not produced in compliance with GMPs, CDER can instruct the district offices to cooperate with the U.S. Customs Service in detaining the manufacturer’s product when it is offered for entry into the United States. In such a situation, the warning letter may also threaten to detain the manufacturer’s products at U.S. entry points or notify the manufacturer that detention will occur. Customs, which controls the points where foreign shipments enter the United States, ensures that adulterated pharmaceutical products are either exported from the United States or destroyed. In fiscal year 1996, CDER determined that the pharmaceutical products made by two foreign manufacturers should be detained. Timeliness of Inspection Reports Has Improved, but Delays in Taking Prompt Enforcement Actions Continue FDA’s 1988 internal evaluation found that delays in the submission of final inspection reports by investigators made it difficult for FDA to take prompt enforcement action against foreign manufacturers that did not comply with federal regulations that ensure the safety, purity, and quality of pharmaceutical products. Since then, FDA has taken several actions that have reduced the average time required by investigators to submit foreign inspection reports to headquarters. Despite this improvement, only about a quarter of the warning letters FDA issued in fiscal year 1996 to foreign pharmaceutical manufacturers found to have serious deficiencies met FDA’s timeliness standards. The lack of prompt enforcement action may impair FDA’s ability to prevent foreign manufacturers from exporting contaminated or adulterated pharmaceutical products to the United States. FDA Has Acted to Improve the Timeliness of Enforcement Actions FDA’s 1988 internal evaluation of its foreign inspection program reported that the average length of time required from the completion of an inspection to CDER’s receipt of a final report was slightly more than 3 months. Delays in submitting inspection reports may hinder CDER’s ability to initiate timely enforcement actions to prevent contaminated or adulterated products from entering the United States. To reduce these delays, the evaluation recommended that FDA explore new ways of processing inspection reports. To strengthen its enforcement strategy, FDA revised its timeliness standards for new drug applications in October 1991 by requiring investigators and districts to submit all inspection reports classified as OAI or “voluntary action indicated” (VAI) to CDER within 30 work days of completing inspections. FDA also revised its enforcement policy to require CDER to review OAI inspection reports containing recommendations for warning letters and issue the letters within 15 work days. According to FDA officials, additional changes were made to help investigators submit more timely inspection reports on foreign manufacturers. In the early 1990s, FDA reduced the length of foreign inspection trips from about 6 to 3 weeks as well as the number of inspections an investigator conducted during the trip. The agency also revised inspection requirements for international travel to build time into foreign inspections for investigators to prepare their reports and provided investigators with notebook computers so that they could begin preparing their reports overseas. Inspection Reports Are More Timely, but Many Miss FDA’s Reporting Deadline Although FDA has reduced the average time it takes to submit reports after inspections are completed from slightly more than 3 months to 2, over half of the reports in fiscal year 1996 did not meet FDA’s timeliness standard. Our analysis of 287 foreign inspection reports CDER reviewed during fiscal year 1996 showed that about 42 percent (102) of the inspections that identified GMP deficiencies (either OAI or VAI) were submitted on time or within 30 work days of completing inspections. However, 58 percent (141) of the inspection reports were not timely (see table 2). About half of the inspections with the most serious deficiencies (classified as OAI or requiring official action) were submitted on time and half were not. Most of the OAI inspection reports that were submitted to CDER after the 30-day deadline were submitted within 60 work days. CDER received about one-third of the inspection reports with less serious deficiencies (classified as VAI, allowing foreign manufacturers to voluntarily make corrections) on time; two-thirds were late. FDA reported more recently that its analysis of fiscal year 1997 data showed a modest improvement in the submission times for OAI and VAI inspection reports. FDA reported that in its analysis of 230 foreign inspection reports reviewed during fiscal year 1997, about 47 percent (75) of the inspections that identified GMP deficiencies (either OAI or VAI) were submitted on time. However, 53 percent (85) of the inspection reports were not timely. Our review of inspection reports for China and India showed that regardless of the seriousness of the GMP deficiencies found, CDER did not receive the majority of the inspection reports within the 30-work day requirement. Specifically, 22 of the 36 OAI and VAI inspection reports (61 percent) we reviewed for China and India were not submitted on time. Although there was no one reason for the late submissions, CDER officials told us that an investigator may return to the United States 3 weeks after conducting his first inspection, making it impossible for him or her to submit an inspection report within 30 work days. Some investigators told us that the paperwork, which includes preparing numerous documents and exhibits to support the deficiencies observed, is time-consuming. In addition, after returning to their district offices, some investigators stated that they are often confronted with competing demands on their time, such as responding to problems with domestic pharmaceutical manufacturers. FDA Enforcement Actions Still Take Too Long Although FDA established a 15-work-day standard for issuing warning letters, about one out of four warning letters issued by CDER during fiscal year 1996 was issued on time. The extent of these delays can be significant. For example, CDER took 4 months (80 work days) to issue a warning letter to one Chinese manufacturer inspected in September 1994. In the inspection report, received by CDER 2 months after the inspection, the investigator noted 20 significant deviations from U.S. GMPs and wrote that the manufacturer was incapable of producing the injectable pharmaceutical product for which it was seeking approval. The investigator wrote that “Virtually all of the processing equipment for the first phases of processing is filthy, in extreme state of disrepair, and was removed during this inspection.” Despite the severity of the inspection findings, it was not until March 1995 that CDER sent a warning letter to the manufacturer. As shown in table 3, it took more than 15 work days to issue 23 of the 30 warning letters sent to foreign pharmaceutical manufacturers. After receiving the inspection reports from investigators, it took CDER between 21 and 148 work days to issue the 23 late warning letters, with an average of 57 work days. According to a CDER official, CDER experienced staffing shortages during the period we examined that delayed the review of incoming foreign inspection reports. More recently, FDA reported that its analysis of fiscal year 1997 data showed a substantial improvement in the time CDER spent in processing warning letters. FDA reported that 30 percent or 3, of the 10 warning letters issued to foreign pharmaceutical manufacturers during fiscal year 1997 were sent within 15 work days. On average, FDA issued the 10 warning letters in about 24 work days. However, compared with the number of warning letters issued during fiscal year 1996, FDA issued two-thirds fewer warning letters during fiscal year 1997. Our analysis of inspections conducted in China and India between January 1, 1994, and May 15, 1996, showed that CDER did not issue any of the six warning letters within the agency’s 15-work-day standard. The number of work days from CDER’s receipt of inspection reports to the issuance of these warning letters ranged from 24 to 86 days, with an average of 40 days. In one case, a February 1994 inspection of a plant in India making an antibacterial agent identified serious problems, including failure to ensure that the proper manufacturing process was followed and inadequate testing of impurities in the product and water used by the plant. The investigator also found that two deficiencies identified during a 1985 FDA inspection had not been fully corrected to meet U.S. quality standards.Given the significance of the deficiencies found during the 1994 inspection, the investigator and his district office recommended that CDER (1) not approve the new drug application, (2) advise FDA district offices to deny entry into the United States of any pharmaceutical products from this manufacturer, and (3) pursue additional enforcement actions against pharmaceutical products from the manufacturer that were already distributed in the United States. Notwithstanding the seriousness of the problems or the recommended enforcement action, it took 2 years for CDER officials to determine that they had not taken any enforcement action against this foreign manufacturer. While CDER officials agreed with the district recommendation and planned to issue a warning letter, the letter was never sent to this foreign pharmaceutical manufacturer because CDER lost track of it during staffing changes. In March 1996, CDER officials determined that they had allowed this foreign manufacturer to continue shipping already approved bulk pharmaceutical products to the United States, even though the inspection had identified manufacturing problems such as unacceptable impurity testing procedures, no periodic review of the production process, and the failure to investigate product yields that were lower than the specified amount. In another case, it took CDER about 3 months to issue a warning letter to a foreign pharmaceutical manufacturer operating with 17 serious GMP deficiencies. FDA inspected this foreign manufacturer in April 1995, after receiving several new drug applications listing the manufacturer as a supplier of bulk pharmaceutical chemicals for use in U.S. finished drug products. The investigator found that the manufacturer did not have an appropriate impurity testing system and identified questionable results from impurity testing. The investigator believed that these questionable results represented a deliberate attempt to conceal instances in which the pharmaceutical products contained higher levels of impurities than permitted by U.S. standards. As a result, the investigator and his district office recommended that CDER not approve the new drug applications and that it issue a warning letter to the manufacturer. Notwithstanding the serious nature of the investigator’s findings, it took ORA about 2 months to submit the inspection report to CDER and another month for CDER to review the report. On August 1, 1995, slightly more than 3 months after the inspection, CDER issued a warning letter stating that it would not approve any applications listing this foreign pharmaceutical manufacturer as a supplier. During the time it took CDER to act on the serious deficiencies and possible fraud identified by the investigator, a U.S. finished-drug manufacturer discovered that several containers labeled as a bulk pharmaceutical chemical product from the same foreign manufacturer contained an herbicide rather than a bulk chemical. FDA Verifies Corrective Actions in Only About Half the Cases in Which Serious Deficiencies Are Identified Members of the Congress and industry representatives have been concerned about the consistency of FDA inspections and subsequent enforcement actions taken against domestic and foreign pharmaceutical manufacturers. In FDA’s 1993 internal evaluation, these concerns were attributed to differences in how field investigators and headquarters staff evaluated foreign inspection results and determined the appropriate follow-up activity. Moreover, the internal evaluation acknowledged that there was a perception that FDA relied on foreign facilities to correct manufacturing deficiencies because there were insufficient resources to conduct follow-up inspections to confirm that corrective actions had been implemented. Our analysis of the foreign inspection reports reviewed during fiscal year 1996 showed that in about half the instances in which field staff concluded that the severity of inspection findings warranted a reinspection, headquarters disagreed. For domestic manufacturers with a history of serious GMP manufacturing problems, FDA typically conducts a reinspection to verify that promised corrective actions have been implemented. However, current FDA policy does not address the need for verifying the corrective actions of foreign pharmaceutical manufacturers in instances in which FDA headquarters downgrades the severity of inspection findings. As a result of downgrading, FDA conducted far fewer reinspections of foreign manufacturers than was recommended by its investigators. Without reinspections, FDA cannot adequately verify that foreign manufacturers have corrected serious deficiencies that could affect the safety, purity, and quality of their pharmaceutical products. FDA’s 1993 Internal Review Identified Differences in the Evaluation of Inspection Findings That Affected the Frequency of Reinspections In the 1993 internal discussion paper, FDA managers found that agency headquarters’ personnel downgraded the severity of the manufacturing deficiencies identified in foreign inspections and the need for reinspecting violative foreign manufacturers. However, they stated that FDA did not downgrade the severity of inspection findings for domestic manufacturers that had similar deficiencies. According to the review, this was caused by different FDA units being responsible for reviewing and evaluating inspection results and planning reinspections of foreign and domestic pharmaceutical manufacturers to verify corrective actions. The discussion paper identified several instances in which approval of new drug applications was withheld, based on significant GMP deficiencies discovered during domestic inspections, whereas similar deficiencies found at foreign manufacturing facilities resulted in the approval of applications. In the discussion paper, FDA managers stated that differences between the evaluations of foreign and domestic inspection results existed for two reasons. First, unlike for domestic inspections, decisions regarding the severity of the manufacturing deficiencies identified during foreign inspections are made by CDER staff rather than by the field investigators who actually conducted the inspections and their district office managers who endorse their recommendations. Second, they indicated that a perception existed that FDA has too few resources to conduct a reinspection of a foreign manufacturer to verify that corrections have been made. According to the review, this leads CDER staff to “trust” a foreign manufacturer to correct serious manufacturing deficiencies. The review described several instances in which significant GMP deficiencies at foreign facilities received little or no enforcement action, while similar deficiencies at domestic facilities resulted in product recalls or application denials. To correct this problem, the discussion paper recommended that district offices, where the investigators are located, rather than CDER be responsible for evaluating the results of foreign inspections and determining the appropriate enforcement action, including the need for reinspecting the manufacturer. FDA officials disagreed with the assertion that its inspection and enforcement programs were applied disparately to domestic and foreign pharmaceutical manufacturers. Further, they argued that district offices already had this responsibility. CDER Often Downgrades Investigators’ Recommended Classifications of Inspection Findings Our analysis of FDA computer data of foreign inspection reports reviewed during fiscal year 1996 showed that CDER and field investigators often disagree on the classification of inspection findings and the severity of the enforcement action that should be taken against foreign pharmaceutical manufacturers when GMP deficiencies are found. For 82 of the 287 foreign inspections reviewed during this period, field investigators concluded that the severity of the GMP deficiencies they observed warranted that CDER initiate official action against the manufacturers. The investigators’ district offices also endorsed their classifications of these inspections and their recommendations for enforcement action before these were forwarded along with the inspection reports and the form 483s to CDER. However, CDER officials downgraded the inspection classifications and recommendations for enforcement action in 41 of these inspections, based on foreign manufacturers’ promises to implement corrective actions. CDER officials decided that rather than OAI, 40 of these inspections should be classified as VAI and 1 should be classified as “no action indicated” (NAI). Conversely, CDER officials upgraded the field investigators’ classifications and recommendations for enforcement action in 11 foreign inspections and classified them OAI rather than VAI. In instances in which inspections found serious GMP deficiencies but CDER downgraded the inspection classifications, FDA’s procedures allow foreign manufacturers to continue exporting pharmaceutical products to the United States without reinspections to evaluate whether they comply with U.S. quality standards. The classification of an inspection determines to a large degree whether a reinspection is conducted. The OAI classification is the most serious and requires FDA to reinspect the manufacturer to verify that it has improved its production processes to comply with GMPs. When CDER does not accept the investigators’ recommendations and classifies inspections as VAI rather than OAI, foreign manufacturers are allowed to voluntarily correct their deficiencies and respond in writing to FDA about the corrections made. FDA officials have acknowledged that they sometimes base their downgrades of inspection classifications and approvals of new drug applications on foreign manufacturers’ promises to implement corrective actions. They contend that during the next inspection, whenever it may be, FDA confirms that the corrections were made. Our analysis of FDA computer data of foreign inspection reports reviewed during fiscal year 1997 showed that CDER and field investigators continue to disagree on the classification of inspection findings and the severity of the enforcement action that should be taken against foreign pharmaceutical manufacturers when GMP deficiencies are found. For 49 of the 230 foreign inspections reviewed during this period, field investigators concluded that the severity of the GMP deficiencies they observed warranted that CDER initiate official action against the manufacturers. However, CDER officials downgraded the inspection classifications and recommendations for enforcement action in 32 of these inspections. CDER officials decided that rather than classify these inspections OAI, 32 of the 49 inspections (65 percent) should be classified VAI. CDER officials also upgraded the field investigators’ classifications and recommendations for enforcement action for two foreign inspections and classified them OAI rather than VAI. FDA officials believe that in some instances the agency can adequately verify that foreign manufacturers have corrected serious deficiencies without reinspecting them. They said that foreign pharmaceutical manufacturers nearly always respond in writing concerning corrective actions taken as a result of the observations listed on the FDA form 483. They said that these responses typically include copies of the manufacturer’s documentation of the corrective actions taken, such as photographs, laboratory test results, and corrected manufacturing procedures. Consequently, FDA officials said they can evaluate a manufacturer’s corrective actions to ensure the safety, purity, and quality of its pharmaceutical products without conducting a reinspection based on the deficiencies found, the documentation provided, and the manufacturer’s history of implementing corrective action. While we recognize that there may be instances in which documentation could suffice to verify the correction of manufacturing deficiencies, inspections of facilities in China and India that we reviewed give instances in which such documentation may not have been sufficient. A pre-approval inspection of a bulk drug manufacturer in India found several deficiencies in the procedures used to test impurity levels in the product being manufactured. Although ORA personnel recommended withholding approval of the new drug application until corrective actions had been implemented, CDER changed the final inspection classification based on its review of the manufacturer’s written explanation of the actions it was taking to correct the deficiencies identified during the inspection. CDER did not request a reinspection to verify that the corrective actions had been taken, even though FDA documents raised questions about the trustworthiness of the manufacturer. According to these documents, FDA had been notified several years earlier that this manufacturer had informed the U.S. Department of Commerce that it was no longer making a particular pharmaceutical product, despite evidence that the manufacturer was still shipping the product to the United States. In another case, FDA conducted a for-cause inspection of a bulk pharmaceutical manufacturer in India to investigate reports that the manufacturer was using chloroform in its manufacturing process (a substance that had been found at higher than acceptable levels in the bulk pharmaceutical chemical). While the investigators found that the manufacturer was no longer using chloroform, they identified other deficiencies in how the company was measuring the impurities present in other bulk drug products that an FDA chemist characterized as “incompetence bordering on fraud.” The investigators recommended from these deficiencies that the manufacturer be considered an unacceptable source of bulk pharmaceutical chemicals. CDER disagreed with this recommendation after reviewing the manufacturer’s response to the investigators’ findings and accepted the manufacturer as a supplier of bulk pharmaceutical chemicals without verifying that it had corrected deficiencies in its impurity testing procedures. FDA Conducts Infrequent Routine Inspections of Foreign Pharmaceutical Manufacturers FDA’s 1988 and 1993 internal evaluations found that while FDA routinely conducted surveillance inspections of domestic pharmaceutical manufacturers, foreign manufacturers were typically inspected only when they were listed in new drug applications. The evaluations concluded that this practice, which FDA said was because of limited resources, was unreasonable and unfair to domestic manufacturers. In addition, FDA’s 1993 evaluation concluded that in the absence of reinspections, FDA could not adequately verify that foreign manufacturers corrected deviations from GMPs that had been observed during prior FDA inspections. Both evaluations recommended that FDA increase the frequency of its inspections of foreign manufacturers that supply approved pharmaceutical products to the United States. FDA has authority to inspect foreign pharmaceutical manufacturers exporting their products to the United States under the Food, Drug, and Cosmetic Act. The purpose of the foreign inspection program is to ensure that internationally manufactured pharmaceutical products meet the same GMP standards for quality, safety, and efficacy that are required of domestic manufacturers. However, FDA is not required to inspect foreign pharmaceutical manufacturing facilities every 2 years as it is required by statute to do for domestic pharmaceutical manufacturers that must be registered with the agency. Enforcing GMP compliance through routine surveillance inspections is FDA’s most comprehensive program for monitoring the quality of marketed pharmaceutical products. FDA also uses routine surveillance inspections to verify that manufacturers have corrected all less-serious GMP deficiencies that were observed in prior FDA inspections. Each year, FDA classifies about 65 percent of its foreign pharmaceutical inspections as VAI, which means that deviations from GMPs were found but they were not serious enough to warrant FDA intervention to ensure that corrections were made. In such instances, manufacturers agree to voluntarily correct any manufacturing procedures that do not comply with U.S. GMPs. FDA’s foreign inspection program has been predominantly a pre-approval inspection program—that is, most inspections of foreign manufacturers occur only when they are listed in new drug applications, with no routine follow-up thereafter. We found that the majority of FDA’s foreign inspections of pharmaceutical manufacturers were conducted to ensure that before a new drug application was approved, each manufacturer listed as a supplier of a bulk pharmaceutical chemical used in the manufacture of the finished pharmaceutical product had been inspected within the previous 2 years and found to comply with GMPs. During fiscal year 1995, about 80 percent of FDA’s foreign inspections were of pharmaceutical manufacturers listed in new drug applications. The remaining 20 percent consisted of routine surveillance inspections of accepted foreign pharmaceutical manufacturers. Consequently, FDA had few opportunities to verify that foreign pharmaceutical manufacturers had implemented prescribed corrective actions in response to prior inspections where less-serious GMP deviations were observed and were producing pharmaceutical products in compliance with GMPs. FDA officials could not tell us how often accepted foreign manufacturers are inspected. FDA has inspected about 1,100 pharmaceutical manufacturers since the foreign inspection program began in 1955. For each fiscal year from 1990 through 1996, FDA conducted about 100 routine surveillance inspections of accepted foreign pharmaceutical manufacturers annually. At this rate, assuming that resources for the program remain constant, FDA will inspect each accepted foreign pharmaceutical manufacturer only once every 11 years, provided it is not listed on a new drug application. Of the 39 inspections we reviewed for pharmaceutical manufacturers in China and India from January 1, 1994, through May 15, 1996, 11 (28 percent) were routine inspections of manufacturers producing approved pharmaceutical products rather than inspections conducted as part of FDA’s review of new drug applications. On average, we found that approximately 4 to 5 years elapsed between routine inspections of manufacturers in China and India producing approved pharmaceutical products for the U.S. market, more than twice FDA’s 2-year inspection requirement for domestic pharmaceutical manufacturers. FDA Plans to Conduct More Routine Inspections of Foreign Pharmaceutical Manufacturers In June 1997, FDA’s foreign inspection working group proposed a strategy for scheduling more routine surveillance inspections of accepted foreign pharmaceutical manufacturers. Led by the Deputy Commissioner of Operations, the group was asked to review the program and identify areas for improvement. The working group found that serious deviations from GMPs were identified more often in foreign pre-approval inspections (42 percent), compared with 18 percent at U.S. manufacturers. They concluded that by relying primarily on pre-approval inspections, FDA did not provide the necessary assurance that imported pharmaceutical products were manufactured in compliance with GMPs. The foreign inspection working group proposed that FDA’s foreign inspection program include more routine surveillance inspections and fewer pre-approval inspections. To accomplish this, they suggested that FDA conduct fewer pre-approval inspections of accepted foreign manufacturers. Instead, they recommended that FDA use information from routine surveillance inspections in approving new drug applications in which accepted foreign manufacturers are listed. Recognizing that FDA does not have sufficient resources for frequent inspections of all foreign manufacturers of pharmaceutical products imported into the United States, the working group proposed using risk-based criteria to prioritize the foreign manufacturers that FDA inspects. FDA’s four-tier surveillance inspection strategy would vary the frequency of routine surveillance inspections depending on the public health risk associated with an accepted foreign manufacturer of an approved pharmaceutical product. Foreign pharmaceutical manufacturers whose prior inspections found serious deviations from GMPs would be placed in tier 1 and inspected annually. Routine surveillance inspections of all other foreign pharmaceutical manufacturers would vary from 3 to 6 years. Foreign manufacturers of pharmaceutical products that pose higher public health risks, such as sterile pharmaceutical products, would be placed in tier 2 and inspected every 3 years. Foreign manufacturers producing 10 or more pharmaceutical products for the U.S. market and those producing nonsterile bulk ingredients used in sterile finished pharmaceutical products would be placed in tier 3 and inspected every 5 years. All other foreign pharmaceutical manufacturers would be placed in tier 4 and inspected every 6 years (see table 4). The working group estimated that when the strategy is fully implemented, 60 percent of FDA’s foreign inspections will be routine surveillance inspections. The remaining 40 percent will be inspections of foreign pharmaceutical manufacturers listed in new drug applications. FDA began implementing its four-tier surveillance inspection strategy in fiscal year 1997 by including routine surveillance inspections within its pre-approval inspections. FDA reported that 151 of the 230 foreign pharmaceutical inspections conducted during fiscal year 1997 (66 percent) were classified pre-approval and routine surveillance inspections. In addition, FDA planned to conduct routine surveillance inspections of about 150 accepted foreign pharmaceutical manufacturers placed in tiers 1 and 2. This group includes manufacturers that produce sterile pharmaceutical products and manufacturers that had prior inspections that revealed serious deviations from GMPs. FDA reported, however, that it conducted only 60 inspections of these manufacturers. As a result, although FDA conducted more routine surveillance inspections, most foreign pharmaceutical inspections still are limited predominantly to manufacturers listed in new drug applications rather than those considered high risk. In developing its new four-tier surveillance inspection strategy, however, FDA did not include all foreign pharmaceutical manufacturers that it should consider for a routine surveillance inspection. According to FDA data, about 3,200 foreign manufacturers have submitted information to FDA listing the pharmaceutical products that they intend to export to the United States. However, FDA prioritized for routine surveillance inspections only the 1,100 foreign pharmaceutical manufacturers that it had previously inspected. Consequently, FDA’s scheduling strategy does not account for almost two-thirds of the foreign manufacturers that may be exporting pharmaceutical products to the United States. Moreover, according to the FDA official in charge of developing the surveillance inspection strategy, FDA may never inspect the majority of foreign manufacturers placed in tiers 3 and 4. However, while FDA has recognized that it does not have sufficient resources to routinely inspect all foreign manufacturers of pharmaceutical products imported into the United States, its strategy does not ensure that every foreign manufacturer exporting pharmaceutical products to the United States complies with U.S. quality standards. Serious Problems Persist in Managing Foreign Inspection Data Although both FDA’s 1988 and 1993 internal evaluations identified serious problems in its foreign inspection data systems, the agency still lacks a comprehensive, automated system for managing its foreign inspection program. Instead, the information FDA needs to identify the foreign pharmaceutical manufacturers it is responsible for inspecting, manage its foreign inspection workload, and monitor inspection results and enforcement actions is contained in 15 different computer systems, very few of which are integrated. As a result, essential foreign inspection information is not readily accessible to the different FDA units that are responsible for planning, conducting, and reviewing inspections and taking enforcement actions against foreign manufacturers. While FDA’s working group recently proposed several actions that FDA officials hope will correct these data system problems, they have not been implemented. Lack of Comprehensive Automated Information System Inhibits Effective Management of Foreign Inspection Data FDA’s 1988 internal evaluation found that its automated field management information system did not contain complete information for 37 percent of the foreign inspections that FDA conducted during fiscal years 1982 through 1987. Specifically, the Program Oriented Data System (PODS) did not contain the results of 673 of the 1,813 foreign inspections that FDA investigators had conducted during this period. Moreover, the system did not contain any data for 251 of these inspections (14 percent). The evaluation attributed the missing inspection results to PODS not being updated after CDER’s review and classification of the inspection reports. The evaluation recommended that FDA revise its procedures for entering foreign inspection data in PODS. FDA’s 1993 internal evaluation found that essential data on foreign pharmaceutical manufacturers were not readily accessible to agency personnel. The evaluation indicated that comprehensive data for a foreign pharmaceutical manufacturer should include (1) its inspection history, (2) the results of its last FDA inspection, (3) the identification of responsible company personnel, (4) its U.S. agent or representative, (5) the products that it supplied to the United States, and (6) the domestic manufacturers and distributors that it supplied. The evaluation found that comprehensive foreign inspection information could be obtained only by searching multiple computerized databases and FDA headquarters’ files. For example, the evaluation noted several instances in which ORA investigators conducting domestic inspections suspected that U.S. manufacturers had received adulterated bulk pharmaceutical chemicals from foreign manufacturers. However, the investigators’ efforts to substantiate these suppositions were hampered because they could not readily gain access to comprehensive data for foreign pharmaceutical manufacturers. The evaluation recommended that FDA use its field management information system to provide agencywide access to complete data for all foreign manufacturers shipping pharmaceutical products to the United States. In 1994, FDA began using a new information system to support the foreign inspection program. The Travel and Inspection Planning System (TRIPS) was specifically developed to assist FDA’s foreign inspection planning staff in managing foreign inspection assignments and the program’s budget. TRIPS is also used to monitor whether the inspection report has been completed as well as the results of the inspection. However, TRIPS is accessible to only ORA headquarters staff. As a result, foreign inspection data are not readily accessible to the different FDA units responsible for conducting foreign inspections and reviewing inspection results. FDA plans to make data from TRIPS more broadly available within the agency when it upgrades its field management information system in fiscal year 1998. TRIPS and PODS have not significantly improved the quality of FDA’s foreign inspection data. Our analysis of data recorded in TRIPS and PODS disclosed that these systems did not contain the results of 111 of the 759 inspections (15 percent) FDA conducted of foreign pharmaceutical manufacturers between January 1, 1994, and May 15, 1996. For 68 of the 111 inspections, the database did not identify the foreign manufacturer that was inspected. TRIPS and PODS also did not include the correct inspection results for 10 of the 39 pharmaceutical manufacturers FDA inspected in China and India during this period. Specifically, the inspection results were missing for two of these manufacturers and were incorrect for eight others. The database errors in recording the results of inspections conducted in China and India occurred because the systems were not updated after CDER staff reviewed and classified the inspection reports. Without complete and accurate data, FDA cannot ensure that all “high-risk” foreign pharmaceutical manufacturers are targeted for more frequent routine surveillance inspections. We also found that essential foreign inspection data are not readily accessible to the different FDA units responsible for planning and conducting domestic and foreign inspections, and conducting import operations. The information that FDA needs for identifying foreign pharmaceutical manufacturers, verifying their compliance with federal laws and regulations, and screening foreign-produced pharmaceutical products for importation is dispersed among 15 automated databases, most of which do not interface. FDA’s multiple and unlinked databases inhibit the effective management of the foreign inspection program by impeding the flow of foreign inspection data to agency personnel for use in screening foreign pharmaceutical products offered for entry into the United States. For example, table 5 illustrates how the lack of linkage between 8 of FDA’s 15 databases not being linked impedes the flow of essential foreign inspection data. The first four databases described in the table are used by FDA’s district offices to support import operations. The four other databases described in the table are used by FDA headquarters staff for monitoring foreign pharmaceutical manufacturers’ compliance with federal statutes and regulations. However, because these systems do not interface, comprehensive data about foreign manufacturers are not readily available to FDA district personnel screening imported pharmaceutical products. Consequently, much of the same data must be retrieved from one automated system to be manually entered into others. Moreover, staff must search multiple data systems to obtain a comprehensive profile of a foreign pharmaceutical manufacturer. FDA also cannot easily match foreign manufacturers that have listed with the agency with their compliance status and the pharmaceutical products that are imported into the United States. FDA’s foreign inspection working group concluded in June 1997 that the agency continues to be plagued by having too many databases that do not automatically interface. FDA is relying on a new automated field management information system to provide agencywide accessibility to comprehensive foreign inspection data. The Field Accomplishments and Compliance Tracking System is expected to replace approximately 22 computerized databases and support automated interfaces with several existing databases. The first installment of FACTS, which is to include an inventory of foreign and domestic pharmaceutical manufacturers, is scheduled to go on line during fiscal year 1998. FDA also plans to develop additional FACTS components to assist the agency in managing its foreign inspection workload and compliance activities. These components will be included in the second installment of FACTS, which is scheduled for fiscal year 1999. Incomplete List of Foreign Manufacturers Shipping Drugs to the United States Hinders Inspection Planning FDA’s 1988 internal evaluation found that the agency did not maintain an inventory of all foreign pharmaceutical manufacturers that were subject to FDA regulation. At that time, the only computerized file of foreign manufacturers shipping pharmaceutical products to the United States was maintained on a personal computer that could be accessed only from within one FDA unit. The file listed the foreign pharmaceutical manufacturers that FDA had inspected and the results of the last inspection. The internal evaluation concluded that this file was inadequate because it did not contain an inspection history for each foreign pharmaceutical manufacturer that had advised FDA that it intended to ship pharmaceutical products to the United States. As a result, FDA could not ensure that it was aware of, and therefore inspecting, all foreign pharmaceutical manufacturers that were under its jurisdiction. FDA’s 1988 evaluation recommended that the agency develop a comprehensive inventory of all foreign manufacturers shipping pharmaceutical products to the United States that could be used to improve long-range inspection planning and scheduling. To use resources better and increase knowledge agencywide, the evaluation also recommended that this inventory be available on FDA’s automated field information system. FDA’s 1993 internal evaluation found the same problem. According to the evaluation, the lack of an inventory of the foreign manufacturers that were shipping pharmaceutical products to the United States made it virtually impossible for FDA to inspect foreign manufacturers as frequently as domestic pharmaceutical manufacturers. The evaluation detailed several instances in which a database with a comprehensive history of each establishment’s previous inspections would have assisted in identifying problems in foreign pharmaceutical manufacturers. FDA’s 1993 evaluation recommended that the agency use its automated field information system to develop an accurate and comprehensive inventory of all foreign manufacturers shipping pharmaceutical products to the United States. It remains difficult for FDA to determine the number of foreign manufacturers shipping pharmaceutical products to the United States that should be considered for periodic inspections. Recently, an FDA official told us that the agency had to search four data systems just to determine the number of foreign manufacturers that should be considered for routine postapproval surveillance inspections. They found that the systems did not include a common data element to permit them to easily identify a foreign manufacturer from system to system. Because the names and addresses of foreign manufacturers are sometimes incomplete or inaccurate, FDA officials found that matching data among the systems was an arduous, manual, and inconclusive effort. The June 1997 report by FDA’s foreign inspection working group acknowledged that the agency still lacked a complete list of foreign manufacturers that were shipping pharmaceutical products to the United States. According to the report, about 3,200 foreign pharmaceutical firms were listed with FDA as indicating their intent to ship products to the United States. However, FDA internal databases indicated that only about 1,100 pharmaceutical firms had been inspected by the agency. FDA officials could not explain why the remaining 2,100 firms had not been inspected. The foreign inspection working group proposed two options for developing an official inventory of all foreign manufacturers that ship pharmaceutical products to the United States. One option would be for FDA to seek authority to require foreign pharmaceutical manufacturers to register and update their registration information annually. The other would use data from existing information systems to develop an official establishment inventory of foreign pharmaceutical manufacturers. FDA’s efforts to reconcile data from several of its databases to more accurately estimate the number of manufacturers that it should consider for inspection under its four-tier inspection strategy should identify all foreign manufacturers that are shipping pharmaceutical products to the United States. When completed by April 1998, FDA should have a comprehensive inventory of all foreign manufacturers shipping pharmaceutical products to the United States. This information could then be used to improve FDA’s planning and scheduling of foreign pharmaceutical inspections. Conclusions Since 1955, FDA has inspected foreign pharmaceutical manufacturing facilities to ensure that drug products exported to the United States meet the same standards of safety, purity, and quality required of domestic manufacturers. However, two internal FDA evaluations in the past 10 years identified serious problems with the foreign inspection program that raised questions about FDA’s ability to ensure that American consumers are protected from contaminated or adulterated drug products. FDA has taken some action to address these problems. However, we found indications that certain aspects of the foreign inspection program still need improvement. FDA continues to experience problems in ensuring that inspection reports are submitted in a timely manner and that necessary enforcement actions are promptly initiated to prevent contaminated and adulterated pharmaceutical products from entering the United States. In addition, when FDA headquarters downgrades the severity of the inspection classifications recommended by field investigators, FDA is not verifying corrective actions that foreign manufacturers have promised to take to resolve serious manufacturing deficiencies. This impairs FDA’s ability to ensure that American consumers are protected from potentially serious health risks posed by adulterated drug products. FDA’s risk-based inspection strategy recognizes that the agency does not have sufficient resources to routinely inspect all foreign manufacturers of pharmaceutical products imported into the United States. However, even though the strategy is intended to direct inspection resources according to risk, FDA’s foreign inspection program continues to be driven by new drug applications and the agency acknowledges that it may never inspect most foreign manufacturers exporting pharmaceutical products to the United States. Recommendations to the Commissioner of the Food and Drug Administration To improve the effectiveness of FDA’s foreign inspection program to ensure that only safe, pure, and high quality drugs are imported into the United States, we recommend that the Commissioner of FDA ensure that serious manufacturing deficiencies are promptly identified and enforcement actions are initiated by requiring investigators to prepare inspection reports and CDER to issue warning letters within established time periods and reexamine and revise FDA’s foreign inspection strategy to provide adequate assurance that all foreign manufacturers exporting approved pharmaceutical products to the United States comply with U.S. standards. At a minimum, the strategy should include (1) timely follow-up inspections of all foreign manufacturers that have been identified as having serious manufacturing deficiencies and that promised to take corrective action and (2) periodic surveillance inspections of all foreign pharmaceutical manufacturers, not just high-risk manufacturers. Agency Comments and Our Response In commenting on a draft of this report, FDA took issue with a number of our findings and recommendations. As discussed earlier, FDA believes it has made substantial improvement in the timeliness of inspection reports and enforcement actions. While we recognize FDA’s progress, we note that the agency is still falling short of its standards for timeliness. As a result, we believe that FDA needs to monitor its investigators and CDER to ensure that they comply with established time periods in preparing inspection reports and issuing warning letters. FDA was critical of our draft on several counts. FDA said we had accepted the recommendations in the 1993 discussion paper without verifying their validity or feasibility. FDA claimed that the findings and recommendations in the 1993 discussion paper were flawed in significant ways that limited its usefulness to the agency. We note, however, that subsequent to the discussion paper, in a 1995 memorandum to the agency’s Assistant Inspector General, FDA officials reported that they had thoroughly reviewed the discussion paper, investigated the issues raised, verified program weaknesses, and had either begun or agreed to implement 10 of the 13 recommendations contained in the discussion paper. FDA also took issue with how our report described the processes followed by its district and headquarters for classifying domestic and foreign inspection reports. Specifically, FDA stated that the review performed by the supervisor or team leader in the district office is not considered to be a district endorsement of the investigator’s recommendation. However, our review of FDA documents that describe the process for classifying domestic and foreign inspection reports supports our characterization. FDA issued guidance to its district offices in September 1996 indicating that beginning in fiscal year 1997, before inspection reports are forwarded to CDER, they “will be reviewed and endorsed by district management consistent with local procedures and timeframes for domestic reports.” Also, in its memorandum to the Assistant Inspector General, FDA officials reported that district offices had began endorsing foreign drug inspection reports before the 1993 discussion paper was issued. FDA did not concur with our recommendation for conducting more frequent inspections of all foreign manufacturers that have been identified as having serious manufacturing deficiencies and have promised to take corrective action. FDA incorrectly suggests that our recommendation was based on the premise that a final classification that is lower than the recommended classification is always wrong if it results in a less-serious classification. Rather, our report questions FDA’s ability to verify the adequacy of some corrective actions that foreign manufacturers promised to take to resolve serious manufacturing deficiencies without reinspecting them. FDA also did not concur with our recommendation regarding the implementation of its routine surveillance inspection strategy. Given further clarification of the strategy, we have modified our recommendation. FDA’s written comments on a draft of this report are reproduced in appendix I. 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A recorded menu will provide information on how to obtain these lists. | Summary: Pursuant to a congressional request, GAO reviewed the Food and Drug Administration's (FDA) efforts to correct problems identified in earlier evaluations of its foreign drug inspection program, focusing on FDA's efforts to: (1) prepare inspection reports and take enforcement actions against foreign pharmaceutical manufacturers in a timely manner; (2) improve the consistency with which FDA evaluates the results of foreign inspections and conducts reinspections to verify that foreign pharmaceutical manufacturers have corrected serious deficiencies; (3) conduct routine inspections of foreign pharmaceutical manufacturers to monitor their compliance with U.S. quality standards; and (4) improve the management of data needed for planning inspections, monitoring inspection results, and taking enforcement actions. GAO noted that: (1) FDA has taken several actions to address problems with its foreign inspection program that were identified in two previous internal evaluations; (2) although FDA has improved the timeliness with which investigators submit inspection reports, in fiscal year (FY) 1996, almost 60 percent were still submitted later than called for by agency standards, including half the reports that identified the most serious deficiencies in manufacturing quality; (3) during FY 1996 and FY 1997, headquarters review personnel continued to downgrade the classifications of inspections recommended by its field investigators who conducted the inspections; (4) most of the decisions to downgrade the classifications were based on foreign manufacturers' promises to implement corrective actions; (5) as a result, FDA conducted fewer reinspections of these facilities to verify that foreign manufacturers had corrected serious manufacturing deficiencies; (6) FDA conducts infrequent routine inspections of foreign manufacturers to ensure that they continue to comply with U.S. quality standards, although routine surveillance inspections constitute FDA's most comprehensive program for monitoring the quality of marketed pharmaceutical products; (7) most inspections of foreign pharmaceutical manufacturers are performed to approve the marketing of new products; (8) routine surveillance inspections of manufacturers producing approved pharmaceutical products already marketed in the United States accounted for only 20 percent of FDA's foreign inspections during FY 1995; (9) as a result, routine inspections of foreign pharmaceutical manufacturers occur with far less frequency than the 2-year interval required for domestic manufacturers; (10) FDA has been striving to improve its management of data needed for planning inspections, monitoring inspection results, and taking enforcement actions; (11) at present, FDA relies on 15 separate systems to identify foreign pharmaceutical manufacturers, plan foreign inspection travel, track inspection results, and monitor enforcement actions; (12) as a result, essential foreign inspection data are not readily accessible to the different FDA units that are responsible for planning, conducting, and reviewing inspections and taking enforcement actions against foreign manufacturers; and (13) FDA is developing a comprehensive, agencywide automated system to provide better data for managing its foreign inspection program. | 11,499 | 632 | gov_report | en |
Write a title and summarize: Condensin-mediated chromosome condensation is essential for genome stability upon cell division. Genetic studies have indicated that the association of condensin with chromatin is intimately linked to gene transcription, but what transcription-associated feature (s) direct (s) the accumulation of condensin remains unclear. Here we show in fission yeast that condensin becomes strikingly enriched at RNA Pol III-transcribed genes when Swd2. 2 and Sen1, two factors involved in the transcription process, are simultaneously deleted. Sen1 is an ATP-dependent helicase whose orthologue in Saccharomyces cerevisiae contributes both to terminate transcription of some RNA Pol II transcripts and to antagonize the formation of DNA: RNA hybrids in the genome. Using two independent mapping techniques, we show that DNA: RNA hybrids form in abundance at Pol III-transcribed genes in fission yeast but we demonstrate that they are unlikely to faciliate the recruitment of condensin. Instead, we show that Sen1 forms a stable and abundant complex with RNA Pol III and that Swd2. 2 and Sen1 antagonize both the interaction of RNA Pol III with chromatin and RNA Pol III-dependent transcription. When Swd2. 2 and Sen1 are lacking, the increased concentration of RNA Pol III and condensin at Pol III-transcribed genes is accompanied by the accumulation of topoisomerase I and II and by local nucleosome depletion, suggesting that Pol III-transcribed genes suffer topological stress. We provide evidence that this topological stress contributes to recruit and/or stabilize condensin at Pol III-transcribed genes in the absence of Swd2. 2 and Sen1. Our data challenge the idea that a processive RNA polymerase hinders the binding of condensin and suggest that transcription-associated topological stress could in some circumstances facilitate the association of condensin. Mitotic chromosome condensation is essential for genome integrity. When defective, chromosomes often remain entangled and fail to segregate properly in anaphase. A key driver of chromosome condensation is the highly conserved condensin complex. Condensin is made of five sub-units (SMC2Cut14, SMC4Cut3, CAP-D2Cnd1, CAP-GCnd3 and CAP-HCnd2, name of the human protein followed by its name in fission yeast) and it is one of the main components of mitotic chromosomes [1]. In vitro, purified condensin can introduce positive supercoils into a relaxed plasmid in the presence of topoisomerase I [2], [3]. These observations support the idea that condensin shapes mitotic chromosomes by changing the topology of chromatin around its binding sites. However, the mechanisms underlying the association of condensin with chromatin remain poorly understood (reviewed in [4]). Several studies have illustrated the paradoxical relationships linking gene transcription and the localization of condensin. From pro- to eukaryotes, condensin is preferentially enriched at highly transcribed genes [5], [6], [7], [8], suggesting that some highly conserved transcription-associated feature (s) that predate (s) the appearance of nucleosomes help to recruit condensin. However, experiments in yeast indicated that RNA polymerases must be silenced before condensin can bind, at least at repetitive sequences such as the rDNA or the sub-telomeres [9], [10]. These somewhat contradictory observations could potentially be reconciled if one hypothesizes that a by-product of the transcription process facilitates the recruitment of condensin. In this study, we have considered that such a by-product could be R-Loops or transcription-associated topological stress. R-Loops result from the formation of stable DNA: RNA hybrids in the genome. As a consequence of the hybridization of the RNA to the template, the non-transcribed strand of the DNA remains single-stranded (reviewed in [11]). Interestingly, the hinge domain of the Smc2/Smc4 heterodimer in condensin shows high affinity in vitro for single-stranded DNA [12], [13]. Moreover, a recent study proposed that chromatin is less accessible to restriction enzymes in mutants where R-Loops accumulate, consistent with the idea that R-Loop formation favours chromatin compaction [14]. Interestingly, fission yeast condensin can disassemble DNA: RNA hybrids in vitro [15] and its chicken counterpart localizes to CpG islands [6], which constitute major R-Loop forming regions in the genome [16]. Taken together, these observations support the idea that R-Loops and condensin could interact functionally in vivo [14]. According to the twin supercoiled domain model, high rates of transcription induce positive supercoiling of the chromatin in front of the elongating polymerase, whilst negative supercoiling accumulate upstream of the polymerase [17]. As such, highly expressed genes represent regions of the genomes that accumulate topological stress. As confirmed in vivo recently, this stress is monitored by topoisomerase I and topoisomerase II [18], [19], [20]. Interestingly, in vitro assays have indicated that condensin binds preferentially to positively supercoiled plasmids in the presence of ATP [21]. Whether or not this transcription-associated topological stress contributes to the binding of condensin in vivo has not been addressed. In order to clarify the functional relationships between transcription and chromosome condensation, we recently carried out a genetic screen in fission yeast to identify deletions of transcription-associated factors that would rescue a condensin deficiency [22]. For this, we isolated loss-of-function mutations that could rescue the thermo-sensitivity of the condensin mutant cut3-477 [23]. Two of the mutations we isolated were the deletions of swd2. 2 (swd2. 2Δ) and sen1 (sen1Δ) [22]. Swd2. 2 is a non-essential component of the Cleavage and Polyadenylation Factor (CPF), the complex responsible for 3′end maturation of RNA Pol II transcripts in yeast (reviewed in [24]), where it acts to maintain the proper levels of CPF-associated phosphatases [22]. Fission yeast Sen1 is the homologue of human Senataxin and has been shown to unwind DNA: RNA hybrids in vitro [25]. Budding yeast Sen1 is involved in transcription termination [26] but its role in fission yeast has not been characterized. Here we show that both factors act directly at Pol III-transcribed genes to limit the association of condensin and the accumulation of topological stress. Furthermore, topological stress at Pol III-transcribed genes facilitates the association of condensin when Swd2. 2 and Sen1 are missing. On their own, the deletions of swd2. 2 (swd2. 2Δ) and sen1 (sen1Δ) partly restored growth of cut3-477 cells at the restrictive temperature (Figure 1A) and reduced the proportion of anaphase cells displaying chromosome segregation defects (Figure 1B). Combining both deletions (sen1Δswd2. 2Δ) resulted in a stronger suppressor effect (Figure 1AB). The double mutant sen1Δswd2. 2Δ also suppressed the other condensin mutant cut14-208 (Figure S1). Strikingly, Chromatin Immunoprecipitation (ChIP) analysis in cycling cell populations showed that the localization of condensin was altered at specific loci when Swd2. 2 and Sen1 were both missing: its recruitment increased significantly at genes transcribed by RNA Pol III (Gln. 04, Met. 07, Ser. 13, Pro. 09, Tyr. 04, Gly. 05,5S rRNA, Arg. 04 on Figure 1C), whereas it was significantly reduced at the rDNA arrays (18S&Rfb2). The binding of condensin remained unaffected at kinetochores (cnt1) or at highly transcribed Pol II genes (Act1, Adh1, Fba1 and SPAC27E2. 11c). The sequences of all the primers used in this study are available on Table S1. The mitotic indexes of both cell populations (swd2. 2+sen1+ and swd2. 2Δsen1Δ) were comparable (Figure 1D), ruling out that the changes in the association of condensin are due to indirect, cell-cycle defects. These data established that Sen1 and Swd2. 2 act to limit the localization of condensin at Pol III-transcribed genes. The reasons why the association of condensin at the rDNA arrays is reduced in the absence of Swd2. 2 and Sen1 will be explained elsewhere. We found previously that Swd2. 2 associates with Pol III-transcribed genes and that lack of Swd2. 2 restored the localization of condensin at Pol III-transcribed genes in the condensin-deficient mutant cut3-477 [22]. Here, we show that Sen1 is also significantly enriched at Pol III-transcribed genes and that its binding is independent of Swd2. 2 (Figure 2A). Furthermore, affinity purification of Sen1 followed by mass-spectrometry analysis of its associated proteins identified most sub-units of the RNA Pol III complex as its most stable binding partners (Table S2). We confirmed this interaction by showing that the RNA Pol III sub-unit Rpc25 co-precipitates with Sen1 (Figure 2B). Note however that Sen1 did not co-precipitate with Sfc6, a sub-unit of TFIIIC (Figure S2), a complex required for the association of RNA Pol III with chromatin [27]. ChIP analysis showed that the association of Rpc25 with chromatin was significantly increased in the absence of Sen1 (Figure S3) or in swd2. 2Δsen1Δ cells (Figure 2C&D). In swd2. 2Δsen1Δ cells, the stabilization of RNA Pol III on chromatin was associated with an increase in the steady-state level of tRNAs, as detected by RT-qPCR analysis (Figure 2E). Taken together, these experiments concur to show that Swd2. 2 and Sen1 play a direct role at Pol III-transcribed genes, where they limit the association of RNA Pol III and the accumulation of transcripts. These results show that the accumulation of condensin at Pol III-transcribed genes in swd2. 2Δsen1Δ cells is concomitant with an enhanced transcriptional activity. It was recently argued that budding yeast Sen1 limits the accumulation of DNA: RNA hybrids, including at Pol III-transcribed genes [28]. Fission yeast Sen1 similarly was shown to display a DNA: RNA helicase activity in vitro [25]. These observations and the additional arguments detailed in the introduction prompted us to test the possibility that R-Loops could represent a transcription by-product facilitating the association of condensin with chromatin. We speculated that lack of Sen1 and Swd2. 2 could result in the accumulation of R-Loops at Pol III-transcribed genes where they might contribute to increase the association of condensin. To establish whether or not R-Loops form at Pol III-transcribed genes in fission yeast, we first monitored by ChIP the chromatin association of RNase H1, one of the endogenous enzymes known to disassemble R-Loops. More specifically, we introduced at the endogenous locus a point mutation (D129N) in the fission yeast RNase H1 (Rnh1), because the same mutation was shown to weaken the catalytic activity of human RNase H1 [29]. Consistent with this, the D129N mutation did stabilize the interaction of Rnh1 with Pol III-transcribed genes (Figure 3A). Furthermore, the interaction of Rnh1D129N with Pol III-transcribed genes was lost upon over-expression in vivo of RnhA, the RNase H1 enzyme from E. coli (Figure 3B). Upon over-expression, RnhA itself did not stably associate with Pol III-transcribed genes (Figure S4), showing that the loss of Rnh1D129N from Pol III-transcribed genes upon over-expression of RnhA cannot be explained by its mere replacement by bacterial RnhA. Finally, Figure S5 shows that the association of Rnh1D129N with the rDNA repeats increased significantly in the absence of topoisomerase I (top1Δ), consistent with the observations reported previously that lack of Top1 triggers the accumulation of R-Loops at rDNA in budding yeast [30]. This confirmed that Rnh1D129N was able to detect significant changes in R-Loop accumulation. Taken together, these data show that ChIP with Rnh1D129N is a reliable way to identify R-Loop forming regions in fission yeast. We sought to confirm the formation of R-Loops at genes transcribed by RNA Pol III using another approach. A method that is commonly used to map R-Loop forming regions in yeast is to perform ChIP using the S9. 6 antibody because of its high affinity for DNA: RNA hybrids [31]. ChIP requires formaldehyde cross-linking followed by sonication of the chromatin. We found that the ability of S9. 6 to detect R-Loops generated after transcription in vitro was greatly diminished both by formaldehyde cross-linking and by sonication (Figure S6). We do not know at this stage whether this is because R-Loops are partly destroyed by these treatments or because these treatments reduce the affinity of the antibody for R-Loops. To circumvent these issues, we extracted genomic DNA from unfixed cells, digested soluble RNA using RNase A and sheared the DNA using a cocktail of restriction enzymes (see Methods). Dot blot analysis using the S9. 6 antibody confirmed that our procedure largely preserved R-Loops (Figure 3C). We then performed DNA: RNA immuno-precipitation (DRIP) using the S9. 6 antibody in stringent conditions, in the presence of 500 mM NaCl. As expected, the DRIP signal at 18S, the canonical R-Loop forming region within the rDNA repeats [30], increased significantly in the absence of RNase H1 and RNase H2 (rnh1Δrnh201Δ cells) and disappeared almost entirely upon treatment of the genomic DNA with commercial RNase H (Figure 3D). On the contrary, the DRIP signal detected at a non-transcribed region NT (chr I, 3009300-3009500, [32]) remained low both in rnh1Δrnh201Δ cells and upon treatment with RNase H. Those controls demonstrated that the signals we detected using DRIP were specific. In agreement with the results obtained using ChIP of Rnh1D129N as a reporter for the presence of R-Loops, we detected strong DRIP signals at Pol III-transcribed genes in the absence of RNase H1 and RNase H2 (Figure 3D). In conclusion, the two methods we have set up to map R-Loop forming regions establish that R-Loops are a prominent feature of Pol III-transcribed genes in fission yeast. Using ChIP of Rnh1D129N, we established that R-Loops accumulate to similar levels at Pol III-transcribed genes in cycling cells (>90% of interphase cells) and in cells synchronized in early mitotis (Figure S7A). Consistent with this, ChIP established that the association of RNA Pol III with chromatin is largely maintained in mitosis (Figure S7B). Taken together these experiments support the idea that transcription at Pol III-transcribed genes is maintained in mitosis, at a time when condensin is loaded on chromosomes in fission yeast. Finally, lack of Swd2. 2 and Sen1 resulted in a small but significant increase in the formation of R-Loops at some but not all Pol III-transcribed genes (Figure S8). Note however that this increase could be due to the fact that Pol III transcription is stimulated in the absence of Swd2. 2 and Sen1 (Figure 2C&D). As such, these observations therefore do not prove that Swd2. 2 and Sen1 antagonize R-Loop formation at Pol III-transcribed genes directly. To establish whether R-Loops at Pol III-transcribed genes could contribute to the accumulation of condensin, we prevented the formation of stable R-Loops by over-expressing RnhA. ChIP analysis showed that over-expression of RnhA did not reduce the amount of condensin recruited at Pol III-transcribed genes in swd2. 2Δsen1Δ cells (Figure 3E) or in wild-type mitotic cells (Figure S9). These data concur to demonstrate that stable, long-lived R-Loops play little or no part in recruiting condensin. Note that over-expression of RnhA did not interfere either with the association of RNA Pol III (Figure S10A) or Sen1 (Figure S10B). Because Xenopus condensin shows greater affinity in vitro for positively supercoiled DNA [21], we speculated that the cue facilitating the accumulation of condensin at Pol III-transcribed genes in the absence of Swd2. 2 and Sen1 could be local topological constraints. Consistent with an increase in topological stress in swd2. 2Δsen1Δ cells, ChIP analysis detected strong accumulation of topoisomerase I (Top1) at most loci (Figure 4A), although the protein levels of Top1 remained unaffected (Figure 4B). We also detected enhanced accumulation of topoisomerase II (Top2), mostly at Pol III-transcribed genes (Figure 4C), when the protein levels of Top2 remained unaffected (Figure 4D). Transcription-associated topological stress was recently shown to destabilize nucleosomes [19]. At some but not all Pol III-transcribed genes that we tested, we detected a significant reduction in the recruitment of histone H3 (Figure 4E) in swd2. 2Δsen1Δ cells, which is consistent with the local depletion of nucleosomes. The concomitant accumulation of Top1 and Top2 and the depletion of nucleosomes suggest that topological stress is greater at Pol III-transcribed genes in swd2. 2Δsen1Δ cells. We speculate that the increased transcription of Pol III-transcribed genes in swd2. 2Δsen1Δ cells could contribute at least in part to this enhanced topological stress. As R-Loops unwind the DNA, it was possible that the abundance of R-Loops formed at Pol III-transcribed genes (Figure 3) could contribute to this topological stress. To test this possibility, we monitored by ChIP the localization of Top2 upon over-expression of RnhA. Surprisingly, the localization of Top2 was not altered at Pol III-transcribed genes upon over-expression of RnhA, whilst it was reduced at the Pol I-transcribed 18S (Figure S11). This suggested that the impact of R-Loop formation on the surrounding chromatin depends on where in the genome R-Loops form. Based on these results, we envisaged two possible models to explain the increased localization of condensin at Pol III-transcribed genes in the absence of Swd2. 2 and Sen1: either the accumulation of Top1 and/or Top2 helps to recruit and/or stabilize condensin, or topological stress facilitates the association of condensin at Pol III-transcribed genes. We previously identified the deletion of Top1 (top1Δ) as a suppressor of cut3-477 [22], suggesting that the accumulation of Top1 that results from lack of Swd2. 2 and Sen1 is unlikely to facilitate the association of condensin with chromatin. Figures 5A&B show that the triple deletion swd2. 2Δsen1Δtop1Δ was a better suppressor of cut3-477 than the double deletion swd2. 2Δsen1Δ. This genetic evidence suggested that failure to monitor topological stress in top1Δ cells might facilitate the association/function of condensin. In support of this, ChIP analysis showed that there was a small but significant increase in the association of condensin at most Pol III-transcribed genes in cells deleted for Swd2. 2, Sen1 and Top1 (swd2. 2Δsen1Δtop1Δ cells) (Figure 5C). Taken together, these data support the following model: the absence of Swd2. 2 and Sen1 increases the transcriptional activity at Pol III-transcribed genes and this might contribute to enhance local topological constraints. These constraints, either directly or indirectly, contribute to recruit or maintain condensin at Pol III-transcribed genes (Figure 5D). To establish whether topological stress was sufficient to stimulate the association of condensin with chromatin, we monitored the association of condensin in the temperature-sensitive Top2 mutant top2-191 ([33]) at the semi-restrictive temperature of 28°C. This analysis showed that the association of condensin was not significantly disrupted in these conditions (Figure S12A). Similarly, lack of Top1 on its own did not significantly impact the association of condensin (Figure S12B). Taken together, these observations suggest that topological stress on its own is not sufficient to stimulate the association of condensin with chromatin. In order to explain that condensin localizes to highly expressed genes from pro- to eukaryotes, whatever the RNA polymerase involved, we first hypothesized that a transcription by-product could facilitate the association of condensin with chromatin (see Introduction). We speculated that this mechanism could represent the ancestral way of recruiting condensin to chromatin. Complementary cis-acting factors would then have evolved to stabilize the interaction of condensin with specific loci, as shown previously (reviewed in [4]). In this study we specifically considered two transcription by-products as potential condensin-attracting features: R-Loop formation and transcription-associated topological stress. Both features have been described both in pro- and eukaryotes and they generate structures (single-stranded DNA and positive supercoiling) for which condensin has been shown to display high affinity in vitro. Our data are not consistent with the idea that stable R-Loops could be involved in recruiting condensin. Similarly, topological stress on its own was not sufficient to disrupt the localization pattern of condensin. However, our data show that topological stress facilitated the association of condensin at Pol III-transcribed genes when Swd2. 2 and Sen1 were missing. These observations are consistent with the recent demonstration that supercoiling at highly expressed genes contributes to the establishment of topological domains and small-range chromosome compaction in Caulaboacter crescentus [34]. How could topological stress create a better binding site for condensin at Pol III-transcribed genes in the absence of Swd2. 2 and Sen1? First, condensin might simply have a higher affinity for supercoiled chromatin, as suggested by the observation that condensin associates preferentially in vitro with positively supercoiled plasmids [21]. Alternatively, or in addition, topological stress might work by facilitating nucleosome eviction [19]. Consistent with the latter, budding yeast condensin associates preferentially with nucleosome-free regions, especially at Pol III-transcribed genes [12]. To explain that lack of Top1 only facilitates the association of condensin at Pol III-transcribed genes when Swd2. 2 and Sen1 are missing, we speculate that the level of topological stress has to go over a certain threshold in order to attract/stabilize condensin. This threshold would be reached in the chromatin around Pol III-transcribed genes when Swd2. 2 and Sen1 are missing but not when Top1 only is missing. The biology of R-Loops is a rapidly expanding field of investigation, and many observations now demonstrate that R-Loops control genome stability and gene expression in multiple ways (reviewed in [35]). It is therefore essential to establish reliable methods to map R-Loop forming regions in genetically tractable organisms such as yeast to address the many functions of R-Loops in vivo. We presented evidence that the commonly used S9. 6 ChIP method to map R-Loop forming regions in yeast is challenged by the fact that R-Loops, or at least their recognition by the S9. 6 antibody, are partly sensitive to formaldehyde cross-linking and sonication. To circumvent this problem, we have developed two reliable alternatives to map R-Loop forming regions in fission yeast. Both of our methods concur to demonstrate that RNA-Pol III transcribed genes are major R-Loop forming regions in fission yeast. R-Loops have also been detected at Pol III-transcribed genes in budding yeast ([28]), suggesting that R-Loop formation is a conserved feature of Pol III transcription, at least in yeast. We would like to argue that the two methods we have set up are complementary: not only do they map R-Loop forming regions but their use in parallel can also give information regarding the stability of R-Loops formed at different loci. Our data show that RNase H1 is most abundant at Pol III-transcribed genes throughout the cell-cycle, suggesting that R-Loops are constantly formed and detected by RNase H1 there. Our data also show that over-expression of RnhA in vivo counter-acts R-Loop formation more efficiently at Pol III-transcribed genes than within the rDNA for example (18S, Figure 3B). On the contrary, DRIP only yields significant signals at Pol III-transcribed genes when RNase H1 and RNase H2 are missing (rnh1Δrnh201Δ cells), whilst the DRIP signals at the rDNA (18S) are significant in wild-type cells, when RNase H1 and RNase H2 are fully active. At Pol III-transcribed genes, DRIP signals increase 10-20 fold in rnh1Δrnh201Δ cells, whilst they only increase ∼3-fold at the rDNA (18S). Our interpretation of these data is that R-Loops formed at 18S are stable and a relatively poor substrate for RNase H1, whilst R-Loops formed at Pol III-transcribed genes are unstable and a good substrate for RNase H1. A corollary to these observations is that DRIP is probably better suited to detect long-lived, stable R-Loops. This might explain why DRIP did not detect significant R-Loop formation at Pol III-transcribed genes in human cells ([16], [36]). We conclude that using both R-Loop mapping methods in parallel could provide indications of the relative stability of R-Loops at different loci. The reasons why R-Loops formed at Pol III-transcribed genes are labile are still unclear but we speculate that R-Loops formed at Pol III-transcribed genes might be smaller than those formed at the 18S because the Pol III transcription units are much smaller. Further studies will be required to understand the consequences of R-Loop formation at Pol III-transcribed genes and how the half-life of an R-Loop might influence its function. R-Loop formation has been shown to be associated with increased phosphorylation of histone H3 on Serine 10 and reduced chromatin accessibility [14]. In turn, the phosphorylation of histone H3 on Serine 10 facilitates the interaction between adjacent nucleosomes, thereby promoting chromatin compaction [37]. We showed previously that to constitutively increase the levels of histone H3 phosphorylated on Serine 10 by deleting PP1 phosphatase (dis2Δ) was not sufficient to significantly improve chromosome segregation when condensin was deficient [22], suggesting that H3-S10-mediated chromatin compaction cannot compensate for the deficiency of condensin. Here we presented evidence that stable R-Loops do not significantly contribute to the recruitment of condensin. Taken together, these observations concur to establish that R-Loop-mediated chromatin compaction is distinct from condensin-mediated chromosome condensation. Our data also suggest that the action of condensin is more fundamental to building a mitotic chromosome than R-Loop-mediated chromatin compaction. Our data have highlighted unexpected ways by which proteins involved in the metabolism of RNA can affect chromosome segregation and genome integrity. Published data demonstrated conclusively that mutations in such factors in general and in Sen1 in particular resulted in chromosome instability (CIN) in yeast, in a mechanism involving R-Loop formation antagonizing replication fork progression ([38], [39] and reviewed in [35]). Here on the contrary, our data show that deletions of two such factors, Swd2. 2 and Sen1, facilitate the segregation and stability of chromosomes when condensin is deficient, in a mechanism that does not require stable R-Loop formation. In addition, our data show that Swd2. 2 and Sen1 keep topological stress under control at Pol III-transcribed genes. We speculate that the enhanced transcription at Pol III-transcription associated with lack of Swd2. 2 and Sen1 could contribute to such stress. However, we cannot exclude the possibility that RNA Pol III-dependent transcription is also defective in other ways that could explain the accumulation of topological stress when Swd2. 2 and Sen1 are missing. The answer to this question will require further studies. Beautiful in vitro approaches demonstrated unequivocally that budding yeast Sen1 contributes to transcription termination of some RNA Pol II transcripts ([26]). It is not yet known whether fission yeast Sen1 has the same function. As fission yeast Sen1 is not essential for viability whilst its budding yeast counterpart is, it is possible that the function of Sen1 has diverged in fission yeast. This idea is supported by our data showing that RNA Pol III is likely to be the most stable binding partner of Sen1 in fission yeast and that Sen1 antagonizes Pol III-dependent transcription. On the contrary, a recent study aimed at identifying the binding partners of RNA Pol III in budding yeast did not identify Sen1, suggesting that the interaction between Sen1 and RNA Pol III is not as stable and/or abundant in budding yeast [40]. Further work is required to understand the function of fission yeast Sen1 at Pol III-transcribed genes. Previous studies had concluded that the inhibition of RNA Pol I or RNA Pol II in mitosis was a pre-requisite for the binding of condensin at repetitive sequences [9], [10], suggesting that a processive RNA polymerase is a hindrance to the binding of condensin on chromatin. Here we challenge this idea by showing that an enhanced recruitment of condensin at Pol III-transcribed genes is associated with an increase in the expression of the same genes. These data show that, at least at Pol III-transcribed genes, an active polymerase is not an obstacle for the binding of condensin. A complete list of all of the strains used in this study is given in Table S3. Standard genetic crosses were employed to construct all strains. Rnh1-GFP, Sen1-GFP, and Top1-3flag were generated using a standard PCR procedure. To obtain Rnh1D129N, Rnh1 was PCR amplified and cloned into pCRII (Life technologies). Site-directed mutagenesis was then used to mutate the residue D129 into N (GAC to AAC) using Quickchange protocols (Stratagene). Overlapping PCR was used to add a C-terminus GFP tag and a cassette of resistance to kanamycin (KanR) to the mutagenized Rnh1 in order to integrate the mutagenized Rnh1 at the endogenous Rnh1 locus. After yeast transformation, proper integrants were selected by PCR and western blot and were sequenced to verify the presence of the mutation. The plasmid over-expressing RnhA tagged with 1xFLAG at its N-terminus was obtained from Eun Shik Choi and Robin Allshire (WTCCB, Edinburgh, UK). In order to stably integrate the plasmid in the genome, it was linearized by digestion with MluI and then transformed in to yeast according to standard procedures. 1,5. 108 cells were treated with 1% formaldehyde (Sigma) at 17°C for 30′. After extensive washes with cold PBS, cells were frozen in liquid Nitrogen. Frozen cells were then broken open using a RETSCH MM400 Mill and then resuspended in cold lysis buffer (Hepes-KOH 50 mM pH 7,5, NaCl 140 mM, EDTA 1 mM, Triton 1%, Na-deoxycholate 0,1%, PMSF 1 mM). The lysats were then sonicated at 4°C using a Diagenode sonicator. Immuno-precipitation was done overnight at 4°C using Protein A-coupled Dynabeads previously incubated with the anti-GFP A11122 antibody (Invitrogen) or using Protein G-coupled Dynabeads previously incubated with the anti-myc 9E10 antibody (Sigma) according to the manufacturer' s instructions. Beads were washed successively with (5′ incubation on rotating wheel): Wash I buffer (20 mM Tris pH 8,150 mM NaCl, 2 mM EDTA, 1% Triton-X100,0, 1% SDS), Wash II buffer (20 mM Tris pH 8,500 mM NaCl, 2 mM EDTA, 1% Triton-X100,0, 1% SDS) and Wash III buffer (20 mM Tris pH 8,1 mM EDTA, 0,5% Na-deoxycholate, 1% Igepal, 250 mM LiCl). After two additional washes in TE pH 8, the beads were resuspended in 10% Chelex resin (Biorad) and incubated at 98°C for 10′. After addition of 2 µL of 10 mg/mL of proteinase K, the mixture was incubated at 43°C for 1 hour, then for another 10 mn at 98°C. After centrifugation, the supernatant was collected and analyzed by qPCR. 8. 108 cells were frozen in liquid nitrogen, broken open using a RETSCH MM400 Mill and then resuspended in cold lysis buffer (Hepes-KOH 50 mM pH 7,5, NaCl 140 mM, EDTA 1 mM, Triton 1%, Na-deoxycholate 0,1%). After phenol/chloroform purification and ethanol precipitation, the DNA was resuspended in TE pH 8 and split into two samples. Both samples were digested with BsrGI, EcoRI, HindIII, SspI and XbaI according to the manufacturer' s instructions and RNase H was added to one of the two samples. After digestion, each sample was divided into two and incubated overnight at 4°C in IP buffer (100 mM MES pH 6,6, NaCl 500 mM, 0,05% Triton, 2 mg/mL BSA) in the presence of either Protein A-coupled Dynabeads or Protein A-coupled Dynabeads previously incubated with the S9. 6 antibody according to the manufacturer' s instructions. The beads were then washed three times in IP buffer. After two additional washes in TE pH 8, the beads were resuspended in 10% Chelex resin (Biorad) and incubated at 98°C for 5′. After addition of 2 µL of 10 mg/mL of proteinase K, the mixture was incubated at 43°C for 30′, then for another 5′ at 98°C. After centrifugation, the supernatant was collected and analyzed by qPCR. Immunoprecipitation was carried out as described previously [22], except that cells were broken open using a RETSCH MM400 Mill. To purify Sen1-associated proteins (Table S2), a protein extract was prepared from 109 cells expressing GFP-tagged Sen1 from the endogenous locus. After immuno-precipitation with 15 µL of magnetic beads, the beads were washed three times with 1 mL of lysis buffer and twice with 1 mL of PBS containing 0,02% Tween. The beads samples were then subjected to in-solution reduction, carbamidomethylation and tryptic digestion. After acidification with 10%Trifluoroacetic Acid the samples were centrifuged 3 times to eliminate the beads. Peptide sequences were determined by mass spectrometry performed using a LTQ Velos instrument (Dual Pressure Linear Ion Trap) equipped with a nanospray source (Thermo Fisher Scientific) and coupled to a U3000 nanoLC system (Thermo Fisher Scientific). A MS survey scan was acquired over the m/z range 400–1600 in Enhanced resolution mode. The MS/MS scans were acquired in Normal resolution mode over the m/z range 65–2000 for the 20 most intense MS ions with a charge of 2 or more and with a collision energy set to 35eV. The spectra were recorded using dynamic exclusion of previously analyzed ions for 0. 5 min with 50 millimass units (mmu) of mass tolerance. The peptide separation was obtained on a C18 PepMap micro-precolumn (5 µm; 100 Å; 300 µm×5 mm; Dionex) and a C18 PepMap nanocolumn (3 µm; 100 Å; 75 µm×200 mm; Dionex) using a linear 90 min gradient from 0 to 40%, where solvent A was 0. 1% HCOOH in H2O/CH3CN (95/5) and solvent B was 0. 1% HCOOH in H2O/CH3CN (20/80) at 300 nL/min flow rate. Protein identification was performed using the MASCOT Algorithm from the Proteome Discoverer software v1. 1 (Thermo Fisher Scientific) against the UniProtKB database reduced to Schizosaccharomyces pombe species [UniProt release 2013_12]. These were performed as previously described [22]. | Title: RNA Processing Factors Swd2.2 and Sen1 Antagonize RNA Pol III-Dependent Transcription and the Localization of Condensin at Pol III Genes Summary: Failure to condense chromosomes prior to anaphase onset can lead to genome instability. The evolutionary-conserved condensin complex drives chromosome condensation, probably by changing the topology of chromatin around its binding sites. Condensin localizes to regions of high transcription, suggesting that some transcription-associated feature (s) direct its association with chromatin. Here we considered that transcription-dependent DNA: RNA hybrids or topological stress could be involved in recruiting condensin. Our data show that condensin is indeed enriched at regions accumulating DNA: RNA hybrids but that they are not involved in its recruitment. Rather, we identify a mutant combination where increased transcription by RNA Pol III is associated locally with stronger topological stress. Strikingly the localization of condensin is dramatically enhanced at the same loci and we show that topological stress contributes to this enhanced association. Our data strengthen the idea that transcription creates the environment necessary to recruit condensin in mitosis. | 9,101 | 255 | lay_plos | en |
Write a title and summarize: Illustration DR "EN DANSE CLASSIQUE INDIENNE, les ghungroos, ces bracelets de cheville décorés de grelots, sont symboles de rythme, de son, de musique, et se doivent d'être accordés en permanence avec les autres instruments. Ils sont fabriqués par des artisans de Bombay ou de New Delhi. Dès qu'on les porte, notre corps se transforme à son tour en un instrument de musique. J'ai eu la chance de commencer la danse très jeune, à 6 ans, en entrant dans la meilleure école de danse de Bombay, le collège de danse classique Nalanda. COMPTE TENU DE MA TAILLE, LES PREMIERS GHUNGROOS, offerts par mon professeur, ne comptaient que deux fois vingt-cinq grelots. Une tradition appelée guru-shishya parampara régit les relations entre le maître et son disciple; mon maître M. Attibuddh a donc béni mes premiers ghungroos avant que je les utilise pour la première fois. Je les ai conservés. J'en offre à mon tour à de jeunes danseurs talentueux. Les ghungroos que j'utilise désormais (photo) sont très précieux et peuvent être considérés comme des bijoux, que je transporte dans un coffret spécial. Ils comptent trois cents grelots au total. Lors des représentations, j'ai entre deux et trois kilos à chaque jambe. Leur entretien exige de changer certains grelots régulièrement et de les réviser tous les six mois. Ce qui me lie à mes ghungroos est de l'ordre du spirituel. Je ne suis pas superstitieuse, mais je leur parle avant chaque représentation. D'une certaine façon, ils me connectent au monde." A voir "Bharati, il était une fois l'Inde." Palais des Congrès, 2, place de la Porte-Maillot, Paris-17e. Mo Porte-Maillot. Du 23 au 25 novembre. De 38 € à 90 €. En tournée en France. www.bharatitheshow.com Propos recueillis par Jérôme Badie | Title: Les ghungroos de Bhavna Pani Summary: La comédienne et danseuse bollywoodienne Bhavna Pani est l'héroïne du spectacle musical "Bharati, il était une fois l'Inde", déjà plébiscité dans une vingtaine de pays par 1,5 million de spectateurs. Ici, elle nous parle des ghungroos, instruments indispensables à son art qu'elle porte aux chevilles lors des représentations et dont elle ne se sépare jamais. | 456 | 104 | mlsum_fr | fr |
Write a title and summarize: SECTION 1. SHORT TITLE. This Act may be cited as the ``Presidential Debate Reform Act''. SEC. 2. ESTABLISHMENT OF PRESIDENTIAL DEBATE COMMISSION. Title III of the Federal Election Campaign Act of 1971 (2 U.S.C. 431 et seq.) is amended by adding at the end the following new section: ``presidential debate commission ``Sec. 323. (a) Establishment.--Not later than 6 months before the date of each general election for the offices of President and Vice President of the United States (beginning with the general election held in 2000), the President shall appoint a Presidential Debate Commission (hereafter in this section referred to as the `Commission') in accordance with this section with respect to such election. ``(b) Membership.-- ``(1) In general.--The Commission shall be composed of 3 members appointed by the President as follows: ``(A) 1 member shall be from among a list of nominees submitted by the chair of the Republican National Committee. ``(B) 1 member shall be from among a list of nominees submitted by the chair of the Democratic National Committee. ``(C) 1 member (who shall not be a member of the Republican or Democratic Parties) shall be from among a list of nominees submitted jointly by the chairs of the Republican National Committee and the Democratic National Committee. ``(2) Qualifications.--Members of the Commission may be from the public or private sector, and may include Federal, State, or local officers or employees, members of academia, nonprofit organizations, or other interested individuals. ``(3) Vacancies.--Any vacancy shall be filled in the same manner as the original appointment not later than 10 days after the vacancy occurs. ``(4) Compensation.--Members of the Commission shall receive no compensation for service on the Commission, but shall be allowed travel expenses, including per diem in lieu of subsistence, at rates authorized for employees of agencies under subchapter I of chapter 57 of title 5, United States Code, while away from their homes or regular places of business in the performance of service for the Commission. ``(c) Powers; Meetings.--Except as provided in subsection (d), decisions made by the Commission shall be made by unanimous consent of the commissioners. The Commission shall meet at a time and a site agreed upon by each of the members. ``(d) Staff.-- ``(1) Executive director.--With the approval of the majority of the Commission's members and without regard to the provisions of title 5, United States Code, governing appointments in the competitive service, the Commission shall appoint an executive director, who shall be paid at a rate not to exceed the rate of basic pay payable for level V of the Executive Schedule under section 5315 of title 5, United States Code. ``(2) Other personnel.--With the approval of the majority of the Commission's members, the Commission may appoint a secretarial assistant and such other staff as the Commission considers appropriate, without regard to the provisions of title 5, United States Code, governing appointments in the competitive service and without regard to the provisions of chapter 51 and subchapter III of chapter 53 of that title relating to classifications and General Schedule pay rates, except that the rate of pay for any such personnel may not exceed 75 percent of the rate of pay for the Executive Director. ``(3) Temporary and intermittent services.--The Commission may procure temporary and intermittent services to the same extent as is authorized by section 3109(b) of title 5, United States Code. ``(e) Duties.--It shall be the duty of the Commission to establish a schedule of debates in accordance with subsection (f) as follows: ``(1) One preliminary debate. ``(2) Not more than 2 Vice Presidential debates. ``(3) Not less than 2 or more than 4 Presidential debates. ``(f) Debates Described.-- ``(1) Preliminary debates.--A preliminary debate shall take place no sooner than 90 days and no later than 60 days before a Presidential election. The time and place of the preliminary debate shall be announced by the Commission no later than 14 days before the scheduled preliminary debate. A preliminary debate shall involve any person who has declared himself a candidate for the position of President of the United States who is either on the ballot in all 50 States or is the choice of 5 percent of likely voters to be President of the United States, as determined by the Commission. Factors to be taken into account include nationally recognized polling data. The format shall be decided by the Commission. The attendance by any candidate at the preliminary debate is optional. ``(2) Vice presidential debates.--Vice Presidential debates shall take place at least 7 days following the preliminary debate. The time and date of all Vice Presidential debates shall be announced no later than 14 days prior to the first Vice Presidential debate. All Vice Presidential debates shall involve persons who are the Vice Presidential candidates to qualified Presidential candidates described in paragraph (4). The format of debates shall be decided by the Commission. ``(3) Presidential debates.--Presidential debates shall take place no sooner than 7 days following the preliminary debate. The time and date of all qualified debates shall be announced no later than 21 days prior to the first scheduled qualified debate. The format of debates shall be decided by the Commission, with at least 1 being of the single moderator format. Presidential debates shall involve persons who are qualified Presidential candidates described in paragraph (4). ``(4) Qualified presidential candidate defined.--In this subsection, a `qualified Presidential candidate' is a candidate for President of the United States who is the choice of not less than 5 percent of likely voters, to be determined by the Commission taking into account only the polling data collected no sooner than 1 day after the conclusion of the preliminary debate. ``(g) Authorization of Appropriations.--There are authorized to be appropriated to each Commission appointed under this section such sums as may be necessary to carry out its activities with respect to the election involved. ``(h) Termination.--Each Commission appointed under this section shall terminate on the date following the day of the election for which the Commission was appointed.''. SEC. 3. REDUCTION IN AMOUNT OF FEDERAL PAYMENTS FOR PARTY CONVENTIONS OF PARTIES NOT PARTICIPATING IN COMMISSION DEBATES. Section 9008 of the Internal Revenue Code of 1986 is amended by adding at the end the following new subsection: ``(i) Reduction in Payments for Parties Not Participating in Debates Certified by Presidential Debate Commission.-- ``(1) In general.--If the nominee for President of the United States or Vice President of the United States of a party receiving payments under this section does not certify to the Commission that the nominee will participate in all applicable debates scheduled by the Presidential Debate Commission pursuant to section 323 of the Federal Election Campaign Act of 1971 with respect to a general election (other than a preliminary debate described in section 323(f)(1) of such Act), the amount of the payment to which the party is otherwise entitled under this section for the nominating convention for the following general election shall be reduced by the percentage described in paragraph (2). ``(2) Reduction percentage described.--The percentage described in this paragraph with respect to a party is the amount (expressed as a percentage) equal to-- ``(A) the number of Presidential and Vice Presidential debates scheduled by the Presidential Debate Commission with respect to an election that the party's nominee did not attend; divided by ``(B) the total number of such debates scheduled by the Commission with respect to the election.''. | Title: Presidential Debate Reform Act Summary: Presidential Debate Reform Act - Amends the Federal Election Campaign Act of 1971 to direct the President to establish a Presidential Debate Commission (Commission) six months before each general election for the offices of President and Vice President beginning with the general election in 2000. Directs the Commission to establish: (1) one preliminary debate; (2) not more than two vice presidential debates; and (3) not fewer than two nor more than four presidential debates. Authorizes appropriations. Amends the Internal Revenue Code to reduce the amount of Federal payments for a party's nominating convention for the following general election if the party's nominee for President or Vice President does not certify to the Commission that the nominee will participate in all applicable Commission debates (other than a preliminary debate). | 1,781 | 178 | billsum | en |
Summarize: LeBron James returned to the Cleveland hardwood, playing the first half of a preseason game against the Maccabi Tel Aviv that the Cavaliers went on to win handily. James sunk his first shot back in a Cavaliers jersey, stepping up for a long-range three pointer to open the scoring for Cleveland. The four-time MVP scored 12 in the first half, then watched from the bench icing his knees and back while the Cavaliers went on to beat the visiting team from Tel Aviv. Battle: Cleveland Cavaliers' LeBron James pulls a loose ball from Maccabi Tel Aviv's Jeremy Pargo, himself a former Cavalier. James has been nursing an 'iffy' back in the run-up to the season, sitting out practice Friday and looking to avoid unnecessarily aggravating his back problems. The Cavaliers showed they had more firepower in their arsenal, going 28-16 against Maccabi with LeBron out of the game. New York Times reporting on the game suggested though fans were happy their star was back, the realism of LeBron needing Cleveland less than Cleveland needed him had set in. Instead, Cleveland sports fans seemed more excited that night to watch the Cleveland Browns pull off a come-from-behind victory against the Titans in Tennessee. The post-game attention on James took a negative turn, as all Twitter wanted to talk about was his hair, which unlike LeBron has not returned. 'Lebron's hairline ebbs and rises like the tides,' said user Tweetgood Mac, referencing photos of James in the off-season with a fuller head of hair. Scalped: James's stock took a beating on Twitter, where users called out how the four-time MVP's headband has been inching back recently to cover his hairline. Gone curl: Twitter users called out James, who had shot a sneaker commercial where it looked like his hair had returned. Dealt: Some users joked about LeBron's hairline while others made genuine pleas for James to finally give up the ghost and go bald. Untouchable: James takes a shot over Yogev Ohanyon of Maccabi Tel Aviv as the Cavaliers went on to rout what is considered to be Europe's top team. Sitting out: James watches from the bench in the first quarter, later sitting out the second half with ice on his back and knees. Reporters who had traveled from Israel to see how well Maccabi stacked up against American talent, swarmed the recently returned Cavalier, pressing him about playing under his new coach. 'You guys know the new coach more than I do,' James said. 'I've only been with him for a couple weeks.' The night was also memorable for Cavaliers head coach David Blatt, who was playing against the team he had coached for six seasons back in the Euroleague. 'Personally this is a bit of an emotional game for me,' said Blatt. 'I'm playing against the team from which I came and the place from whence I came. Obviously there's some mixed emotions there.' James now has until Saturday to rest up before confronting his former Miami Heat in a preseason game that's being held in Rio de Janeiro as part of the NBA's Global Games series. Cleveland plays their season opener at home against the New York Knicks October 30 | Summary: The four-time MVP scored 12 in the first half of an exhibition game against Maccabi Tel Aviv, then rested his 'iffy' back in the second half. After the game, Twitter users focused on Lebron's receding hairline and implored James to 'give it up and go bald' The game was bittersweet for Cavaliers head coach David Blatt, who spent six years coaching Tel Aviv before coming to Cleveland. Cleveland routed Tel Aviv 107-80 and face the Miami Heat next Saturday in Rio de Janeiro. | 740 | 120 | cnn_dailymail | en |
Summarize: Actus Quartus. Scoena Prima. Enter Harrie Hotspurre, Worcester, and Dowglas. Hot. Well said, my Noble Scot, if speaking truth In this fine Age, were not thought flatterie, Such attribution should the Dowglas haue, As not a Souldiour of this seasons stampe, Should go so generall currant through the world. By heauen I cannot flatter: I defie The Tongues of Soothers. But a Brauer place In my hearts loue, hath no man then your Selfe. Nay, taske me to my word: approue me Lord Dow. Thou art the King of Honor: No man so potent breathes vpon the ground, But I will Beard him. Enter a Messenger. Hot. Do so, and 'tis well. What letters hast there? I can but thanke you Mess. These Letters come from your Father Hot. Letters from him? Why comes he not himselfe? Mes. He cannot come, my Lord, He is greeuous sicke Hot. How? haz he the leysure to be sicke now, In such a iustling time? Who leades his power? Vnder whose Gouernment come they along? Mess. His Letters beares his minde, not I his minde Wor. I prethee tell me, doth he keepe his Bed? Mess. He did, my Lord, foure dayes ere I set forth: And at the time of my departure thence, He was much fear'd by his Physician Wor. I would the state of time had first beene whole, Ere he by sicknesse had beene visited: His health was neuer better worth then now Hotsp. Sicke now? droope now? this sicknes doth infect The very Life-blood of our Enterprise, 'Tis catching hither, euen to our Campe. He writes me here, that inward sicknesse, And that his friends by deputation Could not so soone be drawne: nor did he thinke it meet, To lay so dangerous and deare a trust On any Soule remou'd, but on his owne. Yet doth he giue vs bold aduertisement, That with our small coniunction we should on, To see how Fortune is dispos'd to vs: For, as he writes, there is no quailing now, Because the King is certainely possest Of all our purposes. What say you to it? Wor. Your Fathers sicknesse is a mayme to vs Hotsp. A perillous Gash, a very Limme lopt off: And yet, in faith, it is not his present want Seemes more then we shall finde it. Were it good, to set the exact wealth of all our states All at one Cast? To set so rich a mayne On the nice hazard of one doubtfull houre, It were not good: for therein should we reade The very Bottome, and the Soule of Hope, The very List, the very vtmost Bound Of all our fortunes Dowg. Faith, and so wee should, Where now remaines a sweet reuersion. We may boldly spend, vpon the hope Of what is to come in: A comfort of retyrement liues in this Hotsp. A Randeuous, a Home to flye vnto, If that the Deuill and Mischance looke bigge Vpon the Maydenhead of our Affaires Wor. But yet I would your Father had beene here: The qualitie and Heire of our Attempt Brookes no diuision: It will be thought By some, that know not why he is away, That wisedome, loyaltie, and meere dislike Of our proceedings, kept the Earle from hence. And thinke, how such an apprehension May turne the tyde of fearefull Faction, And breede a kinde of question in our cause: For well you know, wee of the offring side, Must keepe aloofe from strict arbitrement, And stop all sight-holes, euery loope, from whence The eye of reason may prie in vpon vs: This absence of your Father drawes a Curtaine, That shewes the ignorant a kinde of feare, Before not dreamt of Hotsp. You strayne too farre. I rather of his absence make this vse: It lends a Lustre, and more great Opinion, A larger Dare to your great Enterprize, Then if the Earle were here: for men must thinke, If we without his helpe, can make a Head To push against the Kingdome; with his helpe, We shall o're-turne it topsie-turuy downe: Yet all goes well, yet all our ioynts are whole Dowg. As heart can thinke: There is not such a word spoke of in Scotland, At this Dreame of Feare. Enter Sir Richard Vernon. Hotsp. My Cousin Vernon, welcome by my Soule Vern. Pray God my newes be worth a welcome, Lord. The Earle of Westmerland, seuen thousand strong, Is marching hither-wards, with Prince Iohn Hotsp. No harme: what more? Vern. And further, I haue learn'd, The King himselfe in person hath set forth, Or hither-wards intended speedily, With strong and mightie preparation Hotsp. He shall be welcome too. Where is his Sonne, The nimble-footed Mad-Cap, Prince of Wales, And his Cumrades, that daft the World aside, And bid it passe? Vern. All furnisht, all in Armes, All plum'd like Estridges, that with the Winde Bayted like Eagles, hauing lately bath'd, Glittering in Golden Coates, like Images, As full of spirit as the Moneth of May, And gorgeous as the Sunne at Mid-summer, Wanton as youthfull Goates, wilde as young Bulls. I saw young Harry with his Beuer on, His Cushes on his thighes, gallantly arm'd, Rise from the ground like feathered Mercury, And vaulted with such ease into his Seat, As if an Angell dropt downe from the Clouds, To turne and winde a fierie Pegasus, And witch the World with Noble Horsemanship Hotsp. No more, no more, Worse then the Sunne in March: This prayse doth nourish Agues: let them come. They come like Sacrifices in their trimme, And to the fire-ey'd Maid of smoakie Warre, All hot, and bleeding, will wee offer them: The mayled Mars shall on his Altar sit Vp to the eares in blood. I am on fire, To heare this rich reprizall is so nigh, And yet not ours. Come, let me take my Horse, Who is to beare me like a Thunder-bolt, Against the bosome of the Prince of Wales. Harry to Harry, shall not Horse to Horse Meete, and ne're part, till one drop downe a Coarse? Oh, that Glendower were come Ver. There is more newes: I learned in Worcester, as I rode along, He cannot draw his Power this fourteene dayes Dowg. That's the worst Tidings that I heare of yet Wor. I by my faith, that beares a frosty sound Hotsp. What may the Kings whole Battaile reach vnto? Ver. To thirty thousand Hot. Forty let it be, My Father and Glendower being both away, The powres of vs, may serue so great a day. Come, let vs take a muster speedily: Doomesday is neere; dye all, dye merrily Dow. Talke not of dying, I am out of feare Of death, or deaths hand, for this one halfe yeare. Exeunt. Omnes. Scaena Secunda. Enter Falstaffe and Bardolph. Falst. Bardolph, get thee before to Couentry, fill me a Bottle of Sack, our Souldiers shall march through: wee'le to Sutton-cop-hill to Night Bard. Will you giue me Money, Captaine? Falst. Lay out, lay out Bard. This Bottle makes an Angell Falst. And if it doe, take it for thy labour: and if it make twentie, take them all, Ile answere the Coynage. Bid my Lieutenant Peto meete me at the Townes end Bard. I will Captaine: farewell. Enter. Falst. If I be not asham'd of my Souldiers, I am a sowc't-Gurnet: I haue mis-vs'd the Kings Presse damnably. I haue got, in exchange of a hundred and fiftie Souldiers, three hundred and odde Pounds. I presse me none but good House-holders, Yeomens Sonnes: enquire me out contracted Batchelers, such as had beene ask'd twice on the Banes: such a Commoditie of warme slaues, as had as lieue heare the Deuill, as a Drumme; such as feare the report of a Caliuer, worse then a struck-Foole, or a hurt wilde-Ducke. I prest me none but such Tostes and Butter, with Hearts in their Bellyes no bigger then Pinnes heads, and they haue bought out their seruices: And now, my whole Charge consists of Ancients, Corporals, Lieutenants, Gentlemen of Companies, Slaues as ragged a Lazarus in the painted Cloth, where the Gluttons Dogges licked his Sores; and such, as indeed were neuer Souldiers, but dis-carded vniust Seruingmen, younger Sonnes to younger Brothers, reuolted Tapsters and Ostlers, Trade-falne, the Cankers of a calme World, and long Peace, tenne times more dis-honorable ragged, then an old-fac'd Ancient; and such haue I to fill vp the roomes of them that haue bought out their seruices: that you would thinke, that I had a hundred and fiftie totter'd Prodigalls, lately come from Swine-keeping, from eating Draffe and Huskes. A mad fellow met me on the way, and told me, I had vnloaded all the Gibbets, and prest the dead bodyes. No eye hath seene such skar-Crowes: Ile not march through Couentry with them, that's flat. Nay, and the Villaines march wide betwixt the Legges, as if they had Gyues on; for indeede, I had the most of them out of Prison. There's not a Shirt and a halfe in all my Company: and the halfe Shirt is two Napkins tackt together, and throwne ouer the shoulders like a Heralds Coat, without sleeues: and the Shirt, to say the truth, stolne from my Host of S[aint]. Albones, or the Red-Nose Inne-keeper of Dauintry. But that's all one, they'le finde Linnen enough on euery Hedge. Enter the Prince, and the Lord of Westmerland. Prince. How now blowne Iack? how now Quilt? Falst. What Hal? How now mad Wag, what a Deuill do'st thou in Warwickshire? My good Lord of Westmerland, I cry you mercy, I thought your Honour had already beene at Shrewsbury West. 'Faith, Sir Iohn, 'tis more then time that I were there, and you too: but my Powers are there alreadie. The King, I can tell you, lookes for vs all: we must away all to Night Falst. Tut, neuer feare me, I am as vigilant as a Cat, to steale Creame Prince. I thinke to steale Creame indeed, for thy theft hath alreadie made thee Butter: but tell me, Iack, whose fellowes are these that come after? Falst. Mine, Hal, mine Prince. I did neuer see such pittifull Rascals Falst. Tut, tut, good enough to tosse: foode for Powder, foode for Powder: they'le fill a Pit, as well as better: tush man, mortall men, mortall men Westm. I, but Sir Iohn, me thinkes they are exceeding poore and bare, too beggarly Falst. Faith, for their pouertie, I know not where they had that; and for their barenesse, I am sure they neuer learn'd that of me Prince. No, Ile be sworne, vnlesse you call three fingers on the Ribbes bare. But sirra, make haste, Percy is already in the field Falst. What, is the King encamp'd? Westm. Hee is, Sir Iohn, I feare wee shall stay too long Falst. Well, to the latter end of a Fray, and the beginning of a Feast, fits a dull fighter, and a keene Guest. Exeunt. Scoena Tertia. Enter Hotspur, Worcester, Dowglas, and Vernon. Hotsp. Wee'le fight with him to Night Worc. It may not be Dowg. You giue him then aduantage Vern. Not a whit Hotsp. Why say you so? lookes he not for supply? Vern. So doe wee Hotsp. His is certaine, ours is doubtfull Worc. Good Cousin be aduis'd, stirre not to night Vern. Doe not, my Lord Dowg. You doe not counsaile well: You speake it out of feare, and cold heart Vern. Doe me no slander, Dowglas: by my Life, And I dare well maintaine it with my Life, If well-respected Honor bid me on, I hold as little counsaile with weake feare, As you, my Lord, or any Scot that this day liues. Let it be seene to morrow in the Battell, Which of vs feares Dowg. Yea, or to night Vern. Content Hotsp. To night, say I Vern. Come, come, it may not be. I wonder much, being me[n] of such great leading as you are That you fore-see not what impediments Drag backe our expedition: certaine Horse Of my Cousin Vernons are not yet come vp, Your Vnckle Worcesters Horse came but to day, And now their pride and mettall is asleepe, Their courage with hard labour tame and dull, That not a Horse is halfe the halfe of himselfe Hotsp. So are the Horses of the Enemie In generall iourney bated, and brought low: The better part of ours are full of rest Worc. The number of the King exceedeth ours: For Gods sake, Cousin, stay till all come in. The Trumpet sounds a Parley. Enter Sir Walter Blunt. Blunt. I come with gracious offers from the King, If you vouchsafe me hearing, and respect Hotsp. Welcome, Sir Walter Blunt: And would to God you were of our determination. Some of vs loue you well: and euen those some Enuie your great deseruings, and good name, Because you are not of our qualitie, But stand against vs like an Enemie Blunt. And Heauen defend, but still I should stand so, So long as out of Limit, and true Rule, You stand against anoynted Maiestie. But to my Charge. The King hath sent to know The nature of your Griefes, and whereupon You coniure from the Brest of Ciuill Peace, Such bold Hostilitie, teaching his dutious Land Audacious Crueltie. If that the King Haue any way your good Deserts forgot, Which he confesseth to be manifold, He bids you name your Griefes, and with all speed You shall haue your desires, with interest; And Pardon absolute for your selfe, and these, Herein mis-led, by your suggestion Hotsp. The King is kinde: And well wee know, the King Knowes at what time to promise, when to pay. My Father, my Vnckle, and my selfe, Did giue him that same Royaltie he weares: And when he was not sixe and twentie strong, Sicke in the Worlds regard, wretched, and low, A poore vnminded Out-law, sneaking home, My Father gaue him welcome to the shore: And when he heard him sweare, and vow to God, He came but to be Duke of Lancaster, To sue his Liuerie, and begge his Peace, With teares of Innocencie, and tearmes of Zeale; My Father, in kinde heart and pitty mou'd, Swore him assistance, and perform'd it too. Now, when the Lords and Barons of the Realme Perceiu'd Northumberland did leane to him, The more and lesse came in with Cap and Knee, Met him in Boroughs, Cities, Villages, Attended him on Bridges, stood in Lanes, Layd Gifts before him, proffer'd him their Oathes, Gaue him their Heires, as Pages followed him, Euen at the heeles, in golden multitudes. He presently, as Greatnesse knowes it selfe, Step me a little higher then his Vow Made to my Father, while his blood was poore, Vpon the naked shore at Rauenspurgh: And now (forsooth) takes on him to reforme Some certaine Edicts, and some strait Decrees, That lay too heauie on the Common-wealth; Cryes out vpon abuses, seemes to weepe Ouer his Countries Wrongs: and by this Face, This seeming Brow of Iustice, did he winne The hearts of all that hee did angle for. Proceeded further, cut me off the Heads Of all the Fauorites, that the absent King In deputation left behinde him heere, When hee was personall in the Irish Warre Blunt. Tut, I came not to hear this Hotsp. Then to the point. In short time after, hee depos'd the King. Soone after that, depriu'd him of his Life: And in the neck of that, task't the whole State. To make that worse, suffer'd his Kinsman March, Who is, if euery Owner were plac'd, Indeede his King, to be engag'd in Wales, There, without Ransome, to lye forfeited: Disgrac'd me in my happie Victories, Sought to intrap me by intelligence, Rated my Vnckle from the Councell-Boord, In rage dismiss'd my Father from the Court, Broke Oath on Oath, committed Wrong on Wrong, And in conclusion, droue vs to seeke out This Head of safetie; and withall, to prie Into his Title: the which wee finde Too indirect, for long continuance Blunt. Shall I returne this answer to the King? Hotsp. Not so, Sir Walter. Wee'le with-draw a while: Goe to the King, and let there be impawn'd Some suretie for a safe returne againe, And in the Morning early shall my Vnckle Bring him our purpose: and so farewell Blunt. I would you would accept of Grace and Loue Hotsp. And't may be, so wee shall Blunt. Pray Heauen you doe. Exeunt. Scena Quarta. Enter the Arch-Bishop of Yorke, and Sir Michell. Arch. Hie, good Sir Michell, beare this sealed Briefe With winged haste to the Lord Marshall, This to my Cousin Scroope, and all the rest To whom they are directed. If you knew how much they doe import, You would make haste Sir Mich. My good Lord, I guesse their tenor Arch. Like enough you doe. To morrow, good Sir Michell, is a day, Wherein the fortune of ten thousand men Must bide the touch. For Sir, at Shrewsbury, As I am truly giuen to vnderstand, The King, with mightie and quick-raysed Power, Meetes with Lord Harry: and I feare, Sir Michell, What with the sicknesse of Northumberland, Whose Power was in the first proportion; And what with Owen Glendowers absence thence, Who with them was rated firmely too, And comes not in, ouer-rul'd by Prophecies, I feare the Power of Percy is too weake, To wage an instant tryall with the King Sir Mich. Why, my good Lord, you need not feare, There is Dowglas, and Lord Mortimer Arch. No, Mortimer is not there Sir Mic. But there is Mordake, Vernon, Lord Harry Percy, And there is my Lord of Worcester, And a Head of gallant Warriors, Noble Gentlemen Arch. And so there is, but yet the King hath Drawne The speciall head of all the Land together: The Prince of Wales, Lord Iohn of Lancaster, The Noble Westmerland, and warlike Blunt; And many moe Corriuals, and deare men Of estimation, and command in Armes Sir M. Doubt not my Lord, he shall be well oppos'd Arch. I hope no lesse? Yet needfull 'tis to feare, And to preuent the worst, Sir Michell speed; For if Lord Percy thriue not, ere the King Dismisse his power, he meanes to visit vs: For he hath heard of our Confederacie, And, 'tis but Wisedome to make strong against him: Therefore make hast, I must go write againe To other Friends: and so farewell, Sir Michell. Exeunt. | Summary: Scene One At the rebel camp near Shrewsbury, a messenger brings Hotspur news that his father is sick. This bodes poorly for the rebels, since they need the full support of Northumberland to maintain their military force. Additionally, Northumberland is needed to help lead the troops into battle, since his persona is well known and provides inspiration to the men. Hotspur's cousin Vernon arrives with news that the king and young Hal are leading armies against the gathered forces. Hotspur is eager to meet Hal in battle, and comments that when they meet only one of them will survive. However, Vernon has even worse news in that Glyndwr is unable to assemble his army as fast as needed, and will be unlikely to join the rebels at Shrewsbury. Act Four, Scene Two Falstaff has assembled an array of troops who are mostly incompetent. In order to earn money for himself, he conscripted young lovers and men of some wealth who did not want to fight, and who were therefore willing to pay him a fee for being released from duty. The remainder of his infantry is mostly made up of former prisoners and other poor men. Hal arrives, and wonders at the "pitiful rascals". He tells Falstaff to hurry up and meet the army at Shrewsbury, where the king has already set up camp. Falstaff comments that he will arrive at the end of the fray, yet at the beginning of the feast, implying he will reap the spoils of the war for himself. Act Four, Scene Three Hotspur and Douglas are arguing with Vernon and Worcester about when to lead the battle charge. They want to attack that night already, but Vernon counsels them to wait until the next morning for reinforcements to arrive. Sir Walter Blunt arrives as a messenger from King Henry. He begs the rebels to tell him what their grievance is, and says the king will make amends to them if their complaints are valid. Hotspur tells Blunt that Bolingbroke had only returned to England to reclaim his title to Lancaster, not to overthrow Richard II. Hotspur claims to recognize the claim to the throne made by the Earl of March. Blunt asks if that is the message he should take to Henry IV. Hotspur instead tells Blunt that his uncle Worcester will visit the king the next day, and that he will withdraw for a short while. Act Four, Scene Four The Archbishop of York is afraid that Hotspur will be unable to defeat King Henry. Since he is a part of the rebellion, the Archbishop is scared that Henry will come after him as soon as Hotspur loses. To protect himself, the Archbishop sends Sir Michael with letters to his close friends and noblemen, begging them for military support. | 4,903 | 611 | booksum | en |
Write a title and summarize: JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50–60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0. 42, p = 7×10−15) and controls (OR = 0. 53, p = 2×10−5). In contrast, the DQB1*06: 03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1. 63, p = 0. 006), and controls (OR = 2. 69, p = 1×10−5). The German dataset confirmed these findings (OR = 0. 54, p = 1×10−4 and OR = 1. 58, p = 0. 03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06: 03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention. Progressive multifocal leukoencephalopathy (PML) was first described neuropathologically during the fifties by Karl Erik Åström [1]. It took until 1971 when JC virus (JCV) was isolated from brain tissue of a patient with PML, since then JCV was accepted as the causative agent of PML [2]. PML used to be a rare demyelinating disease of the central nervous system, mainly seen in patients with lymphoproliferative disease or AIDS. Now several different drugs that interfere with immune functions, such as natalizumab, efalizumab, mycophenolate mofetil, fumaric acid, rituximab, tacrolimus, and possibly azathioprine, cyclosporine and cyclophosphamide have been associated with an increased risk of developing PML. For natalizumab and efalizumab the strongest associations were seen in patients without an underlying disease that predispose for PML itself [3]–[7]. Thus, it is of major importance to develop measures to prevent or treat the condition, including understanding of factors allowing persons to acquire the virus, as carriers, a requisite for later risk for PML. In patients with multiple sclerosis (MS) treated with natalizumab previous immunosuppressive therapy, an increased duration of therapy, and the positive detection of anti-JCV IgG antibodies as surrogate for the infection with JCV have been established as risk factors for PML [8]–[12]. The anti-JCV antibody status in MS patients is determined by a commercial two step-ELISA. Around 40–50% of the adults are anti-JCV antibody negative [11], [13]–[15]. The cut-off of the commercial assay have been validated in large multicentre cohorts of MS patients with data on JC viruria available, and the false negative rate (sero-negative, but DNA excretion in urine) was estimated with around 2. 5% [9]–[11]. In contrast, a recent study that also measured JCV excretion in urine in a comparably small study population (n = 67) indicated a much higher false negative rate of 37%, however, these cases displayed considerably lower JCV DNA copy numbers in the urine. Hypothetically, a vast majority of persons might be exposed to an ubiquitous virus such as JCV, proposed as contamination marker for human excretions, [16] but differ in replicative activity of a persistent asymptomatic infection, and potentially connected to this, the individual level of immune response to the virus. This view would fit with recent serological observations of a continuous anti-JCV reactivity in larger populations, [17] and might imply that actually not the true absence of the JCV infection, but rather the level of the replicative activity of the persistent JCV infection determines the individual risk of developing PML [18]. This risk might then critically depend on host genetic factors that determine the immune response to the virus, and protect from e. g. the spread of the virus from places of peripheral persistency or latency to the brain. Genes of particular interest in this respect are the HLA class I and class II genes where different variants with different peptide presenting abilities may affect the effectiveness of CD4+ and CD8+ T cell immune defence. Our aim was therefore to test the host genetic regulation of HLA genes in the immune response to JCV. We used anti-JCV antibody status and anti-JCV antibody levels as surrogate for the identification of persons carrying a JCV infection in significant and clinically relevant levels and tested association to HLA class I and class II genes. Clinical characteristics and demographic data of the included patients and controls are displayed in table 1. Anti-JCV antibody status and levels were determined in the same laboratory for all individuals with an ELISA based method [9]. In this study we selected the HLA complex for scrutiny in view of its potent immune regulatory functions. We performed a meta-analysis of association of markers on chromosome 6 for both anti-JCV antibody status and normalized anti-JCV antibody levels (anti-JCV nOD) of results obtained in the three separate cohorts of individuals shown in table 1. This indicated a strong association signal in the HLA class II region for both anti-JCV antibody status and anti-JCV nOD values (figure 1). The most significant markers for the two analyses (rs34454257 for the anti-JCV antibody status and rs3129860 for anti-JCV nOD values) map 42. 6 and 145. 7 kb upstream of the HLA-DRB1 gene in the direction of the HLA class I genes. With this association signal on chromosome 6p21, it was of interest to determine the particular class II gene variants which were associated. Several HLA-alleles showed association to anti-JCV antibody status in both Scandinavian MS cases and controls (Table 2). The table is organised based on common established extended haplotypes found in the Caucasian population [19]–[21]. It is noteworthy that the DRB1*15-DQA1*01: 02-DQB1*06: 02-haplotype, the most strongly associated MS genetic risk factor, was found to be negatively associated with the positive detection of anti-JCV antibodies. The OR for DRB1*15 was 0. 42 in Scandinavian MS cases and 0. 53 in controls. This association was replicated in German MS cases (OR for DRB1*15 0. 54 Table 3). Other alleles in this haplotype, DQB1*06: 02 and DQA1*01: 02, also showed strong protective associations, as expected, since they are in LD with DRB1*15: 01. In contrast, the DRB1*13-DQA1*01: 03-DQB1*06: 03-haplotype was positively associated with anti-JCV antibody status, with an OR = 1. 62 in Scandinavian MS cases, OR = 1. 55 in Swedish controls (Table 2) and OR = 1. 58 in German MS cases (Table 3). In addition the DRB1*03-DQA1*05-DQB1*02 and DQA1*05-DQB1*03: 01 haplotypes showed a positive association to anti-JCV antibody status, while the DQA1*05-DQB1*01: 01-haplotype was negatively associated with anti-JCV antibody status among controls. The DRB1*15-DQA1*01: 02-DQB1*06: 02-haplotype also showed an association to lower anti-JCV nOD levels in a linear regression analysis among JCV seropositive individuals, with a significance level of p≤0. 001 in the Scandinavian cohorts (Table 4). For DQB1*06: 02 beta was between −0. 218 and −0. 366 in the different cohorts (Table 4 and 5). DRB1*13 showed an association to higher anti JCV nOD levels among Scandinavian MS cases, p = 0. 02, beta = 0. 197, but not in German MS cases or Swedish controls (Table 4 and 5). In addition DQB1*03: 01 and DQA1*05 showed an association to higher transformed anti-JCV nOD levels among Swedish controls (Table 4). Most of the HLA associations to both anti-JCV antibody status and anti-JCV nOD levels remained similar when other nominally associated HLA alleles for the same gene are included in the regression analysis (Table 2 to 5). The OR for the association of the presence of DRB1*15 and for DRB1*15 homozygotes for JCV antibody status did not differ, suggestive of a dominant DRB1*15 effect (Figure 2A). Conversely, the DRB1*13 homozygotes showed a slightly stronger association compared to presence of DRB1*13, although the 95%CI do overlap. DRB1*13/15 heterozygotes were not significantly associated with JCV seropositivity indicating that the effect of the two haplotypes counteract each other. Similar results were seen for the DQA1 locus (Figure 2B), but here the DQA1*01: 03/05 heterozygotes are associated with an OR as high as 5. 23. Consistent with the effect on the qualitative anti-JCV status, the DRB1*15 haplotype appeared to act dominantly also on anti-JCV nOD levels as presence of DRB1*15 showed a similar association to DRB1*15 homozygotes, while the DRB1*11 haplotype had an additive effect (Table 6). The effect of these two haplotypes cancel each other out as DRB1*11/15 heterozygotes showed no association to anti-JCV nOD levels. We reanalysed the association of SNPs on chromosome 6 to anti-JCV antibody status and anti-JCV nOD levels when including all HLA alleles that remained associated in the multivariate analysis as covariates. This lead to an almost complete abolishment of the association peak on chromosome 6, with the most significant remaining associations being p = 0. 0001 for a handful of markers (data not shown). This indicates that the association we observed in the HLA region was almost completely explained by the HLA alleles listed in tables 2–4. We here demonstrate a host genetic HLA complex mediated influence on anti-JCV antibody status and anti-JCV antibody levels as surrogate for the susceptibility of the infection with JCV or the activity of the infection with JCV, respectively. We report a strong negative association with anti-JCV antibody positivity, and to a lesser extent, to anti-JCV nOD levels, for the HLA-DRB1*15-DQA1*01: 02-DQB1*06: 02-haplotype in all three datasets. In contrast, the DRB1*13-DQA1*01: 03-DQB1*06: 03-haplotype is associated to increased signs of JCV carriage as assessed serologically. We further find that the DRB1*15-DQA1*01: 02-DQB1*06: 02 haplotype acts dominantly, one copy being sufficient to reduce the ability to form anti-JCV antibodies while the DRB1*13-DQA1*01: 03-DQB1*06: 03 haplotype acts in an additive fashion. Neither of the haplotypes dominates over the other. A recent study demonstrated considerable variation in which JCV peptides were recognized by T cells [22]. A most straight forward interpretation of the present findings is that the DRB1*15: 01 haplotype displays class II molecules that are especially able to present JCV antigens/peptides that are instrumental in activating CD4+ T cells that support the elimination or control of the virus upon exposure to the host. Hence, the opposite would be valid for the haplotype associated with increased carriage of the JCV. Thus hypothetically a large proportion of those persons being sero-negative might have encountered the virus, but had an efficient immune response following primary infection, with low viral turnover or the lack of viral persistency, and low anti-JCV IgG as consequence. Recent serological studies support such a concept: antibody reactivity as measured by ELISA resembles a continuum from non-reactive to highly reactive in particular in persons not excreting the virus in urine [9]. This led to the introduction of a second-step confirmation test when determining the anti-JCV sero-status. However, this pattern of continuous reactivity is also seen with alternative assay formats, which suggest that a vast majority of persons have been exposed to JCV, but have a level of the antibody response to JCV below the assay cut-off, possibly due to an efficient control of the virus with low viral turn-over [13], [17]. This would also explain the higher false negative rate of serological studies observed in recent publications [23], [24]. Although CD8+ cells, restricted by class I molecules are critical in eliminating virus infected cells, antigen specific CD4+ HLA class II restricted cells are crucial for providing T cell help through a variety of cytokines and activation of antigen presenting dendritic cells [25]. The findings may pave the way for finding epitopes in JCV critical for immune defence which could impact on vaccination strategies. Any direct clinical implications of the data, or use, for example in risk stratifications, remain to be determined. The DRB1*13-DQA1*01: 03-DQB1*06: 03-haplotype shows a positive association to anti-JCV antibody serostatus, and was also to higher anti-JCV nOD levels. Hypothetically, a less effective viral immune control with higher viral turnover may be consistent with a chronically higher stimulation of the B cell arm of the immunity resulting in higher antibody levels. This might help us understand why patients that develop PLM during therapy with natalizumab had increased anti-JCV antibody levels already prior to development of PML, and why it might be rational to include the level of the anti-JCV response into PML risk stratification strategies [26]. Recent data suggests that PML-specific viral mutations are acquired intra-individually e. g. in the VP1-region and the regulatory region of the viral genome [27], [28]. It is tempting to speculate that viral PML-specific mutations, although being a random event, are more likely to occur in persons with an inefficient control of the infection with JCV. The host genetic data presented here might therefore be a first step helping to understand how the interplay of host- and viral genetic factors might lead to the development of PML in some, but not all persons exposed to certain immunosuppressive therapies. Our study is however lacking a sufficient number of cases of PML and is therefore not designed and empowered to test this directly. There is one previous paper studying the HLA association to PLM [29]. In this paper 123 Caucasian PML cases, the majority whom were HIV positive, were compared with a large group of HIV positive individuals. The study was limited to the association of HLA class I antigens. While A3 was found to be nominally negatively associated with PML, B18 was found to be positively associated. We do not find any of these alleles associated with anti-JCV antibody formation in our study. However, the A3 association to PML possibly is explained by the same effect as the DRB1*15-DQA1*01: 02-DQB1*06: 02 association we see in our study, considering that A3 can be present on the same extended haplotype. Studies in larger cohorts of PML patients with appropriate controls testing the association of class II antigens are warranted. A recent investigation has studied the stimulation of CD4+ T cells by pools of JCV peptides among healthy donors with different HLA-DRB1 alleles [22]. For haplotypes where we see an increased OR for sero-status and positive correlation to JCV-Ab levels (DRB1*13 and DRB1*03) they observe reduced stimulation of CD4+ cells, while the opposite was true for DRB1*15. Hence, both antibody response and T-cell response to JCV infection are affected by HLA-class II antigens, which is consistent with our observations of potent HLA class II gene variant effects in large cohorts of persons. HLA associations to some viral infections have been seen previously. The HLA class II genes were recently reported as host genetic factors influencing the IgG response to EBNA1, an Epstein Barr virus-related protein [30]. In addition, there are well documented class II allelic influences on Hepatitis C [31] and recently a highly associated SNP in the HLA region was demonstrated in relation to human papilloma virus infection [32]. HLA class II associations have also been seen in chronic hepatitis B infections as well as response to hepatitis B vaccination [33]–[35]. Association to the HLA class I related MICB gene have also been reported to hypovolemic shock caused by dengue viral infection and HIV viral load [36], [37]. Another MIC gene, MICA has been associated to hepatitis C virus induced hepato cellular carcinoma [38]. In our data, after adjusting the association for HLA class II associated alleles the most strongly associated marker in the class I region is rs3094014 (p<0. 02) which is in LD with both the MICB (r2 0. 76 for rs3132468 associated with dengue fever) and MICA (r2 0. 90 for rs2596542 reported to be associated with hepatitis C virus induced hepato cellular carcinoma) using European 1000 genomes and HapMap data and may therefore represent the same signal. Interestingly, the DRB1*15 haplotype is also the most strongly associated genetic risk factor for MS [39]. Consistent with this, the demographic data in our study suggests that anti-JCV antibody positivity is somewhat lower among MS cases (59%), compared to controls (66%, p = 0. 02). A protection against the establishment of a persistent JCV infection with positive detection of anti-JCV antibodies provided by the DRB1*15 haplotype would then explain the lower sero-prevalence among cases. The presence of an association with the DRB1*15-haplotype in controls also indicates that the association is not likely due to an aberrant immune response to JCV infection in MS cases. In conclusion, we here demonstrate strong associations of class II gene variants on JCV infection. Hence, CD4+ T cells, restricted by class II molecules are crucial in the host control of JCV infection. Our data is of importance for a better understanding of JCV infection and virus-host interactions, and might pave the way for new developments for an improved PML risk stratification, and preventive or curative future anti-JCV therapies. The study was approved by the regional ethical committees in each country involved; Stockholm regional Ethical Review Board (Sweden), the Ethical review boards at the Heinrich-Heine Universität Düsseldorf and the Technische Universität München (Germany) and the Danish Ethical Committee Review Board for Copenhagen and Frederiksberg (Denmark). All participants provided written informed consent. A Scandinavian dataset consisting of 2015 Swedish persons with MS from two separate studies EIMS [40] and IMSE [41] with 1259 population based controls, and 157 Danish MS patients treated with natalizumab in Copenhagen. HLA-genotypes and anti-JCV antibody status were available for 1621 MS cases and 1064 controls (table 1). A German dataset of 745 MS patients, 718 with GWAS data, was used for replication. The cohort was recruited from multiple sites in Germany and included persons treated with interferon-beta for at least 6 months. GWAS genotyping for these MS cases had been performed in the same laboratory with the same chip as the Scandinavian datasets. HLA-genotypes came from three different sources. Low resolution Sequence Specific amplification (Olerup, Saltsjöbaden, Sweden) [42] were for genotyping of 2115 Swedish cases and controls for HLA-A, 2140 for HLA-DRB1, and 161 for HLA-C. For HLA-B a Luminex based reverse PCR-SSO (One Lambda, Inc., Canoga Park, CA, USA) was used for 173 persons [39]. And finally imputation either using HLA*IMP [43] with genotypes from the IMSGC WTCCC2 MS GWAS, [44] or with HLA*IMP: 2 [45] using genotypes from the Immunochip [46] was used. The former was used for both the Danish and German cohort while both were used in the Swedish cohort. Imputed HLA data was available for 1105 Swedish persons from the IMSGC WTCCC2 and for 2220 Swedish persons using Immunochip genotypes. In cases where the genotypes for any individual were discordant between platforms, the following order of precedence was used: classical, Immunochip imputed, GWAS imputed. A quality value for allele probability of 0. 7 was used as a threshold for imputed HLA genotypes. In this study we used SNP genotypes from MS GWAS study to analyse association to the HLA region [44]. Genome-wide SNP markers were genotyped as part of the IMSGC WTCCC2 MS GWAS on the Human660-Quad chip, and genotype calling and markers were quality controlled as previously described [44]. Cases with previous intravenous IgG treatment were excluded. In the Scandinavian cohort all persons were of Scandinavian ancestry, and all MS cases fulfilled the McDonald or Poser criteria for MS. For the German MS cases, a total number of 749 cases were GWAs genotyped; 25 persons were removed as they were outliers in the principal component analysis (PCA), 4 were removed due to unsuccessful genotyping, and 2 because of natalizumab treatment at blood draw. JCV serology response was determined from plasma or serum using a two-step assay, [9] performed at Focus Diagnostics (Cypress, CA, USA) and sponsored by Biogen Idec (Cambridge, MA, USA). In the first step of the ELISA assay optical density (OD) were measured. Samples with OD>0. 25 were considered positive while samples with OD<0. 10 were considered negative. For samples in the intermediary interval (0. 10–0. 25) a second assay step was used to determine the percentage of inhibition during a pre-incubation with soluble JCV-like particles. Samples in this intermediary interval with an inhibition >40% were considered positive while those with an inhibition <40% were classified as negative. The assay has been estimated to have a false negative rate for JCV carriage of 2–3%. For the quantitative analysis, normalised OD values (nOD) from the first step ELISA were transformed using rank based transformation in the GenABEL-package in R [47]. | Title: JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants Summary: JC virus infection can lead to progressive multifocal leukoencephalopathy in individuals with a compromised immune system, such as during HIV infections or when treated with immunosuppressive or immunomodulating therapies. Progressive multifocal leukoencephalopathy is a rare but potentially fatal disease characterized by progressive damage of the brain white matter at multiple locations. It is therefore of importance to understand the host genetic control of response to JC virus in order to identify patients that can be treated with immunomodulating therapies, common treatments for autoimmune diseases, without increased risk for progressive multifocal leukoencephalopathy. This may also lead to development of preventative or curative anti-JC virus therapies. We here identify genetic variants being associated with JC virus antibody development; a negative association with the human leucocyte antigen DRB1*15-DQA1*01: 02-DQB1*06: 02 haplotype and a positive association with the DRB1*13-DQA1*01: 03-DQB1*06: 03 haplotype among controls and patients with multiple sclerosis from Scandinavia. We confirmed the associations in patients with multiple sclerosis from Germany. These associations between JC virus antibody response and human leucocyte antigens imply that CD4+ T cells are crucial in the immune defence and lay the ground for development of therapy and prevention. | 5,854 | 333 | lay_plos | en |
Summarize: CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of U.S. application Ser. No. 251,862 filed Oct. 3, 1988 now U.S. Pat. No. Des. 313,804. TECHNICAL FIELD The invention is an agricultural earth working tool for placing seeds and fertilizers in soil. The tool has a furrow opener with abrasive resistant plastic side plates and a plastic press plate that places fertilizer in a band in the soil and seed in rows above and adjacent opposite sides of the band of fertilizer. BACKGROUND OF THE INVENTION It is common practice to use agricultural earth working implements having a plurality of tools to open furrows and deposit seeds and fertilizers into the soil. The tools have upwardly directed shanks with furrow openers having side members attached to the lower ends thereof. The furrow openers operate to deposit bands of fertilizer into the soil at a depth greater then the depth of seed. It is economically and environmentally advantageous to use only the amount of fertilizer required to support the crop. The band of fertilizer must be placed in the soil where it is accessible to the plants during the growing season. This requires accurate and consistent location of seed and fertilizer in the soil. Examples of earth working tools having furrow openers that attempt separate soil locations of seed and fertilizer are shown in U.S. Pat. Nos. 4,278,036; 4,388,878; 4,417,530 and 4,638,748. The furrow openers have metal points, press plates and side members that move in the soil. These parts must remain clean and free of soil to avoid excessive draft load and obstruction of fertilizer injection ports. Under some soil conditions soil will adhere and build up on the press plates and side members of the furrow openers. This causes wide furrows which exposes the seed and fertilizer, causes excessive draft loods; and plugs the fertilizer discharge openings. The furrow opener of the invention overcomes soil build up problems of the prior fertilizer and seed planting structures. SUMMARY OF INVENTION The furrow opener of the invention when mounted on a shank of an earthworking tool is used to place a band of fertilizer in the soil and deposit seed in rows in the soil above and adjacent opposite sides of the band of fertilizer. The seed is placed in rows on a firm seed bed formed by the furrow opener above and laterally adjacent opposite sides of the fertilizer. This fertilizing and seeding operation provides improved soil structure for effective seed germination and crop development. The furrow opener has a press plate and side plates mounted on a frame. The press and side plates can be separately removed from the frame to facilitate repair and replacement of the plates. The press plate and side plates are one-piece abrasion and impact resistant plastic members, such as ultra high molecular weight polyethylene, having a low coefficient of friction that are releasably mounted on the frame. The plastic press plate and side plates allow the opener to move through the soil with minimum draft load and eliminates soil build up on the furrow opener. The fertilizer discharge openings in the plastic press plate remain open as the soil does not collect on the press plate. The press plate provides a continuous firm seed bed above the band of fertilizer that promotes seed germination. The press plate is a generally flat abrasion and impact resistant and low friction plastic member having forwardly tapering sides and a generally flat bottom surface. Metal wear plates can be secured to opposite sides of th bottom of the press plate to reduce wear in abrasive soil. The bottom surface is inclined downwardly and rearwardly when mounted on the frame. A single bolt holds press plate on the frame. The side plates are one-piece impact and abrasion resistant and low friction plastic members mounted on the frame above the press plate. Each side plate has a linear bottom edge, a generally triangular shaped forward portion and a generally rectangular shaped rear portion. The forward portion has an upwardly and rearwardly inclined edge that fits under ears on the frame to retain the side plate on the frame. A bolt secures the rear portion of the side plate to the frame. When the bolt is released, the edge of the side plate can be moved from under the ears to remove the side plate from the frame. The rear portions of the side members have inwardly directed extensions located rearwardly of and above the trailing edge of the press plate. The edges located above seed accommodating spaces reduce soil flow into the spaces and minimize bouncing and turning of seed as it is dispensed into rows adjacent opposite sides and above the band of fertilizer. A seed dispenser operates to discharge seed to the areas under the extensions onto the first seed bed above and adjacent opposite sides of the band of fertilizer in the soil. The seed dispenser has downwardly diverging tubular members joined at a seed divider edge for separating seed carried in a tube leading to an air planting apparatus and directing seed into the tubular members. The seed is dispensed from the outlet ends of the tubular members into separate rows of seed. The lateral distance between the rear portions of the side plates can be adjusted to selectively increase or decrease the width of the seed rows. DESCRIPTION OF DRAWING FIG. 1 is a side elevational view, partly sectioned, of a combined furrow opener and press wheel for use with an air seed planter to place seed and fertilizers in the soil; FIG. 2 is a front elevational view of the furrow opener of FIG. 1; FIG. 3 is a rear elevational view of the furrow opener; FIG. 4 is a side elevational view of the furrow opener; FIG. 5 is a top plan view of the furrow opener; FIG. 6 is a bottom view of the furrow opener; FIG. 7 is a large sectional view taken along the line 7--7 of FIG. 5; FIG. 8 is an enlarged sectional view taken along line 8--8 of FIG. 5; FIG. 9 is an enlarged sectional view taken along line 9--9 of FIG. 4; FIG. 10 is an enlarged sectional view taken along line 10--10 of FIG. 4; FIG. 11 is an enlarged sectional view taken along the line 11--11 of FIG. 4; FIG. 12 is a top plan view of a modification of the furrow opener of the invention; and FIG. 13 is an enlarged sectional view taken along line 13--13 of FIG. 12. DESCRIPTION OF PREFERRED EMBODIMENT Referring to FIG. 1, there is shown a combined furrow opener and press wheel indicated generally at 10 usable with a chisel plow or field cultivator and an air seed planter to place seed 11 and fertilizer 12 and soil 13. The field cultivator has a conventional tool bar 14 carrying a clamp indicated generally at 16 for attaching a curved shank 24 to tool bar 14. Clamp 16 includes an upright support 17 mounted on tool bar 14 with a plurality of bolts 18 and a front plate 19. A generally horizontal box support 21 is pivoted to the lower end of support 17 with a transverse pivot pin 22. Box support 21 has a channel that accommodates the upper end of shank 24. A bolt 26 secures shank 24 to box support 21. A compression spring 23 interposed between the top of upright support 17 and box support 21 operates to bias shank 24 in a forward position to hold an earth working tool or furrow opener, indicated generally at 27, in soil 13. An example of a clamp to connect shank 24 to tool bar 14 is shown by Wade in U.S. Pat. No. 3,098,529, incorporated herein by reference. Other types of clamps and connecting structure can be used in lieu of clamp 16. A plurality of bolts 28 secure earth working tool 27 to the lower end of shank 24. The implement is moved in a forward direction, as indicated by arrow 29, to precision place seed 11 and fertilizer 12 in elongated bands or rows in soil 13. When earth working tool 27 hits a rock or like obstruction tool 27 pivots backward and upwardly as indicated by arrow 31 against the biasing force of spring 23. As soon as tool 27 has passes the obstruction spring 23 returns tool 27 back to its earth working position. Earth working tool 27 has a frame indicated generally at 32 that is secured to the lower end of shank 24. Side plates 33 and 34 are attached to opposite sides of frames 32. A bottom shelf or press plate 36 is connected to the bottom of tool 27 adjacent the lower edges of side plates 33 and 34. Plates 33, 34 and 36 are constructed of an abrasion and impact resistant plastic, such as ultra high molecular weight polyethylene containing glass fibers. The plastic material also has a low coefficient of friction so that soil will not adhere to it. A plastic material which has these qualities and is suited to molding and machining to the required shape is ultra high molecular weight polethylene plastic containing glass fibers. One product of this type is marketed by Poly Tech Industries, Inc. Monticello, Ga. The soil even under wet conditions does not adhere to the low friction plastic side plates 33 and 34 and press plate 36. The plastic side plates 33 and 34 and press plate 36 allows the earth working tool to flow through the soil with a minimum of draft load and without the soil buildup on the earth working tool. The ultra high molecular weight plastic of side plates 33 and 34 and press plate 36 is impact resistant as they have elastic memory characteristics that allow plates 33, 34, and 36 to return to their original position after they have been deformed by a rock or other obstruction in the soil. The plastic materials of press plate 36 also function as an insulator so that when anhydrous amonia is injected into the ground press plate 36 does not freeze up. As shown in FIGS. 2 and 4, frame 32 has a body 37 provided with a hole 38 and an elongated slot 39 for accommodating bolts 28 that attach the tool to the lower end of shank 24. Body 37 has a downwardly projected leg 41 that is turned normal to the plane of body 37. A wear resistant metal point or shoe 42 is secured by welds 43 to leg 41. Shoe 42 penetrates and breaks the soil into a furrow for the band of fertilizer 12 during movement of the tool in the soil. As shown in FIGS. 3 and 5, frame 32 includes side braces 44 and 46 that are secured to the upper end of body 37 and extend downwardly and rearwardly to a cross plate 47. A pair of side bars 48 and 49 extend forwardly from opposite ends of cross plate 47 to the back of leg 41. As seen in FIG. 10, side bars 48 and 49 are secured by welds to leg 41. Referring to FIGS. 2, 4, and 5, side plate 33 is mounted on frame 32 with a pair of ears 52 and 53 secured to a side of body 37. Ears 52 and 53 can be a single ear or tab joined to body 37. A bolt 54 secures a rear portion of side plate 33 to side bar 49 as seen in FIG. 11. The forward edge of side plate 33 fits under ears 52 and 53 as shown in FIGS. 9 and 10. When bolt 54 is removed side plate 33 can be removed from frame 32 and replaced with another side plate. Side plate 34 is retained on body 37 with a pair of ears 56 and 57 secured to body 37, as shown in FIGS. 9 and 10, and a bolt 60, as shown in FIG. 7. Ears 56 and 57 can be a single ear secured to body 37. Bolt 60 is removable from side bar 48 to allow the side plate 34 to be removed from frame 32 and replaced with a new side plate. Turning to FIGS. 6 and 7, press plate 36 has a generally flat bottom surface 58 and upwardly and forwardly inclined front surface 59. Bottom surface 58 has side recesses or grooves 95 and 96 accommodating hard metal wear plates or inserts 97 and 98. Wear plates 97 and 98 have bottom surfaces co-extensive with bottom surface 58 of press plate 36 and rear end sections that project rearwardly from the back of press plate 36. The bottom surfaces of wear plates can be chrome coated to increase wear life. The rear end sections of plates 97 and 98 located at the bottom of the seed dispensing spaces 91 and 92 form grooves in the soil seed bed for the seed and reduce churning and bouncing of the seed and soil in spaced 91 and 92. As shown in FIG. 4, a bolt 99 threaded into a center hole in wear plate 97 secures wear plate to press plate 36. Bolt 99 can be removed to permit end-to-end turning and replacement of wear plate 97. A similar bolt (not shown) secures wear plate 98 to press plate 36. The midsection of front surface 59 has an elongated slot 61 that accommodates the lower end of tube 62 for carrying fertilizer to an area immediately behind shoe 42. Tube 62 has an open lower end 63 in front of press plate 36. Tube 62 is an elongated plastic tube that leads to the fertilizer dispensing apparatus (not shown) of the implement. Tube 62 carries granular fertilizer as well as anhydrous amonia. Press plate 36 has a hole 64 for accommodating a second tube (not shown) for dispensing additional fertilizer or herbicides into the soil behind shoe 42. Press plate 36 is mounted on cross bar 51 with a bolt 67. The head of bolt 67 is located in a countersunk bore 66 so that bolt 67 does not interfere with the movement of bottom surface 58 of press plate 36 over the soil. Bolt 67 retains rear end 68 of press plate 36 in engagement with the lower edge of cross plate 47, as seen in FIG. 7. As shown in FIGS. 1, 3, 5, 6, and 7, a seed dispenser indicated generally at 71 is mounted on the rear of cross plate 47. Seed dispenser 71 is operable to divide the seed and deposit the seed in separate parallel rows in the seed bed above and adjacent opposite sides of the band of fertilizer 12 as shown in FIG. 5. The seed is delivered to the seed dispenser 71 through a hose 72 that is connected to an air seed planter apparatus (not shown). Hose 72 is coupled to an enlarged corrugated de-acceleration tube 73. As shown in FIG. 8, the seed is dispensed into de-acceleration tube 73 along with air. The enlarged internal passage 74 of tube 73 reduces the speed of the flowing air and causes the seed to engage the corrugations on the sidewalls of the tube. The seed is uniformly mixed with the air moving through passage 74 so that the seed-to-air ratio is substantially constant. The lower end of de-acceleration tube 73 has downwardly and inwardly directed cone shaped outlet 76 that is attached to an upright tube 77 with a band clamp 78. The air and seed flows into passage 88 of tube 77 and into passages 81 and 84 of downwardly diverging tubular members or tube branches 79 and 83. Branch 79 has an exit or outlet end 82. Branch 83 has an exit or outlet end 86. Outlet ends 82 and 86 are laterally spaced from each other so that the seed is dispensed into parallel rows onto a firm seed bed behind press plate 36. The firm seed bed serves as a moisture barrier that promotes seed gernimation. This is particularly advantagous in dry soil conditions. Branches 79 and 83 have a common divider edge 87 that is located in alignment with the longitudinal axis of passage 88 of tube 77. The divider edge function to divide the air stream and cause the seed and air to be diverted into passages 81 and 84 of branches 79 and 83. Since the seed-to-air ratio is substantially constant a substantially equal quanity of seed is diverted into each of passages 81 and 84 during the operation of the air seed planter. Divider edge 84 also splits the air stream that is moving through passage 88 into two substantially equal streams that flow through branch passages 81 and 84 which carry the speed through passages 81 and 84 and outlet ends 82 and 86 respectively. Arrow 89 indicate the flow of the air and the seed in passages 81 and 84. Referring FIGS. 3 and 5, outlet ends 82 and 84 of branches 79 and 83 are located adjacent spaces 91 and 92 on the insides of the rear portions of side plates 33 and 34. The seed dispensed into spaced 91 and 92 is deposited into the soil in parallel rows as indicated in FIG. 5. Side plates 33 and 34 have inwardly turned corner projections or extensions 93 and 94 that extend over the spaces 91 and 92 to minimize the movement of soil into spaces 91 and 92 and prevent the plugging of outlet ends 82 and 86. Projections 93 and 94 also reduce churning and bouncing of the seed directed into spaces 91 and 92 by the diverging tubular members 79 and 83. The earth working tool 10 having furrow opener 27 is used to incorporate an amount of fertilizer into the soil that supports only the searsons growth of the crop. Excessive amounts of fertilizer are not required thereby reducing fertilizer costs and losses which are enviormentally incompatible. The precision placement of fertilizer and seed in the soil is particularly advantagous in low fertility testing soils. The fertilizer is placed in a band in the soil at the time of seed planting which reduces wind and water erosion as well as cost and labor of separate fertilizer applications. The seed is placed on a firm seed bed in rows adjacent opposite sides and above the band of fertilizer. The rows of seed and band of fertilizer are in a vertical T zone in the soil bed wherein the fertilizer is accessible to plants during the growing season. Press plate 36 and wear plates 97 and 98 attached thereto compress the soil forming a moisture barrier whereby seed is placed in soil having a moisture content that promotes seed germination. Referring to FIG. 1, a packer wheel assembly indicated generally at 200 is located behind the earth working tool 10 to compress the soil into firm contact with seeds 11 and fertilizer 12. Packer wheel assembly can be the wheel assembly disclosed in U.S. Pat. No. 4,579,071. A U-shaped member 201 is attached with U-bolts 202 to mid-portion of the shank 24. The U-shaped member pivotly supports an arm tool 4 that is attached to a wheel 206 with an axle 207. A pair of wheels can be attached to arm 204 to compress the soil as indicated by arrows 209 above the rows of seed 11. Torsion spring 208 engagable with arm 204 biases wheel 206 in a downward direction. Other types of packer wheel assemblies can be used with earth working tool 27. Referring to FIGS. 12 and 13, there is shown a modificaion of the earth working tool indicated generally at 127 of the invention. Tool 127 has the same as tool 27 identified with the same reference numerals having a prefix of 1. Earth working tool 127 has been laterally adjusted to increase the distance between the rows of seed 11. Spacers 196 and 197 are located between the side bars 148 and 149. Bolts 154 and 160 secure the side plates 133 and 134 to the spacers 196 and 197 and side bars 148 and 149 as shown in FIG. 13. Spacers 196 and 197 have a genrally triangular configuration with outer surfaces and surface engagement with the side bars 148 and 149 and the surfaces of the side plates 133 and 134. A width of the spacers 196 and 197 can be selected to provide for a desired lateral spacing of the lateral rows of seed 11. Wear plates 197 and 198 are secured to opposite sides of press plate 136. While there has been shown and described preferred embodiments of the invention, it is understood that changes in the structure, materials, and arrangement of structure can be made by those skilled in the art without departing from the invention. The invention is defined in the following claims. | Summary: A furrow opener and press wheel for an agricultural implement to place fertilizer and seed at different depths in soil has replaceable abrasive resistant plastic side plates and a press plate to avoid soil build up and plugging of fertilizer discharge openings. The lateral distance between the side plates is adjustable so that seeding width can be changed. A seed divider attached to the furrow opener separates the seed into lateral rows on opposite sides of a band of fertilizer placed in the soil below the press plate. | 5,132 | 108 | big_patent | en |
Summarize: XIV. HESTER AND THE PHYSICIAN. Hester bade little Pearl run down to the margin of the water, and play with the shells and tangled sea-weed, until she should have talked awhile with yonder gatherer of herbs. So the child flew away like a bird, and, making bare her small white feet, went pattering along the moist margin of the sea. Here and there she came to a full stop, and peeped curiously into a pool, left by the retiring tide as a mirror for Pearl to see her face in. Forth peeped at her, out of the pool, with dark, glistening curls around her head, and an elf-smile in her eyes, the image of a little maid, whom Pearl, having no other playmate, invited to take her hand, and run a race with her. But the visionary little maid, on her part, beckoned likewise, as if to say,--"This is a better place! Come thou into the pool!" And Pearl, stepping in, mid-leg deep, beheld her own white feet at the bottom; while, out of a still lower depth, came the gleam of a kind of fragmentary smile, floating to and fro in the agitated water. Meanwhile, her mother had accosted the physician. "I would speak a word with you," said she,--"a word that concerns us much." "Aha! and is it Mistress Hester that has a word for old Roger Chillingworth?" answered he, raising himself from his stooping posture. "With all my heart! Why, Mistress, I hear good tidings of you on all hands! No longer ago than yester-eve, a magistrate, a wise and godly man, was discoursing of your affairs, Mistress Hester, and whispered me that there had been question concerning you in the council. It was debated whether or no, with safety to the common weal, yonder scarlet letter might be taken off your bosom. On my life, Hester, I made my entreaty to the worshipful magistrate that it might be done forthwith!" "It lies not in the pleasure of the magistrates to take off this badge," calmly replied Hester. "Were I worthy to be quit of it, it would fall away of its own nature, or be transformed into something that should speak a different purport." "Nay, then, wear it, if it suit you better," rejoined he. "A woman must needs follow her own fancy, touching the adornment of her person. The letter is gayly embroidered, and shows right bravely on your bosom!" All this while, Hester had been looking steadily at the old man, and was shocked, as well as wonder-smitten, to discern what a change had been wrought upon him within the past seven years. It was not so much that he had grown older; for though the traces of advancing life were visible, he bore his age well, and seemed to retain a wiry vigor and alertness. But the former aspect of an intellectual and studious man, calm and quiet, which was what she best remembered in him, had altogether vanished, and been succeeded by an eager, searching, almost fierce, yet carefully guarded look. It seemed to be his wish and purpose to mask this expression with a smile; but the latter played him false, and flickered over his visage so derisively, that the spectator could see his blackness all the better for it. Ever and anon, too, there came a glare of red light out of his eyes; as if the old man's soul were on fire, and kept on smouldering duskily within his breast, until, by some casual puff of passion, it was blown into a momentary flame. This he repressed, as speedily as possible, and strove to look as if nothing of the kind had happened. In a word, old Roger Chillingworth was a striking evidence of man's faculty of transforming himself into a devil, if he will only, for a reasonable space of time, undertake a devil's office. This unhappy person had effected such a transformation, by devoting himself, for seven years, to the constant analysis of a heart full of torture, and deriving his enjoyment thence, and adding fuel to those fiery tortures which he analyzed and gloated over. The scarlet letter burned on Hester Prynne's bosom. Here was another ruin, the responsibility of which came partly home to her. "What see you in my face," asked the physician, "that you look at it so earnestly?" "Something that would make me weep, if there were any tears bitter enough for it," answered she. "But let it pass! It is of yonder miserable man that I would speak." "And what of him?" cried Roger Chillingworth, eagerly, as if he loved the topic, and were glad of an opportunity to discuss it with the only person of whom he could make a confidant. "Not to hide the truth, Mistress Hester, my thoughts happen just now to be busy with the gentleman. So speak freely; and I will make answer." "When we last spake together," said Hester, "now seven years ago, it was your pleasure to extort a promise of secrecy, as touching the former relation betwixt yourself and me. As the life and good fame of yonder man were in your hands, there seemed no choice to me, save to be silent, in accordance with your behest. Yet it was not without heavy misgivings that I thus bound myself; for, having cast off all duty towards other human beings, there remained a duty towards him; and something whispered me that I was betraying it, in pledging myself to keep your counsel. Since that day, no man is so near to him as you. You tread behind his every footstep. You are beside him, sleeping and waking. You search his thoughts. You burrow and rankle in his heart! Your clutch is on his life, and you cause him to die daily a living death; and still he knows you not. In permitting this, I have surely acted a false part by the only man to whom the power was left me to be true!" "What choice had you?" asked Roger Chillingworth. "My finger, pointed at this man, would have hurled him from his pulpit into a dungeon,--thence, peradventure, to the gallows!" "It had been better so!" said Hester Prynne. "What evil have I done the man?" asked Roger Chillingworth again. "I tell thee, Hester Prynne, the richest fee that ever physician earned from monarch could not have bought such care as I have wasted on this miserable priest! But for my aid, his life would have burned away in torments, within the first two years after the perpetration of his crime and thine. For, Hester, his spirit lacked the strength that could have borne up, as thine has, beneath a burden like thy scarlet letter. O, I could reveal a goodly secret! But enough! What art can do, I have exhausted on him. That he now breathes, and creeps about on earth, is owing all to me!" "Better he had died at once!" said Hester Prynne. "Yea, woman, thou sayest truly!" cried old Roger Chillingworth, letting the lurid fire of his heart blaze out before her eyes. "Better had he died at once! Never did mortal suffer what this man has suffered. And all, all, in the sight of his worst enemy! He has been conscious of me. He has felt an influence dwelling always upon him like a curse. He knew, by some spiritual sense,--for the Creator never made another being so sensitive as this,--he knew that no friendly hand was pulling at his heart-strings, and that an eye was looking curiously into him, which sought only evil, and found it. But he knew not that the eye and hand were mine! With the superstition common to his brotherhood, he fancied himself given over to a fiend, to be tortured with frightful dreams, and desperate thoughts, the sting of remorse, and despair of pardon; as a foretaste of what awaits him beyond the grave. But it was the constant shadow of my presence!--the closest propinquity of the man whom he had most vilely wronged!--and who had grown to exist only by this perpetual poison of the direst revenge! Yea, indeed!--he did not err!--there was a fiend at his elbow! A mortal man, with once a human heart, has become a fiend for his especial torment!" The unfortunate physician, while uttering these words, lifted his hands with a look of horror, as if he had beheld some frightful shape, which he could not recognize, usurping the place of his own image in a glass. It was one of those moments--which sometimes occur only at the interval of years--when a man's moral aspect is faithfully revealed to his mind's eye. Not improbably, he had never before viewed himself as he did now. "Hast thou not tortured him enough?" said Hester, noticing the old man's look. "Has he not paid thee all?" "No!--no!--He has but increased the debt!" answered the physician; and as he proceeded his manner lost its fiercer characteristics, and subsided into gloom. "Dost thou remember me, Hester, as I was nine years agone? Even then, I was in the autumn of my days, nor was it the early autumn. But all my life had been made up of earnest, studious, thoughtful, quiet years, bestowed faithfully for the increase of mine own knowledge, and faithfully, too, though this latter object was but casual to the other,--faithfully for the advancement of human welfare. No life had been more peaceful and innocent than mine; few lives so rich with benefits conferred. Dost thou remember me? Was I not, though you might deem me cold, nevertheless a man thoughtful for others, craving little for himself,--kind, true, just, and of constant, if not warm affections? Was I not all this?" "All this, and more," said Hester. "And what am I now?" demanded he, looking into her face, and permitting the whole evil within him to be written on his features. "I have already told thee what I am! A fiend! Who made me so?" "It was myself!" cried Hester, shuddering. "It was I, not less than he. Why hast thou not avenged thyself on me?" "I have left thee to the scarlet letter," replied Roger Chillingworth. "If that have not avenged me, I can do no more!" He laid his finger on it, with a smile. "It has avenged thee!" answered Hester Prynne. "I judged no less," said the physician. "And now, what wouldst thou with me touching this man?" "I must reveal the secret," answered Hester, firmly. "He must discern thee in thy true character. What may be the result, I know not. But this long debt of confidence, due from me to him, whose bane and ruin I have been, shall at length be paid. So far as concerns the overthrow or preservation of his fair fame and his earthly state, and perchance his life, he is in thy hands. Nor do I,--whom the scarlet letter has disciplined to truth, though it be the truth of red-hot iron, entering into the soul,--nor do I perceive such advantage in his living any longer a life of ghastly emptiness, that I shall stoop to implore thy mercy. Do with him as thou wilt! There is no good for him,--no good for me,--no good for thee! There is no good for little Pearl! There is no path to guide us out of this dismal maze!" "Woman, I could wellnigh pity thee!" said Roger Chillingworth, unable to restrain a thrill of admiration too; for there was a quality almost majestic in the despair which she expressed. "Thou hadst great elements. Peradventure, hadst thou met earlier with a better love than mine, this evil had not been. I pity thee, for the good that has been wasted in thy nature!" "And I thee," answered Hester Prynne, "for the hatred that has transformed a wise and just man to a fiend! Wilt thou yet purge it out of thee, and be once more human? If not for his sake, then doubly for thine own! Forgive, and leave his further retribution to the Power that claims it! I said, but now, that there could be no good event for him, or thee, or me, who are here wandering together in this gloomy maze of evil, and stumbling, at every step, over the guilt wherewith we have strewn our path. It is not so! There might be good for thee, and thee alone, since thou hast been deeply wronged, and hast it at thy will to pardon. Wilt thou give up that only privilege? Wilt thou reject that priceless benefit?" "Peace, Hester, peace!" replied the old man, with gloomy sternness. "It is not granted me to pardon. I have no such power as thou tellest me of. My old faith, long forgotten, comes back to me, and explains all that we do, and all we suffer. By thy first step awry thou didst plant the germ of evil; but since that moment, it has all been a dark necessity. Ye that have wronged me are not sinful, save in a kind of typical illusion; neither am I fiend-like, who have snatched a fiend's office from his hands. It is our fate. Let the black flower blossom as it may! Now go thy ways, and deal as thou wilt with yonder man." He waved his hand, and betook himself again to his employment of gathering herbs. [Illustration: Mandrake] [Illustration] | Summary: Hester and the Physician Hester resolves to ask Chillingworth to stop tormenting the minister. One day she and Pearl encounter him near the beach, gathering plants for his medicines. When Hester approaches him, he tells her with a smirk that he has heard "good tidings" of her, and that in fact the town fathers have recently considered allowing her to remove the scarlet letter. Hester rebuffs Chillingworth's insincere friendliness, telling him that the letter cannot be removed by human authority. Divine providence, she says, will make it fall from her chest when it is time for it to do so. She then informs Chillingworth that she feels it is time to tell the minister the truth about Chillingworth's identity. From their conversation, it is clear that Chillingworth now knows with certainty that Dimmesdale was Hester's lover and that Hester is aware of his knowledge. A change comes over Chillingworth's face, and the narrator notes that the old doctor has transformed himself into the very embodiment of evil. In a spasm of self-awareness, Chillingworth realizes how gnarled and mentally deformed he has become. He recalls the old days, when he was a benevolent scholar. He has now changed from a human being into a vengeful fiend, a mortal man who has lost his "human heart. Saying that she bears the blame for Chillingworth's tragic transformation, Hester begs him to relent in his revenge and become a human being again. The two engage in an argument over who is responsible for the current state of affairs. Chillingworth insists that his revenge and Hester's silence are" fate. Let the black flower blossom as it may. he exclaims to her. Now go thy ways, and deal as thou wilt with yonder man. | 3,212 | 413 | booksum | en |
Summarize: A young Paralympic hopeful has been able to wrap presents and pull Christmas crackers for the first time – thanks to a new bionic hand. Lyndon Longhorne, 19, lost both his legs, his right arm and the fingers on his left hand after suffering meningitis as a baby. Previously, the teenager said pulling crackers, cutting up turkey and playing board games were a struggle, but this year his Christmas has been transformed by having the gadget fitted. Last September Dragon's Den star Duncan Ballantyne accompanied Mr Longhorne to have new prosthetic legs and a new knee joint fitted. Lyndon Longhorne, 19, has been fitted with a bionic hand which has allowed him to pull crackers, cut up turkey and play board games for the first time. The hand can sense signals from the muscles in his arm. Mr Longhorne lost both his legs, his right arm and the fingers on his left hand after suffering meningitis as a baby. He was fitted with prosthetic legs (pictured) and a new knee joint on his right leg last September. This has allowed him to walk unaided and pass his driving test. This meant he was able to manoeuvre his knee without having to physically use his hand to turn it right or left. Since then, Mr Longhorne has learned to walk unaided, passed his driving test. He is also an avid swimmer, and is currently training six days a week, hoping to swim for England in the 2016 Paralympics in Rio. Mr Longhorne, of Crook, County Durham, says the bionic hand has changed his life. He said: 'I am able to open and close my hand with ease and even to different degrees using the bionic hand. 'It means I can grasp objects using the muscles in my arms and it has made a huge difference to my life.' The hand has two sensors inside which are able to read the signals sent from the muscles in his arm; one muscle tells the hand to close and the other to open. Made by prosthetics company RSLSteeper and called the 'Bebionic' hand, it is attached to his stump by suction. Mr Longhorne added: 'I am still learning to use it, it is controlled by electro-magnetic sensors which are attached to the muscles in my arm. 'I can now easily lift things and walk around holding them, which is a huge novelty for me. 'I wear it the majority of the time and I've found that I'm actually alright at wrapping presents. Mr Longhorne had a Bebionic bionic hand fitted, attached to his stump using suction. It's socket is fitted with two electrodes which are able to read the signals sent from his muscles. It's manufacturers say it has 14 different grip patterns, allowing amputees to carry out a wide range of basic tasks. It automatically senses when a gripped item is slipping and adjusts the grip to secure it, i's manufacturers claim. 'The hand has really helped me a lot over Christmas.' Mr Longhorne, who is studying business management and sport at the University of Salford, explained that he had to try three hands before making his final decision. He said: 'I wore each of the hands for about six weeks and kept a diary of each of them and then the consultant and I made a decision together to go for this one, it's easy to operate and it's very light. 'I'm still getting used to it I haven't even had it a month yet, but I can do things now that I couldn't before, like getting books off higher shelves in the library and carrying those around. 'Cutting food is easier as well. It's basic things, but they make a difference.' The hand follows on from a knee joint called the VGK ('Very Good Knee'), which meant he no longer had to manually turn his knee with his hand. He is currently trialling another knee called the C-Leg, which he was fitted with several weeks ago. As a result he has even greater flexibility of movement, and says he finds it easier to climb the stairs. As he lost his right leg above the knee, and his left below, he only needs one bionic joint on his right. Mr Longhorne added he has had a 'good year', after passing his driving test in May and moving away to university. He said: 'It was scary learning to drive at first. The hand's manufacturers claim it has 14 grip patterns giving amputees a wide range of movements. 'I can do things now that I couldn't before, like getting books off higher shelves in the library and carrying those around. Cutting food is easier as well,' Mr Longhorne said. The instructor said there was no reason I couldn't learn to drive using my legs, so I had about ten lessons and went in for my test and passed with one minor. 'It's given me so much freedom, I don't have to rely on anyone to take me places I can just get in the car and go wherever I want. 'I've had a lot of support from Duncan Bannatyne and I'm really grateful for that. He came to all of my appointments with me to get my legs and he's been great. 'I wouldn't be driving now without him.' He now in training six days a week for the 2016 Paralympics in Rio, which includes swimming and gym sessions. 'I just want to continue with university, get a good degree and see where life takes me,' he said. 'If I go to Rio then that's a bonus.' | Summary: Lyndon Longhorne, now 19, suffered deadly infection meningitis as a baby. He lost both his legs, his right arm and the fingers on his left hand. Had prosthetic limbs fitted last year as well as a bionic knee on his right leg. Is training six days a week to swim in the 2016 Paralympics in Rio. Now has a bionic hand which detects muscle movement in his arm. | 1,233 | 97 | cnn_dailymail | en |
Write a title and summarize: In the short-germ beetle Tribolium castaneum, waves of pair-rule gene expression propagate from the posterior end of the embryo towards the anterior and eventually freeze into stable stripes, partitioning the anterior-posterior axis into segments. Similar waves in vertebrates are assumed to arise due to the modulation of a molecular clock by a posterior-to-anterior frequency gradient. However, neither a molecular candidate nor a functional role has been identified to date for such a frequency gradient, either in vertebrates or elsewhere. Here we provide evidence that the posterior gradient of Tc-caudal expression regulates the oscillation frequency of pair-rule gene expression in Tribolium. We show this by analyzing the spatiotemporal dynamics of Tc-even-skipped expression in strong and mild knockdown of Tc-caudal, and by correlating the extension, level and slope of the Tc-caudal expression gradient to the spatiotemporal dynamics of Tc-even-skipped expression in wild type as well as in different RNAi knockdowns of Tc-caudal regulators. Further, we show that besides its absolute importance for stripe generation in the static phase of the Tribolium blastoderm, a frequency gradient might serve as a buffer against noise during axis elongation phase in Tribolium as well as vertebrates. Our results highlight the role of frequency gradients in pattern formation. The anterior-posterior (AP) axis of arthropods, annelids, and vertebrates is partitioned into segments. The French flag model, in which threshold concentrations of morphogen gradients are interpreted by downstream genes to partition a developing tissue [1], [2], provides the main theoretical framework explaining segmentation in Drosophila. Specifically, gradients of maternal factors span the AP axis of Drosophila providing positional information to downstream gap genes, which in turn diffuse in the syncytial blastoderm to form more localized morphogen gradients. Both maternal and gap gene gradients provide further positional information to the pair-rule genes whose striped expression is the first indication of segmentation in the embryo [3]. In Drosophila, all segments form more or less simultaneously in a syncytial blastoderm of fixed AP axis length. In contrast, vertebrate segmentation (somitogenesis) takes place sequentially in an elongating and cellularized embryo. A different model, the ‘clock and wavefront’ explains segmentation in vertebrates [4], [5]. Multiple genes (hairy/enhancer-of-split and genes of Notch, Wnt and FGF signaling pathways) show oscillatory expression in the presomitic mesoderm (PSM) of the vertebrate embryo and are thought to be constituents of a molecular clock [6], [7]. In cells located anterior to a wavefront, oscillations are arrested into stable stripes. The wavefront is thought to be defined by a moving threshold that forms within the overlapping posterior gradients of Wnt and FGF [8], [9] and an opposing retinoic acid gradient [10]. Oscillations seem to arrest gradually (i. e. they are modulated by a frequency gradient) as evidenced by kinematic expression waves that sweep the PSM from posterior to anterior [7]. In most short-germ arthropods, anterior segments form in a blastoderm, as in Drosophila, while posterior segments form subsequently during the germband stage out of a population of cells at the posterior end of the embryo (termed the ‘growth zone’) [11], reminiscent of somitogenesis in vertebrates. Although it is conceivable that short-germ arthropods utilize a ‘French flag’-based segmentation mechanism in the blastoderm and a ‘clock and wavefront’ mechanism in the germband, it has recently been shown that a segmentation clock operates in both the germband [12] and blastoderm [13] of the short-germ insect Tribolium castaneum, where waves of pair-rule gene expression (specifically Tc-even-skipped (Tc-eve) ) propagate from posterior to anterior [13]. The identification of factors that provide positional information for segmentation in the blastoderm of short-germ arthropods has been controversial [14]–[18]. Demonstration of the clock-based nature of short-germ segmentation fuels this debate as attention now turns to the search for factors functioning as a wavefront. The homeodomain transcription factor Caudal (Cad) has been implicated as playing a prominent role in AP patterning in arthropods since its expression overlaps with the newly forming stripes [19]. Cad is required for segmentation in the Drosophila abdomen [20], and for posterior patterning in other species [21], [22]. It plays an even more prominent role in non-diptran insect segmentation; it is required for trunk segmentation in Nasonia vitripennis [23] and for both trunk and gnathal segmentation in Tribolium castaneum [24] and Gryllus bimaculatus [25]. However, the exact role of Cad in segmentation is still not known. Here we test the hypothesis that the posterior gradient of Tribolium cad (Tc-cad) expression regulates the oscillation frequency of pair-rule gene expression to produce kinematic waves in the Tribolium blastoderm. We found that the expression of Tc-eve was abolished in strong Tc-cad RNAi knock-down embryos, but in weak Tc-cad knock-down embryos, the Tc-eve expression domain was posteriorly shifted and its oscillation frequency reduced. Perturbing the Tc-cad gradient in different ways by knocking-down its regulators further demonstrated that the extension, intensity, and slope of the Tc-cad gradient correlated with the extension, frequency, and width of Tc-eve expression waves, respectively. As shown by computer simulations, these observations are consistent with the hypothesis that Tc-cad functions as a frequency gradient regulating the spatiotemporal dynamics of pair-rule gene oscillation in Tribolium. These observations, combined with the continued expression of Tc-cad in a posterior gradient suggest that Tc-cad also acts as a wavefront in the elongating germband. Our study highlights the concept of a frequency gradient as a pattern formation mechanism. Using computer modeling, we also showed that a graded frequency profile might even be essential within the clock-and-wavefront model as a buffer against noise. The wave dynamics of Tc-eve in Tribolium can be explained by assuming a posterior-to-anterior gradient that positively regulates the frequency of Tc-eve oscillations [13]. Tc-cad is an obvious candidate to encode such a frequency gradient because its mRNA expression forms a posterior-to-anterior gradient that overlaps the Tc-eve expression waves arising at the posterior throughout Tribolium segmentation (Figure 1 A–D). Since studying segmentation in the germband phase of Tribolium development is hindered by the truncation phenotype generated by most segmentation gene knock-downs, we largely restricted our analysis to the stripes that form during the blastoderm stage. The expression of Tc-cad in the blastoderm (Figure 1 E) is approximated with reasonable accuracy by a posterior-to-anterior linear gradient that plateaus at the posterior end (Figure 1 F; Text S3). We used three descriptors to characterize this gradient: maximum posterior (plateau) value, position of anterior border, and slope (Figure 1 F). We analyzed the temporal dynamics of the Tc-cad gradient by calculating its three descriptors at 14–17 and 17–20 hours after egg lay (AEL) (Figure 1 G), spanning the formation of the first and second Tc-eve expression stripes in wild type (WT) [13] (analysis of later times was precluded by primitive pit formation, asterisk in Figure 1 C). As shown in Figure 1 G, the anterior border of Tc-cad expression gradient did not experience a significant shift during the formation of the first and second Tc-eve stripes, (which is also evident in Figure 1 A, B). However, both the maximum posterior value and the slope of the Tc-cad gradient increased over time. This indicates that the Tc-cad gradient was building up during the formation of the first and second Tc-eve stripes, but did not undergo a substantial shift along the AP axis (Figure 1 H). Characterizing Tc-cad gradient dynamics with higher temporal resolution (Figure S1) indicates that this buildup phase occurred between 14 to 16 hours AEL (i. e. before completion of the first Tc-eve stripe), after which the gradient was more or less static. This argues against a substantial influence of Tc-cad temporal dynamics on the wave dynamics of Tc-eve expression in the blastoderm. By the time the third stripe formed in the germ rudiment, the Tc-cad gradient had retreated toward posterior (Figure 1 C). The spatial distribution of Tc-cad renders it a probable wavefront candidate in a clock-and-wavefront model. In the traditional model, a wavefront should retract posteriorly (like Tc-cad expression during the germband stage). However, a static but smooth gradient (like Tc-cad expression during the formation of first and second Tc-eve stripes in the blastoderm) that modulates the frequency of Tc-eve oscillation is, in principle, capable of forming a striped expression pattern (Movies S1, lower panel) [13], [26]. Taking the initial buildup phase of the Tc-cad gradient into consideration (Movies S1, upper panel) yields similar results. However, this buildup phase is expected to slow down the formation of the first stripe (Figure S2). This agrees with experiment, since the first cycle of Tc-eve oscillations starts at 13. 5 hours AEL and ends at 17 hours AEL (i. e. the first stripe takes 3. 5 hours to form), while the second cycle starts at 17 hours AEL and ends at 20 hours (i. e. the second stripe takes 3 hours to form) [13]. However, this is not obvious in the timing results presented here (see below), since we chose to start our analysis at 14 hours AEL. In both vertebrates and arthropods, canonical Wnt is a positive regulator of cdx/cad [25], [27]–[29]. Once bound by Wnt ligand, the receptor Frizzled recruits the β-catenin destruction complex (comprising Axin, APC, and other factors), rendering β-catenin free to enter the nucleus and bind Pangolin (TCF) with the help of Legless (Lgs), Pygopous (Pygo) and other coactivators [30] to activate Wnt targets. In Tribolium, wnt1 and wnt8 are expressed at the posterior pole of the blastoderm, and at the posterior end of the growth-zone in the germband [31], which is expected to produce a posterior gradient of Wnt activity, the formation of which is enhanced by the anterior localization of Wnt repressors in the blastoderm [28], [32]. Manipulating Wnt activity affected Tc-cad expression in the Tribolium blastoderm. Knocking down Tc-lgs (a positive Wnt regulator) by means of maternal RNAi (Methods) shifted the Tc-cad expression gradient posteriorly (compare Figure 2 C–C′ to Figure 2 A–A′). In addition, the posterior maximum value of Tc-cad and slope of the gradient were reduced in Tc-lgs RNAi embryos compared to WT (Figure 2 D–D″). Knocking down Tc-apc1 (a negative Wnt regulator) repositioned the Tc-cad gradient anteriorly (Figure 2 G–H″). Interestingly, the maximum posterior value of the Tc-cad expression gradient at 14–17 hours AEL was lower in Tc-apc1 RNAi embryos than in WT embryos (Figure 2 H), but eventually reached WT levels by 17–20 hours AEL (Figure 2 H′). Thus, it appears that the Tc-cad expression gradient takes longer to mature in Tc-apc1 RNAi than in WT embryos, which might be indicative of early negative Wnt regulation of Tc-cad. Knocking down another Wnt regulator, Tc-pan, also perturbed the Tc-cad expression gradient. Pan, a component of the activator complex, also acts as a repressor in the absence of nuclear β-catenin [33]. Hence, we expected Wnt activity to be reduced posteriorly but increased anteriorly in Tc-pan RNAi embryos compared to WT, resulting in a shallower Wnt gradient across the blastoderm, and consequently a shallower Tc-cad gradient. As expected, the border of the Tc-cad gradient in Tc-pan RNAi embryos shifted anteriorly, the gradient reached a lower maximum posterior value, and the slope was lower compared to WT (Figure 2 E–F″). In Drosophila, two Hox3 type genes are involved in early patterning: bicoid (bcd), which is expressed anteriorly and plays a major role in AP patterning, and zerknüllt (zen), which is expressed dorsally and specifies the amnioserosa [34]. Tribolium lacks bcd [17] but one of its zen homologs, Tc-zen1, is expressed both anteriorly and dorsally [35]. Anterior expression precedes dorsal expression and is suspected to play a role in AP patterning [36]. As shown in Figure 2 I–J″, the Tc-cad gradient in Tc-zen1 RNAi embryos shifted anteriorly, but had the same slope and maximum posterior expression level as WT, indicating that Tc-zen1 represses Tc-cad anteriorly (see Figure 2 B for a summary of Tc-cad regulation). In Tribolium, Tc-eve is expressed in waves that shrink while propagating from posterior to anterior (Figure 3 A) [13]. Tc-eve and Tc-cad RNAi embryo display similar phenotypes lacking all post oral segments, and previous studies implicate cad in the regulation of eve in arthropods [24], [25]. Axis elongation is an essential component of the clock-and-wavefront model. We have previously shown that blastoderm segmentation in Tribolium seems to be clock-based [13]. Despite the lack of axis elongation at the blastoderm stage, we did not exclude the possible existence of a retreating frequency gradient (wavefront). In the current study, we provide evidence that Tc-cad expression acts as a frequency gradient that modulates pair-rule gene oscillations in the blastoderm. Although a static step frequency gradient (i. e. suddenly dropping from non-zero to zero frequency) does not possess any patterning capacity, a static but gradually decreasing frequency gradient can generate a striped pattern [26]. Indeed, the first two stripes of Tc-eve form during a time period when the Tc-cad gradient is largely static. After the formation of the first two stripes, Tc-cad expression then abruptly retreats to the prospective growth zone (Figure 1 C). Later during axis elongation in the germband stage, Tc-cad expression retreats posteriorly with every newly forming Tc-eve stripe (Figure 1 D). However, in principle, a step frequency gradient is capable of generating a striped pattern during the germband retraction phase. In vertebrates, a transition from high to low frequency (termed the ‘arrest front’) is thought to be determined by a threshold within a retracting posterior gradient. Such a mechanism might be very sensitive to the location of the threshold. Uncertainty in threshold location due to noise might lead to the generation of noisy patterns. On the other hand, gradually arresting oscillations would average out the noise and make the mechanism independent of precise threshold location. To investigate this, we developed two computer models for the clock-and-wavefront mechanism: one that utilizes a step frequency gradient by applying a threshold on a retracting smooth gradient (threshold-based model), and the other utilizes a smooth retracting frequency gradient without applying any thresholds (threshold-free model). Both generated similar striped patterns in the absence of noise (Figures 6 A–D; Movies S7 and S8). We then investigated the performance of both models after introducing random fluctuations in the intensity of the posterior gradient at each cell. This is expected to result in independent random shifts in threshold locations across the lateral axis of the embryo, which ultimately leads to salt-and-pepper noise at the stripe borders; however, the threshold-free model is more robust to this type of noise than the threshold-based model (Figures 6 E–H; Movies S9 and S10). In Drosophila, maternal cad mRNA (Dm-cad) is ubiquitously expressed in the early blastoderm [37]. A posterior-to-anterior protein gradient of Dm-Cad forms due to translational repression by a reciprocal gradient of Dm-Bicoid [38]. Dm-Cad acts as an activator of posterior gap [39] and pair-rule genes [40] and binds to the enhancers of these genes [41], [42]. However, the mild segmentation defects in embryos in which the shape of Dm-Cad gradient has been altered argues against its function as a morphogen gradient [20], [43]. In the wasp Nasonia vitripennis, Nv-cad plays a more prominent role in activating gap and pair-rule genes, and a limited positioning role [23]. In the cricket Gryllus bimaculatus, Gb-cad was found to activate the pair-rule gene Gb-eve, and activate and position gap gene domains. This indicates that cad might act as a morphogen gradient in non-dipteran insects. In this study, we described similar results in Tribolium. We showed that in strong Tc-cad RNAi, expression of Tc-eve was abolished (Figure S2 A); while in weak Tc-cad RNAi, Tc-eve expression was posteriorly shifted (Figure 3 B). However, a morphogen gradient acting through concentration thresholds is less likely to act in positioning the highly dynamic pair-rule gene expression domains in Tribolium. Instead, we argue that Tc-cad regulates the frequency of a pair-rule clock to produce the observed wave dynamics. Three cad homologs are found in mouse: Cdx1, Cdx2, and Cdx4. They are expressed in nested domains in the posterior end of the embryo. The Cdx1–Cdx2 double mutant exhibits fused somites [44], suggesting a role in somitogenesis. However, the Cdx1–Cdx2 double mutant also shows down-regulation of some caudalizing factors involved in somitogenesis (such as wnt3a) that are themselves Cdx regulators [45], [46]. Cdx genes also directly regulate Hox genes in a dose dependent manner [47], [48], and even regulate their activation times [49]. In summary, cad (-related) genes are involved in posterior patterning in many species. While it is not clear whether they play a permissive or instructive role, there is evidence that they might act as a morphogen gradient for gap genes in basal insects (like in Gryllus) and for Hox genes in vertebrates. In this study, we showed that Tc-cad regulates the spatiotemporal dynamics of Tribolium pair-rule genes in a dose dependent manner, stressing the instructive role of cad in the development of a non-dipteran insect. However, we cannot exclude the possibility that Tc-cad regulates pair-rule genes indirectly. Indeed, Tc-cad and Wnt might cross-regulate in a positive feedback loop to form identical gradients. In this case, it is hard to decide which is the direct regulator (or whether both Wnt and Tc-Cad are direct regulators) of Tc-eve expression without performing detailed cis-regulatory analysis of the Tc-eve locus. In the original formulation of the clock-and-wavefront model, the anterior-to-posterior movement of a step frequency profile (i. e. suddenly dropping from non-zero to zero frequency) over an oscillating field of cells sequentially generates a striped pattern in an anterior-to-posterior order [4]. Later, this mechanism was modified by assuming a graded frequency profile to accommodate the observation that oscillations organize into kinematic waves in the chick PSM [7]. Several efforts have been made to identify molecular gradient (s) that regulate the frequency of the vertebrate segmentation clock. A posterior-to-anterior Wnt activity gradient was found to define the PSM oscillation domain in the mouse [50], [51]. Furthermore, down-regulation of Wnt activity reduced the clock frequency in both mouse and chick [52]. However, elevated and flattened constitutive stabilization of β-catenin in the mouse PSM only extended the oscillation domain, arguing against a role for the shape of Wnt activity gradient in segmentation [50]. A posterior-to-anterior FGF gradient in the PSM was found to define where oscillations arrest [9], [53], [54], but manipulating the level of FGF signaling does not alter the clock period [9], [52]. A gradient of Her13. 2 in zebrafish was suggested to modulate clock frequency through heterodimerization with other zebrafish clock constituents: Her1 and Her7 [55], [56]. However, this idea was recently challenged and an alternative model of gradual switching between two oscillatory modules was suggested [57]. It is not known whether the gradual arrest of oscillations and the resulting kinematic waves in vertebrates have any functional role or are a mere peculiarity, since, based on computer simulations of the clock-and-wavefront model, stripe widths depend only on the wavefront velocity and the maximum clock period, not on the shape of the frequency profile [5]. Although used for cosmetic means within the clock-and-wavefront model, a graded frequency profile (even a static one) by itself has a patterning capacity [26]; kinematic waves were observed in an oscillating Zhabotinskii chemical reaction, where a reactant controlling the frequency of oscillation is distributed in a gradient [58], [59]. Since a static step frequency profile is unable to generate any stripes, the patterning capacity of a graded frequency profile might explain how blastodermal Tc-eve stripes in Tribolium form in the absence of axis elongation. Although the possibility of a yet unidentified frequency gradient that sweeps across the blastoderm still exists, we showed in this study that a strong candidate for the frequency gradient in Tribolium, Tc-cad, does not appreciably shift during the formation of the first two Tc-eve stripes (Figure 1 G, H). In addition to its necessity in the absence of axis elongation, a graded frequency profile renders the clock-and-wavefront robust against noise in wavefront gene expression, as shown by computer simulations (Figure 6 and Movies S7, S8, S9, S10). This improvement in robustness might be due to the distributed nature by which oscillations are arrested in a graded frequency profile, in contrast to the total reliance on a single threshold in a step frequency profile. This and other recent works reinforce the importance of the concept of a frequency (or phase) gradient in sequential patterning [60], [61]. In clock-based segmentation models that utilize a static frequency gradient, stripes continue to shrink and never stabilize (although stripe shrinkage rate decreases with time, Movie S1). Stripe stabilization can be achieved by the retraction of the frequency gradient, kick-starting another ‘stabilizing’ genetic program that completely freezes the stripes. Such a stabilizing program might further refine the stripes and/or split them into secondary stripes. Interestingly, in the germband stage (where Tc-cad retracts continuously along with germband elongation), once a Tc-eve stripe forms, it splits into two secondary (segmental) stripes [13], whereas in the blastoderm stage, the first Tc-eve stripe does not split until Tc-cad expression completely retreats towards the posterior, at which time the second Tc-eve stripe is already formed and the third stripe is starting to emerge (Figure 1 B–D). This suggests a link between Tc-cad retraction and Tc-eve splitting. Stabilizing and refinement/splitting strategies might rely on auto- and cross-regulatory interactions between pair-rule genes or on a reaction diffusion mechanism [62] or both. In situ hybridization was performed using DIG-labeled RNA probes and anti-DIG: : AP antibody (Roche). Signal was developed using NBT/BCIP (BM Purple, Roche), or Fast Red/HNPP (Roche). Immunocytochemistry was performed using anti-Eve (mouse monoclonal antibody 2B8, hybridoma bank, University of Iowa) as primary, and anti-mouse: : POD as secondary antibody (ABC kit, Vector). AlexaFluor 488 tyramide (Invitrogen) was used to give green fluorescent signal. All expression analyses were performed using embryos from uninjected GA-1 strain (WT) or adult GA-1 females injected with double-stranded RNA (ds RNA) of the gene of interest. dsRNA was synthesized using the T7 megascript kit (Ambion) and mixed with injection buffer (5 mM KCl, 0. 1 mM KPO4, pH 6. 8) before injection. Used dsRNA concentrations: 200 ng/µl for severe Tc-cad, 7. 5 ng/µl for mild Tc-cad, 200 ng/µl for Tc-lgs, 200 ng/µl for Tc-pan, 1 µg/µl for Tc-apc1,1 µg/µl for Tc-zen1, and 200 ng/µl; 1 µg/µl for Tc-lgs; Tc-zen double RNAi. One hour developmental windows were generated by incubating one hour egg collections at 23–24°C for the desired length of time. For 3-hour developmental windows, eggs were collected after three hours instead of one hour. The beetles were reared in whole-wheat flour supplemented with 5% dried yeast. | Title: Caudal Regulates the Spatiotemporal Dynamics of Pair-Rule Waves in Tribolium Summary: One of the most popular problems in development is how the anterior-posterior axis of vertebrates, arthropods and annelids is partitioned into segments. In vertebrates, and recently shown in the beetle Tribolium castaneum, segments are demarcated by means of gene expression waves that propagate from posterior to anterior as the embryo elongates. These waves are assumed to arise due to the regulation of a molecular clock by a frequency gradient. However, to date, neither a candidate nor a functional role has been identified for such a frequency gradient. Here we provide evidence that a static expression gradient of caudal regulates pair-rule oscillations during blastoderm stage in Tribolium. In such a static setup, a frequency gradient is essential to convert clock oscillations into a striped pattern. We further show that a frequency gradient might be essential even in the presence of axis elongation as a buffer against noise. Our work also provides the best evidence to date that Caudal acts as a type of morphogen gradient in the blastoderm of short-germ arthropods; however, Caudal seems to convey positional information through frequency regulation of pair-rule oscillations, rather than through threshold concentration levels in the gradient. | 6,230 | 301 | lay_plos | en |
Write a title and summarize: SECTION 1. SHORT TITLE. This Act may be cited as the ``American Indian Transportation Improvement Act of 1997''. SEC. 2. FINDINGS. Congress finds that-- (1) the Federal Government has a responsibility to promote the general welfare of the United States by supporting interstate, national, and international commerce through the use of Federal resources to assist States, Indian tribes, and local governments in the development and maintenance of physical infrastructure, including roads, highways, byways, bridges, and other transportation-related structures; (2) there exists a unique legal and political relationship between the United States and tribal governments and a unique Federal responsibility to American Indians and Alaska Natives; (3) under law and practice, the United States has undertaken a trust responsibility to protect and preserve Indian tribes, Indians, and tribal assets and resources; (4) this Federal responsibility includes working with tribal governments and their members to improve the condition of the physical infrastructure used by tribes for their economic well-being; (5) the demonstrated need for improvements to physical infrastructure on Indian land is acute, and the Federal Government should assist in making the improvements and in developing tribal and private mechanisms to achieve the goals of economic self-sufficiency and political self-determination; (6)(A) Indian tribes of the United States are served by over 50,000 miles of roads nationwide; (B) the road system of the Bureau of Indian Affairs constitutes about 21,000 miles, or 42 percent, of roads serving Indian tribes; (C) State and county roads make up the largest percentage, about 49 percent, of roads serving Indian tribes; and (D) tribal roads account for approximately 5 percent, and private and Federal roads (other than Bureau of Indian Affairs roads) make up the small balance of approximately 4 percent, of roads serving Indian tribes; (7)(A) the Indian reservation roads program established under the Intermodal Surface Transportation Efficiency Act of 1991 (Public Law 102-240) is targeted at the Bureau of Indian Affairs road system that constitutes less than \1/2\ of the total mileage of roads on Indian reservations in the United States; (B) only 11 percent of the Bureau of Indian Affairs roads are rated as being in good condition; and (C) of the unpaved Bureau of Indian Affairs roads, 90 percent are known to be in poor condition and none of the unpaved roads are rated as being in good condition; (8)(A) annual funding of the Indian reservation roads program, through the Highway Trust Fund, as authorized by the Intermodal Surface Transportation Efficiency Act of 1991, has become the major source of funding for new road construction on Indian land in the United States; (B) the Bureau of Indian Affairs road construction budget has virtually vanished; and (C) the Bureau of Indian Affairs continues to provide minimal funding of about $25,000,000 per fiscal year for road maintenance of its road system; (9)(A) in the late 1950's, Bureau of Indian Affairs road construction and maintenance funding reached a high of $10,000,000 per fiscal year for the first time in history; (B) by 1979, Bureau of Indian Affairs road budgets for construction and maintenance reached their peak of almost $80,000,000 per fiscal year, and then declined rapidly; (C) in the Surface Transportation Assistance Act of 1982 (Public Law 97-424), the funding levels for the Indian reservation roads program stabilized at about $100,000,000 through the Highway Trust Fund for each of fiscal years 1984 through 1986; (D) the Surface Transportation and Uniform Relocation Assistance Act of 1987 (Public Law 100-17) reduced the annual Highway Trust Fund authorization to $80,000,000 for each of fiscal years 1987 through 1991; and (E) in almost every fiscal year since fiscal year 1992, the Indian reservation roads program has been funded at $191,000,000 per fiscal year; (10)(A) Indian reservation roads are needed to support economic development activities, education, health, and virtually every aspect of reservation life; and (B) some of the most scenic highways in the United States are on Indian reservations; (11)(A) at current and historic levels of funding, Indian road conditions continue to fall behind national standards; and (B) to help alleviate some of the poor transportation conditions on Indian reservations in the United States, there is a need to increase the level of funding, from the Highway Trust Fund, for the Indian reservation roads program to $300,000,000 per fiscal year, from the current level of $191,000,000 per fiscal year; and (12) Federal assistance described in this section should be provided in a manner that recognizes the rights of Indian self- determination and self-governance by providing the assistance, to the maximum extent practicable, directly to Indian tribal governments. SEC. 3. INDIAN RESERVATION ROADS. (a) In General.--Section 1003(a)(6)(A) of the Intermodal Surface Transportation Efficiency Act of 1991 (Public Law 102-240; 105 Stat. 1919) is amended-- (1) by striking ``1992 and'' and inserting ``1992,''; and (2) by inserting before the period at the end the following: ``, $250,000,000 for fiscal year 1998, $275,000,000 for fiscal year 1999, and $300,000,000 for each of fiscal years 2000 through 2002''. (b) Mass Transportation Services.--Section 1032(d) of the Intermodal Surface Transportation Efficiency Act of 1991 (23 U.S.C. 202 note; 105 Stat. 1975) is amended by inserting before the period at the end the following: ``and not more than 3 percent of the funds allocated for Indian reservation roads for a fiscal year may be used for providing mass transportation services to Indian tribes''. (c) Maintenance.--Section 204(b) of title 23, United States Code, is amended in the second sentence by inserting before the period at the end the following: ``and, in the case of Indian reservation roads, maintenance thereof''. SEC. 4. APPORTIONMENT ADJUSTMENTS. Section 1015 of the Intermodal Surface Transportation Efficiency Act of 1991 (23 U.S.C. 104 note; 105 Stat. 1943) is amended-- (1) by striking ``1997'' each place it appears and inserting ``2002''; and (2) in subsection (a)(1), by inserting after ``Federal lands highways program'' the following: ``(other than funds for a public land highway constructed on an Indian reservation)''. SEC. 5. SCENIC BYWAYS PROGRAM. Section 1047 of the Intermodal Surface Transportation Efficiency Act of 1991 (23 U.S.C. 101 note; 105 Stat. 1996) is amended-- (1) in subsection (b)-- (A) by inserting ``and Indian tribes'' after ``the States'' each place it appears; (B) by striking ``term is'' and inserting ``terms are''; and (C) by inserting ``or Indian tribe'' after ``State''; (2) in subsection (c), by inserting ``or Indian tribe'' after ``State''; and (3) in subsection (d)-- (A) in the first sentence-- (i) by striking ``There'' and inserting the following: ``(1) In general.--Subject to paragraph (2), there''; and (ii) by striking ``1995, 1996, and 1997'' and inserting ``1995 through 2002''; and (B) by adding at the end the following: ``(2) Indian tribes.--Not less than 1 percent of the funds made available to the Secretary for a fiscal year under paragraph (1) shall be used by the Secretary to make competitive grants to Indian tribes for the planning, design, and development of Indian tribe scenic byway programs.''. SEC. 6. DEFINITIONS. Section 101(a) of title 23, United States Code, is amended by inserting after the undesignated paragraph defining ``Indian reservation roads'' the following: ``The term `Indian tribal transportation department' means the department, commission, board, or member of an Indian tribe that is charged by its laws with the responsibility for highway construction. ``The term `Indian tribe' has the meaning given the term in section 4 of the Indian Self-Determination and Education Assistance Act (25 U.S.C. 450b).''. SEC. 7. CERTIFICATION ACCEPTANCE. Section 117(a) of title 23, United States Code, is amended-- (1) by inserting ``or Indian tribe'' after ``any State'' each place it appears; (2) by inserting ``or Indian tribal transportation department'' after ``State highway department''; and (3) by inserting ``or tribal'' after ``with State''. SEC. 8. TRANSPORTATION ENHANCEMENT ACTIVITIES. Section 133(d)(2) of title 23, United States Code, is amended-- (1) by striking ``10 percent'' and inserting the following: ``(A) In general.--Subject to subparagraph (B), 10 percent''; and (2) by adding at the end the following: ``(B) Indian tribes.--Not less than 1 percent of the funds made available to a State for a fiscal year under subparagraph (A) shall be transferred to, and used by, the Secretary to make competitive grants to Indian tribes for transportation enhancement activities.''. SEC. 9. INDIAN RESERVATION BRIDGES. Section 144(g) of title 23, United States Code, is amended by striking paragraph (4) and inserting the following: ``(4) Indian reservation bridges.--Notwithstanding subsection (e), an amount equal to 1 percent of the highway bridge replacement and rehabilitation program funds available to be apportioned to States under this section shall be allocated to the Secretary for projects to replace, rehabilitate, paint, or apply calcium magnesium acetate to highway bridges that are part of the Indian reservation road system, with priority given to bridges with the highest level of deficiency (as determined in accordance with the National Bridge Inspection Standards of the Bureau of Indian Affairs).''. SEC. 10. INDIAN TECHNICAL CENTERS. Section 326(c) of title 23, United States Code, is amended in the second sentence-- (1) by striking ``$6,000,000 per fiscal year for each of the fiscal years 1992, 1993, 1994, 1995, 1996, and 1997'' and inserting ``$10,800,000 for each of fiscal years 1992 through 2002''; and (2) by inserting before the period at the end the following: ``and including at least $1,000,000 per fiscal year for each of the Indian technical centers established under subsection (b)''. SEC. 11. HIGHWAY SAFETY PROGRAMS. Section 402(i) of title 23, United States Code, is amended-- (1) by striking ``and `political subdivision of a State' includes'' and inserting ``and''; and (2) in the first proviso, by striking ``to the Secretary of the Interior'' and inserting ``for Indian tribes''. SEC. 12. MASS TRANSIT SET-ASIDE. Section 5338(h) of title 49, United States Code, is amended-- (1) in paragraph (2), by striking ``and'' at the end; (2) in paragraph (3), by striking the period at the end and inserting ``and''; and (3) by adding at the end the following: ``(4) not less than 1.0 percent is available for transportation services to Indian tribes-- ``(A) under an allocation formula, which shall be established by the Secretary of Transportation through negotiations with Indian tribes; and ``(B) with respect to any fiscal year commencing before the formula is established under subparagraph (A), under an allocation formula established by the Administrator of the Federal Transit Administration of the Department of Transportation.''. | Title: American Indian Transportation Improvement Act of 1997 Summary: American Indian Transportation Improvement Act of 1997 - Amends the Intermodal Surface Transportation Efficiency Act of 1991 to: (1) extend and increase through FY 2002 the authorization of appropriations for Indian reservation roads under the Federal lands highway program; (2) permit up to three percent of the funds allocated for Indian reservation roads for a fiscal year to be used for providing mass transportation services to Indian tribes; and (3) exclude funds made available under the Federal lands highway program for a public land highway constructed on an Indian reservation from the apportionment adjustments, hold harmless provisions. (Sec. 5) Revises requirements regarding the scenic byway programs to: (1) require the Secretary of Transportation to provide technical assistance and make grants to Indian tribes for the planning and development of Indian tribe scenic byway programs; (2) provide for a Federal share of 80 percent for the costs of planning and development of Indian tribe scenic byway programs; and (3) extend such programs through FY 2002, requiring that not less than one percent of funds made available for a fiscal year be used to make competitive grants to Indian tribes for the planning and development of Indian tribe scenic byway programs. (Sec. 6) Amends Federal law concerning highways to define the terms: (1) "Indian tribal transportation department"; and (2) "Indian tribe." (Sec. 7) Revises the requirement regarding acceptance by the Secretary of certification relating to certain highway or other transportation construction projects to include Indian tribes. (Sec. 8) Revises the requirement regarding the allocation of apportioned funds for highway safety programs to require that not less than one percent of the ten percent of funds made available to a State under the surface transportation program for transportation enhancement activities for a fiscal year be transferred to, and used by, the Secretary to make competitive grants to Indian tribes for transportation enhancement activities. (Sec. 9) Repeals requirements regarding set asides for Indian reservation bridges under the highway bridge replacement and rehabilitation program. Replaces them with a requirement providing for an amount equal to one percent of the highway bridge replacement and rehabilitation program funds available to be apportioned to States, to be allocated to the Secretary for projects to replace, rehabilitate, paint, or apply calcium magnesium acetate to highway bridges that are part of the Indian reservation road system, with priority given to bridges with the highest level of deficiency. (Sec. 10) Revises the requirement with respect to the set aside for technical assistance centers to: (1) extend and increase through FY 2002 the amount of funding set aside for technical and financial support for such centers; and (2) require that the set aside amount include at least $1 million per fiscal year for each of the Indian technical centers established. (Sec. 11) Revises requirements relating to highway safety programs to: (1) remove reference to "political subdivision of a State" with respect to the application of the requirements on Indian reservations; and (2) require that 95 percent of funds for highway safety programs on Indian reservations be apportioned to Indian tribes (currently such funds are apportioned to the Secretary of the Interior). (Sec. 12) Amends Federal law concerning transportation to revise the requirement relating to the set-asides from the Mass Transit Account of the Highway Trust Fund to require that not less than one percent is available for transportation services to Indian tribes: (1) under an allocation formula, to be established by the Secretary through negotiations with Indian tribes; and (2) with respect to any fiscal year commencing before the formula is established, under an allocation formula established by the Administrator of the Federal Transit Administration. | 3,060 | 820 | billsum | en |
Summarize: Sono stati 186 i nuovi casi accertati Covid in Campania. Dato sensibilmente più basso dei giorni precedenti (il 29 agosto erano 431), ma questo dipende anche dal numero di tamponi esaminati, che di domenica sono sempre di meno (5.196 rispetto ai 15.652 del giorno precedente, con una percentuale di positività quindi del 3,58%. Complessivamente in Campania sono stati registrati 445.306 dall'inizio dell'epidemia, con 428.178 guariti e 7.729 morti. Il bollettino del 30 agosto, diffuso nel pomeriggio di ieri dall'Unità di Crisi della Regione Campania, aggiorna anche il numero dei decessi: si registrano ulteriori 9 vittime, di cui 8 nelle 48 precedenti e 1 morta in precedenza ma registrata il 29 agosto (i dati dei bollettini sono, come sempre, relativi alla situazione della mezzanotte precedente). Più dettagliata la tabella diffusa dalla Protezione Civile nazionale, che riporta anche il numero dei guariti (+402) e quello degli attualmente positivi, ovvero delle persone contagiate e che risultano ancora infette: in Campania ce ne sono 9.399 (225). I ricoverati in ospedale sono 384, di cui 366 (+8) in degenza ordinaria e area non critica, su 3.160 posti disponibili (tra offerta pubblica e privata) e 18 (-1) in Rianimazione, su 656 posti letto disponibili nelle strutture sanitarie regionali. | Summary: In Campania ci sono 186 nuovi positivi Covid, emersi dall'analisi di 5.196 tamponi (tra antigenici rapidi e molecolari). Cala, seppur molto lentamente, il tasso di incidenza settimanale (da 62,62 a 62,55 nuovi positivi per 100mila abitanti); occupato il 9,5% dei posti letto in area non critica e il 2,74% di quelli in Terapia Intensiva. | 346 | 108 | fanpage | it |
Summarize: One of Britain's worst boxers who is so bad he describes himself as a 'human punchbag' is getting back in the ring despite losing his last 50 fights in a row. Robin Deakin, 27, won his first professional bout in 2006 but has lost every bout since then and currently has the worst professional record in the country. He has been knocked out 12 times in his last 50 fights and has performed so badly that he even had his British boxing licence taken away. Beaten: Boxer Robin Deakin collapses in the ring as he is defeated by Ryan Taylor (right) in London. Robin has lost 50 fights in a row and is thought to be Britain's worst boxer. Human punchbag: Robin Deakin (right) is hit in the face by Ran Taylor as he is defeated in January 2012. He has lost 50 fights in a row after winning his first bout. Defeated: Robin gets checked over by a doctor after being defeated by Ryan Taylor in January 2012. But rather than give up, Robin got a permit issued in Germany so he can carry on fighting. Despite his half a century of losses, he is preparing for his next clash against an as yet unnamed fighter in London on March 1. Robin, of East Tilbury, Essex, said: 'I've been a human punch bag. I'd love a title. I'll probably never get one, but I feel like I deserve it. 'My record doesn't reflect my abilities really. There have been several times where I think I should have won on points, or got a knockout, and the decision has gone the other way. 'I think people expect me to lose now - but you can bet that I try my best to win every single time I step in the ring. Despite my record boxing is all I know, all I live for.' Robin turned professional after a successful amateur career which saw him win 40 out of 75 bouts, including making it to the semi-finals of the British Youth Championships. Defeated: Robin Deakin (left) is beaten again - this time by Billy Morgan in February 2011 as he wracked up 50 losses in a row. Another defeat: Robin Deakin is hit in the face by Billy Morgan during their bout in 2011. In total, Deakin has lost 50 out of his 51 professional fights and lost his licence. Fight club: Super featherweight Billy Morgan (right) defeats Robin Deakin in Bethnal Green, London, in February 2011. It's a knockout: Bill Morgan (right) swings his fist at Robin Deakin on the way to victory during their bout in Bethnal Green, London, in February 2011. But since then he has one of the worst boxing records of all time. turning pro records office BoxRec say he has one of the worst boxing records of all time. He said: 'When fights have been set up for me, they haven't always had my best interests at heart - I've been paying people's mortgages and it's cost me my licence. 'You look at boxers like Amir Khan and they have one big fight a year, at one point I had 19 fights in 24 weeks. Defeated again: Tommy Caris (right) has Robin Deakin on the ropes as he defeats him in a lightweight contest in Olympia, Liverpool, in January 2012. Loser again: George Michael Carman (right) hits Robin as he is defeated in December 2011. He has now clocked up 50 defeats in a row. 'I would get a call saying someone has dropped out and can I take their place. One fight I had seven hours' notice, and most of that was spent on a train to Birmingham.' Born with a club foot, Robin endured 60 operations and could not walk until he was six. He said: 'I've been boxing for 21 years. I took it up to build my own confidence, make my legs stronger and make people proud of me. I think I'm still doing that. 'I hope my comeback will make the British boxing authority give me back my licence so I can carry on living my dream.' His record is still better than Peter Buckley who quit the sport in 2008 after losing 256 out of 300 professional fights. Victory: George Michael Carman holds his arms aloft after defeating Deakin on points in December 2011. The UK's boxing regulatory authority, the British Boxing Board of Control, suspended Deakin's licence in 2012 when they began worrying for his health after sustaining so many blows to the head. BBBC General Secretary Robert Smith said: 'What needs to be stated here is that he has no British Boxing Board of Control licence. 'He had his licence withdrawn for his own interests. Robin's forthcoming fight is nothing to do with the BBBC. 'If he wishes to reapply for his licence, that will be considered, but he had his licence taken away for his best interests. 'The sad thing here is that Robin is a very nice young man. Everybody likes him, and he's mad on boxing. We felt for his own welfare he should be stopped. 'We have a duty of care to individuals and we would never knowingly sanction a fight with somebody incapable of boxing.' Mr Smith added: 'The record looks worse than it is. He always put up a good show. He always did his very very best. 'He has had his time, and we wish him the best in any future endeavours.' Clunking fist: Lewis Pettitt swings a punch at Robin Deakin in October 2010 as 'Britain's worst boxer' is defeated again. Beating: Robin takes a hit from Lewis Pettitt. After winning his first ever fight in 2006, the 'human punchbag' has now lost 50 bouts in a row | Summary: Robin Deakin, 27, won his first fight in 2006 but has lost every one since. He has been knocked out 12 times as he wracked up 50 defeats. Deakin has performed so badly he had his boxing licence taken away. But he hasn't given up the fight and instead got a permit issued in Germany. He will take on his next opponent on March 1 despite his terrible record. | 1,366 | 99 | cnn_dailymail | en |
Summarize: Investigation: Sir Cliff Richard with his 'Man Friday' Father John McElynn who is said to be supporting him through the crisis. The BBC was plunged into a new crisis last night after it was publicly blasted by police over its role in the shock Sir Cliff Richard sex abuse investigation. In an extraordinary attack on the broadcaster’s standards, furious South Yorkshire Police accused the Corporation of breaking its own guidelines. The force took the highly unusual step of announcing it had written an official letter of complaint to Director-General Lord Tony Hall over the Corporation’s controversial coverage of the case. The BBC caused a sensation with its coverage when the star’s Berkshire penthouse was searched for five hours last week. The force revealed it had been contacted ‘weeks ago’ by a BBC reporter who had found out about their ongoing top-secret investigation into shock allegations that Sir Cliff had sexually assaulted a boy at a 1980s concert. In an astonishing statement published late yesterday, police said they had been ‘reluctant’ to co-operate with the broadcaster but believed if they did not, the BBC would run the story anyway, potentially jeopardising the highly sensitive investigation. South Yorkshire Police admitted striking an unprecedented deal whereby the BBC would be given exclusive information in advance of the raid – allowing them to show it live on TV – ‘in return for delaying publication’ of their story. Sir Cliff – who strongly denies the allegations – also expressed anger that the BBC was tipped off about the search before he was. Scroll down for videos. Controversial: BBC reporter David Sillito provides news of the raid on Sir Cliff Richard's Berkshire home on Thursday, with police vehicles in the background. The police also blasted the BBC for. its ‘disappointing’ failure to make it clear the police had not been the. original source of the story. And they called for an investigation into. the source of the ‘original leak’ to the BBC, piling on the pressure. South. Yorkshire Police said: ‘A letter of complaint has been sent to the. Director-General of the BBC, making it clear that the broadcaster. appears to have contravened its editorial guidelines.’ Last night, Andrew Bridgen, Tory MP for North-West Leicestershire, said: ‘What the BBC has done. amounts to blackmail. ‘I. think there should be an external inquiry to find out what happened,. not an internal BBC one. This is shocking behaviour by a publicly funded. national broadcaster.’ Last night, the BBC insisted: ‘A BBC journalist approached South Yorkshire Police with information about the investigation. ‘The BBC agreed to follow normal journalistic practice and not to publish a story that might jeopardise a police inquiry.’ Sources. said the publicly funded broadcaster had ‘very unusually’ agreed to the. police’s request on Friday to make clear they had not been the source. Senior figures last night said the televised police raid broke all the rules on contact between press and police. Rank. and file police officers are said to be angry that the BBC – which. suffered a crisis over its failure to expose Jimmy Savile’s abuse –. ‘bounced’ police into allowing cameras and even a helicopter to witness. the search. In other developments, it can be revealed that:. A planned screening of Sir Cliff’s much-loved film Summer Holiday could be pulled from the Bank Holiday schedule by ITV. The. 1963 musical is due to be shown on ITV3 on Sunday afternoon during the. Bank Holiday weekend.An insider said: ‘We will keep the situation under. review and will make any schedule changes that we. deem. appropriate.’ The drama surrounding Sir Cliff began on Thursday. lunchtime when the BBC broadcast exclusive reports that police were. searching a penthouse apartment in Sunningdale, Berkshire, belonging to. the star. Camera crews were. already in place to watch teams of officers in unmarked cars arriving at. the premises, while a news helicopter flew overhead. It. then emerged that South Yorkshire Police were carrying out the raid as. part of an investigation into allegations that Richard had sexually. abused a young boy during a Billy Graham rally at a Sheffield stadium in. June 1985. Under pressure to explain the circumstances of the televised raid, the BBC denied it had been tipped off by the force. Instead,. the police revealed they had been working with the BBC on the. investigation before the pop star’s empty home was searched on Thursday. As of last night, the BBC had received 77 complaints from members of the public about its handling of the case. Of. these, 46 said there had been too much coverage and the other 31. expressed concern about how the Corporation had known about the police. raid in advance. The elected crime tsar for South Yorkshire, who holds the Chief Constable to account, last night stepped into the growing row. Shaun. Wright, the Labour Police and Crime Commissioner, is said to be taking. the situation ‘very seriously’. He summoned his office’s chief executive. and lawyer yesterday to start drawing up a timeline of what happened,. and will hold a meeting tomorrow to decide what action to take next. A. spokesman for Mr Wright said: ‘In light of the outcomes of the Leveson. Inquiry, the Commissioner will be looking very carefully at the. catalogue of events which took place in relation to this investigation. and any necessary actions will be taken.’ Cliff Richard has already spoken out against the BBC, claiming they were alerted to the raid before he was. Meanwhile, officers within the force were said to be ‘very, very angry’ about the collaboration with the BBC. A. police source said last night: ‘South Yorkshire Police felt they were. being pushed into going in to investigate at this early stage. They felt. very pressurised into doing it. ‘It’s. totally unacceptable to brief the media prior to an investigation. without the condition that there will be no media coverage until the. police have been to an address and secured it. 'For the police to have turned up and found the BBC waiting there for them is unacceptable.’ The BBC declined to comment on allegations it pressurised the force. Sir. Cliff – who is said to be being supported during the crisis by his ‘Man. Friday’ Father John McElynn – emerged from his Portugal villa early. yesterday evening for a game of mixed doubles on his tennis court. Smiling broadly, the star wore a red baseball cap and a white top with the number 72 on. ‘He was clearly trying to get away from his troubles doing what he loves most,’ said a near neighbour. Sir. Cliff said in a statement on Thursday that he had been aware of. ‘completely false’ allegations against him online for many months. Sorry we are not currently accepting comments on this article | Summary: BBC showed footage of police officers raiding Cliff Richard's home. South Yorkshire Police have sent letter of complaint to Director-General. Sir Cliff has already voiced anger that BBC knew of raid before he did. The South Yorkshire crime tsar launched a probe into the police's deal with the BBC;. A BBC producer sent an email to staff instructing them to delete from their playlists any of the pop legend's songs;. Sir. Cliff, who was in Portugal when the police raid took place and was. playing tennis with friends there last night, could fly back to be. interviewed under caution as early as today;. More than 75 people have complained about the BBC's coverage of the case;. A planned screening of Sir Cliff's much-loved film Summer Holiday could be pulled from the Bank Holiday schedule by ITV. | 1,556 | 181 | cnn_dailymail | en |
Summarize: These crawls are part of an effort to archive pages as they are created and archive the pages that they refer to. That way, as the pages that are referenced are changed or taken from the web, a link to the version that was live when the page was written will be preserved.Then the Internet Archive hopes that references to these archived pages will be put in place of a link that would be otherwise be broken, or a companion link to allow people to see what was originally intended by a page's authors.The goal is to fix all broken links on the web. Crawls of supported "No More 404" sites. Rapper Meek Mill arrives at the criminal justice center in Philadelphia on Nov. 6. (AP) Meek Mill was a rising teenage rapper when he first appeared in front of Philadelphia County Court of Common Pleas Judge Genece Brinkley, facing a number of drug and gun charges. A decade has passed, and Mill has amassed a national fan base and a sizable fortune from concert tours and record sales. But the criminal case that once sent Mill to prison for several months is far from over and has recently gained renewed and widespread national attention. [Pennsylvania Supreme Court orders Meek Mill immediately be granted bail] Mill is back behind bars for violating a probation that has lasted several years. His lawyers have appealed that decision, and also asked Brinkley to recuse herself from the case. On Tuesday, the Pennsylvania Superior Court denied the 30-year-old rapper’s emergency bail request, instructing Brinkley to rule “without further delay” on a bail petition filed by Mill’s attorneys Nov. 16. Three days later, the judge denied the motion for bail. In her decision, released Monday, Brinkley called the rapper a “danger to the community” and a flight risk. One of Mill’s attorney said the judge’s decision “continues her long pattern of unfair treatment of him” and vowed to file an immediate appeal. For weeks, the case has become a rallying cry for criminal justice reform in Philadelphia, where Meek Mill’s image is plastered on billboards, newsstands and public buses, and where crowds have taken to the streets to protest what they see as unusually harsh punishment and an overreach of judicial power. Brinkley, the judge, has been under scrutiny, and her Philadelphia home has been scouted by news vans. She was condemned by some on social media, where #JUSTICE4MEEK and #FREEMEEKMILL have been gaining traction. Who is Meek Mill? Mill, born Robert Rihmeek Williams, grew up around music. The nephew of Philadelphia hip-hop legend Grandmaster Nell of Punk Funk Nation began freestyle rapping at age 12, according to a 2011 profile by the Philadelphia Inquirer. Mill also was no stranger to poverty and violence. His father was killed in a robbery when Mill was very young. As a kid who lived with his mother in the projects in North Philadelphia, Mill fought on the streets and dealt drugs, he told Vice in 2013. He later became a figure in Philadelphia’s underground rap music scene and, by 2008, he had built a strong online following by posting his performances on YouTube and had released his first single, “In My Bag.” Soon came stardom. His debut studio album, “Dreams and Nightmares,” was released in 2012. “Dreams Worth More than Money,” released in 2015, was on the Billboard 200 chart for two weeks. His most recent album, “Wins & Losses,” debuted at No. 3 on the chart. Why is he in prison? Mill was arrested Jan. 24, 2007, on charges including drug possession and carrying a firearm without a license. Almost exactly two years later, Mill was found guilty, and Brinkley sentenced him to 11½ to 23 months in prison, followed by five years of probation. Robert Williams, a.k.a. Meek Mill. (Pennsylvania Department of Corrections/AP) He was released after eight months in 2009 for good behavior, and Mill picked up where he had left off in the music scene. But for several years, his criminal past clouded his otherwise successful career. He had violated his probation several times, usually for traveling out of Pennsylvania without court approval or without checking with his probation officer, and found himself in and out of Brinkley’s courtroom. In 2013, Brinkley ordered Mill to take etiquette classes, saying they were “more important than any concerts he might have,” the New York Daily News reported. In 2014, Brinkley revoked Mill’s probation after he again traveled out of town without the court’s permission. He was jailed for five months. In 2016, Brinkley placed Mill on electronic monitoring for 90 days, ordered him to do community service and barred him from traveling. Mill’s original five-year probation was extended several times during this time period. [‘Unjust and heavy-handed’: Jay-Z slams Meek Mill prison sentence for probation violation] This past year, Mill was arrested twice, first for a fight at an airport in St. Louis (the charges were later dropped) and again after he was seen on video doing dirt-bike stunts on Manhattan streets. He also tested positive for the painkiller Percocet. On Nov. 7, Mill was back in Brinkley’s courtroom, where the judge made clear that the recent violations were the last straw. “I gave you break after break, and you basically just thumbed your nose at this court,” she told Mill, the Philadelphia Inquirer reported. Mill begged for mercy, saying he did not intend to disrespect the court’s orders. “I’m human. I’m not perfect... You gave me the ladder to do what I have to do to prevail in my struggle,” he told the judge, according to the Inquirer. “I made it this far, I can’t really go back and start over.” The judge sent Mill to prison for two to four years, even though an assistant district attorney and Mill’s probation officer had recommended that he not be incarcerated. Mill is now being held in a 1,175-bed medium-security prison in Chester, Pa. He isn’t eligible for parole for at least two years. What are people saying? Brinkley’s decision immediately drew condemnation, with some pointing at the mass incarceration of black people in the United States. Hundreds of fans, as well as former Philadelphia 76er Julius Erving, Eagles player Malcolm Jenkins and rapper Rick Ross, rallied near Philadelphia’s City Hall on Monday to protest Mill’s imprisonment. In a New York Times op-ed, Jay-Z said Mill’s incarceration shows, yet again, how the criminal justice system “entraps and harasses” black people. “He has been on probation for basically his entire adult life. For about a decade, he’s been stalked by a system that considers the slightest infraction a justification for locking him back inside,” Jay-Z, whose Roc Nation manages Mill, wrote, adding later: “Taxpayers in Philadelphia, Meek Mill’s hometown, will have to spend tens of thousands of dollars each year to keep him locked up, and I bet none of them would tell you his imprisonment is helping to keep them safer.” Colin Kaepernick didn’t stay silent, either. “Meek Mill is a victim of this systemic oppression,” Kaepernick said in a lengthy Instagram post, adding that there needs to be some kind of reform to keep people from incarceration over “nonviolent parole violations.” [For Father’s Day, Jay Z pens op-ed about a predatory bail system that separates families] One of Mill’s attorneys, Brian McMonagle, who represented comedian Bill Cosby in his sexual assault trial, said the sentence was “excessive, unjust, unfair.” “There is no good reason for him to be sitting in prison today. None... We believe that this is such a wrong. The only way that it can be righted is to bring him home,” McMonagle told CBS Philly. In late November, the Rev. Al Sharpton met with Mill in prison, then told reporters that the musician “is representative of many people in institutions like this that do little or nothing; they’re violated and their lives, their businesses are ruined,” the Associated Press reported. What are the accusations against the judge? Mill’s defense team is appealing his sentence. A motion filed in November asked for Brinkley to remove herself from the case, saying she had “assumed a nonjudicial, essentially prosecutorial role” in revoking Mill’s probation, the Philadelphia Inquirer reported. Defense attorneys point to a previous probation-violation hearing during which Brinkley told Mill that she went to a soup kitchen to make sure that Mill was feeding the homeless as part of his community service. “It was only when you realized that I came there to check on you that you decided to serve meals,” she told Mill, according to the Inquirer. Defense attorneys found that questionable, saying that by checking in on Mill, Brinkley made herself a “fact witness” as to whether Mill was following the court’s orders. Brinkley has been accused, too, of offering “inappropriate personal and professional advice” to Mill. During a private meeting in the judge’s chambers last year, she allegedly asked Mill to record a version of Boyz II Men’s “On Bended Knee” — and to include her name in it. Mill declined the request, saying he doesn’t sing ballads and doesn’t give “shout-outs” to people in his songs, according to Joe Tacopina, one of Mill’s attorneys. “Okay, suit yourself,” Brinkley said, according to Tacopina, who wasn’t in the meeting. Tacopina also accused Brinkley of advising Mill to drop Jay-Z’s management company and return to Philadelphia-based Charles “Charlie Mack” Alston. A bus with a message of support for Meek Mill drives in view of City Hall in Philadelphia on Nov. 15. (AP) Mill’s defense team has filed other motions to modify his sentence and bail. Brinkley has avoided making public comments about Mill’s case. Pennsylvania’s code of judicial conduct, as in other states, prohibits judges from making public statements on pending cases. Brinkley has been a judge in the Philadelphia County Court of Common Pleas, which hears both civil and criminal cases, since 1993. She graduated with a degree in political science from Spelman College and obtained her law degree from Temple University. What are legal experts saying? Mill’s predicament is not at all new, but it has attracted more attention probably because of his celebrity. Jules Epstein, law professor and director of advocacy programs at Temple University, said technical probation violations — which can include testing positive for drugs and staying out after a certain curfew — routinely send people back to jail. “The standards before a judge revokes probation when there is only a technical violation are supposed to be a little more stringent,” he told The Washington Post. “Because we don’t want to send people back to jail. It’s very costly. It’s not very helpful. But one of the grounds for revoking probation and putting someone in jail is to vindicate the authority of the court.” Epstein declined to comment about Mill’s sentence or the allegations that the rapper’s legal team has made against Brinkley. But speaking generally, he said that judges “have to maintain their role as judges,” and their inability to do so raises serious questions about their impartiality. “Here’s what I think. Mr. Mill is incredibly lucky because he’s got a lot of money and a lot of friends with money,” Epstein said, adding later: “Mr. Mill is on the radar because of his prominence, but the problem of technical violations and parole revocations is off the radar, but happening every day to poor people.” Lou Natali, a retired defense attorney, thinks Mill’s chances of success in appealing his sentence are slim. “He’s not going anywhere with a claim of an excessive sentence or abuse of discretion,” Natali told the Inquirer. “There’s no law that helps him on that.” People walk past a placard posted on a newsstand with a message of support for imprisoned rapper Meek Mill in Philadelphia on Friday. Mill’s imprisonment on a probation violation has set off a flurry of legal appeals, criticism of the criminal justice system, newspaper opinion pieces, rallies, billboards and bus ads. (Matt Rourke/AP) This post has been updated. Read more: Meek Mill has discovered a big stage worth sharing NFL endorses criminal-justice reform bill in the midst of anthem debate A bill to reduce the federal prison population is necessary — but far from sufficient Drake, Meek Mill and their bitter feud about ghostwriting in hip-hop People walk past a placard posted on a newsstand with a message of support for imprisoned rapper Meek Mill, in Philadelphia, Friday, Dec. 1, 2017. Mill’s imprisonment on a probation violation has set... (Associated Press) People walk past a placard posted on a newsstand with a message of support for imprisoned rapper Meek Mill, in Philadelphia, Friday, Dec. 1, 2017. Mill’s imprisonment on a probation violation has set off a flurry of legal appeals, criticism of the criminal justice system, newspaper opinion pieces,... (Associated Press) PHILADELPHIA (AP) — A Philadelphia judge says Meek Mill will stay in prison because he's a "danger to the community." Common Pleas Judge Genece Brinkley on Friday denied a motion allow the 30-year-old rapper to be bailed out of a Pennsylvania correctional facility. Mill's attorney says they plan to appeal her ruling, saying it continues a "long pattern of unfair treatment." Her decision comes after the state Superior Court last week told her to act "without further delay" on a 2-week-old request to free the rapper. Mill was sentenced last month to two to four years for violating probation on a roughly decade-old gun and drug case. Mill's probation officer and a prosecutor had recommended he not be jailed. His imprisonment has sparked backlash in opinion pieces, rallies, billboards and bus ads. | Summary: A Philadelphia judge says Meek Mill will stay in prison because he's a "danger to the community." Common Pleas Judge Genece Brinkley on Friday denied a motion to allow the 30-year-old rapper to be released from a Pennsylvania correctional facility on bail, reports the AP. Mill's attorney says they plan to appeal her ruling, saying it continues a "long pattern of unfair treatment." NBC Philadelphia, which notes the ruling was released Monday, reports Mill's team also wants Brinkley to recuse herself, saying she took on an "essentially prosecutorial" role in the case and once asked the rapper to name-drop her in a song. Her decision comes after the state Superior Court last week told her to act "without further delay" on a 2-week-old request to free the rapper. Mill was sentenced last month to two to four years for violating probation on a roughly decade-old gun and drug case. Mill's probation officer and a prosecutor had recommended he not be jailed. The Washington Post notes most of his probation violations are related to him leaving Pennsylvania without getting the court's OK or touching base with his probation officer. His imprisonment has sparked backlash in opinion pieces, rallies, billboards, and bus ads. The Inquirer reports Jay-Z twice halted a Friday show in Philly to talk about the case, saying, "If you see a young man put on probation for 11 years since he was 19 years old, that man is being stomped by the system. That man is in jail for doing wheelies and breaking up a fight," referring to probation-violating incidents Brinkley referenced during sentencing in November. | 3,304 | 383 | multi_news | en |
Summarize: BACKGROUND OF THE INVENTION The present invention relates to a target assembly for pinball games, and more particularly, to a target assembly of the type which includes a target member mounted between two posts for rotation about a horizontal axis. The target is dimensioned and arranged so that, in the rest position thereof, it is engageable by a pinball rolling between the two posts to spin the target about the horizontal axis and actuate associated indicating and/or scoring means. Prior spinning target assemblies have comprised numerous parts which required time-consuming and complicated assembly on the playfield board of the pinball game. More particularly, such prior spinning target assemblies included two multi-part post assemblies individually mountable on the playfield board which were spanned by a U-shaped bracket, between the arms of which a multi-part metal spinning target was mounted. A crank mechanism interconnected the target shaft and the contacts of a switch assembly which was independently mounted beneath the playfield board. In addition to the complicated initial assembly of these prior devices, servicing thereof and replacement of parts was also quite cumbersome. Thus, in order to replace the spinner, it was necessary to remove two screws to demount the U-shaped bracket from the post assemblies and, if it was desired to change the crank mechanism, it was necessary to have access to both the top and bottom surfaces of the playfield board. Furthermore, the prior devices required the stocking of a large number of individual parts. SUMMARY OF THE INVENTION The present invention provides an improved spinning target assembly which avoids the disadvantages of the prior art assemblies while affording additional structural and operating advantages. It is a general object of the present invention to provide an improved spinning target assembly which has a minimal number of parts and can be quickly and easily mounted on the playfield board. It is another object of this invention to provide a spinning target assembly of the type set forth, wherein the spinning target member and the switch-actuating linkage can be replaced entirely from above the playfield board and without the use of tools. It is another object of this invention to provide a spinning target assembly of the type set forth, which provides a cam-type switch actuating mechanism of simple and economical construction. These and other objects of the invention are attained by providing a spinning target assembly for a pinball game having a playfield board on which a pinball rolls, the target assembly comprising an integral one-piece frame member having two substantially parallel spaced-apart post portions interconnected only adjacent to one end thereof by a base portion, the frame member being mountable on the associated playfield board with only the distal ends of the post portions extending above the playfield board, and a target member carried by the post portions therebetween and above the playfield board for rotation about a horizontal axis, the target member having a normal rest position in which it is engageable by an associated pinball rolling between the post portions for spinning the target member about the axis. The invention consists of these and other novel features and a combination of parts hereinafter fully described, illustrated in the accompanying drawings, and particularly pointed out in the appended claims, it being understood that various changes in the details may be made without departing from the spirit, or sacrificing any of the advantages, of the invention. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a front elevational view in partial vertical section of a spinning target assembly constructed in accordance with and embodying the features of the present invention, shown mounted in position on the playfield board of the pinball game; FIG. 2 is a view in vertical section taken along the line 2--2 in FIG. 1; FIG. 3 is an enlarged fragmentary view in vertical section of the spinning target member of the present invention; FIG. 4 is a view in vertical section taken along the line 4--4 in FIG. 3; FIG. 5 is a vertical sectional view of the frame of the spinning target assembly of FIG. 1, and illustrating the associated post cap; FIG. 6 is a bottom plan view of the spinning target assembly of FIG. 1, with a portion of the switch mechanism broken away more clearly to illustrate the construction; FIG. 7 is an enlarged top plan view of one of the post portions of the frame, taken along the line 7--7 in FIG. 5; FIG. 8 is a fragmentary view in vertical section of the post portion of FIG. 7, taken along the line 8--8 therein, and additionally illustrating the relationship of the associated cap; FIG. 9, is a fragmentary view in vertical section of the post of FIG. 7, taken along the line 9--9 therein, and illustrating the relationship of the associated cap; and FIG. 10 is a bottom plan view of the cap illustrated in FIG. 9. DESCRIPTION OF THE PREFERRED EMBODIMENT Referring to FIG. 1 of the drawings, there is illustrated a spinning target assembly, generally designated by the numeral 20, constructed in accordance with and embodying the features of the present invention and adapted to be mounted on the playfield board 21 of the pinball game. The playfield board 21 has a top surface 22 and a bottom surface 23 and is provided with cylindrical holes 24 therethrough. In use, a pinball 25 rolls along the top surface 22 of the playfield board 21 in a well-known manner. Referring now also to FIGS. 2, 5 and 6 of the drawings, the spinning target assembly 20 includes an integral one-piece frame, generally designated by the numeral 30, which is preferably molded of a suitable plastic material. The frame 30 includes an elongated base 31 having part-circular attachment ears 32 projecting therefrom, each of the ears 32 having a cylindrical hole therethrough for receiving an associated fastener 33, such as a screw or the like, for securing the base 31 to the bottom surface 23 of the playfield board 21. An electrical switch 35 is fixedly secured to the bottom of the base 31, as by screws 36, the switch 35 having an upper, relatively long contact arm 37 and a lower, relatively short contact arm 38 supported by an underlying support arm 39, all for a purpose to be explained more fully below. Integral with the base 31 respectively adjacent to the opposite ends thereof and extending upwardly therefrom respectively through associated ones of the holes 34 in the playfield board 21 are two elongated cylindrical posts, generally designated by the numerals 40 and 50. Each of the posts 40 and 50 has a circularly cylindrical outer surface at the lower end thereof, with the portions of the posts extending above the playfield board 21 being substantially frustoconical in shape, the post 50 being slightly shorter than the post 40, for a purpose explained more fully below. The post 40 has a cylindrical bore 41 extending longitudinally axially therethrough. The post 40 has a generally annular recess 42 formed in the bottom thereof and extending upwardly thereinto approximately half the length thereof, the remaining material between the bore 41 and the recess 42 forming a tubular wall 43 connected by support webs 44 to the outer wall of the post 40 (see FIG. 5). Formed in the outer surface of the post 40 above the upper end of the recess 42 is a circumferential groove 45 for seating therein an annular resilient bumper 45a. Extending radially through the post 40 a predetermined distance from the distal end thereof is a cylindrical bore 46. The post 50 is slightly different in construction from the post 40. More specifically, the post 50 has a cylindrical bore 51 extending longitudinally axially therethrough, but of a substantially smaller diameter than the bore 41. The bottom of the post 50 has a generally annular recess 52 formed therein extending thereinto approximately half the length thereof. The remaining material between the bore 51 and the recess 52 forms a tubular wall 53 which is connected by support webs 54 to the outer wall of the post 50. Formed in the outer surface of the post 50 above the upper end of the recess 52 is a circumferential groove 55, for seating therein an annular, resilient bumper 55a. Referring also to FIGS. 7 through 9 of the drawings, the post 50 has a generally rectangular recess formed centrally in the top thereof and extending longitudinally downwardly therefrom a predetermined distance and communicating with the bore 51. Formed in the side wall of the post 50 at the top or distal end thereof and in the side thereof facing the post 40 is a generally rectangular notch 57 which communicates with the recess 56, but extends downwardly only about half the depth of the recess 56. The notch 57 has a part-cylindrical bearing portion 58 formed centrally of the bottom wall thereof substantially coaxially with the bore 46 and the post 40. Two apertures 59 are respectively formed in the post 50 substantially 90° in opposite directions circumferentially from the center of the notch 57 and spaced from the top of the post 50 a distance approximately equal to the depth of the notch 57. Referring now also to FIGS. 3 and 4 of the drawings, the spinning target assembly 20 also includes a spinner, generally designated by the numeral 60, which includes a rectangular target body 61 rotatably mounted between the posts 40 and 50 by a shaft generally designated by the numeral 62. The opposite ends 63 and 64 of the shaft 62 are substantially coaxial and respectively extend from the opposite ends of the target body 61. A central portion 65 of the shaft 62 is embedded within the target body 61 and is displaced from the axis of the shaft ends 63 and 64. Fixedly secured to the end 64 of the shaft 62 eccentrically with respect thereto is a generally oval-shaped cam 66. In use, the end 63 of the shaft 62 is inserted into the bore 46 and the end 64 of the shaft 62 is dropped into the notch 57 from thereabove. The spinner 60 then rests in a mounted position illustrated in FIG. 1, with the shaft end 64 seated in the bearing portion 58 of the notch 57, and with the cam 66 disposed in the recess 56. A connecting rod 67 is disposed in the bore 51 of the shaft 62 with the lower end thereof resting upon the distal end of the upper switch contact arm 37, and with the upper end thereof disposed in camming engagement with the cam surface of the cam 66. It will be appreciated that, as the spinner 60 rotates about the axis of the shaft ends 63 and 64, the cam 66 drives the connecting rod 67 in a vertical reciprocating motion, thereby deflecting the upper switch contact arm 37 into and out of contact with the lower switch contact arm 38 for repeatedly actuating the switch 35. Referring in particular to FIGS. 1, 5 and 8 through 10 of the drawings, the post 50 is provided with a cap, generally designated by the numeral 70, which has a generally frustoconical body 71, provided centrally of the lower surface thereof with a depending generally rectangular plug 72. Integral with the body 71 and depending therefrom at the perimeter thereof is a generally rectangular retaining arm 73. Also integral with the body 71 and at diametrically opposed points thereon respectively spaced about 90° circumferentially from the retaining arm 73 are two resilient latch arms 75, each extending downwardly a predetermined distance beyond the distal end of the retaining arm 73. Each of the latch arms 75 is provided adjacent the distal end thereof with a radially inwardly extending latch finger 76. The installation and operation of the spinning target assembly will now be described. It will be understood that the frame 30, including the base 31 and posts 40 and 50, is an integral one-piece structure to which the switch 35 is preassembled to form a unit which is mounted on the playfield board 21 from therebelow. Thus, the posts 40 and 50 are inserted through the corresponding holes 24 in the playfield board 21 and the base 31 is secured to the playfield board 21 with fasteners 33. The connecting rod 67 may be inserted into the bore 51 either before or after mounting of the frame 30 on the playfield board 21. Next, the bumpers 45a and 55a are fitted over the tops of the posts 40 and 50 and seated respectively in the grooves 45 and 55. Then, the spinner 60 is mounted in place by inserting the shaft end 63 into the bore 46 and dropping the shaft end 64 in the bearing portion 58 of the notch 57, as described above, with the cam 66 disposed in the recess 56. Finally, the cap 70 is mounted in place in its retaining position, illustrated in FIG. 1. In this regard, the plug 72 is dimensioned to fit into the top of the recess 56 and the retaining arm 73 is dimensioned to fit in the notch 57. The latch arms 75 are resiliently spread slightly so as to slide down along the outer surface of the post 50 until the latch fingers 76 respectively snap into engagement in the side apertures 59 to latch the cap 70 in its retaining position. It will be appreciated that, in this retaining position, the plug 72 and the retaining arms 73 are respectively engageable with the cam 66 and the shaft end 64 to present upward movement of the shaft 62 from the post 50, the length of the shaft 62 being such as to prevent lateral movement thereof from its mounted position. The height of the body 71 is such that when the cap 70 is mounted in its retaining position on the post 50, its top surface is at the same height above the playfield board 21 as is the top of the post 40. The displacement of the central portion 65 of the shaft 62 from the axis of rotation thereof serves to weight the spinner 60 so that it will always come to rest in the vertical orientation illustrated in FIGS. 1 through 3 of the drawings. The dimension of the target body 61 is such that when it is in its rest position, it is spaced from the top surface 22 of the playfield board 21 and from the posts 40 and 50 by distances less than the diameter of the pinball 25. Thus, it will be understood that when a pinball 25 rolls between the posts 40 and 50 it will engage the target body 61, causing the spinner 60 to spin about the axis of the shaft 62, the resulting rotation of the cam 66 causing a cammed actuation of the switch 35 through the connecting rod 67 in the manner described above. The bumpers 45a and 55a serve to protect the posts 40 and 50 from impacts of the pinball 25 thereon. It is a significant feature of the present invention that the cap 70 can be removed by simply manually spreading the latch arms 75 and lifting the cap 70 from its retaining position. Thus, the spinner 60 can be replaced or serviced from above the playfield board 21 without the use of any tools. It will be appreciated that while the cam 66 has been disclosed as having a shape to effect one closure of the switch contact arms 38 and 39 for each revolution of the spinner 60, the cam 66 could have other shapes to effect more than one closure of the switch contacts for each rotation of the spinner 60. In a constructional model of the present invention, the frame 30 is molded of a polycarbonate material, while the target body 61 and the cam 66 are preferably formed of nylon. In this regard, the target body 61 is molded around the central portion 65 of the shaft 62 so that the central portion 65 is embedded in the target body 61. It will be understood that other plastic materials could be utilized for the target body 61 and the cam 66, but the cam 66 is preferably formed of a self-lubricating material. From the foregoing, it can be seen that there has been provided an improved spinning target assembly for a pinball game, which assembly is of simple and economical construction and is characterized by ease of assembly on the playfield board of a pinball game. In particular, there has been provided a spinning target assembly in which the spinner can be easily replaced from above the playfield board without the use of tools. | Summary: A spinning target assembly for a pinball game includes a molded one-piece frame having a base adapted to be secured to the underside of the playfield board and two spaced-apart upright posts which project through complementary openings in the playfield board and extend a predetermined distance thereabove. A spinner is rotatably mounted between the posts and includes a shaft having an offset central portion which is encapsulated in a molded plastic target. One end of the shaft has secured thereto a cam received in a recess in the top of one post for camming engagement with a connecting rod which extends downwardly through a longitudinal bore in the one post for actuation of the contacts of a switch mounted on the base, and the other end of the shaft is rotatably received in a radial bore in the other post. A cap is removably latched to the top of the one post to retain in place the cam and the associated end of the shaft. | 4,002 | 206 | big_patent | en |
Summarize: Story highlights National September 11 Memorial Museum is open to the public in New York The exhibition halls are filled with personal things as well as oral histories and photos Museum curator had the difficult task of deciding how much tragedy to show The museum is also about how people can be good to one another in times of crisis, curator says When does the ordinary -- letters, gloves, wallets -- become extraordinary? When the objects tell a story: a stack of personal letters that fell to the ground after a hijacked plane plowed into the World Trade Center; leather gloves worn in the recovery effort; a red wallet belonging to a woman who worked for Cantor Fitzgerald. Tragedy turns the mundane into memorial. Something as simple as a wallet can evoke the immense sadness of a day like September 11, 2001. JUST WATCHED Objects into icons: The 9/11 memorial Replay More Videos... MUST WATCH Objects into icons: The 9/11 memorial 03:08 JUST WATCHED Obama: 'Those we lost live on in us' Replay More Videos... MUST WATCH Obama: 'Those we lost live on in us' 08:23 Objects big and small from the greatest terrorist attack on American soil now make up a museum dedicated to that tragedy and the 2,983 people who perished. It is one of America's largest and most ambitious memorial museums, almost entirely subterranean and erected in the graveyard of Osama bin Laden's victims. A police officer found Genni Gambale's red wallet on the roof of a Marriott hotel, a few blocks south of the Trade Center, days after the attacks. In the wallet were a scorched American Express Corporate card, a $115 coupon for Lenscrafters, a Brooklyn Public Library card, pennies, nickels, dimes. Construction worker Frank Silecchia found a crossbeam in the rubble that resembled a cross. It became a key exhibit at the new museum. Now under thick Plexiglass, the wallet tells of a life cut short. Gambale was one of many trapped on the upper floors after American Airlines Flight 11 plowed into the North Tower at 8:46 a.m. She was 27. The National September 11 Memorial Museum opened in May for the 9/11 community -- survivors, families, rescuers. Shortly after it opened to the general public. The place in itself is an artifact, built in the bedrock of tragedy. Within it are 12,500 objects, 1,995 oral histories and 580 hours of film and video. "An airplane hangar full of largely bruised, contorted artifacts" formed the basis of the museum, says curator Jan Ramirez. They are objects that cheated destruction. They survived the obliteration of the material world and assumed an otherworldly quality. But they also could inflict pain again. From the beginning, Ramirez and all those who worked under museum director Alice Greenwald faced a flurry of contradictions and dilemmas over what to show, how much to reveal. Where the twin towers once soared are now two sunken granite pools, positioned in the footprints of the giant buildings that came crashing down that day. They are meant to be places of reflection and mourning. What was the museum's intent? Was it to illustrate a narrative of what happened on September 11? Or would it be a repository for the study of an American tragedy? If it were the latter, the museum would have to collect objects much more broadly. "We decided to take that path. We decided to be ambitious and daring," Ramirez said. Firefighter James Wind rushed to the scene to help. The first thing he saw was his fire company's heavily damaged truck. But with that decision came new concerns and obstacles. How do you portray horror without overwhelming people who come to visit? How do you memorialize things that people might rather not remember? The museum, said Ramirez, is sure to be emotionally overwhelming to anyone who survived September 11, to all New Yorkers, and perhaps even to the millions of people who watched the events of that day unfold on television. She described the helmets of firefighters that were donated by their families. Some were so brutalized that it's not hard to imagine the severe trauma to the heads those helmets were meant to protect. "We all had our different thresholds about what was the right thing to do," Ramirez said. "We want to remind people why 9/11 was unlike any other day the country has experienced. But we did not want to cross a threshold where a visitor's empathy shuts down. That would be a horrible misfire of our objectives." So some things in the museum are clearly marked and separated in alcoves. In one section are images of people jumping to their deaths from the towering infernos. "In the end we felt this was part of the morning's indelible horror," Ramirez said. "To edit that out might arouse suspicion about what else we edited out." The museum collected items from survivors, families of the dead, first responders, cleanup workers and agencies that were part of the investigation. Objects like Gambele's wallet were precious to families. In many cases, bodies were never recovered or identified. Objects were all the families got back. Other objects mean something to survivors. Hazem Gamal worked for OppenheimerFunds on the 34th floor of the South Tower. He stored personal letters in a filing cabinet in his office. In December 2001, a demolition consultant, Ray Coleman, discovered the letters amid the rubble. He was amazed by them. New York police officer David Brink picked up a pair of gloves from a hospitality tent for recovery workers. Someone had written the words, "Thank you" on them. Nothing else Coleman had seen was discernible. No chair, table, computer. Everything was pulverized or mangled beyond recognition. But these letters were intact, only slightly singed and waterlogged. The clip holding them together had rusted. Coleman kept the letters for a year. He was afraid that if he called the owner, he might learn that he had died. Finally, in November 2002, he dialed Gamel's home. Then he returned the letters. He included this note written in pencil on engineer's paper: "I hope that you will cherish these papers, and cherish your family," he wrote. "If this project did anything for me, it has taught me to love every minute, love my family and friends, and take time to do the things that are really important." Others donated personal property that helps viewers understand their loved ones better. Brian Sweeney's wife donated a handmade Viking helmet; he was so proud of his Viking heritage. "It creates a sense of joy," Ramirez said. "They were enjoying life. It's the opposite of the ideology of ending life." Sweeney, a former Navy pilot, was on United Airlines Flight 175. His last words to his wife were recorded in a voice mail shortly before the hijacked plane crashed into the South Tower: JUST WATCHED Take a look inside new 9/11 museum Replay More Videos... MUST WATCH Take a look inside new 9/11 museum 04:12 "If things don't go well, and it's not looking good, I just want you to know I absolutely love you. I want you to do good, go have good times. Same to my parents and everybody, and I just totally love you, and I'll see you when you get there." New York police officer David Brink donated a suitcase full of things to the museum, including a pair of gloves he picked up in a hospitality tent set up at ground zero. Brink, like other recovery workers, used his hands to scour through a wasteland of debris. He had to change out his gloves frequently because they got so damaged. One day, he picked up a pair of leather gloves and didn't notice until later, when he was in the wreckage, that someone had taken a ballpoint pen to the palms of the gloves and written, "Thank you." He didn't know where the gloves came from or who had written those words. The hospitality tents had equipment and supplies donated by people from all over America. The gloves could have been from a firefighter in California or a school kid in Indiana or a housewife in Iowa, Brink thought. But the "Thank you" helped him get through trying days. Over the years, some objects became symbols of 9/11. One was the fire truck that belonged to the New York Fire Department's Ladder Company 3. On September 11, Capt. Paddy Brown and Lt. Kevin Donnelly had rushed with their crew from Manhattan's East Village to the North Tower minutes after Flight 11 struck. The firefighters made their way up the skyscraper to find and evacuate victims. Some people later said the sight of the firefighters gave them a sense of calm in the midst of terror. A short while later, 11 members of Ladder 3 were dead as the North Tower crumpled. James Wind, a member of Ladder 3, was off that day. But he made his way to ground zero to help. When he arrived on the scene, he saw his company's truck. The ladder was bent down to the bumper. The front of the truck was on fire but it was still running and the lights were on. "That truck was battered around like a ping-pong ball," Wind said. "It was a beast, but there was a bigger beast that took it." An officer always carries a list of his men and leaves a copy in the truck. Wind reached in and looked at the second list. He hoped beyond hope but knew: He was probably looking at names of the dead. They were his friends, his brothers. He knew their wives, their lives. He'd seen them almost every day for years. He wants visitors to see the mangled truck at the museum. "Live your life," he said, "but be aware. This can happen still." Construction worker Frank Silecchia felt damaged from days of recovery efforts. He'd already worn through several pairs of boots -- the steel was so hot at the site that it melted the soles. He'd volunteered to help with the hope of finding a survivor. He found none. On Day 3, he helped carry out three bodies from 6 World Trade Center and paused to look out at the destruction. A 17-foot-long crossbeam weighing at least two tons had landed at a perfect vertical angle. Silecchia saw a cross. He dropped to his knees in tears. He believed it was a sign from God. He found renewed strength to carry on. "Evil destroyed that building," Silecchia said, "and faith rose out if it." A few days later, he showed his discovery to a Franciscan priest named Father Jordan, who pushed to get the World Trade Center cross lifted out of the wreckage and preserved near the site. Silecchia believes the museum will be like walking through a horror show for some visitors. He hopes that seeing the cross there will bring comfort, just as it did for him 13 years ago. Ramirez, the museum's curator, said regardless of religious belief, people found inspiration in the cross and that is why it was included in the museum. She hopes the ordinary objects in the exhibit stand as testament to courage, kindness and human resiliency. Ramirez considers herself and her colleagues at the September 11 museum third responders. They are the people who set evidence aside; the people whose job it was to give meaning to ordinary objects. "It's a collective story about how people can be good to one another in times of crisis," she said. "We've put out our first draft of history." Skip in Skip x Embed x Share CLOSE USA TODAY looks at the National 9/11 Memorial Museum. (From May 15th) Robert Deutsch, USA TODAY President Obama speaks during the opening ceremony for the National September 11 Memorial Museum at Ground Zero in New York City. (Photo: Pool photo by Getty Images) NEW YORK — The National September 11 Museum, which President Obama praised at its dedication Thursday as "a sacred place of healing," has in its development years repeatedly aroused bitter divisions over how to tell the story of the terror attacks. The museum, which opens to the public Wednesday, has faced what urban anthropologist Elizabeth Greenspan calls "controversy after controversy.'' Disputes have ranged from the disposition of human remains to the $24 general admission price. Greenspan, author of The Battle for Ground Zero, says much of the contention has stemmed from the institution's dual, and often conflicted, mission: to commemorate those who died in the 2001 attacks, and to explain the attacks themselves. Jeffrey Melnick, a University of Massachusetts Boston cultural historian who has studied 9/11, says the museum's problem is the one that bedeviled redevelopment of the entire 16-acre World Trade Center site: "Too many different stakeholders trying to do too many different things in one place.'' And possibly trying to do it too soon. Greenspan says the history that the museum seeks to convey to visitors "is still delicate.'' Among the controversies in which the museum has been embroiled over the past eight years: • Whether unidentified human remains recovered from Ground Zero should be kept in a private medical examiner's office site in the subterranean museum. When a solemn procession took remains to the museum Saturday, some relatives showed their opposition by standing with black tape over their mouths. • Whether the exhibit, by displaying the hijackers' photographs and names, glorifies them and insults their victims' memories. The museum compromised by using small head shots marked as FBI evidence. • Whether a brief explanatory film narrated by NBC's Brian Williams about the 9/11 conspiracy unfairly links al-Qaeda terrorism with Islam. An imam who sat on an interfaith clergy museum advisory committee resigned in protest, but the museum stuck by the film. • Whether the presence in the museum of the "Ground Zero Cross,'' a cross section of steel I-beams found in the rubble that inspired many recovery workers, constitutes an endorsement of Christianity by a public institution. An atheist group has appealed a lower court ruling that there was no church-state problem. Because of these and other issues, some family members have said they'll boycott the museum. But on Thursday at least one 9/11 survivor said he found the experience powerful. Tim Brown, a 51-year-old retired firefighter, said he lost 93 friends in the department on 9/11. He said he was moved to tears when he visited the museum's memorial section and saw the wall of photos of those who died that day. "There were so many (firefighters) who died that sometimes you forget who lived and who died,'' he said. "So you see someone's photo here, and say, 'I forgot he died.' It's hard for us.'' Now that the museum is opening, will divisions begin to heal? Don't bet on it, said Greenspan: "I think there'll be even more debate. We have to go through that to get to a more consensual place.'' She was echoed by Jefferson Crowther, whose son Welles died a hero helping other workers flee the South Tower. "This is America,'' he said. "Everyone's got a bone to pick.'' NEVER FORGET: Your photos of the 9/11 museum and memorial Read or Share this story: http://usat.ly/1ltMooh In the footprint of Ground Zero, the site of the tragedy that killed more than 2,000 people, President Obama and New York political leaders gathered to remind us that the emotional weight of Sept. 11, 2001, still hasn't lifted. They, along with hundreds of people, were gathered to dedicate the 9/11 Museum, which opens to the public Monday. The dedication began with a children's choir singing the song "Somewhere" from the musical West Side Story—their voices echoing in the cavernous room bordered by the walls that formed the original bedrock of the Twin Towers. At the event were Barack and Michelle Obama, Bill and Hillary Clinton, along with former New York City Mayor Rudy Giuliani, current Mayor Bill de Blasio, New York Gov. Andrew Cuomo, and New Jersey Gov. Chris Christie. Notably absent from the event was George W. Bush. Read President Obama's full remarks from the event: Mayor Bloomberg, Governor Cuomo, honored guests, families of the fallen: In those awful moments after the South Tower was hit, some of the injured huddled in the wreckage of the 78th floor. The fires were spreading. The air was filled with smoke. It was dark. They could barely see. It seemed as if there was no way out. And then there came a voice—clear, calm, saying he had found the stairs. A young man, in his 20s, strong, emerged from the smoke, and over his nose and his mouth, he wore a red handkerchief. He called for fire extinguishers to fight back the flames. He attended to the wounded. He led those survivors down the stairs to safety, and carried a woman on his shoulders down 17 flights. Then, he went back, back up all those flights, then back down again, bringing more wounded to safety, until that moment when the tower fell. They didn't know his name. They didn't know where he came from, but they knew their lives had been saved by the man in the red bandanna. Again, Mayor Bloomberg, distinguished guests, Mayor DeBlasio, Governors Christie and Cuomo, the families and survivors of that day, to all those who responded with such courage, on behalf of Michelle and myself and the American people, it is an honor for us to join in your memories. To recall and to reflect, but above all, to reaffirm the true spirit of 9/11—love, compassion, sacrifice—and to enshrine it forever in the heart of our nation. Michelle and I just had the opportunity to join with others on a visit with some of the survivors and families—men and women who inspire us all—and we had the chance to visit some of the exhibits. And I think all who come here will find it to be a profound and moving experience. I want to express our deep gratitude to everybody who was involved in this great undertaking, for bringing us to this day, for giving us this sacred place of healing and of hope. Here at this memorial, at this museum, we come together. We stand in the footprints of two mighty towers, graced by the rush of eternal waters. We look into the faces of nearly 3,000 innocent souls, men and women and children of every race, every creed, from every corner of the world. We can touch their names and hear their voices and glimpse the small items that speak to the beauty of their lives—a wedding ring, a helmet, a shining badge. Here we tell their story so that generations yet unborn will never forget. Of coworkers who led others to safety. The passengers who stormed the cockpit. Our men and women in uniform who rushed into an inferno. Our first responders who charged up those stairs. A generation of service members—our 9/11 generation—who have served with honor in more than a decade of war. A nation that stands tall and united and unafraid because no act of terror can match the strength or the character of our country. Like the great wall and bedrock that embrace us today, nothing can ever break us. Nothing can change who we are as Americans. On that September morning, Allison Crowther lost her son, Welles. Months later, she was reading the newspaper, an article about those final minutes in the towers. Survivors recounted how a young man wearing a red handkerchief had led them to safety. And in that moment, Allison knew. Ever since he was a boy, her son had always carried a red handkerchief. Her son, Welles, was the man in the red bandanna. Welles was just 24 years old, with a broad smile and a bright future. He worked in the South Tower on the 104th floor. He had a big laugh, a joy of life, and dreams of seeing the world. He worked in finance, but he had also been a volunteer firefighter. And after the planes hit, he put on that bandanna and spent his final moments saving others. Three years ago this month, after our SEALS made sure that justice was done, I came to Ground Zero. And among the families here that day was Allison Crowther, and she told me about Welles and his fearless spirit. And she showed me a handkerchief like the one he wore that morning. And today, as we saw on our tour, one of his red handkerchiefs is on display in this museum. And from this day forward, all those who come here will have a chance to know the sacrifice of a young man who, like so many, gave his life so others might live. Those we lost live on in us—in the families who love them still, in the friends who remember them always, and in a nation that will honor them now and forever. And today it is my honor to introduce two women forever bound by that day united in their determination to keep alive the true spirit of 9/11: Welles Crowther's mother, Allison, and one of those he saved, Ling Young. | Summary: President Obama today helped dedicate the National September 11 Memorial Museum, and his comments opened with the recollection of a man who "emerged from the smoke, and over his nose and his mouth, he wore a red handkerchief." It was Welles Crowther, a 24-year-old working on the South Tower's 104th floor who, as Obama explained, had carried a red handkerchief with him since he was a child. And on 9/11, the "man in the red bandana" was a hero: "He called for fire extinguishers to fight back the flames. He attended to the wounded. He led those survivors down the stairs to safety, and carried a woman on his shoulders down 17 flights. Then, he went back, back up all those flights, then back down again, bringing more wounded to safety, until that moment when the tower fell.... And today, as we saw on our tour, one of his red handkerchiefs is on display in this museum. And from this day forward, all those who come here will have a chance to know the sacrifice of a young man who, like so many, gave his life so others might live." In advance of his comments, Obama, the first lady, and former NYC Mayor Michael Bloomberg toured the museum, whose seven stories hold artifacts from the attack, including what CNN calls the "ordinary": leather gloves (used during the recovery effort), a red wallet (owned by a Cantor Fitzgerald employee), a $2 bill (from the wallet of a victim who gave his wife one, too, as a reminder of their second chance at love). USA Today reports that 9/11 survivors, the victims' families, and first responders can visit for free between now and when it opens to the public (admission: $24) on Wednesday. | 4,867 | 410 | multi_news | en |
Summarize: Image caption Julia Pastrana's remains were returned to Mexico from Norway An indigenous woman exhibited in 19th-Century Europe as the "world's ugliest woman" has been buried in her native Mexico some 150 years after her death. Julia Pastrana, who suffered from a genetic condition that covered her face in hair, performed in circuses as a freak of nature. After she died in 1860, her American husband toured with her embalmed body, which ended up in Norway. Her remains were returned this week for a proper burial, after a long campaign. People flocked to the town of Sinaloa de Leyva on Tuesday where Julia Pastrana was laid to rest in a white coffin adorned with white roses. "Imagine the aggression and cruelty of humankind she had to face, and how she overcame it. It's a very dignified story," said Sinaloa Governor Mario Lopez. "A human being should not be the object of anyone," Father Jaime Reyes Retana told mourners. 'Place in history' Julia Pastrana, who was born in 1834, suffered from hypertrichosis which covered her face in hair and had a jutting jaw. Image caption Campaigners wanted Pastrana to have the dignity denied her in life Because of her appearance she was called a "bear woman" or "ape woman". In the 1850s, she met and married US impresario Theodore Lent who took her round freak shows, where she would sing and dance. She died in 1860 in Moscow after giving birth to a son who had the same condition and lived for only a few days. But Julia Pastrana's story did not end there as Lent continued to tour with their embalmed bodies. The corpses finally ended up in Norway, where, in a further twist in 1976, they were stolen, dumped and recovered by the police. The remains ended up in storage at the University of Oslo. Mexican artist Laura Anderson Barbata began a campaign for Julia Pastrana's body to be returned home in 2005, with Mexican officials subsequently lending their weight to her request. "I felt she deserved the right to regain her dignity and her place in history, and in the world's memory," Ms Barbata told the New York Times. An indigenous Mexican woman put on display in Victorian-era Europe because of a rare genetic condition that covered her face in thick hair was buried in her home state on Tuesday in a ceremony that ends one of the best-known episodes from an era when human bodies were treated as collectible specimens. With her hairy face and body, jutting jaw and other deformities, Julia Pastrana became known as the "ape woman" after she left the Pacific coast state of Sinaloa in 1854, when she was 20, and was taken around the United States by showman Theodore Lent, according to a Norwegian commission that studied her case. She sang and danced for paying audiences, becoming a sensation who also toured Europe and Russia. She and Lent married and had a son, but she developed a fever related to complications from childbirth, and died along with her baby in 1860 in Moscow. Her remains ended up at the University of Oslo, Norway. After government and private requests to return her body, the university shipped her remains to the state of Sinaloa, where they were laid to rest. "Julia Pastrana has come home," said Saul Rubio Ayala, mayor of her hometown of Sinaloa de Leyva. "Julia has been reborn among us. Let us never see another woman be turned into an object of commerce." After a Roman Catholic Mass in a local church, Pastrana's coffin was carried to the town cemetery and buried as a band played traditional music. "The story is so important," said visual artist Laura Anderson Barbata, who campaigned for Pastrana's return to Sinaloa. "Bringing her back here is a way of recovering it." Pastrana's repatriation is part of a broader movement among museums and academic institutions to send human remains gathered during the European colonization of Latin America, Africa and Asia back to their countries and tribal lands. Hundreds of thousands of remains have left cultural institutions in the U.S., Europe and Australia since the repatriation movement began in the late 1980s, when a new generation of anthropologists, archeologists curators began grappling with the colonial legacies of their disciplines, said Tiffany Jenkins, author of "Contesting Human Remains in Museum Collections: the crisis of cultural authority." "They've been symbolic, in a way, of making an apology," Jenkins said. Institutions in Scandinavian countries have come to the movement somewhat later than their counterparts in other parts of Europe and in the United States, where more than a half-million sets of remains and artifacts have been returned to Native American tribes, she said. "Norway has become in recent times more uncomfortable about their holding of human remains," she said. Mexican Ambassador Martha Barcena Coqui, who is based in Copenhagen, Denmark, formally received Pastrana's coffin at a Feb. 7 ceremony at Oslo University Hospital in the Norwegian capital before the coffin was flown to Mexico. "You know I have mixed feelings," the ambassador said. "In one way, I think she had a very interesting life and maybe she enjoyed visiting and traveling and seeing all the places, but at the same time I think it must have been very sad to travel to these places not as a normal human being but as a matter of exhibition, as something weird to be talked about." Jan G. Bjaalie, head of the Institute of Basic Medical Sciences at the University of Oslo, said he was happy that they had "finally been able to grant a worthy end to her life." "Today, it's almost incomprehensible that a circus used corpses for entertainment purposes. Hers was used in a way we today would consider to be completely reprehensible," he said. "It's important that we now have a clear end to the way she was treated." ___ Weissenstein reported from Mexico City. Associated Press Writer Matti Huuhtanen contributed from Helsinki, Finland. “I felt she deserved the right to regain her dignity and her place in history, and in the world’s memory,” Ms. Barbata said by telephone from Oslo last week. “I hoped to help change her position as a victim to one where she can be seen in her entirety and complexity.” Photo Pastrana was born in Mexico in 1834. She had two rare diseases, undiagnosed in her lifetime: generalized hypertrichosis lanuginosa, which covered her face and body in thick hair, and gingival hyperplasia, which thickened her lips and gums. A Mexican customs administrator bought Pastrana in 1854 and began showing her throughout the United States and Canada, part of a growing business of traveling exhibitions displaying human oddities. (Though slavery had been abolished in Mexico decades earlier, many circus performers were still sold.) In New York Pastrana married Theodore Lent, an impresario who became her manager. “She was definitely in love with Mr. Lent,” says Jan Bondeson, a rheumatologist at Cardiff University in Wales, whose book “A Cabinet of Medical Curiosities” includes a chapter on Pastrana. “I am certain the reason he married her was that he could keep control of her and the not unconsiderable earnings.” Lent toured his wife throughout Europe, where some newspapers and books described her appearance unsparingly: “gorillalike” or “revolting in the extreme.” Some felt her appearance masked other qualities, however. Francis Buckland, a British natural historian, wrote in an 1868 book that Pastrana had a sweet singing voice, “great taste in music and dancing, and could speak three languages.” He added, “She was very charitable, and gave largely to local institutions from her earnings.” In 1859 Pastrana became pregnant by Lent while touring. Her infant inherited her hypertrichosis and died hours after his birth in Moscow, and Pastrana died from complications five days later. Lent soon began exhibiting the embalmed bodies of his wife and son. He later found a bearded woman in Germany whom he married and billed as Pastrana’s sister, “Zenora Pastrana.” The couple traveled, and Zenora performed alongside the bodies. Photo After Lent’s death, Pastrana’s body was exhibited widely, most recently by a Norwegian fairground operator in the early 1970s. In 1976 thieves broke into a warehouse owned by the fairground’s heir and stole the bodies of Pastrana and her son. Advertisement Continue reading the main story The Norwegian police later found her remains in a trash-hauling bin, with an arm dismembered. The child’s body was damaged beyond repair, but the police transferred Pastrana’s body to the Institute of Forensic Medicine at the University of Oslo, where she was placed in storage. The body was later moved to a climate-controlled room of anatomical specimens in the university’s Institute of Basic Medical Sciences. “By ending up as part of a collection in a basement, she lost any trace of dignity,” Ms. Barbata said. “My ultimate dream goal was that she should go back to Mexico and be buried.” Newsletter Sign Up Continue reading the main story Please verify you're not a robot by clicking the box. Invalid email address. Please re-enter. You must select a newsletter to subscribe to. Sign Up You agree to receive occasional updates and special offers for The New York Times's products and services. Thank you for subscribing. An error has occurred. Please try again later. View all New York Times newsletters. In 2005, during a residency in Oslo, Ms. Barbata began petitioning the university for Pastrana’s repatriation. “With the initial replies I was getting, I thought it was going to be very difficult,” she said. But Ms. Barbata, who is 54, continued to apply pressure. In September 2005, she placed a death notice for Pastrana in an Oslo newspaper and had a Mass said for her there. (Pastrana was Roman Catholic.) In 2008 Ms. Barbata sent documents making her case for Pastrana’s release to Norway’s National Committee for the Evaluation of Research on Human Remains. Last June that panel offered its opinion that “it seems quite unlikely that Julia Pastrana would have wanted her body to remain a specimen in an anatomical collection.” Jan G. Bjaalie, the head of the Institute of Basic Medical Sciences in Oslo, said by Skype that the university had been open to the idea of Pastrana’s return but “we were not in a position simply to send remains to someone who would ask for them.” Photo A breakthrough came after the current governor of Sinaloa, Mario López Valdez, joined Ms. Barbata’s cause last year and petitioned for Pastrana’s repatriation. The Mexican ambassador to Denmark, Norway and Iceland, Martha Bárcena Coqui, offered to work with the university to accept the body. “We understood that she must have suffered enormously during her lifetime and that her remains did not receive the respect they deserved for many years,” Ms. Coqui said by e-mail. The institute agreed to begin the process of transferring Ms. Pastrana to Mexican custody last August. Advertisement Continue reading the main story Last Thursday Ms. Barbata confirmed the identity of Pastrana’s body in Oslo before the coffin was sealed. Ms. Barbata and a University of Oxford forensic anthropologist, Nicholas Márquez-Grant, noticed that Pastrana’s feet still had bolts and metal rods that were used for exhibiting her body. The bolts were removed and placed at the foot of her coffin. “Her hands were tiny and perfect,” Ms. Barbata said. Pastrana will be buried on Tuesday in a cemetery in Sinaloa de Leyva, a town near her birthplace. She has become a minor celebrity in the Mexican press. Maria Luisa Miranda Monrreal, the director of the Sinaloa Cultural Institute, held a news conference last week and said the burial marked an end to a cycle “of exploitation.” Governor Valdez, who has criticized the press for scaring away tourists by focusing on the drug violence in Sinaloa, will attend the service. His letter last year to Norway’s human-remains ethics board appealed for Pastrana’s return out of a “respect for human dignity and a high sense of justice.” For Ms. Barbata and others who have wished for this moment, Tuesday’s burial will offer a sweet though long-overdue resolution. “Her story has always had a bad ending,” said Jonathan Fielding, a New York-based actor who directed a production of Mr. Prendergast’s play about Pastrana last year at Amphibian Stage Productions in Fort Worth, where Ms. Culebro is artistic director. “The big difference is that now it has an appropriate ending.” | Summary: The "world's ugliest woman" has been laid to rest-153 years after she died. Born with a genetic condition that covered her face in thick hair, Julia Pastrana was called "bear woman" by husband/manager Theodore Lent and described in an 1854 New York Times ad as the "link between mankind and the ourang-outang"; less kind papers called her "revolting in the extreme." She died six years later, at age 26, in childbirth (her hair-covered son also died), but Lent carted her embalmed body to audiences throughout Europe for decades, reports the BBC. The story gets stranger still: Lent later married a bearded woman who he dubbed Pastrana's sister; she performed alongside the body. Pastrana's remains were stolen from a warehouse in Norway in 1976, and later found in the garbage; they were transferred to the University of Oslo, where they spent decades in storage. She finally found her way back to Mexican soil this week, thanks to a campaign Mexican artist Laura Anderson Barbata launched in 2005 to bring Pastrana home. | 2,900 | 247 | multi_news | en |
Summarize: Notable Recent Developments1 On July 29, Secretary of State John Kerry and Secretary of Commerce Penny Pritzker traveled to New Delhi for the 5 th U.S.-India Strategic Dialogue, where they met with newly-seated Indian Prime Minister Narendra Modi and External Affairs Minister Sushma Swaraj, among others. In a joint statement, the two sides reviewed bilateral dialogues and working groups on issues ranging from science and technology to regional security and counterterrorism. Post-dialogue press interactions suggested that the bulk of the dialogue focused on trade and investment, energy, and climate change. The two sides intend to re-convene the moribund U.S.-India Trade Policy Forum, and to expand the framework of dialogue on commercial ties and technology exchange. They established a new Joint Working Group on Climate Change with the stated goal of laying the foundation for an "ambitious climate change agreement for the post-2020 period." Secretary of Defense Chuck Hagel will travel to India in August to attempt to reinvigorate the defense partnership. On July 10, new Indian Finance Minister Arun Jaitley presented a partial-year national budget, widely seen as an early measure of the new government's interest in pursuing substantive new economic reforms. Most independent observers were cautiously optimistic about the outlook for such reforms, although some expressed disappointment that the government did not lay out a clear path toward its stated goals of opening markets and attracting new investment, and did not address the issue of intellectual property rights protection. The budget did not touch major subsidy and social welfare programs initiated by the preceding government, highlighting the constraints of India's historical tendency toward populist initiatives meant to safeguard the poor. The new budget does, however, pledge to raise foreign direct investment caps in the insurance and defense sectors up from 26% to 49%, but still falls short of the majority allowance that many Indian and international business interests had hoped for. On July 31, New Delhi blocked a World Trade Organization (WTO) trade facilitation agreement that was negotiated among 160 countries, including India, in Bali in December 2013. the Indian government insisted on extending the negotiating period, citing its displeasure with the pace of separate negotiations over a so-called peace clause for its food security programs, which would preclude a challenge to these programs on subsidy grounds. Some analysts suspect that Prime Minister Modi is giving a nod to the interests of his country's hundreds of millions of farmers, a demographic not typically supportive of his ruling party. Member governments saw the trade facilitation deal as a breakthrough in the drawn-out Doha Round of multilateral negotiations, and some worry that its obstruction could delegitimize the WTO. Following Secretary Kerry's meeting with Modi, a senior State Department official said that Indian decision "sends a confusing wrong signal and undermines the very message that India is seeking to send." New Delhi has expressed hope that differences can be resolved when the WTO reconvenes in September. Overview and Commentary IndiaâSouth Asia's dominant actor with more than 1.2 billion citizens and Asia's third-largest economyâoften is characterized as a nascent great power and "indispensable partner" of the United States, one that many analysts view as a potential counterweight to China. For the past decade, Washington and New Delhi have been pursuing a "strategic partnership" based on shared values and apparently convergent geopolitical interests. Numerous economic, security, and global initiatives are underway. In 2005, the United States and India signed a 10-year defense framework agreement to expand bilateral security cooperation. The two countries since have engaged in numerous and combined military exercises, and major U.S. arms sales to India are underway. The value of all bilateral trade has grown significantly, although the recent global economic downturn has stunted that growth. Bilateral trade in goods and services was worth more than $97 billion in 2013; a total that has been fairly static for two years. Two-way investment also flourishes. Indians receive about two-thirds of all H1-B (nonimmigrant work) U.S. visas, and some 100,000 Indian students are attending American universities. The influence of a relatively wealthy and outspoken Indian-American community of roughly three million is reflected in Congress's largest country-specific Senate and House caucuses. President Barack Obama's Administration has sought to build upon the deepened U.S. engagement with India begun by President Bill Clinton in 2000 and expanded during much of the previous decade under President George W. Bush. A bilateral Strategic Dialogue forum, established in 2009, met for the fourth time in New Delhi in June 2013; a fifth meeting, also in New Delhi concluded on July 31, 2014. Still, independent analysts in both countries worry that the partnership has lost momentum in recent years. Some saw a notable cooling of U.S.-India ties in 2013 with the serious diplomatic dispute triggered by the December arrest of Indian consular official Devyani Khobragade in New York. And there are longer-running and more serious disagreements over intellectual property rights protection; market access; U.S. immigration law; and stalled efforts to initiate civil nuclear cooperation, among others. In May 2014, India's national election resulted in a convincing and historic win for the Bharatiya Janata Party (BJP or "Indian Peoples Party") and its prime ministerial candidate, then-Gujarat state Chief Minister Narendra Modi. The new Indian leader is known as a strong-willed and effective, if perhaps autocratic, administrator. His reputation has been burnished by Gujarat's impressive economic performance during his 15-year tenureâthe state accounts for more than 20% of all Indian exports while being home to only 5% of the population. Garnering an outright majority in Parliament for the first time in 30 years, Modi's new government promises fresh U.S. engagement with an Indian leader reputed to be more pro-trade and pro-business than the socialist-oriented ones of the past, and who vows to implement a more assertive Indian foreign policy that could see the country shift away from its traditional "non-alignment" approach to global politics. President Obama and other top U.S. officials have expressed an interest in revitalizing bilateral fora so as to further boost trade and investment flows, deepen security cooperation, and otherwise solidify the geopolitical alignment with India. One area of potential friction relates to a guiding ideology of the new Indian government: the BJP was born in 1980 as the political wing of the Rashtriya Swayamsevak Sangh (RSS or "National Volunteer Organization") a militant Hindu and social service group (roughly 82% of Indians are Hindu and another 14% Muslim). Prime Minister Modiâhimself a longtime RSS memberâand his party maintain a firmly Hindu nationalist perspective. He also is a controversial andâamong someâeven reviled figure due to persistent suspicions about his possible role in horrific communal rioting in Gujarat in 2002 that left up to 2,000 people dead, most of them Muslims. Although multiple high-level investigations into Modi's alleged role have resulted in no formal charges, human rights groups and other analysts still widely accuse him of being complicit in the anti-Muslim violence, or at least showing gross dereliction of duty in his response. Such accusations led the Bush Administration to deny Modi a visa in 2005, and the U.S. government subsequently had no official contacts with Modi until he met with the U.S. ambassador to India in late 2013. Some Members of Congress have continued to express deep concerns about Modi's past and his commitment to religious freedom. Many observers warn that a BJP-majority government could have dire consequences for human and civil rights in India, especially if it chooses to implement openly Hindu majoritarian policies. However, President Obama wasted no time in ending speculation on the visa issue by immediately inviting Prime Minister Modi to visit Washington, DC (Secretary of State John Kerry subsequently told an Indian audience that there is no doubt that the Indian leader will receive a U.S. visa). Modi is set to visit the U.S. capital in late September. Following the election, Secretary Kerry congratulated India for the successful democratic exercise and Modi for his victory while calling the bilateral friendship "absolutely vital." On Capitol Hill, Members of both chambers took positive note of India's democratic exercise and its new government, and expressed recognition of the importance of the bilateral relationship. To date, 88 House Members are signatories to a letter asking congressional leadership to convene a Joint Session for the Indian leader to address. Committees in both the Senate and House held hearings on U.S.-India relations in July. In D.C. policy circles, there is no consensus view on India's new government beyond a general agreement that Prime Minister Modi must confront a multitude of difficult problems and choices, and that the domestic Indian expectations of their new leader are so broad and so high that they are very unlikely to be met. Most agree that it will be exceedingly difficult, if not virtually impossible, for Modi to fulfill voters' economic aspirations given the significant restraints presented by India's federal system, by still widespread resistance to fiscal stimulus in an environment of high deficits, and by an expectation of potentially decisive political opposition in Parliament's upper chamber. One U.S.-based commentator characterized Washington's reaction to India's election results as "a mix of curiosity, hope, and concern." In this view, the interest is evoked by the strong electoral win of a Delhi outsider, the optimism emanates mainly from the business community, which anticipates a stronger reform impulse, and the worries are about the potentially negative effects of past U.S. shunning of Modi, as well as his record of taking a hardline posture toward India's religious minorities. On this last point, another analyst contends that the trajectory of U.S.-India relations transcends any single leader and that there have been no signs that Modi will rock this boat as prime minister. Notably, Modi never appeared to discriminate against any U.S. firms in Gujarat during the post-2005 visa ban period. A minority view contends that conceiving of the United States and India as "natural partners" is misguided. In this account, New Delhi's implicit approval of Russia's early 2014 aggression in Ukraineâstrongly opposing sanctions on Moscow and calling its interests in Crimea "legitimate"âis a recent demonstration that U.S. and Indian strategic interests can and do continue to diverge. In the words of two prominent observers, "[T]he linkages between the United States and India remain more aspirational than accomplished, with many unfulfilled expectations." Meanwhile, a senior Indian analyst conveys a perspective among some that recent changes in regional and global circumstancesâespecially those that have Washington focused on crises in regions where New Delhi plays a negligible roleâhave "tended to lower the salience of this 'indispensable partnership' in the eyes of both partners." While the chances for a "dramatic resuscitation" of bilateral ties may be poor in the short-run, many analysts continue to urge Washington to view a stronger India as being in America's interests. Undergirding this argument is the assumption that New Delhi's future economic and security policies are highly likely to take courses that benefit the United States, even if indirectly. U.S. officials thus are encouraged to demonstrate full openness to working with the Modi government, in part as a means of ameliorating the raw sensitivities many Indians appear to have about national respect, sensitivities that were exposed by the Khobragade incident in a fierce reaction that surprised many observers in the United States. These analysts also offer that Washington can demonstrate for New Delhi that U.S. leaders are serious about the rebalance to Asia and that India can play a vital role in such policy, perhaps especially in the area of maritime security and codes of conduct. A Historic Election and New Delhi's New Government23 In April and May of 2014, India once again broke its own record by conducting the largest democratic exercise in human history: Of its 815 million eligible voters in 29 states and 7 union territories, a record 66.4% turned out to seat a new Lok Sabha (House of the People)âthe lower chamber of Parliament and the locus of national powerâand, with it, a new prime minister. The outcome was historic in numerous ways. The victorious BJP won a majority of the body's 543 seats, becoming the first party to do so since 1984 and the first-ever non-Indian National Congress Party to rule India's federal government without coalition partners (the dynastic, Nehru/Gandhi Congress Party suffered what was by far its worst-ever national defeat, although it continues to lead 11 state governments). The BJP's 282 seats allowed the party to elevate Modi to the prime minister's seat, and he was sworn in to office on May 26. Modi is India's first-ever lower-caste prime minister, the first born after the country's 1947 independence, and the first not to have been steeped in Delhi's rarified political circlesâan "outsider" in more ways than one. India's smaller upper parliamentary chamber of a maximum 250 seats, the Rajya Sabha (Council of States), is on a different election schedule from that of the Lok Sabha. This body may review, but not veto, revenue legislation, and has no power over the prime minister or his/her cabinet. Still, the BJP's governance agenda can be impeded in the Rajya Sabha, where the former incumbent Congress Party holds a plurality of seats (68) and can align with other BJP opponents to block certain legislation. Moreover, many key reforms that may be pursued by the new governmentâincluding in tax policy, labor laws, land acquisition, subsidy cuts, and infrastructure project clearanceâwill be dependent on the participation of state governments, only eight of which are currently controlled by the BJP or its allies. Analysts identify convincing reasons to believe that the Indian electorate did not elect Narendra Modi for his bold Hindu nationalism. Instead, Modi's mandate most likely derived from the electorate's acute desire to see uncorrupt governance in New Delhi and a repaired economy with plentiful jobs, and not from support for any parochial agenda. Moreover, with Muslim votes split between the numerous "secular" alternatives to the BJP, Modi's electoral outlook was much improved. Winning a majority of seats with less than one-third of votes cast (the BJP won 31% of the popular vote) was possible only through a significant splintering of the country's "anti-BJP vote." This leads some to argue against the "historic election" narrative: More than two-thirds of votes were cast for non-BJP candidates, the BJP continued to fare poorly in most of the country's south and east, and regional parties continued to account for roughly half of all votes cast. Prime Minister Modi has pared down the size of the cabinet considerably, from 71 ministers under the previous government to 44 today. Key officials include recent BJP President and current Home Minister Rajnath Singh; External Affairs Minister and Overseas Indian Affairs Minister Sushma Swaraj, a BJP parliamentary stalwart; and Arun Jaitley a corporate lawyer now serving as Finance Minister, Defense Minister, and Corporate Affairs Minister. Modi's longtime lieutenant and home minister in Gujarat, Amit Shah, is the new BJP chief. Skeptical observers found in Modi's cabinet picks signs of "business as usual" in India's often venal political culture: 13 cabinet ministers are said to be facing sometimes serious criminal charges and most are over 60-years-old, belying Modi's campaign claims to be a champion of the country's youth. Among the sea of commentaries on Modi are numerous negative portrayals of his personality. While his millions of supporters see in Modi a strong-willed, incorruptible, and effective leader who will defend and enrich the nation, critics take a darker view. Their arguments commonly portray Modi as having a ruthless and dictatorial style of governance. By some accounts, Modi has welcomed being the focus of a cult of personality and has consciously cultivated an autocratic image. Detractors also identify a disregard for rule of law in Gujarat under Modi, including allegations that Gujarati authorities staged at least 20 extrajudicial killings from 2003-2006. Economic Policy Outlook The impressive growth of Indian national wealth, especially that occurring in the middle years of the last decade, has been central to the country's newfound visibility and importance in global political calculations. Most observers foresee India becoming the world's third largest economy by 2030; in purchasing power parity terms, India already has supplanted Japan in share of global GDP. However, India's economic growth rate is at a ten-year low, and fiscal and current account deficits have widened significantly. The country today is in the midst of its worst economic slowdown since the 1980s, with two full years of sub-5% annual growth and persistently high inflation. Experts generally agree that, for India's international influence to continue to growâand thus further boost its attractiveness as a U.S. partnerâthe country's negative economic trends need to be reversed. Modi is widely viewed in Washington as being good for business, especially through efforts to create a more stable and tax-friendly investment climate. Foreign investors, anticipating Modi's win, were seen to be behind the roughly 25% surge in the value of India's top stock index in the 8 months leading up to the election. When the results were announced, another rally led to a new record high and propelled the Mumbai stock market into the world's top ten for the first time ever. During the election campaign, Arun Jaitley, now finance minister, said that luring both foreign and domestic investment into fast-tracked major projects in infrastructure and skills development would be the primary goal of the new government. This tack has been central to the "Gujarat miracle" that Modi may seek to recreate at the national level. Although generally favored by the domestic and international business community, the BJP hardly is a party of "free traders," but rather is home to stiff debate over "pro-market" versus "protectionist" policies. India remains a mostly socialist country with an embedded tradition of state-led welfare initiatives. Thus, predicting future BJP economic policy can be difficult, and, while new space will be opened for private sector initiatives, and within an improved investment climate, a D.C.-based expert contends that this "will not automatically translate into a free rise for either 'India, Inc.' or corporate America." Moreover, even if Modi does move energetically to lure investment and fast-track projects in the country, India's federal system provides state governments with considerable say over reforms in key sectors such as energy infrastructure; in some cases this extends to veto power. Indeed, experts agree that state bureaucracies can present major obstacles to reinvigorating India's investment climate; one recent study revealed that 40 of India's top 50 stalled projects were being held up by red tape at the state level. Foreign Policy Outlook Along with an array of urgent domestic priorities, Modi faces a busy foreign policy schedule to include appearances at five multilateral summit meetings before year's end: the BRICS (Brazil, Russia, India, China, South Africa) summit in July; the UN General Assembly meeting in September; the concurrent East Asian and India-Association of Southeast Nations (ASEAN) summits in November; followed by the G20 and South Asian Association for Regional Cooperation (SAARC) summits later that month. As a campaigner, Prime Minister Modi said little about what kinds of foreign policies he would pursue, and the BJP Manifesto devoted only 1 of its 42 pages to foreign policy discussion, notably vowing a shift toward active alliance-seeking ("a web of alliances"). Modi has, however, lauded the pragmatic approach to foreign relations taken by the previous BJP-led government, which was in power from 1999-2004, and is widely seen as most likely to pursue economic growth through non-confrontational engagement with India's neighbors. This assumption holds even as aides reportedly have promised that an India under Modi's leadership will take a tougher line on territorial disputes with Beijing and rivalry with Islamabad. By inviting the six other SAARC leaders to attend his inauguration in person, Modi was seen to be emphasizing India's relations with its immediate neighbors, including Pakistan. SAARC accounts for all of India's contiguous neighbors but for China. South Asian regionalism is poorly developed, having long been hindered by India-Pakistan antagonisms. Yet New Delhi's recent signals that it will prioritize near relations are lauded by independent analysts and could lead to a more promising environment for economic growth. As a campaigner, Modi singled out Bangladesh as a source of migrant Muslim "infiltrators" while being welcoming of its Hindu "refugees." And Bangladesh's long border with India's West Bengal state gives the Kolkata-based government an outsized role in India-Bangladesh relations. Likewise, the presence of a large ethnic Tamil community in the southern Tamil Nadu state causes the Chennai-based government to monitor the status of the Tamil minority in Sinhala-dominated Sri Lanka. China has been viewed warily by Indians ever since Beijing launched a brief, but bloody 1962 war that created what is still the world's longest disputed border. China long has been a major supporter of Pakistan and is increasing its presence in the Indian Ocean Region in ways that could constrain India's regional influence. The Chinese also are irked by the presence of the Dalai Lama and the Central Tibetan Administration on Indian soil. As an unapologetic nationalist, many prognosticators see Prime Minister Modi as eager to demonstrate his bona fides vis-a-vis Beijing. Yet China has also emerged as India's largest trade partner in recent years. As chief minister, Modi made four business-oriented trips to China and eagerly developed commercial links between Gujarat and China. Greater Chinese investment capital (especially in the vital infrastructure sector), technology, and management skills are welcomed by many in India. Pakistan for decades has confounded India by fueling a separatist insurgency in India's Jammu & Kashmir state, employing Islamist proxy groups that conduct terrorist attacks on Indian soil and overseas interests, and obstructing New Delhi's access to Afghanistan and Central Asia. Prime Minister Modi's leadership, and his status as a Hindu nationalist with a record of hardline rhetoric toward both Pakistan and Muslims, could increase the risk of greater tensions and even open conflict with Pakistan, especially if another major terrorist attack in India is traced to Pakistani soil such as that in 2008 when 163 people were killed in Mumbai, 7 Americans among them. Some such concerns dissipated when Modi invited the Pakistani prime minister to New Delhi to witness his swearing-in. And, here again, experts say Modi likely will seek to balance mutual antagonism with his need to expand the Indian economy, a goal that would only benefit from an increase in what is now relatively miniscule bilateral trade with Pakistan. Japan, according to many analysts, may be the country most ripe for rapidly deepened relations with an India under Narendra Modi, who made two business trips to Japan as Gujarat chief minister. Modi is said to have a warm personal relationship with Japanese Prime Minister Shinzo Abe and Japanese companies have made major investments in Gujarat over the past decade. Abe's firm stance on Chinese expansionism and greater emphasis on the role of Japanese military power may make Japan an increasingly attractive partner for India. Modi describes the two countries as sharing fundamental identity of values, interests and priorities. Afghanistan plays a key role in India's regional policy, and Indian leaders envisage a peaceful Afghanistan that can serve as a hub for regional trade and energy flows. By many accounts, India and Pakistan are vigorously jockeying for influence in Afghanistan, and high-visibility Indian targets have come under attack there, allegedly from Pakistan-based and possibly -supported militants. Prime Minister Modi likely will seek ways to remain deeply engaged with the next Kabul government while avoiding any additional conflict with Islamabad over the Indian presence there. Israel did not receive formal recognition from India until 1992. Yet bilateral relations have blossomed in the 21 st century, with booming trade driven mainly by gemstones and defense wares. Israel now roughly equals Russia in the value of defense exports to India. Prime Minister Modi, with reportedly close ties to Israeli business leaders, visited Israel as chief minister. New Delhi has thus far maintained a studied neutral position on the current conflict in Gaza, and has joined the United States in calling upon both sides to exercise maximum restraint. Iran has had long-standing positive relations with India, but frictions have arisen in the 21 st century as New Delhi has grown closer to Washington. Most recently, India fully cooperated with U.S.-led sanctions by significantly reducing its importation of Iranian oil, at some cost to its relationship with Tehran. Yet Iran remains a key source of hydrocarbons to meet India's growing energy needs, and New Delhi has continued to develop Iran's Chabahar port, in large part to provide India with access to Central Asian markets bypassing Pakistan. Prime Minister Modi's emerging posture toward Iran could be telling, as he may find himself facing mutually exclusive choices between cooperating with Iran or cooperating with those countries seeking to isolate the Islamic theocracy due to its controversial nuclear program. Hindu Nationalism and Related Policy Because Hinduism does not have a specific sacred text to which conformity can be demanded, "Hindu fundamentalist" is not an apt term to describe a purveyor of "Hindutva" or "Hindu-ness." Moreover, for parties such as the BJP and its antecedents, Hinduism as a concept almost always is concurrent with nationalism, the core belief being that India is an inherently Hindu nation, even if establishment of a strictly Hindu state is not a goal. In this regard, proselytizing religionsâIslam and Christianity, in particularâcan be characterized as a threat to the "Hindu nation." Hindu nationalists have a relatively short, but long-standing list of political goals. Leading Hindutva and widely-held RSS aspirations include scaling back laws and government programs designed to benefit the religious minorities, Muslims in particular; establishing a Uniform Civil Code (to replace current personal law based on religious customs and thus standardizing all national laws regarding such topics as marriage, divorce, and inheritance); repealing Article 370 of the Constitution, which grants limited autonomy to the Muslim-majority state of Jammu & Kashmir (a step that, if implemented, would allow citizens from other Indian states to buy property in J&K); redrafting public school textbooks to remove what are alleged to be insults to Hindu gods and excessive praise of the subcontinent's past Muslim rulers; constructing a Ram temple on the site of the Babri Mosque that was razed in 1992 (a policy endorsed in the BJP's 2014 Manifesto); and preventing cow slaughter (cows are deeply revered animals in Hinduism). Issues in U.S.-India Relations Along with the economic, security, and human rights issues discussed below, the United States and India engage closely on myriad other global and multilateral issues, including science and technology; space; healthcare; education; and sustainable growth, energy, and climate change, among others. India, a non-signatory to the Nuclear Nonproliferation Treaty, maintains a nuclear arsenal of an estimated 90-110 warheads, and apparently is working to develop that arsenal's size and sophistication. With the signing of the U.S.-India Civil Nuclear Agreement in 2005, and Congress's 2008 endorsement of that deal, the issue of Indian nuclear weapons has receded from the top-tier position it previously occupied in the relationship. The Administration currently supports India's "phased entry" into several multilateral arms control organizations. Economic and Trade Issues The U.S. government aspires to reach $500 billion in annual bilateral trade with India by 2024, a more than five-fold increase from the $97 billion total in 2013. According to the lead U.S. diplomat for the region, the most immediate need in this regard is to complete Bilateral Investment Treaty (BIT) negotiations to finalize a pact that will "help us move past the choppiness that comes from not having an overarching investment framework" (American foreign direct investment into India topped $28 billion in 2013, and cumulative Indian investment into the United States grew from under $100 million in 2000 to more than $5 billion in 2012). The Obama Administration also continues to raise concerns about the lack of "investment diversity" and urges India to create a "transparent, straightforward way of attracting foreign investment, offering private capital a way to share in India's opportunity." This will entail a setting in which contracts are "upheld and honored across jurisdictions, and perhaps most importantly, intellectual property rights (IPR)âbased on international normsâmust be recognized." The U.S. Trade Representative's annual "Special 301 Report" on the Administration's IPR concerns has listed India every year since its 1989 inception. Currently appearing with nine other countries on the "Priority Watch List," India is singled for its "challenging environment for IPR protection and enforcement." The 2014 report reviews "issues of concern to U.S. and other stakeholders" that include exceptionally high rates of audiovisual piracy, counterfeit pharmaceuticals, high tariffs on medicines, and a weak IPR legal framework and enforcement system. It cites an industry study's finding that rights holders lost sales worth nearly $12 billion in 2012. An "Out-of-Cycle Review" for India, expected to be complete in September, is a tool to boost engagement with certain trading partners so as to address and remedy U.S. concerns. The Obama Administration continues to maintain that Indiaâand its economic connectivity with neighbors to both its east and westâis vital to the prosperity and stability of the entire region. To facilitate connectivity, the Administration seeks to advance initiatives that better link India with Central Asia (via a "New Silk Road") and with Southeast Asia (via the "Indo-Pacific Economic Corridor"). Combined with Modi's more strident nationalism, the new Indian government could, in the view of some analysts, serve to assist the U.S. policy of rebalancing toward Asia. Washington is widely urged to take a pragmatic stance with New Delhi and focus especially on finding ways to resolve outstanding trade-related disputes, perhaps through a reinvigoration of the bilateral Trade Policy Forum, which has not met since 2010. Longer-range goals could be bringing India into wider multilateral trade groupings in the Indo-Pacific region. New Delhi also is eager to import natural gas from the United States. Prime Minister Modiâwho ran a campaign that promised rapid infrastructural improvements, including in the energy sectorâhas emphasized the role of renewable fuels, but India's soaring demand will require it to rely on carbon-based fuels for the foreseeable future. Proponents of exporting liquefied natural gas (LNG) to India argue that doing so would help cement the bilateral partnership while not subjecting U.S. consumers to significantly higher prices. Security and Defense Issues The United States views defense cooperation with India in the context of "common principles and shared national interests" such as defeating terrorism, preventing weapons proliferation, and maintaining maritime security and regional stability. Many analysts view increased U.S.-India security ties as providing an alleged hedge against or counterbalance to growing Chinese influence in Asia, although both Washington and New Delhi routinely downplay such motives. India is in the midst of transforming its military into one with global reach, particularly with a blue-water navy, and the issue of U.S. arms sales to India has taken a much higher profile in the new century, with India planning to spend up to $100 billion over the next decade to update its mostly Soviet-era arsenal. No less significant are bilateral military-to-military contacts. Since 2002, the United States and India have held a series of combined exercises involving all military services. Such relations have been a key aspect of U.S.-India relations in recent yearsâIndia now conducts more exercises and personnel exchanges with the United States than with any other country. Navy-to-navy collaboration appears to be the most robust in terms of exercises and personnel exchanges. The Pentagon is reported to be eager to expand maritime cooperation with New Delhi's new government. Another key facet of the emerging partnership between the United States and India is greatly increased intelligence and counterterrorism (CT) cooperation. Despite meaningful progress in this realm, there appears to be an asymmetry in the willingness of the two governments to move forward: Washington wants more cooperation from India and is willing to give more in return, but officials in New Delhi remain hesitant and their aspirations are more modest. Indian wariness is rooted in lingering distrust of U.S. intentions. New Delhi's rancor at reports of U.S. spying on the BJP is the most recent expression of this. Serious structural impediments to future cooperation also exist in the view of observers in both countries. Chief among these is the fact that, in India, state governments are the primary domestic security actors and there is no effective national-level body with which the U.S. government can engage and coordinate. While in Asia in May, Secretary of Defense Chuck Hagel emphasized the Administration's view that India is a key global partner and that the United States welcomes its increasingly active role in regional institutions. For many observers, reform of India's defense procurement and management systemsâincluding an opening of Indian firms to more effective co-production and technology sharing initiativesâis key to continued bilateral security cooperation, making high-level engagement on the Defense Trade and Technology Initiative (DTTI) a priority. Independent proponents of robust U.S.-India defense links have expressed optimism that Modi may seek and be able to effect further changes in India's FDI caps and offsets policies that currently deter international defense firms from engaging in joint projects. Some also urge the drafting of a revamped formal framework for bilateral defense engagement (the current document, inked in 2005, expires next year), along with a greater diplomatic push to engage the Modi government on regional security matters, Afghanistan perhaps leading among them. Human Rights Concerns Many of India's citizens suffer from human rights abuses. According to the State Department's Country Reports on Human Rights Practices for 2013, the most significant of these include police and security force abuses, including extrajudicial killings, torture, and rape; widespread corruption at all levels of government, leading to denial of justice; and separatist, insurgent, and societal violence.... The law in some states restricts religious conversion, and there were reports of arrests but no reports of convictions under those laws.... Rape, domestic violence, dowry-related deaths, honor killings, sexual harassment, and discrimination against women remained serious problems. Child abuse and forced and early marriage were problems. Trafficking in persons, including widespread bonded and forced labor of children and adults, and sex trafficking of children and adults for prostitution were serious problems. Caste-based discrimination and violence continued, as did discrimination against persons with disabilities and indigenous persons.... Religiously based societal violence remained a problem. Religious freedom may represent the single most fraught issue-area, one with the potential to produce serious differences in the bilateral relationship if Modi seeks to move forward with the emotive, Hindutva initiatives promised in the BJP Manifesto. Domestically, the BJP victory could empower Hindu nationalists in ways that may lead to increased domestic communal frictions and violence. Human rights groups reportedly may find their activities constrained under a Modi government, and they express concerns about Modi's commitment to minority rights, his past willingness to tolerate suppression of free expression, and the vigor with which some of his supporters have quashed dissent. Experts agree that, when it comes to fears of new communal violence, Modi's actual performance in power is key, and to date he appears to understand that domestic divisiveness will only serve to hamper his economic and political ambitions. If India's economic woes substantively continue into next year and beyond, Modi might choose to revert to seeking political support through religious politics, as he did earlier in his career. | Summary: The United States and India have been pursuing a "strategic partnership" since 2004, and a 5 th Strategic Dialogue session was held in New Delhi in late July 2014. A May 2014 national election seated a new Indian government led by the Hindu nationalist Bharatiya Janata Party (BJP) and new Prime Minister Narendra Modi. Top U.S. officials express eagerness to engage India's new leadership and re-energize what some see as a relationship flagging in recent years. High hopes for the engagement have become moderated as expectations held in both capitals remain unmet, in part due to a global economic downturn that has dampened commercial activity. Yet the two countries, estranged through the Cold War period, have now routinized cooperative efforts through myriad working groups on an array of bilateral and global issues. Prime Minister Modi is known as an able administrator, having overseen impressive economic development in 15 years as chief minister of India's Gujarat state. But he also is a controversial figure for his Hindu nationalist views and for communal rioting that killed up to 2,000 people, most of them Muslims, in Gujarat in 2002. His BJP made history by becoming the first party to win an outright parliamentary majority in 30 years, meaning India's federal government is no longer constrained by the vagaries of coalition politics. Domestic and international proponents of Modi's business-friendly policies are hopeful that these circumstances will make for more effective governance and streamlined economic reforms. Detractors, concerned about protecting India's inherently secular nature under a Hindu nationalist government, and worry about future respect for India's freedoms of religion and expression. This report reviews the major current issues in U.S.-India relations, including areas of both cooperation and contention, the latter most visible in trade and economic engagement in recent years. For a brief review of the election, as well as key government officials and parties, see CRS In Focus IF00037, India's Domestic Political Setting, by [author name scrubbed]. | 8,313 | 467 | gov_report | en |
Summarize: Ford demonstrated the pothole-softening technology in a test video with the assistance of ping pong balls. (Photo: Ford video) Ford Motor Co. hopes a new feature on its Fusion Sport midsize sedan will help ease the pain of potholes. When the new model of the country’s third-most popular midsize sedan goes on sale this summer, it will come standard with a system that looks ahead for craters and then prevents the wheel from dropping to the bottom. Here’s how it works: A dozen high-resolution sensors anticipate when the car is about to hit a pothole. They send that information to the onboard computer, which directs the shock absorbers to adjust to their stiffest hydraulic damping level. That prevents the suspension from sagging and lets the tire skip across the void without slamming into the base or opposite side of the hole as harshly. Ford demonstrated the technology in a test video with the assistance of ping pong balls: The wheels of the Fusion Sport don’t harm the balls placed at the bottom of a pothole, but the tires of a rival vehicle touch and crush them. “It reduces the (impact) greatly,” Jason Michener, an engineer who designed the technology, said in an interview. “But there’s always one pothole that no amount of technology will protect you from.” Ford said the pothole mitigation technology will be a first in the midsize sedan category. The automaker is attempting to differentiate itself from segment-leaders Toyota Camry and Honda Accord. High-end Lincolns, including the MKS and MKZ, have the system. It also is debuting in Europe on Ford’s Mondeo, Galaxy and S-MAX. The automaker says it could implement the feature throughout its global lineup. “We saw a need,” Michener said. “One of the biggest things our customers appreciate are nice-looking wheels. The bigger the wheel, the easier it is to damage when you go through potholes.” On Wednesday, the American Automobile Association released a study claiming pothole damage cost U.S. drivers $15 billion in vehicle repairs over the last five years, or about $3 billion annually. “On average, American drivers report paying $300 to repair pothole-related vehicle damage,” John Nielsen, AAA’s managing director of automotive engineering and repair, said. “Adding to the financial frustration, those whose vehicles incurred this type of damage had it happen frequently, with an average of three times in the last five years.” Washington, D.C.-based national transportation research group TRIP estimates pothole damage costs urban motorists an average of $516 a year. Ford developed the Fusion’s pothole mitigation technology after thousands of passes over potholes at its Michigan Proving Grounds in Romeo. In later stages of development, the team tested it on real-world roads throughout Metro Detroit, and would even complain when road crews patched certain holes. “There are some people who like an unresponsive city department,” Michener joked. Potholes are a problem in other countries, too. Last year in the United Kingdom, the Royal Automobile Club responded to more than 25,000 pothole-related breakdowns – a nearly 25 percent increase since 2014, Ford said. Beyond Michigan, Ford has developed a 1.2-mile road course in Lommel, Belgium, that creates precise replicas of some of the worst potholes and road hazards from countries like Austria, France, Germany, Italy, Russia, Spain and Switzerland. The test track isn’t limited to potholes; it contains tricky road surfaces like granite blocks from Belgium, cobbles from Paris and speed bumps from Brazil. Engineers race over the road hazards at speeds up to 45 miles per hour. Sensors record the loads and strains to the suspension and components. “By incorporating these real-world challenges into our test facilities we can develop future vehicles to better cope with challenging conditions,” said Eric-Jan Scharlee, a durability technical specialist at Ford’s Lommel Proving Ground. [email protected] (313) 222-2401 Twitter.com/MikeMartinez_DN Read or Share this story: http://detne.ws/1Xz1r50 When the first El Nino rainstorms rumbled through Southern California followed by cold temperatures, crumbling roadways began to emerge. A new study from AAA reveals that pothole damage has cost U.S. drivers $15 billion in vehicle repairs over the last five years, or approximately $3 billion annually. With two-thirds of Americans concerned about potholes on local roadways, AAA cautions drivers to remain alert to avoid pothole damage, and urges state and local governments to fully fund and prioritize road maintenance to reduce vehicle damage, repair costs and driver frustration. “In the last five years, 16 million drivers across the country have suffered pothole damage to their vehicles, including 15 percent of drivers in the West,” said Dave Skaien, program manager of the Automobile Club of Southern California AAA Approved Auto Repair Program. “The problems range from tire punctures and bent wheels, to more expensive suspension damage.” According to AAA’s survey, middle- and lower-income individuals are the most worried about potholes, with the majority of respondents in households having annual incomes under $75,000 expressing the highest levels of concern over damaged roadways. This is likely due in part to the financial impact, as pothole damage can lead to expensive and extensive vehicle repairs. About 57 percent of drivers in the West said they are concerned about potholes on local roadways. Pothole Repair Costs “On average, American drivers report paying $300 to repair pothole-related vehicle damage,” continued Skaien. “Adding to the financial frustration, those whose vehicles incurred this type of damage had it happen frequently, with an average of three times in the last five years.” To minimize vehicle damage, AAA urges drivers to ensure tires are properly inflated and have adequate tread depth, as they are the only cushion between a pothole and the vehicle. If a pothole strike is inevitable, it is also critical that drivers slow down, release the brakes and straighten steering before making contact with the pothole. To avoid potholes in the roadway, drivers should remain alert, scan the road and increase following distances behind the vehicle ahead. AAA’s members are paying a steep price for bad road conditions, and those costs are expected to rise even higher in the years ahead. Americans rely on our nation’s roads and bridges every day, and more funding is desperately needed to prevent potholes, other unsafe conditions and longer commutes. Congress increased transportation funding in 2015 to help pay for road repair, but as much as $170 billion in additional funding is needed per year to significantly improve America’s roads and bridges. California can take the next step by ensuring that all motorist and highway user taxes and fees go to needed road repairs and improvements, which is not the case today. Every year, AAA responds to more than four million calls for flat tire assistance, many the result of damage caused by potholes. Spare tires, an important feature missing from one-third of 2015 model year vehicles sold, are critical for drivers affected by pothole damage. Tire inflator kits have replaced the spare tire in millions of vehicles over the last 10 model years and, due to their limited functionality, cannot provide even a temporary fix for pothole damage. AAA has called on automakers to put consumer interests first and halt the elimination of spare tires in new models. Tips to Avoid Hitting Potholes: Skaien recommends the following tips to help protect vehicles – and drivers – from the jarring experience of hitting an asphalt crater on Southland roadways: Maintain proper air pressure in all tires to provide as much cushion as possible between the pothole and tire rim. Consult the vehicle owner’s manual or the sticker on the driver’s side door jamb, inner glove box, or inside of the fuel filler flap for the tire manufacturer’s correct pressure. Watch for potholes by leaving plenty of space between your vehicle and the one in front of you. Alert drivers have plenty of time to avoid potholes. Before swerving around a pothole, be sure to check surrounding traffic and lanes to determine if it’s safe to move over. Maintain a safe speed for weather conditions. If a pothole can’t be avoided, slow down, if possible. Hitting a pothole at high-speed increases the chance of tire damage as well as harm to wheels, shocks, struts, steering or suspension. High speed also increases chances of losing control of the vehicle, especially if a series of potholes occurs on a curved or uneven roadway. When driving over more than one pothole, reduce vehicle speed and hold the steering wheel firmly to avoid losing control. If possible, don’t brake directly over a pothole. Applying brakes causes the car’s weight to shift to the front of the vehicle and can increase damage from the impact. “Hitting even one severe pothole could alter the alignment of a wheel from suspension damage resulting in uneven tire wear. Uneven and premature tire wear means the tire will need replacement sooner than necessary and can increase fuel consumption at needless expense,” said Skaien. “A broken shock or strut from hitting a pothole could alter the steering and handling of a vehicle, and create dangers when driving at higher speeds or in tight corners,” Skaien said. Motorists who suspect their vehicle’s suspension components were damaged or broken by a pothole should have their vehicle towed to a high-quality repair facility such as a AAA Approved Auto Repair facility where it can be inspected and serviced, if necessary, the Auto Club recommends. There are more than 7,500 AAA AAR facilities in North America. Information about the more than 400 Southern California AAA-Approved shops can be located at www.AAA.com or by calling your local AAA branch. AAA members receive unique benefits, including priority service, a 24-month/24,000-mile warranty, special discounts, free inspections, dispute resolution assistance and more. Published on Feb 18, 2016 Even though it’s impossible to avoid all potholes while driving, Ford has created an advanced computer-controlled shock absorber system in the new 2017 Fusion V6 Sport that significantly reduces that unpleasant feeling one gets when driving down a pothole-broken road. The new pothole mitigation technology works by actually detecting potholes and ‘catching’ the car’s wheel before it has a chance to drop all the way into the pothole. Fusion Sport is the first midsize sedan in its class to offer this technology, neither the Honda Accord nor the Toyota Camry offer this advanced suspension system | Summary: Potholes aren't just uncomfortable to drive over: The damage caused by them costs America's drivers $3 billion annually, reports the American Automobile Association in a study it released Wednesday. Good thing, then, that Ford's 2017 Fusion V6 Sport sedan should be able to handle them. The American car company has announced that the tech will be implemented for the first time in midsize non-luxury cars-it's already available in high-end Lincolns-a move the Detroit News sees as a bid to distinguish the vehicle from the Toyota Camry and Honda Accord. "It reduces the [impact] greatly," says Jason Michener, who engineered the technology. Still, he clarifies, the protection isn't total: "There's always one pothole that no amount of technology will protect you from." So how does it work? The car doesn't avoid the pothole by driving around it, but rather houses a smart shock-absorbing system that stiffens when sensors detect that a wheel is entering a pothole, reports CNNMoney. This detection, in turn, keeps the wheel in an "elevated" position so that it does not drop down into the pothole. That action then triggers the rear wheel's shock absorber to follow suit. (This video from Ford uses Ping-Pong balls to illustrate.) Ford has a 1.2-mile road course in Belgium full of replicas of some of the worst potholes-and other hazards such as cobblestones and speed bumps-drivers face. Testers get to race over them as fast as 45mph to further test and improve the technology. | 2,394 | 361 | multi_news | en |
Summarize: Background DOD plays a support role in CBRNE consequence management, including providing those capabilities needed to save lives, alleviate hardship or suffering, and minimize property damage caused by the incident. DOD generally provides defense support of civil authorities only when (1) state, local, and other federal resources are overwhelmed or unique military capabilities are required; (2) assistance is requested by the primary federal agency; or (3) NORTHCOM is directed to do so by the President or the Secretary of Defense. DOD has designated U.S. Northern Command (NORTHCOM) to lead the federal military portion of such a support operation in direct support of another federal agency—most often the Federal Emergency Management Agency (FEMA). DOD would be the lead federal agency for CBRNE consequence management or any other civil support mission only if so designated by the President. To be effective, DOD’s efforts must be coordinated with a wide range of federal departments and agencies—including FEMA and the Departments of Health and Human Services and Justice—in order to support 50 states, the District of Columbia, six territories, and hundreds of city and county governments. The National Response Framework establishes the principles that guide all response partners in preparing for and providing a unified national response to disasters. Under the Framework, disaster response is tiered; local government and agencies typically respond immediately after an incident. When additional resources are required, states may provide assistance with their own resources or may request assistance from other states through interstate mutual agreements or the Emergency Management Assistance Compact. Localities and states usually respond within the first several hours of a major incident. The federal government provides assistance to states if they require additional capabilities and request assistance. In the event of a catastrophic incident, such as one involving CBRNE, the framework also calls for federal response partners to anticipate the need for their capabilities before their assistance is requested. The framework lists 15 emergency support functions and designates federal lead agencies in areas such as search and rescue, public health and medical services, and transportation. DOD is a supporting agency for all 15 emergency support functions but is the primary agency only for search and rescue and public works and engineering. Additional tools to guide response efforts are provided by The National Preparedness Guidelines, including National Planning Scenarios, Target Capability and Universal Target Lists, and national priorities. DOD has created significant capabilities that could be used to augment a federal CBRNE response. It also contributes to the organization, training, and equipping of several other state military units focused on consequence management. These include the 22-person National Guard Weapons of Mass Destruction Civil Support Teams that are located in each state and territory); the larger National Guard CBRNE Enhanced Response Force Packages of about 200 soldiers each that are located in 17 states for more expansive response; and the DOD’s CBRNE Consequence Management Response Forces (CCMRF). The Civil Support Teams and CBRNE Emergency Response Force Packages are intended to be part of the state response to an incident and therefore remain under the control of the respective governors, unless they are mobilized into federal service. The CCMRF is intended to be a roughly brigade-sized force (approximately 4,500 troops) that provides the federal military assistance when a CBRNE incident exceeds local and state capabilities—including the Civil Support Teams and CBRNE Enhanced Response Force Packages. The CCMRFs are not whole units by themselves. They are a collection of geographically separated DOD capabilities and units across the military services and consist of such existing specialized capabilities as the U.S. Marine Corps’ Chemical Biological Incident Response Force as well as general capabilities, such as transportation units. Although the CCMRF is intended to be about 4,500 personnel in size, the size of the force that would deploy in support of an actual incident could be modified based on the size of the incident. DOD ultimately plans to have three fully functional CCMRFs. DOD would, if necessary, draw on additional general military forces over and above the CCMRF to provide assistance in the event of one or more major CBRNE incidents. DOD CBRNE Consequence Management Plans and Integration with Other Federal Plans DOD has operational plans for CBRNE consequence management. However, DOD has not integrated its plans with other federal government plans, because the concept and strategic plans associated with the Integrated Planning System mandated by Presidential directive in December 2007 have not been completed. DOD Has Developed Plans for CBRNE Consequence Management Unlike most federal agencies, DOD has had CBRNE consequence management operational plans for over 10 years. DOD, NORTHCOM, and its components have prepared individual plans that address CBRNE consequence management following DOD’s well-established joint operation planning process. This process establishes objectives, assesses threats, identifies capabilities needed to achieve the objectives in a given environment, and ensures that capabilities (and the military forces to deliver those capabilities) are distributed to ensure mission success. Joint operation planning also includes assessing and monitoring the readiness of those units providing the capabilities for the missions they are assigned. DOD and NORTHCOM routinely review and update their plans as part of DOD’s joint planning system. For example, the most recent NORTHCOM CBRNE consequence management plan was completed in October 2008. DOD and NORTHCOM have also developed such planning documents as execute orders that are key to linking immediate action to those plans, as well as scenario-based playbooks to guide the planning, operations, and command and control of military forces for CBRNE efforts. Governmentwide Integrated Planning System Is under Development but Not Yet Complete The Department of Homeland Security (DHS) is leading a governmentwide effort to develop an Integrated Planning System that would link the plans of all federal agencies involved in incident response, including DOD’s; however, this effort is not yet complete. While much in the way of federal guidance has been developed, to be most effective, policy documents must be operationalized by further detailing roles and responsibilities for each entity that may be involved in responding to high-risk or catastrophic incidents. In December 2007, Homeland Security Presidential Directive 8, Annex 1, mandated that the Secretary of Homeland Security, in coordination with the heads of other federal agencies with roles in homeland security, develop an Integrated Planning System to provide common processes for all of the entities developing response plans. The directive also called for the development of strategic plans, concepts of operations plans, and operations plans that would be integrated at the federal, regional, state, and local levels. DHS has grouped the 15 national planning scenarios on which preparedness plans are to be based into 8 scenario sets, of which 5 are CBRNE-related. Each of the scenarios, listed in table 1, includes a description, assumptions, and likely impacts, so that entities at all levels can use them to guide planning. The directive required that the Integrated Planning System be submitted to the President for approval within 2 months of the directive’s issuance in December 2007. As we have reported, the Integrated Planning System was approved in January 2009 by former President Bush, but is currently under review by the new administration, and no time frame for its publication has been announced. The approval of the CBRNE plans required under the directive (see table 2 below) would be a step toward unifying and integrating the nation’s planning efforts. For example, for each National Planning Scenario, a strategic guidance statement is intended to establish the nation’s strategic priorities and national objectives and to describe an envisioned end-state. Strategic guidance statements will have corresponding strategic plans, which are intended to define roles, authorities, responsibilities, and mission-essential tasks. Under each strategic plan, a concept of operations plan will be developed, and federal agencies are further required to develop operations plans to execute their roles and responsibilities under the concept of operations plan. As of today, strategic guidance statements have been approved for all 5 CBRNE-related scenario sets. Four of the 5 required strategic plans have also been completed. The remaining strategic plan (chemical attack) was begun in June 2009 upon the approval of the strategic guidance statement for that scenario. One of the 5 required overall federal concept plans—that for terrorist use of explosives attack—has been completed. As we have previously reported, apart from the sequential timelines required in HSPD Annex 1, FEMA and DHS have no schedule or project plan for completing the guidance and plans. Table 2 shows the status of federal CBRNE strategy and plans called for under HSPD 8 Annex 1. DOD’s plans and those of other federal and state entities cannot be fully integrated until the supporting strategic and concept plans are completed. Current Capability Assessments at Local, State, and Federal Levels May Provide Insufficient Data for DOD to Shape Its Response to CBRNE Incidents A number of efforts to develop capability assessments are under way at local, state, and federal levels, but these efforts may not yet be sufficiently mature to provide DOD with complete data that it can use to shape its response plans for CBRNE-related incidents. For example, FEMA has begun to catalog state capabilities in its preparedness reports and is working on a capability gap analysis. However, DHS faces challenges in developing its approach to assessing capabilities and preparedness. As noted in DHS’s January 2009 Federal Preparedness Report, several key components of the national preparedness system are still works in progress, and not all data required for the federal government to assess its preparedness are available. We have previously reported that state capability data developed by individual states cannot be used to determine capability gaps across states, because the states do not use common metrics to assess capabilities and do not always have the data available that they need to complete their reports. In addition, according to DOD and FEMA, even to the extent that these data are available, states may limit their sharing of sensitive information on capability gaps with DOD entities responsible for developing DOD’s plans and related capabilities. DOD’s Planned Response to CBRNE Incidents DOD has had plans to provide CBRNE consequence management support to civil authorities since before 9/11 and in the last few years has set higher goals in the expectation of being able to provide expanded capabilities through its 3 CCMRFs. However, its ability to respond effectively may be compromised because (1) its planned response times may not meet the requirements of a particular incident, (2) it may lack sufficient capacity in some key capabilities, and (3) it faces challenges in adhering to its strategy for sourcing the CCMRFs with available units. DOD’s Planned Response Times May Be Too Long In 2005, DOD established a standard for itself that called for the ability to respond to multiple, simultaneous catastrophic incidents, and it initiated efforts to create 3 CCMRFs. For the first 3 years, DOD did not regularly assign units to the CCMRF mission, and this decreased DOD’s ability to actually field any of the CCMRFs within the timelines it had established. In October 2008 DOD sourced the first CCMRF, primarily with active force units. A second CCMRF, comprised primarily of reserve units, will assume the mission in October 2009 and a third in October 2010. In the absence of national guidance suggesting what level of response capability DOD should have available within a specified time frame, DOD’s plans use a phased deployment to allow the CCMRF to be able to provide consequence management support to civilian authorities within 48-96 hours of being notified of an CBRNE incident. The earlier phases of the deployment will provide the lifesaving capabilities. However, multiple DOD estimates for some of the more catastrophic scenarios, such as a nuclear detonation, have identified significant gaps between the time certain life saving and other capabilities would be needed and DOD’s planned response times. For example, victims of a nuclear attack would require decontamination, which medical experts have established must be provided within as soon as possible after exposure. If DOD adheres to its planned response times in such a scenario, the capabilities of early responders such as local police and fire departments would likely be overwhelmed before DOD arrived at the incident site. NORTHCOM’s assessment and other DOD estimates demonstrated that, for a number of capabilities, DOD’s response would not be timely. Table 3 shows one estimate of the potential shortfall in decontamination capabilities that could result. The NORTHCOM capability-based assessment similarly suggests that without a national, risk-based determination of DOD’s share of the federal capability requirements, DOD will be unable to determine whether its planned response times should be adjusted. DOD’s Planned Force May Lack Sufficient Capacity in Some Key Capabilities Needed for Catastrophic Incidents In addition to timeliness issues, DOD’s planned force has limited quantities of some of the needed life saving capabilities, such as medical and decontamination services. For example, some nuclear detonation scenarios project that hundreds of thousands could be killed, injured, displaced, contaminated, or in need of medical care. The CCMRF would be able to provide only a small portion of the necessary capability. Although a CCMRF is estimated, under optimal circumstances, to be capable of decontaminating several thousand people per day, some estimates project that the gap between needed decontamination capabilities and what local, state, and other entities could provide would be tens of thousands. DOD recognizes that it may need additional units to augment the CCMRF, and it has made some tentative estimates. However, DOD has not developed contingency plans designating specific units to augment the CCMRF. Unless these units are identified in advance and trained for the mission, they may be unable to deploy rapidly. Without clear plans aligning CCMRF objectives with the projected need for response capabilities and clearly delineating national expectations for timely response, neither DOD nor other entities involved in incident response can be certain that the CCMRFs will be able to respond adequately to mitigate the consequences of a catastrophic CBRNE incident. DOD Faces Challenges in Adhering to Its Strategy for Sourcing the CCMRFS with Available Units In sourcing its 3 CCMRFs, DOD has encountered challenges in implementing an approach that could enhance unit availability and training and readiness oversight for forces that are not assigned to NORTHCOM. DOD originally intended the CCMRF to be comprised entirely of federal active military forces, but the two follow-on CCMRFs will be sourced with large numbers of National Guard and Army Reserve units. The demands of ongoing overseas operations have led DOD to draw more and more heavily on Guard and Reserve forces to fulfill civil support functions. Because National Guard units have responsibilities in their respective states, a competition for resources issue may arise between DOD and the states. For example, while governors may need the same capabilities within the state or to support mutual assistance agreements with other states as would be needed to support a CCMRF, there is no clear understanding between the governors and DOD to ensure that these units will be available if they are needed for a federal mission. Moreover, elements from a single unit can be spread over many states, further complicating the task of coordinating between DOD and each of the states. For example, one Army National Guard aviation company belonging to the CCMRF has elements in Arkansas, Florida, and Alabama. Three different states would be required to make these elements available to form the company. The potential rapid deployment mission of the CCMRF makes it imperative that specific agreements be reached. However, the agreements that have been reached to date are general in nature and do not specify how states are to ensure that Guard units will be available for a CCMRF deployment. Similar issues arise with the Army Reserve. The training demands of the CCMRF mission have caused DOD to authorize additional training days, but according to Army Reserve officials, reservists cannot be compelled to attend training events beyond their annual training requirement. They stated that, as a result, units must rely on the voluntary participation of their personnel for training beyond the requirement, which reduces their assurance that these personnel will be available for other necessary CCMRF training. For example, one reserve company was unable to fulfill all aspects of its mission requirements because of low participation at a training event. Unit officials stated that some of the unit’s members had school or work obligations that conflicted with this training. Moreover, reserve unit officials stated that, unlike active unit officials, they cannot restrict the personal travel of unit members to ensure that they will be available if they are needed to support an unexpected federal CBRNE incident response. These challenges to sourcing the CCMRF increase the risk that DOD’s ability to effectively respond to one or more major domestic CBRNE incidents will be compromised. That risk can be mitigated by plans that integrate the active and reserve component portions of the CCMRF and agreements between DOD and the states on the availability of National Guard units and the duty status under which they would respond to a major incident requiring federal forces. DOD’s decision to change its approach to how NORTHCOM will routinely interact with units designated for the CCMRF will present additional challenges. In 2008, DOD’s sourcing approach was to assign the first CCMRF (primarily active forces) to NORTHCOM and allocate the remaining two CCMRFs (mix of Guard and Army Reserve) to NORTHCOM. Beginning in October 2009, DOD will allocate the units from all three CCMRFs to NORTHCOM, rather than assigning them to the NORTHCOM commander outright. As a result, despite the fact that NORTHCOM’s commander is responsible for commanding the federal military domestic CBRNE response in the continental United States, NORTHCOM will have no CBRNE forces under its direct control. There are advantages to assigning forces directly to NORTHCOM. For example, the command would have direct authority over the units’ day-to-day activities, including training and exercise schedules, and would be better able to monitor readiness. Additionally, there would be fewer administrative steps required for the NORTHCOM commander to activate and deploy the CCMRF in the event of an incident. This would be crucial for deploying the critical initial response elements of the overall force. Under allocation, while DOD’s current approach would provide NORTHCOM with authority over units while they are participating in scheduled NORTHCOM training events, NORTHCOM would have to coordinate with multiple commands to obtain participation from these units. Current guidance states that other commands should make their units available for scheduled NORTHCOM exercises “to the greatest extent possible.” However, NORTHCOM cannot always be assured that units will be available for these exercises. In addition, NORTHCOM remains uncertain about the extent to which it will have oversight of CCMRF units’ day-to-day training activities and be able to confirm that these units are ready to perform their mission even when they are under the authority of another command. DOD Actions on CCMRF Readiness and Training and the Impact of Current Deployments DOD has taken a number of actions in the past year to improve the readiness of its CCMRF units. However, our ongoing work shows that the CCMRF may be limited in its ability to successfully conduct consequence management operations because (1) it does not conduct realistic full force field training to confirm units’ readiness to assume the mission or to deploy rapidly, and (2) conflicting priorities between the CCMRF mission and overseas deployments impact some units’ mission preparation and unit cohesion. DOD Has Taken Actions to Improve CCMRF Readiness The initial assignment of the CCMRF to NORTHCOM in October 2008 and the increased priority DOD has placed on the CBRNE mission have resulted in a number of improvements in unit preparation for the first fielded CCMRF. The Army, in coordination with NORTHCOM and its subordinate commands, has established guidance for both individual and collective training—including joint mission essential task lists—for units designated for the CCMRF. Therefore, for the first time, identified units are conducting individual and collective training focused on the CCMRF mission. For example, key leaders such as brigade task force headquarters personnel and battalion commanders are required to participate in a number of command and control training events to provide them with an understanding of how to organize and conduct operations in a complex interagency environment under catastrophic disaster conditions. Moreover, the increased priority given to the mission in the spring of 2008 has led to units receiving personnel and equipment before they assume the mission and ahead of many other units that do not participate in the CBRNE mission. Extent of Realistic Field Training Impacts CCMRF’s Ability to Perform Effectively Despite units being certified as ready prior to assuming the mission in October 2008, it is unclear whether the CCMRF can effectively perform CBRNE consequence management operations throughout the 1-year mission period to which it is assigned, because the readiness of the entire CCMRF is not confirmed through a realistic field training exercise before the force assumes the mission, nor have its rapid deployment capabilities been fully assessed. Before designated units assume the CBRNE mission, they must be certified by the military services to be trained to perform that mission. However, there is no requirement to provide these units with a full force tactical field training exercise. While units conduct this type of training prior to an overseas deployment, and NORTHCOM and Joint Force Land Component Command (JFLCC) training officials have discussed the desirability of such an exercise, the first CCMRF units have not received this kind of training. Although some CCMRF units have participated in joint field exercises, critical units often did not participate. In addition, the exercises were conducted several months after units had been certified as trained to perform the mission. Units also must demonstrate that they will be able to meet the required response times once they assume the mission. A key aspect of the CCMRF mission is to be able to rapidly deploy each of the three force packages that comprise each CCMRF within a specified response time. One of the primary challenges to a timely response is that CCMRF packages may have to deploy rapidly from their home stations. Deployment readiness exercises are important, because they test units’ abilities to ascertain how quickly staff can be notified and assembled, equipment prepared and loaded, and both staff and equipment moved to the designated point of departure. DOD has provided general guidance that supported commands, such as NORTHCOM, should verify the ability of CCMRF units to activate and deploy. However, DOD has not yet conducted deployment exercises for the entire CCMRF, and it is not clear if its plans for future CCMRFs will include such exercises. In the absence of such exercises, NORTHCOM and DOD will continue to be unable to verify the ability of CCMRF units to deploy. Units’ Preparation for the CCMRF Mission and Efforts to Achieve Unit Cohesion Are Impacted by Other Missions The demands that overseas missions are placing on the Army also may put the effectiveness of the CCMRF mission at risk. While DOD has identified CCMRF as a high priority mission, competing demands associated with follow-on missions may distract from a unit’s focus on the domestic mission. For example, Army units are frequently given the CCMRF mission when they return from an overseas deployment. Because these units are at the beginning of the “reset” phase of the Army Force Generation (ARFORGEN) cycle, they often lack personnel and equipment. Although the Army attempts to accelerate the fill of personnel and equipment to these units, some units may not have received their personnel and equipment in sufficient time to allow them to meet all of the requirements of the CBRNE mission before they assume it. These training and force rotation issues have prevented DOD from providing the kind of stability to the force that would allow units to build cohesiveness. While DOD’s goal has been to assign units for at least 12 months and to set standard start and end dates for each rotation, several critical units have been unable to complete their 1-year CCMRF rotations for fiscal year 2009. As a result, the replacement units who have finished out these rotations have missed important training. For example, the headquarters units for the aviation and medical task forces rotated out of the mission after only 4 and 6 months, respectively, because of competing priorities. Because key leaders from units of the entire force attend a mission rehearsal exercise prior to mission assumption, the replacement of these units after only a few months negated much of the value that was gained from these three task forces working together and precluded the replacement task force leaders from having the same opportunity. CCMRF Requirements Development, Funding, and Oversight DOD is making progress in identifying and providing funding and equipment to meet CCMRF mission requirements; however, its efforts to identify total program requirements have not been completed, and its approach to providing program funding has been fragmented, because funding responsibilities for CCMRF-related costs are dispersed throughout DOD and are not subject to central oversight. CCMRF Mission Requirements Have Not Been Fully Developed The units initially designated for the CCMRF mission did not have fully developed funding and equipment requirements. In addition, the recent NORTHCOM Homeland Defense and Civil Support Capabilities-Based Assessment highlighted a number of systemic capability gaps that need to be addressed and may generate additional funding requirements. Moreover, other important requirements for this mission have not been identified and funded. The Joint Forces Land Component Commander (U.S. Army North—ARNORTH) and the Joint Task Force Civil Support are responsible for developing and approving service-specific equipment unique to the CCMRF’s Joint Mission Essential Tasks. However, to date, mission essential equipment requirements have not been fully developed. While some equipment requirement lists have been developed and are being reviewed by NORTHCOM, equipping officials said that lists have not been developed for non-standard equipment that units may need in order to support civil authorities in a CBRNE environment. As a result, some fiscal year 2008 units have determined requirements based on their own independent mission analyses. Unit officials stated that filling some of the needs they identified—such as the need for non-standard communications equipment that is compatible with civilian equipment—was difficult because the units lacked a documented requirement for their planned acquisition. In addition, the review process did not always include the command organizations that are responsible for the mission. Thus, decisions on what to buy and in what quantity were not consistently vetted to ensure standardization in equipping various units. ARNORTH officials stated that they were in the process of developing mission essential equipment lists and hope to have them completed in time for the next rotation, which begins in October 2009. Extent of Dedicated Funds for Some CCMRF Training Impacts Mission In the spring of 2008, sourcing priority for the CCMRF mission increased substantially within the department, and funding was provided for specific aspects of the mission. For example, funding was provided for NORTHCOM’s training program—which totals more than $21 million annually—for three major exercises associated with the CCMRFs for fiscal year 2010 and beyond, and the Army Reserve has planned funds of more than $37 million for fiscal years 2009 and 2010 to support additional full- time personnel and training days that have been authorized to support the CCMRF mission. In addition, while the military services have not planned funds for equipment specifically for the CCMRF mission, equipment has been purchased with funds left over from past Global War on Terrorism deployments. In other cases, purchase requests for certain equipment were denied by administrative parent commands because, unit officials believed, the equipment was considered non-critical by reviewing officials. Moreover, units must fund their CCMRF training activities from their operations and maintenance accounts, which were developed and approved months before units knew they would be assigned to the CCMRF. According to unit officials, because they do not have dedicated funds for CCMRF in their budgets, they sometimes must take money from other sources to meet what they believe are their highest priorities for the CCMRF mission. Also according to these officials, while the lack of planned funds for the CCMRF has been mitigated to some extent by the mission’s high priority level, they have found it necessary to curtail or cancel some desirable training because funding was unavailable. Army officials told us that if funding shortfalls develop because units lack sufficient funds to conduct both CCMRF and follow-on mission training, units can request additional funds from the Army. However, unless units assess their total funding requirement for the CCMRF and their other designated mission and receive funding based on both missions, CCMRF units may be at risk of not having enough funding to conduct all of their CCMRF training. This, in turn, puts units at risk of not being fully prepared if they are needed to respond to an incident. CCMRF units may face more acute funding issues as the United States begins drawing down in Iraq and as military supplemental funding, such as funding for Global War on Terrorism, is reduced. Because DOD has assigned funding responsibilities across the department and because much of the funding for the CCMRF is coming from existing operations and maintenance accounts, DOD lacks visibility across the department over the total funding requirements for this mission. Without an overarching approach to developing requirements and providing funding, and a centralized focal point to ensure that all requirements have been identified and fully funded, DOD’s ability to carry out this high-priority homeland security mission in an efficient and effective manner is at risk. Agency Comments We provided the Departments of Defense and of Homeland Security an extensive briefing on our preliminary findings. We also provided them a draft of this statement. Neither DOD nor DHS had formal comments, but both provided technical comments, which we incorporated into the statement, as appropriate. We plan to provide this subcommittee and our other congressional requesters with our final report on DOD’s CBRNE consequence management efforts in September 2009. We expect to make a number of recommendations for DOD action at that time. Mr. Chairman, this concludes my prepared statement. I would be happy to respond to any questions that you or other Members of the Subcommittee might have. Contacts and Acknowledgements For questions about this statement, please contact me at (202) 512-5431 or [email protected]. Individuals who made key contributions to this testimony include Joseph Kirschbaum, Assistant Director; Rodell Anderson; Joanne Landesman; Robert Poetta; and Jason Porter. This is a work of the U.S. government and is not subject to copyright protection in the United States. The published product may be reproduced and distributed in its entirety without further permission from GAO. However, because this work may contain copyrighted images or other material, permission from the copyright holder may be necessary if you wish to reproduce this material separately. | Summary: DOD plays a support role in managing Chemical, Biological, Radiological, Nuclear, and High-Yield Explosives (CBRNE) incidents, including providing capabilities needed to save lives, alleviate hardship or suffering, and minimize property damage. This testimony addresses GAO's preliminary observations on DOD's role in CBRNE consequence management efforts and addresses the extent to which (1) DOD's plans and capabilities are integrated with other federal government plans, (2) DOD has planned for and structured its force to provide CBRNE consequence management assistance, (3) DOD's CBRNE Consequence Management Response Forces (CCMRF) are prepared to perform their mission; and (4) DOD has funding plans for the CCMRF that are linked to requirements for specialized CBRNE capabilities. GAO reviewed DOD's plans for CBRNE consequence management and documents from the Department of Homeland Security (DHS) and the Federal Emergency Management Agency. GAO also met with officials from the Undersecretary of Defense for Homeland Defense, U.S Northern Command, U.S. Army Forces Command, U.S. Army North, the National Guard Bureau, and some CCMRF units. DOD has its own CBRNE consequence management plans but has not integrated them with other federal government plans because all elements of the Integrated Planning System mandated by Presidential directive in December 2007 have not been completed. The system is to develop and link planning documents at the federal, state, and local levels. While the system's framework is established, the CBRNE concept and strategic plans that provide further guidance are incomplete. DOD has had operational plans in place and revises these plans regularly. However, until the Integrated Planning System and its associated plans are complete, DOD's plans and those of other federal and state entities will not be integrated, and it will remain unclear whether DOD's CCMRF will address potential gaps in capabilities. With a goal to respond to multiple, near-simultaneous, catastrophic CBRNE incidents, DOD has plans to provide the needed capabilities, but its planned response times may not meet incident requirements, it may lack sufficient capacity in some capabilities, and it faces challenges to its strategy for sourcing all three CCMRFs with available units. Without assigned units and plans that integrate the active and reserve portions of the CCMRF, and agreements between DOD and the states on the availability of National Guard units and the duty status in which they would respond to an incident requiring federal forces, DOD's ability to train and deploy forces in a timely manner to assist civil authorities to respond to multiple CBRNE incidents is at risk. DOD has taken a number of actions in the past year to improve the readiness of units assigned to the CCMRF, increasing both individual and collective training focused on the mission and identifying the mission as high priority. However, the CCMRF has not conducted realistic full force field training to confirm units' readiness to assume the mission or to deploy rapidly. Competing demands of overseas missions may distract from a unit's focus on the domestic mission, and some CCMRF units rotate more frequently than stated goals. These training and force rotation problems have prevented DOD from providing the kind of stability to the force that would allow units to build cohesiveness. DOD is making progress in identifying and providing funding and equipment to meet CCMRF mission requirements; however, its efforts to identify total program requirements have not been completed, and funding responsibilities have been assigned across the department and are not subject to central oversight. When the CCMRF mission priority increased in the spring of 2008, more funding was provided. However, units did not have dedicated funding and thus purchased equipment with existing funding which is also used for other missions. DOD lacks visibility over the mission's total funding requirements. Without an overarching approach to developing requirements and providing funding and a centralized focal point to ensure that all requirements have been identified and funded, DOD's ability to ensure that its forces are prepared to carry out this high priority mission remains challenged. | 6,711 | 870 | gov_report | en |
Summarize: Cliburn gold medalist Vadym Kholodenko moved his wife, Sofya Tsygankova, 30, and 4-year-old daughter, Nika, to Fort Worth this year and is in the process of getting his green card. He plays Bass Hall on Friday night. Vadym Kholodenko, left, with Sofya Tsygankova and daughters Nika, 4, and Michela in Fort Worth in 2014. (Joyce Marshall/Star-Telegram via AP, File) Three years ago, an intense, dark-haired man sat down at a grand piano with no sheet music to show the world why he — and none of his 132 rivals — should win the prestigious, quadrennial Van Cliburn International Piano Competition in Fort Worth. In the competition’s preliminary round, Vadym Kholodenko, a 26-year-old native of Ukraine, blew through a piece by the minimalist composer John Adams, then turned to Sergei Rachmaninoff’s Piano Sonata No. 1 in D minor — a challenging work that typically exceeds 30 minutes and grapples with the devil’s influence on our lives. And Kholodenko made it look like a breeze. Kholodenko went on to win the Cliburn’s 2013 gold medal — earning $50,000, recording and management deals, and a string of concert dates that ran three years. But now the young virtuoso’s life has been struck by tragedy: In what some are calling part of a “curse” related to the Cliburn competition, Kholodenko’s estranged wife Sofya Tsygankova has been charged with murdering their two young children. On March 17, Kholodenko found his daughters — Nika Kholodenko, 5, and Michela Kholodenko, 1 — dead at the home in suburban Fort Worth where he formerly lived with his family. The children’s bodies had no visible trauma, and the cause of their death is not yet known, as the Associated Press reported. But Tsygankova was home with her dead daughters — in “an extreme state of distress,” as authorities noted — and appeared to have been the victim of a stabbing. Days after she was treated and began a mental evaluation, police said Tsygankova killed her daughters before attempting to stab herself, and she now faces capital murder charges as investigators say they are looking into alleged “homicidal violence.” “I’m not going to discuss what she told us. We do have reason to believe the stab wounds were self-inflicted,” David Babcock, police commander in Benbrook, Tex., told WFAA. “She’s still undergoing the mental evaluation. But she’s also held on our charges as well.” The estranged wife of celebrated Ukrainian pianist Vadym Kholodenko is being charged with killing the couple's two daughters - aged five and one - at their home in suburban Fort Worth, Tex., police said on March 21. (Reuters) Like her husband, Tsygankova, 31, was a competitive pianist. She was born in Russia “to a musical family,” one online biography noted, and “began to study music at age 6, and at age 9 won her first all-Russian contest.” She married Kholodenko in 2010, and the family relocated to Fort Worth after Kholodenko won the Cliburn. Kholodenko was often off performing; Tsygankova was committed to learning English. “I have so many friends here and people are so kind to me, so I made the decision to stay,” Kholodenko said in 2014. “I would like to be part of this country.” He added: “It’s better for my daughters to raise [them] here.” Tsygankova said the couple was motivated to move by a skin condition for which her older daughter couldn’t get proper treatment, as well as by her desire to see her husband more often. “We didn’t see a lot of Vadym in Moscow when he’s traveling a lot,” Tsygankova said. “… It would be impossible for him to come home for one day between concerts.” She added: “We wanted to be together, with Vadym, to be a family, and for us, maybe it was the only choice for us to come here.” At first, the family found lodging with Imelda Castro, an immigrant from the Philippines who hosted Kholodenko during the Cliburn competition. “I know how difficult it is not to have anybody when you are new in a place,” Castro said. “They are very good kids. … They are very easy to host and they like my food! That’s important.” And the young couple was grateful. “It was incredible hospitality to have guests for half a year in your house,” Tsygankova said. However, classical pianists, particularly those embroiled in the cutthroat world of piano competitions, are not strangers to passionate music played for scrutinizing audiences under stressful conditions on the road. Something went wrong. Kholodenko and Tsygankova in 2014. (Richard W. Rodriguez, Star-Telegram via AP) The couple moved into their own home in 2014, but filed for divorce in November of last year. Kholodenko moved out, but continued to pick up his daughters in the morning. Police said they were called to the home on two occasions before the young girls’ deaths, but didn’t offer further details. “The loss of my children will be with me forever,” Kholodenko said in a statement to the Fort Worth Star-Telegram. “But I would like to say that I feel the support of the Fort Worth community and all people who are sending me messages all over the world … Wherever I go after this tragedy my heart will stay with the people here of Fort Worth and my daughters will rest in this soil.” The Cliburn expressed condolences. “The Cliburn family is mourning the loss of the precious Kholodenko girls,” Maggie Estes, a spokesman for the competition, said last week. “We are heartbroken and offer our prayers to Vadym and all affected by this overwhelming tragedy.” Some said, however, that winning the Cliburn comes with a “curse.” “That usually refers to careers briefly boosted by winning one of the top prizes in the quadrennial contest, then sinking into second-tier status, or worse,” Scott Cantrell of the Dallas Morning News wrote. Kholodenko in 2013. (Film Still Credit: Larry McConkey, The Cliburn) Cantrell noted tragic outcomes for three Cliburn winners: Steven De Groote, a South African who won the gold in 1977 only to crash a small plane outside Phoenix in 1985, suffering terrible injuries before dying of AIDS in 1989 after receiving a transfusion of tainted blood; Alexei Sultanov, a reportedly difficult teenager who won the Cleburne in 1989 only to suffer strokes and die in 2005; and José Feghali, who shot himself in 2014. “He took things to the absolute edge of the cliff, and it was very exciting to hear,” a Cliburn administrator said after Sultanov’s death. “He wasn’t afraid to take a chance on stage, and there aren’t a lot of pianists who do that. But that worked for him, and it worked against him.” Cantrell said that winning the Cliburn comes with accolades, but it also comes with a grind. “Some performers thrive for years in this rat race, but others become burned out and resentful,” he wrote. “Lengthy periods away from home take tolls on families and relationships, too. Kholodenko was often on tour for long stretches, leaving his wife, newly moved from Russia to Fort Worth, with a young daughter and a baby. You can imagine the stresses.” Kholodenko in 2013. (Ron T. Ennis/ The Fort Worth Star-Telegram,via AP Photo, File) Kholodenko and Tsygankova, after they relocated to Fort Worth, appeared ready to overcome such challenges. Though what happened is not yet clear, it is clear that they didn’t. “It’s very important for me to be here so that I can hear my husband and how he’s practicing,” Tsygankova said in 2014. “Most of the time, his playing teaches me how to do it, and it changes me as a musician also and makes me better.” | Summary: Three years after winning the prestigious gold medal at the Van Cliburn International Piano Competition, pianist Vadym Kholodenko suffered the deaths of his two young children, for which his estranged wife has been charged with capital murder. It's just the latest tragedy to befall a Cliburn winner, Scott Cantrell writes at the Dallas Morning News, citing what is known as "the Cliburn curse." In minor cases, the so-called curse resonates in the form of a pianist failing to live up to expectations or falling into a career slump. More ominous, though, is that three of the 16 winners since the competition began in 1962 have died at an early age. Steven De Groote, winner of 1977 Cliburn, for example, died from a complication of AIDS in 1989. He was 36. That same year, Alexei Sultanov won the gold medal in what one judge labeled "a tremendous scandal." He was left partially paralyzed by a stroke in 2001 and died in his sleep in 2005 at age 35. Then in December 2014, 1985 winner José Feghali shot himself following a battle with depression. He was 53. "Some performers thrive for years in this rat race, but others become burned out and resentful. Lengthy periods away from home take tolls on families and relationships, too," writes Cantrell. "We didn't see a lot of Vadym in Moscow when he's traveling a lot," wife Sofya Tsygankova-a once-competitive pianist, per the Washington Post-told the Fort Worth Star-Telegram in 2014 after moving to Texas. "We wanted to be together, with Vadym, to be a family." | 1,924 | 409 | multi_news | en |
Write a title and summarize: Predictive understanding of cell signaling network operation based on general prior knowledge but consistent with empirical data in a specific environmental context is a current challenge in computational biology. Recent work has demonstrated that Boolean logic can be used to create context-specific network models by training proteomic pathway maps to dedicated biochemical data; however, the Boolean formalism is restricted to characterizing protein species as either fully active or inactive. To advance beyond this limitation, we propose a novel form of fuzzy logic sufficiently flexible to model quantitative data but also sufficiently simple to efficiently construct models by training pathway maps on dedicated experimental measurements. Our new approach, termed constrained fuzzy logic (cFL), converts a prior knowledge network (obtained from literature or interactome databases) into a computable model that describes graded values of protein activation across multiple pathways. We train a cFL-converted network to experimental data describing hepatocytic protein activation by inflammatory cytokines and demonstrate the application of the resultant trained models for three important purposes: (a) generating experimentally testable biological hypotheses concerning pathway crosstalk, (b) establishing capability for quantitative prediction of protein activity, and (c) prediction and understanding of the cytokine release phenotypic response. Our methodology systematically and quantitatively trains a protein pathway map summarizing curated literature to context-specific biochemical data. This process generates a computable model yielding successful prediction of new test data and offering biological insight into complex datasets that are difficult to fully analyze by intuition alone. Signaling networks regulate cell phenotypic responses to stimuli present in the extracellular environment [1]. High throughput “interactome” data provide critical information on the composition of these networks [2], [3], [4], but understanding their operation as signal processing systems is strongly advanced by direct interface with dedicated experimental data representing measured responses of biochemical species in the network (proteins, mRNA, miRNA, etc.) to stimulation by environmental cues in the presence or absence of perturbation [5], [6], [7], [8]. Immediate early responses are dominated by protein post-translational modifications (we focus here on phosphorylation), assembly of multi-protein complexes, and changes in protein stability and localization. Such responses are typically highly context dependent, varying with cell type and biological environment. A critical question for the field is how large scale measurements of these responses can be combined with a signed, directed protein signaling network (PSN) to better understand the operation of complex biochemical systems [9]. PSNs are typically deduced by manual or automated annotation of the literature (e. g. [10]) or directly from high-throughput experimental data (e. g. [11], [12], [13]) using a variety of computational techniques. PSNs are represented as node-edge graphs [14], and although they provide high-level insight into the composition and topology of regulatory networks [15], [16], [17], [18], [19], [20], as currently constituted PSNs are not readily ‘computable’ in that they cannot be used to calculate activation states of the key proteins in a pathway given a set of input cues, nor can quantitative relationships between pathways be determined. This restricts the utility of PSNs for explicit prediction of responses and makes it difficult to compare network representations to functional experimental data. A chief motivation of our current work is to determine how information encoded in a PSN can be made computable and compared to experimental data from a specific cell type, resulting in a context-specific network model. Logic-based models (e. g. [21], [22], [23], [24], [25], [26]; reviewed in [27], [28]) offer one means for converting interaction maps into computable models. We have previously used Boolean logic (BL) to convert a literature-derived signed, directed PSN (comprising for this purpose a ‘prior knowledge network’ [PKN]) into a computable model that could be compared to experimental data consisting largely of the phospho-states of signal transduction proteins in the presence of different ligands and drugs [29]. This approach allowed us to determine which links in the PKN were supported by the data, and generated models that were useful in making predictions about network topology [29] and drug targets [30]. However, Boolean logic has a significant limitation, since real biochemical interactions rarely have simple on-off characteristics assumed by Boolean logic. Thus, we require a means to encode graded responses and typical sigmoidal biological relationships in a logic-based framework. One way to accomplish this is to apply traditional fuzzy logic [FL], as demonstrated previously in modeling continuous input-output relationships to encode a complex signaling network [31], [32]. In the realm of control theory, FL modeling is an established technique for predicting the outputs of complex industrial processes when the influences of inputs cannot be characterized precisely [33], [34], [35]. A central feature of FL is that it accounts for graded values of process states using a virtually unlimited repertoire of relationships between model species or components. However, for past application to biochemical signaling networks, the flexibility of conventional FL modeling necessitated that the network topology be fixed prior to either manual [31] or computational [32] parameter fitting, rendering a formal training of network topology to experimental data infeasible. In this paper we develop and employ a new approach to fuzzy logic modeling of biological networks that we term ‘constrained fuzzy logic’ [cFL] for descriptive purposes. A key feature of cFL modeling is that it limits the repertoire of relationships between model species, enabling the formal training of a PKN to experimental data and resulting in a quantitative network model. To maximize broad dissemination across the computational biology community, we implement cFL in an exisiting software tool CellNetOptimizer v2. 0 (CellNOpt), significantly extended to accommodate the further requirements of cFL while maintaining the BL analytic approach (freely available at http: //www. ebi. ac. uk/saezrodriguez/software. html). We demonstrate the value of the CellNOpt-cFL method by elucidating new information from a recently published experimental dataset describing phospho-protein signaling in HepG2 cells exposed to a set of inflammatory cytokines [36]. We show that a cFL model can be trained against a dataset and then validated by successful a priori prediction of test data absent from the training data. We also establish the benefits of cFL relative to BL in three key areas: (a) generation of new biological understanding; (b) quantitative prediction of signaling nodes; and (c) modeling quantitative relationships between signaling and cytokine release nodes. Particular examples of validated biological predictions include: (i) TGFα-induced partial activation of the JNK pathway and (ii) IL6-induced partial activation of multiple unexpected downstream species via the MEK pathway. Our work demonstrates the technical feasibility of cFL in modeling real biological data and generating new biological insights concerning the operation of canonical signaling networks in specific cellular contexts. Fuzzy logic is a highly flexible methodology to transform linguistic observations into quantitative specification of how the output of a gate depends on the values of the inputs [33], [37], [38], [39]. For example, in the simplest, ‘Sugeno’ form of fuzzy logic, one specifies the following: ‘membership functions’ designating a variable number of discrete categories (“low, medium, high', etc.) as well as what quantitative value of a particular input belongs either wholly or partially to these categories; ‘rules’ designating the logical relationships between the gate inputs and outputs; AND and OR ‘methods’ designating the mathematical execution of each logical relationship; ‘weights’ designating the credence given any rule; and ‘defuzzification’ designating a scheme for determining a final output value from the evaluation of multiple rules [40]. This flexibility is important in industrial process control [41], which aims to use uncertain and subjective linguistic terms to predict how a controller should modulate a process variable to achieve the desired output. However, our goal is to train models on quantitative biological data that are inevitably incomplete in the sense that (i) measurements are not obtained under all possible conditions and (ii) available data are not sufficient to constrain both the topology and quantitative parameters of the underlying networks. Accordingly, we sought to develop a fuzzy logic system that minimizes the number of parameters to avoid over-fitting and simplifies the logic structure to facilitate model interpretability. Because we aim to represent relationships among proteins in enzymatic cascades, mathematical relationships should be biologically relevant. We therefore use a simple Sugeno fuzzy logic gate with a defined form (see Text S1) based on transfer functions (mathematical functions describing the relationship between input and output node values) that approximate the Hill functions of classical enzymology. Our ‘constrained’ fuzzy logic (cFL) framework uses a simplified fuzzy logic gate that is best described by the mathematical representation in Figure 1. The value of an output node of a one-input positive interaction is evaluated using a transfer function. In this paper ‘input-output’ refers to the nodes of a specific cFL logic gate, where ‘nodes’ are molecular species. We use the terms ‘model inputs’ and ‘model outputs’ to denote the overall relationship between model inputs such as ligand stimulation of cells and the collective output of the network (protein modifications or phenotypic states in our application). The transfer function underlying cFL gates is a normalized Hill function with two parameters: (1) the Hill coefficient, n, which determines the sharpness of the sigmoidal transition between high and low output node values and (2) the sensitivity parameter, k, which determines the midpoint of the function (corresponding to the EC50 value in a dose-response curve, Figure 1a). A negative interaction is represented similarly, except that the transfer function is subtracted from one, effectively inverting it (Figure 1b). Varying these parameters allows us to create a range of input-output transfer functions including linear, sigmoidal and step-like (Figure 1a). Moreover, this transfer function is biologically relevant: protein-protein interactions and enzymatic reactions can be described by Hill function formulations to a good approximation [42],. In some cases, use of a normalized function is too restrictive for practical application. For example, if model inputs are purely binary (values of either zero or one), the output of a normalized function would also be zero or one, making it impossible for a cFL gate to achieve intermediate states of activation. Accordingly, our cFL method allows for alternative transfer functions. For example, although the method is not limited to binary model inputs, the ligand inputs of our current work are binary (either present or not). If we used normalized transfer functions to relate these model inputs to downstream outputs, all model species would also be either zero or one. Thus, for these transfer functions, we used a constant multiplied by the binary ligand input value (see Materials & Methods). If more than one input node influences an output node, this relationship is categorized as either an “AND” or “OR” interaction. An AND gate is used when both input nodes must be active to activate the output node, whereas an OR gate is used when either input node must be active. Mathematically, we represent AND behavior by evaluating each input-output transfer function and selecting the minimal possible output node value (i. e., applying the “min” operator, Figure 1c) whereas we select the maximal value (“max” operator; Figure 1d) to evaluate an OR gate. Finally, if both AND and OR gates are used to relate input nodes to an output node, our formalism evaluates all AND gates prior to OR gates. This order of operations corresponds to the disjunctive normal or sum of products form [45]. The process of training a cFL network (CellNOpt-cFL) has two starting requirements. The first is a prior knowledge network (‘PKN’; Figure 2, box A). A PKN depicts interactions among the nodes as a signed, directed graph (such as a PSN) and can be obtained directly from the literature. Alternatively, a large number of commercial (e. g., Ingenuity Systems: www. ingenuity. com; GeneGo: www. genego. com) or academic (e. g., Pathway Commons: www. pathwaycommons. org, reviewed in [46]) pathway databases as well as integrative tools (e. g. [47], [48]) can be utilized to construct a PKN. The second requirement is a dataset describing experimental measurements characterizing node activities following stimulation of and/or perturbations in upstream nodes (ligand and inhibitor treatment in our example; Figure 2, box B). CellNOpt-cFL is then used to systematically and quantitatively compare the hypothesized PKN to the experimental dataset. In practice, available experimental data is usually insufficient to fully constrain both the parameters and topology of the cFL models, and CellNOpt-cFL recovers many models that describe the data equally well. Due to this typical absence of firm structural and parametric identifiability [29], [49], [50], we examine families of models that fit the data equally well rather than attempting to identify a single global best fit. Specifically, we examine interactions in the PKN that were either retained or consistently removed by training. We also use individual models to predict input-output characteristics. This treatment allows us to calculate both an average prediction as well as a standard deviation, which we show below can be useful for discrediting inaccurate predictions. Our method comprises three main stages (Figure 2): first, structure processing converts a PKN into a cFL model; second, model training trains the model to experimental data; and third, model reduction and refinement simplifies trained models. To illustrate CellNOpt-cFL, we examine a simple toy problem of training a PKN of the phospho-protein signaling network response to TGFα and TNFα (Figure 2a. i) to in silico data of activation of several downstream kinases in response to these ligands in the presence or absence of PI3K or MEK inhibition (Figure 2a. ii). In the first step, we streamline the network to contain only measured and perturbed nodes as well as any other nodes necessary to preserve logical consistency between those that were measured or perturbed ([29]; Figure 2, Step 1), resulting in a compressed PKN (Figure 2 box C). In our example, many nodes that were in the original PKN were neither measured nor perturbed experimentally. Because these nodes could be removed without causing logical inconsistencies, they were not explicitly included in the compressed network (Figure 2b). In the second step, we expand the network into the multiple logical relationships (combinations of AND and OR gates) that can relate output nodes to their input nodes (Figure 2, Step 2). For example, our toy PKN was expanded to include all possible two-input AND gates governing the response of nodes with more than one possible input node (Figure 2c). In the third step, we train the cFL models to the data (Figure 2, Step 3). We start by limiting the possible parameter combinations to a subset of discrete parameter values that specify seven allowed transfer functions as well as the possibility that the input does not affect the output node (i. e. the cFL gate is not present). A discrete genetic algorithm determines transfer functions and a network topology that fit the data well by minimizing the mean squared error (MSE, defined in Materials & Methods) with respect to the experimental data. Due to the stochastic nature of genetic algorithms, multiple optimization runs return models with slightly different topologies and transfer function parameters that result in a range of MSEs. Models with an MSE significantly higher than the best models are simply eliminated from further consideration. Models with similar MSEs but different topology and parameters result from the insufficiency of the data to constrain the model such that each model fits the data well albeit with slightly different features. We consider each individual in this group as a viable model, and all are included for subsequent analysis. Thus, after multiple independent optimization runs using the discrete genetic algorithm to train the expanded PKN against the data, a family of models with transfer functions chosen from a discrete number of possibilities is obtained. For each of these models, we generate unprocessed models (Figure 2, box F) by removing all cFL gates that are logically redundant with other cFL gates (e. g., in the gate “ (B AND C) OR B activate D”, the AND gate is logically redundant with the “B activates D” gate). These gates are removed because they increase model complexity by using multiple logic gates to encode a relationship that can be specified by a simpler gate. In our toy example, a family of twenty unprocessed models was obtained by training the expanded map (Figure 2c) to in silico data (Figure 2a. ii.) using the discrete genetic algorithm. The unprocessed models from different optimization runs had similar topologies with the exception of the gate describing the relationship of MEK to its input nodes: TGFα and Akt (Figure 2d, brown and green dashed gates). Sixteen of the unprocessed models described the activation of MEK as depending only on TGFα (brown, dashed gate) whereas four described activation using the AND NOT gate (green, dashed gate). In the model reduction and refinement stage (Steps 4–6), we determine which gates can be removed altogether as well as AND gates that can be replaced with one-input cFL gates without significantly affecting the MSE. We implemented the non-exhaustive heuristic search procedure described below on each unprocessed model and illustrate its application to our toy example (Figure 3). In the fourth step, we remove or replace all gates for which the alteration does not increase the MSE of the unprocessed model over some threshold, which we term the ‘reduction threshold’. We use a range of reduction thresholds such that each unprocessed model results in several models, one for each reduction threshold used. Following this step, the resultant models are considered reduced models. In the fifth step, we fix the model topology to that obtained during Step 4 and treat the transfer function parameters in each reduced model (Figure 2, Step 5) as continuous parameters rather than the discrete set of transfer function parameters required for use of the discrete genetic algorithm. We use a Sequential Quadratic Programming method (Text S1) to refine the model parameters and further improve the fit of the models to the experimental data. The resulting models are termed reduced-refined models, which have a range of MSEs depending on the reduction threshold used (Figure 3a). In the sixth and final step, we specify a reduced-refined model to represent each unprocessed model (Figure 2, Step 6). For each unprocessed model, we choose the reduced-refined model that has the fewest number of fitted transfer function parameters without increasing the MSE above a defined ‘selection threshold. ’ The selection threshold is chosen by comparing the average number of parameters in the family of models to the average MSE of the models (Figure 3b). The net result is a set of reduced-refined-filtered models (hereafter referred to as filtered models, Figure 2, Box G). In our toy example, the filtered models have identical topology and in no case does Akt inhibit MEK activation (Figure 2e). This topology is, in fact, the topology from which the in silico data was derived. The ability of cFL to fit intermediate values made it possible to recover the correct model topology, whereas BL did not identify the correct model, and a gate linking TGFα to PI3K was consistently missing (Figure 2e, dashed arrow). Specifically, BL was unable to return the correct topology because nodes downstream of PI3K (Akt and JNK) were partially activated (0. 32 and 0. 19, respectively) under conditions of TGFα stimulation, and a BL model that included the TGFα to PI3K gate had a higher error (MSE = 0. 56) than a model that omitted the interaction (MSE = 0. 07). In contrast, the improved ability of cFL to model graded activities made it possible to recover the true network topology. While the expansion step (Figure 2, step 2) captures the many possible combinations of AND and OR logic relationships between nodes, it also increases the complexity of the network, resulting in an increase in the size of the optimization problem. Depending on the biological network of interest, some or most of these AND gates might not be biologically relevant. For example, it is unlikely that six receptors must be active in order to activate another species, as would be the case for a six-input AND gate (instead, it is more likely to be a OR gate). A profusion of AND gates also makes the resultant networks difficult to interpret because most AND gates are in only a few models whereas the majority of models contain single-input and OR gates. Thus, the AND gates can effectively appear as system “noise”, interfering with visual assessment as well as computational analysis of the model topologies. Because of these potential complications, the expansion step can be limited to include only AND gates with a few inputs, depending on the complexity one would like to capture with the trained network models. In the current paper, we have limited the search in the discrete genetic algorithm to a set of seven transfer functions. Use of more or fewer transfer functions is possible, but we found that seven transfer functions allowed us to represent a variety of input-output relationships without unduly increasing problem complexity to the point that the discrete genetic algorithm no longer consistently returned models that fit the data well (see Materials & Methods). To test the ability of cFL modeling to analyze real biological data, we modeled a set of measurements describing the response of the HepG2 hepatocellular carcinoma cell line to various pro-survival, pro-death, or inflammatory cytokines in the presence or absence of specific small molecule kinase inhibitors. This dataset was used to construct a recent BL model [29]. Here we ran an independent analysis using the cFL approach and compare the results to the BL previously reported. The dataset comprises measurement of phosphorylation states as markers of activation of 15 intracellular proteins before and 30 minutes after stimulation by one of six cytokines in the presence or absence of seven specific small molecule kinase inhibitors (Figure 4a, Figure S1). The measurements were normalized to continuous values between zero and one using a routine implemented in the MATLAB toolbox DataRail [51], as previously described ([29], see Text S1). The HepG2 dataset was trained to several related PKNs which are enumerated in Table 1 and Figure S2. These PKNs were derived, with various extensions, from the Ingenuity Systems database (www. ingenuity. com) with manual addition of literature data about IRS1 that was obviously missing [29]. The first PKN, termed PKN0 was identical the one used previously for BL modeling [29]. In the course of our analysis, we found it necessary to search the literature for interactions missing in PKN0 but supported by the data, resulting in several PKNs (Table 1). Furthermore, we limited the manner in which the PKNs were expanded in two ways: (1) expansion into all possible two-input AND gates or (2) expansion into a two-input AND gate only when one input was inhibitory. In the second case, the expansion of inhibitory gates was necessary because, in logic terms, an inhibitory gate indicates that the output node is active when the input node is not active. In biological networks, this is true if the output node is constitutively active, which was not observed in the normalized HepG2 data. Thus, in order to accurately model the inhibitory effect, it had to occur in conjunction with activation by some other input node, which is captured by an AND gate. If a PKN was processed with both types of expansion, we include a superscript to differentiate between the two cases – i. e., PKN1a for the expansion of all gates and PKN1i for the expansion of only the inhibitory case. PKN0 was expanded to include all possible two-input AND gates and trained to the HepG2 dataset with CellNOpt-cFL (Figure S2). The 90 unprocessed cFL models obtained after training showed that PKN0 exhibited a poor fit to IL1α-induced protein phosphorylation (Figure S3), a result we had also observed with BL analysis [29], confirming that the poor fit of BL was due to errors in the topology of PKN0 and not the inability of Boolean logic to fit intermediate values. An inspection of systematic model/data disparity (Figure S3) immediately indicated that the models did not fit IL1α-induced phosphorylation of IRS1, MEK and several species known to be modulated by the MEK pathway. In PKN0, no paths between IL1α and MEK or IRS1 were present. Based on careful reading of the literature, we added two links to PKN0: a TRAF6 → MEK link [52], and an ERK → IRS1 link [53]. These links had been inferred by the BL framework [29] and were supported by further literature evidence. To add a link that provided a path between IL1α and MEK in the absence of BL inference results, for simplicity one should first consider links from species that IL1α is already known to activate. In this case, TRAF6 is the most upstream species which experimental evidence suggests can activate MEK [52]. In the case of IRS1 signal activation, the specific phosphorylation site measured should be considered. Our data included measurements of phospho-S636/639, and S636 is a known phosphorylation site of ERK2 [53]. A novel finding from CellNOpt-cFL analysis of the HepG2 data was that IL6 treatment led to phosphorylation of several downstream proteins. Similarly to the links just considered, PKN0 included no paths between IL6 stimulation and these downstream proteins, resulting in an inability to fit this pattern of phosphorylation. Importantly, however, BL analysis would not have recognized this partial activation due to its inability to fit intermediate values (as illustrated in our earlier toy example). Because IL6 was observed to partially activate Akt in the data and known mechanisms exist for this activation [54], we added a prospective IL6R → PI3K link to the PKN, thus providing an extended PKN (PKN1) that we use below for subsequent CellNOpt-cFL analysis. PKN1 was expanded to include all possible two-input AND gates (PKN1a) for a total of 170 discrete parameters corresponding to 105 logic gates. The resultant network was trained to the HepG2 data. Reduction of the PKN1a–derived models indicated that almost all AND gates could be removed or replaced by single-input gates. Since the AND gates appeared to add unnecessary complexity to the cFL models, we also expanded PKN1 to only include AND gates if an input node was inhibitory (PKN1i; Table 1), resulting in only 60 discrete parameters corresponding to 56 logic gates. We then compared the PKN1a- and PKN1i-derived cFL models. The comparison of these two PKN-derived model families revealed a clear tradeoff between model fit and complexity. The more complex PKN1a-derived models were able to fit the data slightly better than the PKN1i-derived models (average unprocessed model MSE of 0. 032±0. 002 compared to 0. 035±0. 002, p<0. 001). However, the more complex PKN1a-derived models contained many more parameters than the PKN1i-derived models both before and after optimization (170 compared to 60 discrete parameters before optimization and an average of 72. 8±4. 9 compared to 66. 6±3. 9 continuous parameters after optimization (p<0. 001); Figure S4). The simpler PKN1i-derived models used fewer initial and final parameters to arrive at a fit to the data only 9% worse than PKN1a-derived models. Since the 9% deviation is in the range of error in the normalized data (error estimated to be 10% by comparing similar stimulation conditions), we focused subsequent analysis on the simpler PKN1i-derived models. For completeness, we include the results of PKN1a-derived models as supplemental information (Figure S5). To determine the statistical significance of our results, we compared the family of 243 unprocessed models with unprocessed models obtained from either training PKN1i to randomized data or training a randomized PKN1i to the data (Table S1). Data was randomized by pairwise exchange of all data values while network topologies were randomized either by generation of an entirely random topology or by random pairwise exchange of gate inputs, gate outputs, or nodes' inputs [29]. When compared to the results of all types of randomization, models trained to the real data and PKN1 were highly significant (P-value <0. 001, Table S1), indicating that the family of trained cFL models fit the data better than expected by random chance. To probe the dependence of the CellNOpt-cFL training process on the quality of the PKN used, we randomly added links to or removed links from the PKN and trained the resultant PKN to the data. As expected, the models derived from PKNs with links randomly removed had a poorer fit to data than those derived from the complete PKN1i (Figure 4b, solid line). Conversely, when links were randomly added to the PKN, cFL-CellNOpt effectively removed the links (Figure S6), resulting in models with similar goodness of fit as models derived from PKN1i (Figure 4b, dashed line). We thus conclude that an incomplete PKN degrades the ability of CellNOpt-cFL to fit the data whereas models derived from a PKN with extraneous links retain this ability. As an initial investigation of model predictive capacity and a check for over-fitting, we performed a ten-fold cross-validation by randomly dividing the HepG2 data into ten subsets and, for each subset, reserving one as a test set while training with the remaining nine data subsets. The similar fits of the training and test data provided evidence that the family of models obtained from this procedure were predictive, and the difference in test and training MSEs did not depend on selection threshold, a measure of model size, suggesting that the models were not over-fit (Figure 4c). Analysis of this cross-validation result combined with a plot of average filtered model size and fit (MSE) as a function of selection threshold (Figure 4d) suggested that a selection threshold in the range 1×10−3 – 1×10−2 would result in a family of models that contain slightly fewer number of parameters than lower thresholds (Figure 4d, dashed line) while retaining the ability to fit the data well (Figure 4d, solid line). We used a threshold of 5. 0×10−3 for the remainder of our analysis unless otherwise noted. Finally, we obtain a family of 243 filtered models for further analysis (Figure 5). By taking note of which cFL gates are removed during the CellNOpt-cFL training and reduction processes, one can generate hypotheses regarding these gates. Table 2 summarizes a set of biological hypotheses readily suggested by our cFL model topologies. Analysis of error between the family of cFL models and experimental data (Figure S7) highlighted consistent error in TGFα-induced partial activation of c-Jun. Both PKN0 and PKN1 allowed for TGFα-induced activation of c-Jun by the JNK pathway via crosstalk from Ras or PI3K to MAP3K1. In the BL methodology, this crosstalk was removed due to the inability to fit partial activation, and no BL model allowed for activation of c-Jun after TGFα stimulation. However, we found that a subset of cFL models accounted for this c-Jun partial activation by including crosstalk between Ras or PI3K and MAP3K1. These models also partially activated JNK after TGFα stimulation, a feature that was inconsistent with the training data (Figure S8). Thus, these models predict that JNK was actually phosphorylated under conditions of TGFα stimulation, but our measurements did not detect it. To test this prediction directly, we undertook de novo measurement of JNK and c-Jun phosphorylation following stimulation with different doses of TGFα (Figure 6a). These new data show that JNK does indeed become phosphorylated upon stimulation of HepG2 cells with TGFα. Thus, the cFL models containing crosstalk from Ras or PI3K to MAP3K1 were the correct models. Combined with Table 2, this analysis highlighted the partial activation of the JNK pathway after TGFα stimulation as a singular instance of crosstalk from a pro-growth ligand to an inflammatory pathway. In support of the significance of our finding here, we note that TGFα-induced JNK activation has been shown to be important for hepatic regeneration [55] and stimulation of DNA synthesis [56] in primary rat hepatocytes. As previously mentioned, PKN0 was unable to fit IL6-induced protein phosphorylation (a feature of the data unappreciated by the BL methodology). Because Akt was observed to be partially phosphorylated under these conditions and we found literature evidence for a prospective IL6R → PI3K link, we added the link to PKN1. However, the media-only condition also induced partial phosphorylation of Akt. Discovery of the partial activation of Akt in the media-only control led us to consider that perhaps the IL6-induced phosphorylation of Akt was simply an assay artifact. Thus, we inserted an Assay → PI3K link into the PKN. This “Assay” node represents cell stress arising from changing environmental conditions during the assay (media change, etc.); it is postulated to activate PI3K because only Akt is consistently active in the untreated control. Having accounted for the potential that IL6-induced partial phosphorylation of Akt was an artifact, we undertook a series of computational experiments to determine the mechanism of IL6-induced phosphorylation of downstream proteins. Upon exposure to IL6, SHP2 has been reported to bind to gp130, a subunit of the IL6 receptor complex. SHP2 is then phosphorylated in a JAK1-dependent manner. This phosphorylation can lead to PI3K/Akt pathway activation through interactions with Gab-1 or IRS1 or Ras/MEK/ERK pathway activation through Grb2 or Gab1 [54]. Thus, our computational experiments were designed to infer which pathway (PI3K/Akt or Ras/MEK/ERK) was mediating the IL6-induced protein phosphorylation. Four families of 150 filtered models were examined, all of which were obtained after training a new PKN to the normalized HepG2 dataset (Table 3, PKN2A – PKN2D). The inability of PKN2A-derived cFL models with only the Assay → PI3K link to fit well the IL6-induced protein phosphorylation data suggested that some other link was necessary to fit this data. In our trained networks, the IL6R → PI3K link was present in only a fraction of the relevant trained models (PKN2B and PKN2C), but the IL6R → Ras link was present in more than 90% of relevant trained models (PKN2C and PKN2D). Additionally, models with IL6R → Ras links were better able to fit the IL6-induced protein phosphorylation. Consequently, our cFL results supported the hypothesis that IL6R activates downstream proteins through the Ras/Raf pathway. This hypothesis is supported by an independent dataset [29], where the IL6-induced protein phosphorylation response was more robust than in the training data (Figures S1 and S9). Inhibition of MEK either alone or in combination with other inhibitors resulted in ablation of downstream protein activation whereas inhibition of PI3K did not (Figure 6b). Thus, we infer that IL6-induced protein phosphorylation was not an assay artifact and was instead mediated by the Ras/Raf pathway. CFL relates nodes in a network with transfer functions that describe quantitative input-output relationships between protein species represented as network nodes. To investigate the ability of the cFL models to predict these transfer functions, we simulated the PKN1i-derived, filtered cFL models to determine the activation state of a specified node under many theoretical combinations of its input nodes. We then plotted the model predictions of quantitative input-output relationships. As one instance, Figure 7 shows the predicted average and standard deviation of the quantitative values of CREB phosphorylation as a function of the activation of upstream nodes, p38 and MEK1/2. The resulting plots indicated that we were able to predict the activation response of CREB to the entire range of p38 and MEK1/2 although training set measurements were limited to a few values of these nodes (Figure 7, black circles). We tested this prediction using a set of data with combinations of ligands and inhibitors not present in the training data ([29], Figure S9). Roughly 20% of the test conditions were also present in the training data set, allowing us to control for differences between both data sets. When we compared this dataset to the predicted transfer functions, we observed that most of the data fell within one standard deviation of the predicted value (Figure 7, green diamonds) with exception of overestimation under conditions of TGFα stimulation. This overestimation is expected, as a comparison of common conditions between the training and test dataset indicated that the normalized experimental values of CREB in the validation dataset were 38±4% lower than that in the training set. This result demonstrates the ability of the trained cFL models to predict the quantitative relationship between nodes in the network. We also found that the family of cFL models was able to fit the phospho-protein signaling response in the validation dataset well, which we demonstrate as supplementary information (Figure S9). We performed a series of nineteen cross-validation experiments to further investigate the ability of our methodology to predict the signaling response under conditions that were not represented in the training data. For each experiment, we used training data from which we had removed the phosphorylation data of a specific protein signal, s, under a single ligand stimulation condition and all inhibitor treatments. Nineteen signal/stimulation combinations were chosen to be test sets according to two criteria: (1) s is at least partially activated under the stimulation condition of interest and (2) s is at least partially activated under some other stimulation condition (Table S2). These criteria ensured that the remaining training data contained some information regarding the activation of s but it did not contain information regarding the activation of s under the stimulation condition of interest. This procedure is a more stringent test for predictive capability than a random cross-validation procedure because training sets from which random data is removed might retain other data with the same information as the removed data (e. g., based on the network topology, Akt phosphorylation in the absence of MEK inhibition is the same as Akt phosphorylation with MEK inhibition, so removing only one of these data points is not a stringent test of predictive capacity). We examined the ability of models trained on reduced training sets (n>45 for each case) to predict phosphorylation of the test protein signals. Because we used each individual in the family of models to predict the test signal, we could determine if the models were constrained in their predictions by examining the coefficient of variance (CV; standard deviation divided by mean) of the prediction. If the CV was high, the models were not constrained to a specific prediction (i. e. the prediction was imprecise), and the average prediction should be discounted. Thus, for these cross-validation results, we compared the precision (CV) and accuracy (MSE) of the models' predictions, where precise and accurate predictions exhibited both a low CV and low MSE (Figure 8a). We found that the families of models trained on these reduced training sets were able to precisely predict phosphorylation of the test protein signals in twelve of the nineteen cases (Figure 8b and c, green field). In six of the test sets, the models did not agree, although their average prediction was reasonably accurate (Figure 8b and c, yellow field). We observed no test sets for which the training sets agreed about an inaccurate prediction (Figure 8b, orange field). In one case (prediction of Iκb signaling under TNFα stimulation), the predicted phosphorylation state was highly inaccurate (MSE >0. 20). However, this prediction was also very imprecise (CV >0. 25), indicating that the average prediction was unreliable (Figure 8b, blue field). Thus, by taking the precision of the models' predictions into account, we were able to discredit an inaccurate prediction. This result underscores the importance of considering consensus among the family of models rather than examining the results of only one cFL model. The ability to quantitatively model protein signal activation with cFL offers the prospect of predicting phenotypic response upon exposure to stimuli and inhibitors. To investigate the ability of cFL to model phenotypic data, we turned to data describing cytokine release three hours after stimulation under the same conditions as the phosphorylation data [36]. As a first approach, we linked the output of our family of cFL models to a partial least squares regression model [6] obtained by regressing normalized data of release of five cytokines (IL1β, IL4, G-CSF, IFNγ, and SDF1α) to the normalized protein phosphorylation measurements (see Text S1). The cFL models linked to a PLSR model were able to model phenotypic response with an accuracy of R2 = 0. 79, near that of the PLSR model (R2 = 0. 81; see Figures S10). However, we found that the correlation indicated by regression coefficients did not lead to easily interpretable insights about phenotype because proteins in the same pathway were also highly correlated with each other. To obtain a more interpretable model, we utilized a second approach where we included nodes specifying cytokine release in the PKN and linked them to a few protein signaling nodes. These nodes were chosen based on principle component analysis: if protein signals in a pathway clustered together in principle component space, the signal most downstream in the pathway was linked to cytokine release. Based on this analysis, the following protein signaling nodes were linked to each cytokine release node: MEK1/2, CREB, GSK3, c-Jun, Hsp27, Iκb, and STAT3 (Table 1, PKN3). We then trained a family of cFL models to the normalized dataset comprised of cytokine release at three hours and protein signaling at thirty minutes. The resultant models were able to fit the cytokine release data reasonably well (R2 = 0. 78 for the average predicted by a subset of best-fitting models, Figure S11). Furthermore, the low frequency of several gates in the resultant family of cFL models (Figure S12, Table S3) indicated that, although the promoters of several of the modeled cytokines contained binding sites of transcription factors are known to be modulated by the MEK1/2, GSK3, and CREB pathways (Table S4), activation of these nodes did not predict cytokine release. Thus, we altered our previous PKN by removing the links between these protein signaling and cytokine release nodes and trained it to the data. The resultant family of cFL models (Figure 9) indicated that STAT3 activation explained cytokine release after IL6 stimulation and other signals (Iκb, c-Jun, and Hsp27) explained cytokine release three hours after TNFα or IL1α stimulation. In this paper, we have described cFL for formal training of a prior knowledge network obtained from a protein signaling network map to experimental data and demonstrated that the ability of cFL to fit intermediate activities was crucial for understanding key features of a biological network. We validated two important biological insights concerning network operation in the HepG2 cells under inflammatory cytokine and growth factor treatment: (i) identification of c-Jun as a downstream locus of crosstalk between growth factor and inflammatory cytokine treatments and (ii) the Ras/Raf/MEK pathway as an avenue for activation of key downstream proteins following exposure of cells to IL6. Both of these insights were dependent on the ability of our cFL models to fit partial protein activation and were thus not appreciated by BL modeling. We note that the ability of cFL to model intermediate activity data comes at the cost of increased model complexity. This complexity calls into question the identifiability of a cFL model (i. e. ability of the CellNOpt-cFL training process to train both parameters and topology given limited data). To address this concern, we considered families of models where each individual model predicted signaling states and the resulting predictions had an average and standard deviation. The standard deviation provided a metric for discrediting predictions for which the models were not constrained. With regard to topology, we considered how often a gate was present in the trained cFL models. This allowed us to determine hypothesized links (those present in the PKN) that were either inconsistent with the data (cFL gates removed from unprocessed models) or only marginally important for fitting the data (cFL gates removed from filtered models). Thus, the consideration of consensus and variation in an ensemble of models allowed us to account for the non-identifiability of any individual model. We also illustrated the use of CellNOpt-cFL to (i) predict quantitative phenotypic response data with the same quality as a regression-based approach and (ii) increase the biological understanding of a phenotypic response by generating hypotheses regarding protein signaling pathways that led to cytokine release. Transcriptional and/or non-transcriptional mechanisms could underlie the biological link between the signaling network activation and cytokine release profiles. We investigated predicted and known transcription factor binding sites in the promoters of relevant genes (Table S4), finding that several transcription factors hypothesized by CellNOpt-cFL to drive cytokine release (STAT3 and NFκB) could, in concert with IRF1, potentially lead to the production and secretion of the observed cytokines. Our subsequent test of this notion by qRT-PCR measurement, however, yielded a negative result; expression of the HepG2-secreted proteins were not significantly up-regulated by IL6 stimulation (data not shown). Thus, it appears more likely that non-transcriptional mechanisms, such as exocytosis of secretory vesicles [57], [58] or proteolytic cleavage of pro-forms at the cell plasma membrane [59], [60], was responsible for the cytokine release observations. The persistent development and application of CellNOpt-cFL and complementary methods ([6], [7], [36] and Melas, et al., submitted) should continue to deepen our understanding of how signaling networks inform phenotypic responses. We have shown that CellNOpt-cFL is useful for systematically and quantitatively comparing experimental datasets to a PKN that summarizes decades of dedicated biochemical studies. However, our aim in this work is not to argue for exclusive use of cFL modeling instead of BL or other modeling approaches, but rather to delineate key advantages of cFL modeling for addressing data with intermediate activity values. Training with CellNOpt-cFL is a more difficult optimization problem that is not efficiently solved for networks much larger than those in this work. The BL optimization problem scales as 2w, where w is the number of gates in the processed PKN, whereas the CellNOpt-cFL optimization problem scales as (1+a) h, where a is the number of transfer functions in the set chosen by the genetic algorithm ( (1+a) ≥2; (1+a) = 8 as formulated here) and h is the number of possible input-output transfer functions in the network (h≥w). Additionally, as was the case with the reformulation of the BL optimization problem with Integer Linear Programming [30], we acknowledge that there may be more efficient, rigorous ways to solve the optimization problem presented by CellNOpt-cFL. When training a prior knowledge network to data, we often encountered the need to add links to the prior knowledge network in order to fully describe the data. In this study, this was done manually simply by searching the literature. In the absence of such information, one should automate the process of testing many candidate links. A simple heuristic procedure such as the one we employed for the BL methodology based on mismatches between the best-fit models and data is one option [29]. Alternatively, more complex reverse engineering techniques could be used. The additional complexity of cFL modeling poses significant complications for the implementation of a simple heuristic or reverse engineering technique, but future efforts should investigate best practices for the automation of this process. An additional prospective application of CellNOpt-cFL is to use a trained cFL model to inform the construction of a model with a different mathematical formalism. One intriguing possibility is that the CellNOpt-cFL methodology might be used to determine topologies to translate into a system of ordinary differential equations (ODEs) with methods such as that presented in [61]. The precise relationship between cFL and ODE parameters is unclear, but the ease of translating from one formalism to the other might be facilitated through the use of continuous AND and OR operators rather than the Min/Max operators utilized in this study. As a first step, we have retrained one of our main results (that presented in Figure 5) using the product of possible outputs to evaluate AND gates and the sum of possible outputs to evaluate OR gates. The models resulting from this procedure (Figure S13) were similar to those obtained previously (Figures 4c, 5), demonstrating the flexibility of this approach to accommodate different AND and OR operators as well as transfer function forms. Such flexibility should aid future attempts to translate CellNOpt-cFL results into other mathematical formalisms. Finally, the dataset used here was gathered for training a BL model. This dataset was explicitly designed to maximally stimulate or inhibit pathways through the application of saturating doses of ligand and drugs. However, cells in vivo face a much more subtle and interesting situation in which ligands are present in combination, often at very different levels. Because cFL can model the graded activation of cell signaling pathways, we suspect that CellNOpt-cFL should prove particularly useful with signaling data collected under more physiological conditions. Our laboratories are currently pursuing experimental studies in this direction. Model compression and expansion was performed with CellNOpt as previously described [29]. The discrete genetic algorithm in the CellNOpt BL variant was adapted so that discrete variables specified a transfer function rather than the gate type. Because our datasets (toy example and HepG2) only contained saturating concentrations of ligand stimulation, the normalized values of ligand model inputs were one or zero. In this instance, using normalized Hill functions to model interactions downstream of these zero or one inputs would result in all downstream nodes also reaching levels of zero or one (a Boolean simulation). To circumvent this issue, we represented interactions linking a ligand input to a downstream component with linear transfer functions with a y-intercept of zero and possible values of slope of 0. 2,0. 3,0. 4,0. 5,0. 6,0. 7, and 0. 8 as well as the absence of the interaction. All other interactions were modeled with the normalized Hill function described in Figure 1 where the following transfer functions were possible: gate not active, approximately linear transfer function (n = 1. 01, k = 68. 5098 chosen for computation efficiency and numerical stability), or sigmoidal transfer function (n = 3) with an EC50 of 0. 2,0. 3,0. 4,0. 5,0. 6, or 0. 7 (Figure S14). These transfer functions were chosen because the models resulting from the training represented many different topologies while still fitting the data well. We found that including a subset of three to five of the aforementioned transfer functions would have also accomplished these goals, but including ten transfer functions resulted in a larger fraction of models that did not fit the data well. This necessitated the addition of a step to choose a subset of well-fitted models from the family of trained models, and this subset did not significantly differ from the family of models obtained with fewer possible transfer functions. Given that more transfer functions allowed us to more accurately represent parameter space, this result implied that the genetic algorithm was converging to poorly-fit local minima because the search space was too large. We therefore concluded that usage of seven transfer functions balanced coverage of search space and ability to identify well-fitting models. Sensitivity is calculated as (1 – EC50) for cFL gates modeled with normalized Hill functions and 0. 5*slope for cFL gates modeled with weighted linear transfer functions. Mean squared error was calculated with the following formulawhere N is the total number of data points, Nsig is the number of protein signals measured, Nstim is the number of cytokine or growth factor stimulations, Ninhib is the number of inhibition conditions used, and xpredi, j, k and xobsi, j, k are the predicted and observed level of the ith protein signal under the jth stimulation and kth inhibition condition, respectively. In some cases, only the MSE of a subset of the data points is calculated for more specific error analysis. In these instances, the previous formula holds, but signal and/or stimulation conditions are constant and indicated with subscripts (e. g. MSEIL6 is the MSE of all signal measurements under all inhibition conditions and IL6 stimulation). Protein phosphorylation and cytokine release were measured as described in [36]. Briefly, cells were incubated with small molecule inhibitor before exposure to ligand. Luminex bead-based bioassays were used to determine protein phosphorylation in cell lysate collected immediately before and 30 minutes after ligand exposure. Three hours after ligand exposure, supernatant was collected and Luminex bead-based bioassay used to measure the amount of cytokine that had been secreted. | Title: Training Signaling Pathway Maps to Biochemical Data with Constrained Fuzzy Logic: Quantitative Analysis of Liver Cell Responses to Inflammatory Stimuli Summary: Over the past few years, many methods have been developed to construct large-scale networks from the literature or databases of genetic and physical interactions. With the advent of high-throughput biochemical methods, it is also possible to measure the states and activities of many proteins in these biochemical networks under different conditions of cellular stimulation and perturbation. Here we use constrained fuzzy logic to systematically compare interaction networks to experimental data. This systematic comparison elucidates interactions that were theoretically possible but not actually operating in the biological system of interest, as well as data that was not described by interactions in the prior knowledge network, pointing to a need to increase our knowledge in specific parts of the network. Furthermore, the result of this comparison is a trained, quantitative model that can be used to make a priori quantitative predictions about how the cellular protein network will respond in conditions not initially tested. | 12,466 | 215 | lay_plos | en |
Summarize: Two of the victims of the fiery Metro-North train crash will be laid to rest Friday, as more details on the six people who died emerge. Checkey Beckford reports. (Published Thursday, Feb. 5, 2015) A mother of three, a museum curator, a research scientist and three finance executives were the six people killed when a Metro-North train crashed into an SUV stuck between crossing gates in Westchester Tuesday, officials and those who knew them tell NBC 4 New York. Ellen Brody, Eric Vandercar, Joseph Nadol, Walter Liedtke, Robert Dirks and Aditya Tomar were identified Wednesday by friends, family and officials as the people who died when a train on the Metro-North's Harlem line crashed into a Mercedes SUV stopped on the tracks in Valhalla. The crash caused the front of the train to burst into flames and the electrified third rail to slice into a train car as the commuter train pushed the SUV nearly 10 car lengths down the tracks. Westchester County Executive Rob Astorino said medical officials are using dental records to definitively identify those who died because all but one were severely burned in the fire. Fifteen people on the train, including the engineer, were hurt, some of them seriously. PHOTOS: Dramatic Images of Metro-North’s Deadliest Crash As families, friends and the tri-state area cope with the tragedy amid an ongoing NTSB investigation into how and why it happened, clearer pictures are emerging of those who died. ELLEN BRODY, SUV DRIVER Brody and her husband, author and journalist Alan Brody, had three daughters in their teens and 20s, and were active in Chabad of the Rivertowns throughout the synagogue's 12 years, according to Rabbi Benjy Silverman. Brody helped found a student news network in her town and was involved in almost everything at her synagogue, friends said. "She was passionate about Judaism, she was passionate about her kids, and she did a great job of fulfilling the values that were important to her," he said. Brody, 49, was identified by the owner of the Chappaqua jewelry store where she worked for 15 years, ICD Contemporary Jewelry. "She was our beloved colleague, and we pray for her and other families whose loved ones were lost and injured in yesterday's tragedy," the owner said in a statement to NBC 4 New York Wednesday. Co-worker and friend Varda Singer said, "I describe her as a saint, because she was the most selfless person." Not knowing how Brody got stuck on the train tracks, makes the tragedy that much more unbearable, Singer said. "She's a very responsible person, a very reliable person," she added. "I just cannot believe that she's gone." Brody was mindful of safety, said Paul Feiner, a longtime friend and the town supervisor in Greenburgh, a community near the crash site. ERIC VANDERCAR, TRAIN PASSENGER Vandercar, a 53-year-old married father, worked for Morgan Stanley for 27 years before leaving his position as executive director of the municipal finance group in January 2014 to work as a senior managing director at Mesirow Financial, according to both companies. "Eric was not only a pillar in our industry, he was a great partner and friend to many," Mesirow Financial said in a statement. "Those of us who worked with Eric for many years at Morgan Stanley are deeply saddened by this tragic loss," a spokesman for the bank said in a statement. "Our hearts and prayers go out to his family at this difficult time." Vandercar was a familiar figure among jam band aficionados who make and circulate live-show recordings, generally with the bands' approval. "Words can't express how devastated we are today,'' the band moe. -- the period is part of the name -- posted on its website Wednesday. Vandercar saw the group play as recently as last month in Jamaica, the band wrote, adding that members would remember him enjoying music and hanging out backstage, "chatting with that easy smile of his.'' Vandercar's family told NBC 4 New York they were meeting with a rabbi and declined to comment further. A woman walking near Vandercar's home said he was "a wonderful husband and loving father." JOSEPH NADOL, TRAIN PASSENGER One of the three finance executive killed in the crash, Nadol, 42, did corporate and investment banking at JPMorgan Chase & Co. He was a managing director and analyst who covered the aerospace and defense industries. He joined JPMorgan in 2001, after five years at Donaldson, Lufkin & Jenrette. Nadol was "a wonderful colleague who always took the time to mentor and encourage junior analysts and represented the highest standards of J.P. Morgan global research," stated an email sent to the firm's employees. "He'll be remembered for his many personal qualities, especially his thoughtfulness toward co-workers and his sense of humor." Nadol earned a bachelor's degree in government at Harvard in 1995 before joining Donaldson, Lufkin & Jenrette as a real estate analyst. He moved to JPMorgan in 2001 and debuted on the All-America Research Team two years later as a runner-up in Aerospace & Defense Electronics. Nadol was "warm, caring and always had an infectious smile on his face," said Steven Packer, a close friend of Nadol who works as a sales account manager at NBC 4 New York. He leaves behind his wife Jen Nadol, an author, and three young children: Joey, Sam and Jacob. ADITYA TOMAR, TRAIN PASSENGER Tomar also worked at JPMorgan --in asset management. In a statement, JPMorgan called the loss of two of its employees "heartbreaking." "Our thoughts and prayers go out to their families, and to the many employees who worked with these colleagues and knew them well. It is a terrible tragedy and loss," the company's statement continued. The Danbury News-Times reports that Dee Persaud, who identified herself as Tomar's mother-in-law, says his loss has left her family "shocked and grieving." WALTER LIEDTKE, TRAIN PASSENGER Liedtke was a "brilliant, respected curator and scholar of Dutch and Flemish paintings who was part of the Met family for 35 years," said Elyse Topalian, vice president for communications for The Metropolitan Museum of Art. "He organized dozens of major exhibitions that brought the works of Rembrandt, Vermeer, Hals, and many other great artists to millions of our visitors. He will long be remembered for his vast knowledge, his wit, and a passion for art that inspired all who came in contact with him," Topalian said in the statement. With a master's degree from Brown University and a doctorate from the University of London's Courtauld Institute, Liedtke taught at Ohio State University for four years in the 1970s before getting a fellowship and then a job at the Met, according to a 2009 interview on the Dutch and Flemish art site Codart. He relished working among its large, specialized curatorial staff -- and its collection. "When asked what my favorite painting in the Met might be, I sometimes explain that historians don't think that way,'' he said, "and then answer frankly that it depends on my frame of mind." ROBERT DIRKS, TRAIN PASSENGER Father Michael Dirks told NBC News his son Robert Dirks was married and had two children, 5-year-old Owen and 2-year-old Phoebe. He earned his bachelor's degree from Wabash College and a PhD in chemistry at the California Institute of Technology, where he met his wife at a bridge tournament. He was a scientist at D.E. Shaw Research in Manhattan, where his wife had also formerly worked. "He was a guy you could always count on," his father told NBC News, saying his son love life, his family and playing the bassoon. His company's website said Robert Dirks worked in the "development of novel computational chemistry methods," but his father told The New York Times his son had an easier way to describe his complex job. "He used to say -- 'Dad, just say I'm a scientist, then they can understand,'" Michael Dirks told the Times. Robert Dirks was born in Bangkok, Thailand, where his mother was from. -- Michael George contributed to this report Copyright Associated Press / NBC New York Those killed in Tuesday's horrific train crash are five people from Westchester County and one man from Connecticut. Ellen Brody (Photo: courtesy) The identities of those killed when an SUV and Metro-North train collided in Valhalla on Tuesday night are now known. The driver was Ellen Brody of Edgemont. The passengers killed were: Eric Vandercar of Bedford, Walter Liedtke of Bedford Hills, Joseph Nadol of New Castle, Robert Dirks of Chappaqua and Aditya Tomar of Danbury, Connecticut. Valhalla train crash: Lost lives remembered A look at those killed: The driver: Ellen Brody Ellen Brody, an Edgemont mother of three, was the SUV driver at the center of the deadly crash, officials said Wednesday. The 49-year-old was returning home from Chappaqua, where she works at a jewelry design shop, when her vehicle was struck at the Commerce Street crossing. Greenburgh Supervisor Paul Feiner said he's known the Brody family, including Ellen and her South African-born husband, Alan, for years. Twists of fate: Last-minute choices haunt commuters NTSB: Train gate was working properly First responders: 'Most horrific thing I ever had to deal with' Harlem Line: Normal service resumes Metro-North crash: Minute-by-minute Witness: 'Terrible crunching sound' and the car was gone "It's not just a tragedy for the town," Feiner said. "It's a personal tragedy for me." The supervisor called Brody "an exceptional" person and recalled her as "Super, super nice." Alan Brody took to his Facebook page Wednesday to express his gratitude to the community his wife loved. "Thank you to those who shared their condolences for the terrible tragedy that took my beloved wife, Ellen, whom so many of you knew," he wrote. Ellen Brody, who worked at Chappaqua's ICD Contemporary Jewelry, was a joy to be around and was in great spirits when she left the store Tuesday, said Virginia Shasha, a sales associate who had known her for a decade. CLOSE Virginia Shasha remembers Ellen Brody. Shasha was a colleague of Brody at ICD Contemporary Jewelry. (Video bySwapna Venugopal Ramaswamy/The Journal News) Swapna Venugopal Ramaswamy "She was a wonderful, wonderful person," Shasha said. "She looked for the best in everyone and brought out the best in everyone." Varda Singer, the owner of the store, said Brody was a dedicated employee. "She cared about other people," Singer said. "She was a great mom, always full of life and energy." Singer described Brody as a "very careful driver" and said she was waiting to hear more about how the accident occurred. Buy Photo Ellen Brody worked at Chappaqua's ICD Contemporary Jewelry. A sign outside ICD on Wednesday mourned her death. (Photo: Swapna Venugopal Ramaswamy/The Journal News) Grace Bennett, publisher of Inside Chappaqua magazine, remembered Brody as someone who always had "a warm smile in every interaction." "Ellen was always professional, courteous, and just had this magnificently upbeat persona," Bennett said. "Her colleagues are devastated right now by the loss. They had a nice relationship with her daughters who called the store manager last night to let them know." Students at Edgemont High School were aware of the tragedy and the school provided them with support, said Bob Bernstein, president of the Edgemont Community Council, a community group. "They are a very prominent Edgemont family," he said. "What a terrible tragedy." The family was active in Chabad of the Rivertowns, a Jewish organization at 303 Broadway, Dobbs Ferry, where Brody's funeral will be held at 10 a.m. Friday. Rabbi Benjy Silverman consoled the bereaved family Wednesday. Police blockades were set up around the family's split-level home, which was surrounded by cars. A security guard who said he was hired by the family stood in front. Lives remembered: Ellen Brody Eric Vandercar, 53, of Bedford Hills, was one of the five people killed aboard a Metro-North Railroad train after it struck a SUV at the Commerce Street crossing in Valhalla. The crash resulted in the third electrified rail to break free and it sliced into the first train car. (Photo: Submitted photo) Passenger: Eric Vandercar Eric Vandercar, 53, of Bedford, was a married father of two and senior managing director and head of municipal funding in the international sales and trading department at Mesirow Financial. A live-music enthusiast, he shared concert tapes with online archives — particularly those of the bands moe., Phish and the Spin Doctors. Numerous friends took to the Internet and social media Wednesday to mourn his death, posting some of the concerts he had shared. On Twitter, Vandercar posted that he was an extreme skier, an advanced scuba diver and a whitewater rafting guide. In October, a week before he attended The Allman Brothers Band's final concert at the Beacon Theater, he tweeted that he had been to 232 of the band's shows there. We lost an old friend last night in the Metro North train tragedy. RIP Eric Vandercar... — ebyron (@ebyron) February 4, 2015 So sad to hear about Eric Vandercar today. Such a tragedy. Listening to his recordings today in memory:https://t.co/qR1JLFXCY6 — mkdevo (@mkdevo) February 4, 2015 Originally from Dutchess County, Vandercar received an MBA with distinction from New York University and bachelor's degrees from the Wharton School and the School of Engineering and Applied Science at the University of Pennsylvania. He joined Mesirow 10 months ago after 27 years at Morgan Stanley. A statement from Deborah Krieps, a managing director and spokeswoman at the Chicago-based firm, said Vandercar was at the forefront of the development and execution of new funding alternatives to replace auction rate preferred securities. "Eric was not only a pillar in our industry, he was a great partner and friend to many," the statement read. "Losing him is a huge loss, personally and professionally. Our entire Mesirow family is hurting and our deepest sympathies are extended to his wife, Jill, and their family." A woman who answered the phone at his home said the family had no immediate comment. Lives remembered: Eric Vandercar Walter Liedtke (Photo: Courtesy) Passenger: Walter Liedtke Walter Liedtke, 69, of Bedford Hills, was a renowned art historian and curator at the Metropolitan Museum of Art in Manhattan, where he organized blockbuster exhibitions of Dutch and Flemish artists, including Rembrandt and Vermeer. Liedtke's career at the Met spanned more than three decades. There, his exhibitions included "Rembrandt/Not Rembrandt" (1995-96); "Vermeer and the Delft School" (2001); and "The Age of Rembrandt" (2007), a widely acclaimed survey of the museum's holdings in 17th century Dutch painting that drew over 500,000 visitors. "It's a terrible loss for the Met," said Tom LaMotte, adding that his neighbor of 33 years was "delightful and caring." LaMotte, 79, said Liedtke woke up early during Monday's snowstorm and used his pickup truck to plow LaMotte's driveway before heading to the Met. "That's the kind of guy he was," LaMotte said. "He will be sorely missed." A native of New Jersey, Liedtke earned his bachelor's degree from Rutgers University and a master's degree in art history from Brown University and a PhD at the Courtauld Institute in London. He taught at Ohio State University from 1975 to 1979 before going to the Met as an Andrew W. Mellon fellow. In addition to his work as a curator, Liedtke was a productive writer, producing dozens of scholarly essays and a half-dozen books, including the first comprehensive, two-volume catalog of Dutch paintings from the Met's collection. One of his most recent exhibitions, "Vermeer's Masterpiece The Milkmaid" (2009), lured more than 300,000 visitors to see a special loan of one of Vermeer's most famous paintings. The exhibit marked the 400th anniversary of Henry Hudson's voyage to New York. "Walter was one of the preeminent scholars of Dutch and Flemish painting, whose contribution to the field lives on in a range of scholarly and popular publications," the Met president, Thomas P. Campbell, wrote in an Instagram post. Liedtke is survived by his wife, Nancy, a math teacher in the Katonah-Lewisboro school district. Lives remembered: Walter Liedtke Passenger: Joseph Nadol Joseph Nadol, 42, of New Castle, was a managing director and analyst for JPMorgan. "Our thoughts and support are with Joe's family during this difficult time," a JPMorgan spokesperson said in a statement. According to media reports, he had three children who attend the Hackley School in Tarrytown. Hackley emailed parents Wednesday to inform them of Nadol's death, according to media reports. Lives remembered: Joseph Nadol Passenger: Robert Dirks Robert Dirks, 36, of Chappaqua, was a research scientist at D.E. Shaw Research, according to the company's website. He earned his bachelor's degree from Wabash College and a PhD in chemistry at Caltech, where worked as a postdoctoral scholar before joining D.E. Shaw Research. "Robert was a brilliant scientist who made tremendous contributions to our own research, and to the broader scientific community, during his eight years at D. E. Shaw Research," the company said in a statement. "He will be deeply missed as both a colleague and a friend. Our hearts go out to his wife Christine and their children." New Castle Supervisor Robert Greenstein said late Wednesday that he was "very saddened" by the accident and the loss of three New Castle community members. On behalf of the Town of New Castle, we want to express our sincere condolences to the families and loved ones of Joseph Nadol of Ossining, Robert Dirks of Chappaqua and Ellen Brody, who worked at a local jewelry store," he wrote in an email. "Our hearts are broken by this tragic accident!" Greenstein said that counseling services are available at Phelps Memorial Hospital in Sleepy Hollow. Lives remembered: Robert Dirks Passenger: Aditya Tomar The remaining crash victim was identified by the MTA as Aditya Tomar, 41, of Danbury, Connecticut. Lives remembered: Aditya Tomar Staff writers Jane Lerner, Alex Taylor, Swapna Venugopal Ramaswamy, Jon Bandler, Matt Spillane, Jorge Fitz-Gibbon and Mark Lungariello contributed to this report. CLOSE Dr. Ivan Miller, Patricia Wrobbel and Dr. Joseph Turkowski talk about Westchester Medical Center's role in treating 12 victims from the wreckage of a Metro-North commuter train in Valhalla Feb. 4, 2015. Video by Joe Larese/The Journal News from left to right: Ellen Brody, Walter Liedtke and Eric Vandercar (Photo: courtesy) Read or Share this story: http://lohud.us/1CZytTg | Summary: The investigation into what caused Tuesday's deadly Metro-North crash in Valhalla, NY, is focusing on how a mother of three described by friends as "responsible" ended up in the crossing as a train hurtled toward her. Ellen Brody, 49, of Edgemont was the driver of the SUV; she was headed home from the Chappaqua jewelry store job she had held for 15 years when witnesses say Brody exited her vehicle after a crossing gate lowered onto it. She re-entered the car, drove forward on the tracks, and was hit; one witness described her as not appearing to be in a hurry. The crash happened in the dark in an area where the tracks are straight, notes the AP. Talking to NBC New York, a friend describes the mom of three daughters, who was married to playwright Alan Brody, as "very responsible," "very reliable," and "a saint, because she was the most selfless person." NTSB investigators are currently reviewing the tracks, interviewing the crew, and looking into whether Brody's Mercedes SUV had a data recorder. The five others who died in the crash, as per NBC: Eric Vandercar, 53, of Bedford Hills wasn't only a seasoned finance executive-he recently exited Morgan Stanley after 27 years to go to a top directorial position at Mesirow Financial-the married father was also said to be an avid skier, whitewater rafting guide, and diver, as per Lohud.com. Staff at NYC's Metropolitan Museum of Art are grieving for one of their own: 69-year-old Walter Liedtke of Bedford Hills, who had worked as a curator and art historian at the Met for more than 30 years, specializing in Dutch and Flemish artists. Aditya Tomar, 41, of Danbury, Conn., was born in India and worked in finance in New York City, his mother-in-law told NBC. She added that the family was "shocked and grieving." Robert Dirks of Chappaqua was a 36-year-old father of two young children. Born in Thailand, Dirks got his PhD from Caltech and worked in the "development of novel computational chemistry methods." Joseph Nadol, 42, of New Castle was managing director and analyst for JPMorgan's US aerospace and defense equity research group; he was reported to have had three children. | 4,453 | 541 | multi_news | en |
Summarize: A British Greenpeace activist facing charges of hooliganism in Russia has told how she felt so isolated in prison that she tapped out messages to fellow inmates on radiator pipes. Alex Harris, 27, said the code 'kept her going' during her time in jail where she was forced to spend 23 hours a day alone in her cell. She was among the so-called Arctic 30 protesters arrested on board a Greenpeace ship in September while demonstrating against oil drilling in the Arctic. Scroll down for video. 'Terrifying': Greenpeace activist Alex Harris speaks about her ordeal in a Russian prison after being released on bail on charges of hooliganism over a protest against oil drilling in the Arctic. Isolated: Ms Harris told how she communicated with fellow inmates by tapping messages on a radiator pipe. Ms Harris, from Exeter, Devon, said she was 'terrified' when she was first taken to the prison in Murmansk. But when she discovered there was a fellow activist next door, she devised a painstaking way to communicate. She told the BBC: 'There was a radiator pipe that ran all the way through the prison. 'We managed to have some conversation on the radiator pipes - one tap was A, two taps was B. Sometimes it took 23 taps to get out one letter. 'Even though we couldn't see each other, it felt like we were together.' British Greenpeace activists Kieron Bryan, left,. and Alexandra Harris, right, have been freed on bail following two. months in a Russian prison after being arrested for attempting to occupy. an Arctic oil platform. Ms Harris said the past two months in prison had been difficult, describing the conditions as 'awful' and the food as 'disgusting' The group were originally charged with. piracy, an offence that carries a 15-year prison sentence, which Ms. Harris feared would mean she could never have children. The new charge has a maximum term of seven years. A. Russian court yesterday granted bail to the last of 30 crew. members detained since their September protest. The decision to. free the ship's Australian radio operator Colin Russell reversed an. earlier ruling and is likely to take diplomatic pressure off Russia as. it prepares to host the upcoming Winter Olympic Games. Freed: Greenpeace activist Anthony Perrett, from Newport has also been released on bail. Russell. was the only member of the multinational Arctic Sunrise crew to have. had his bail request denied in a series of hearings held since November. 18. The campaigners' open-sea protest targeted what will be Russia's first operational oil. rig in the Arctic - a politically sensitive region that President. Vladimir Putin views as the future of the country's energy exporting. might. Earlier this month, Ms Harris skipped for joy when a judge in St Petersburg ruled could be granted bail. ‘This has been the hardest experience. of my life,’ she said afterwards, adding: ‘I will not dishonour. Greenpeace or my country by trying to flee Russia or the investigation.’ Activist Anthony Perrett and. journalist Kieron Bryan have also been bailed. They were among six. British nationals in the ‘Arctic 30’ who were imprisoned following the. protest against drilling in the Arctic. Ms Harris, 27, who acted as. communications officer on Greenpeace’s Arctic Sunrise vessel, said: ‘I’m. really happy. It’s not over yet but there’s light at the end of the. tunnel.’ In a recent letter to her parents, the activist had said she. was ‘trying very, very hard not to lose hope’. ‘Surely my future isn’t. rotting in a prison in Murmansk?!’ she wrote. Speaking at the family home in Dolton,. north Devon, earlier this month, her father Cliff said: ‘This is fantastic news for us. 'It. was nice to see her come into the courtroom with a smile on her face and. holding her head high. 'These must have been two incredibly hard months. for her, and we’re incredibly proud of how she has conducted herself. throughout this ordeal.’ Impounded: A crew member keeps watch aboard a Russian coast guard boat, left, as the Greenpeace ship 'Arctic Sunrise', right, is anchored next to it, in a small bay near Severomorsk, after it was seized by Russian forces. Mr Harris, 63, told how as a child, his daughter idolised David Attenborough and was fascinated by news about the environment. He said: ‘Anything that was detrimental to wildlife she would sit up and take notice. ‘I can remember when she was young she. had a poster up of David Beckham. All of a sudden Beckham was out of. favour and David Attenborough was her new hero. She didn’t actually have. any posters, but she really idolised him.’ Miss Harris joined Greenpeace two. years ago in an office-based role and was on her first field trip when. arrested by the Russians. Her father continued: ‘We didn’t envisage that. this whole situation was going to erupt like it did. We’ve found it. very frightening. These are just ordinary people who care about the. environment. The charges are ridiculous – what happened wasn’t piracy or. hooliganism.’ Greenpeace has warned a spill in. Arctic waters would be highly damaging to the environment and the. extraction of more fossil fuels would add to climate change impacts. Eleven Nobel Peace Prize laureates wrote to Russian president Vladimir. Putin calling for the original piracy charges to be dropped | Summary: Alex Harris, 27, said she was 'terrified' when taken to jail in Murmansk. She was forced to spend 23 hours a day alone in her cell. Used painstaking method to communicate with fellow inmate next door. 'One tap was A, two taps was B. Sometimes took 23 taps to do one letter' She is among 30 charged with hooliganism over Arctic oil drilling protest. | 1,285 | 99 | cnn_dailymail | en |
Summarize: By. Daily Mail Reporter. PUBLISHED:. 12:42 EST, 28 June 2012. |. UPDATED:. 14:25 EST, 28 June 2012. Benefits? Jerry Sandusky may be able to continue collecting his pension while behind bars. Disgraced former Penn State football coach Jerry Sandusky may be able to hang on to his tax-payer funded pension, despite his conviction on dozens of child sex charges. Sandusky reportedly rakes in about $59,000 in pension funds annually - on top of a $148,000 lump-sum payment he received when he retired from Penn State in 1999. Under Pennsylvania's Public Employee Pension Forfeiture Act, a retiree would have to forfeit their pension funds if they were convicted of offenses like theft, obstruction of justice or perjury. However, molestation and child sexual abuse, which Sandusky has been convicted of, are not among them. A spokeswoman for the State Employees' Retirement System said on Wednesday that the agency doesn't speculate. about potential future actions under the Public Employee Pension. Forfeiture Act. But Nicholas Maiale, chairman of SERS, told the Patriot-News that he is looking to pursue a legal review of the board’s options for Sandusky's pension. He told the paper: 'I am a Penn Stater and I am a citizen of Pennsylvania, and we are all morally outraged about this case and what happened to those kids.' However, Maiale told the paper he's 'not optimistic' that the board can do anything about it. A pension system document says forfeiture can also occur when a school employee commits certain sex offenses against a student. Also on Thursday, the Philadelphia Daily News reported that the taxpayers have underwritten an estimated $1.4million in funds for The Second Mile, Sandusky's charity for troubled youth. Although it has been revealed that Sandusky met his victims through the charity, The Second Mile has continued to collect Pennsylvania-sponsored donations totalling up to $122,861 in the current fiscal year, according to the paper. Sandusky was returned to the Centre County Correctional Facility last week he was convicted of 45 out of 48 charges of child sex abuse. Guilty: Jerry Sandusky leaves court in handcuffs after being convicted of sexual assault last Friday. He faces 442 years in prison at his sentencing, which will take place sometime within the next three months. After the verdict, Sandusky's lawyers said they tried to throw in the towel as the trial began because they had too little time to prepare. Experts have said the seven months between Sandusky's November arrest and trial was fast-paced by Pennsylvania standards. Joe. Amendola, Sandusky's lawyer, told The Associated Press: 'We told the. trial court, the Superior Court and the Supreme Court we were not. prepared to proceed to trial in June due to numerous issues, and we. asked to withdraw from the case for those reasons.' Calm: Sandusky showed few signs of emotion as the verdict was read out in court on Friday night. The. issues included a scheduling conflict with a defence team member and. the need to read a cache of documents produced by a lengthy grand jury. investigation. Judge John Cleland denied their request. The attorneys raised other issues that. could be part of the future appeal, saying a mistrial was sought and. denied over a repetition at trial of a brief part of a November. interview Sandusky had with NBC's Bob Costas. Sandusky, 68, was convicted on 45 of. 48 counts of child sexual abuse on Friday night after 21 hours of jury. deliberations. He will likely die in prison. Amendola spoke out as one of the. jurors in the case said he was swayed by the'very convincing' testimony. of eight accusers who said Sandusky molested them for years. Shocking claim: On Thursday night, adopted son Matt Sandusky, seen here at court on June 22, claimed he had been abused by Jerry Sandusky. At work: Sandusky on the sidelines of a Penn State game; he was expected to become the team's head coach after Joe Paterno, who died in January. In custody: Sandusky's attorneys have indicated that they will appeal his conviction. In addition, Sandusky's adopted son came. forward to accuse the disgraced coach of abusing him when he was. between the ages of 8 and 15 - just as jurors were deliberating. Matt Sandusky, now 33, was to take the stand during the trial as a'rebuttal witness' if Jerry Sandusky testified. Jerry Sandusky's lawyers ultimately decided the 68-year-old former coach wouldn't speak in his own defence. Prosecutors say Sandusky met the 10 sex-abuse victims through his charity, The Second Mile, which the coach established in 1977. Experts have said the seven months between Sandusky's November arrest and trial was fast-paced by Pennsylvania standards. Criminal: Sandusky, pictured being escorted to a squad car, is likely to spend the rest of his life in prison. Lockup: Sandusky has been at the Centre County Correctional Facility since he was convicted of 45 out of 48 counts of child abuse. Joe Amendola, Sandusky's lawyer, told The Associated Press: 'We told the trial court, the Superior Court and the Supreme Court we were not prepared to proceed to trial in June due to numerous issues, and we asked to withdraw from the case for those reasons.' The issues included a scheduling conflict with a defence team member and the need to read a cache of documents produced by a lengthy grand jury investigation. Judge John Cleland denied their request. Almost immediately after the verdict, Penn State President Rodney Erickson signalled an openness to quickly settle potential civil lawsuits arising from the convictions, saying the school 'wants to provide a forum where the university can privately, expeditiously and fairly address the victims' concerns and compensate them for claims.' The university recently reported a $1.8billion endowment. Speedy verdict: It took the jury less than two days to reach a conclusion on all of the 48 charges against Sandusky, pictured with his wife Dottie, left. Jailed: The former coach's bail was revoked immediately after the verdict was announced. The conviction of Sandusky brought an end to a horrific saga which has trashed the reputation of a. leading public university - as well as its storied football programme - and ended the career of its president as well. as its legendary head coach, Joe Paterno, who died of cancer in January. After. the verdict was announced in the courtroom in Bellefonte, Pennsylvania,. Sandusky's bail was revoked and he was taken to the Center County. Correctional Facility. Sandusky. showed little emotion as the verdict was read. The judge ordered him to. be taken to the county jail to await sentencing in about three months. In court, Sandusky half-waved toward. family as the sheriff led him away. Outside, he calmly walked to a. sheriff's car with his hands cuffed in front of him. Taken away: Sandusky is being taken to a local jail, where he was placed on suicide watch. Sacked: Penn State head coach Joe Paterno lost his job over claims that he failed to report the allegations about Sandusky; he died in January | Summary: Sandusky makes about $59,000 a year in pension on top of $148,000 in lump sum following his retirement in 1999. Child molestation not included among convictions that lead to forfeiture of retirement benefits. Former Penn State defensive coordinator convicted of 45 out of 48 charges of child abuse and could face up to 442 years in prison. Conviction ends year-long saga which led to firing of legendary Penn State coach Joe Paterno. | 1,745 | 115 | cnn_dailymail | en |
Write a title and summarize: SECTION 1. SHORT TITLE. This Act may be cited as the ``Telecommunications Merger Review Act of 1999''. SEC. 2. FINDINGS. The Congress finds the following: (1) A stated intent of the Congress in enacting the Telecommunications Act of 1996 was to reduce regulation. (2) Under existing law, the Department of Justice and the Federal Trade Commission exercise primary authority to review all mergers, including telecommunications industry mergers. The Federal Communications Commission has only limited authority under the Clayton Act to review telecommunications industry mergers. (3) The Department of Justice and the Federal Trade Commission have extensive expertise in analyzing issues of industry concentration and its effects on competition. The Federal Communications Commission has only limited expertise in analyzing such issues. (4) Notwithstanding the limitations on its Clayton Act jurisdiction and on its substantive expertise, the Federal Communications Commission exercises broad authority over telecommunications industry mergers pursuant to the nonspecific public interest standard and other provisions in the Communications Act of 1934 that allow it to impose terms and conditions on the assignment and transfer of licenses and other authorizations. (5) The Federal Communications Commission's exercise of broad authority over telecommunications industry mergers overreaches its intended statutory authority and its substantive expertise and produces delay and inconsistency in its decisions. (6) Under existing law, parties to a proposed telecommunications industry merger are unable to proceed without the prior approval of the Federal Communications Commission, even if the Department of Justice or the Federal Trade Commission have already approved the merger. (7) The Federal Communications Commission's existing rulemaking and enforcement prerogatives constitute normal and effective means of assuring that all licensees, including parties to a telecommunications industry merger, operate in the public interest. (8) The primary jurisdiction and preeminent expertise of the Department of Justice and the Federal Trade Commission on all matters involving industry concentration and its effects on competition, combined with the Federal Communications Commission's existing rulemaking and enforcement prerogatives, make the exercise of separate telecommunications industry merger approval authority by the Federal Communications Commission unnecessary. (9) Because the duplication of effort, inconsistency, and delay resulting from the Federal Communications Commission's review of telecommunications industry mergers is unnecessary, it imposes unwarranted costs on the industry, on the Commission, and on the public, and it fails to serve the public interest. SEC. 3. REPEAL OF MERGER APPROVAL AUTHORITY. Section 11(a) of the Clayton Act (15 U.S.C. 21(a)) is amended by striking ``in the Federal Communications Commission where applicable to common carriers engaged in wire or radio communication or radio transmission of energy;''. SEC. 4. REPEAL OF AUTHORITY TO CONDITION LICENSES, ETC. (a) Basic Administrative Authority.--Section 4(i) of the Communications Act of 1934 (15 U.S.C. 154(i)) is amended by adding at the end thereof the following: ``The authority of the Commission to impose terms or conditions on the transfer or assignment of any license or other authorization assigned or transferred in a merger or other transaction subject to review by the Department of Justice or the Federal Trade Commission is subject to section 314.''. (b) Public Convenience and Necessity.--Section 214(c) of the Communications Act of 1934 (47 U.S.C. 214(c)) is amended by inserting after ``require.'' the following: ``The authority of the Commission to impose terms or conditions on the transfer or assignment of any such certificate assigned or transferred in a merger or other transaction subject to review by the Department of Justice or the Federal Trade Commission is subject to section 314.''. (c) Restrictions and Conditions Necessary To Carry Out 1934 Act; Treaties; International Conventions.--Section 303(r) of the Communications Act of 1934 (47 U.S.C. 303(r)) is amended by adding at the end thereof the following: ``The authority of the Commission under this paragraph to impose terms or conditions on the transfer or assignment of any license or other authority assigned or transferred in a merger or other transaction subject to review by the Department of Justice or the Federal Trade Commission is subject to section 314.''. (d) Alien-Operated Amateur Radio Stations.--Section 310(d) of the Communications Act of 1934 (47 U.S.C. 310(d)) is amended by adding at the end thereof the following: ``The authority of the Commission to impose terms or conditions on the transfer or assignment of any authorization issued under this section that is assigned or transferred in a merger or other transaction subject to review by the Department of Justice or the Federal Trade Commission is subject to section 314.''. (e) Preservation of Competition in Commerce.--Section 314 of the Communications Act of 1934 (47 U.S.C. 314) is amended to read as follows: ``SEC. 314. PRESERVATION OF COMPETITION IN COMMERCE. ``(a) In General.--Notwithstanding any other provision of law, the Commission has no authority to review a merger or other transaction, or to impose any term or condition on the assignment or transfer of any license or other authorization issued under this Act that is proposed to be assigned or transferred in the course of a merger or other transaction, while that merger or other transaction is subject to review by either the Department of Justice or the Federal Trade Commission. ``(b) Communications Mergers Primarily Reviewable by DOJ and FTC.-- The Department of Justice, or the Federal Trade Commission, has primary authority under existing law to review mergers and other transactions involving the proposed assignment or transfer of any license or other authorization issued under this Act. The Commission may file comments in any proceeding before the Department of Justice or the Federal Trade Commission to review a merger or other transaction involving the proposed assignment or transfer of any license or other authorization issued under this Act if those comments reflect the views of a majority of the Commission. ``(c) Commission Shall Implement DOJ or FTC Decision Without Additional Terms or Conditions.--If-- ``(1) the Department of Justice or the Federal Trade Commission reviews a merger or other transaction involving the proposed assignment or transfer of any license or other authorization issued under this Act; and ``(2) it issues a written decision of absolute or conditional approval of, or issues a written statement of nonintervention in, the proposed merger or other transaction, then the Commission shall authorize the assignment or transfer of any license or other authorization involved in the merger or transaction in accordance with the decision, if any, or as proposed, if a written statement of nonintervention is issued. The Commission may not impose any other term or condition on the assignment or transfer of the license or other authorization so assigned or transferred, or impose any other obligation on any party to that merger or transaction. ``(d) Commission Review of Mergers Absent DOJ or FTC Pronouncement.-- ``(1) In general.--The Commission may not review any application for assignment or transfer of a license or other authorization issued under this Act in connection with a merger or other transaction unless neither the Department of Justice nor the Federal Trade Commission issues a decision or statement described in subsection (c)(2) in connection with that merger or other transaction. ``(2) 60-day turnaround.--The Commission shall conclude any review of a merger or other transaction it may conduct under paragraph (1) within 60 days after the date on which the Department of Justice and the Federal Trade Commission, whichever is appropriate, issues such a decision or statement. ``(3) Presumption; default approval.--In reviewing an application under paragraph (1), the Commission shall apply a presumption in favor of unconditional approval of the application. If the Commission fails to issue a final decision within the 60-day period described in paragraph (2), the application shall be deemed to have been granted unconditionally by the Commission.''. | Title: Telecommunications Merger Review Act of 1999 Summary: Amends the Communications Act of 1934 (the Act) to mandate that the FCC has no authority to review a merger or other transaction (merger), or to impose any term or condition on the assignment or transfer of any license or other authorization (license) issued under the Act that is proposed to be assigned or transferred in the course of a merger, while that merger is subject to review by either the Department of Justice (DOJ) or the Federal Trade Commission (FTC). Empowers DOJ and FTC with primary authority to review mergers involving the proposed assignment or transfer of any license issued under the Act. Authorizes the FCC to file comments in any such proceeding. States that, if DOJ or FTC reviews a merger and issues either a written decision of approval or a written statement of nonintervention in such merger, then the FCC shall authorize the assignment or transfer of any license involved therein. Prohibits the FCC from imposing any other term or condition on the assignment or transfer of such license, or imposing any other obligation on any party to such merger. Prohibits the FCC from reviewing any application for assignment or transfer of a license issued under the Act in connection with a merger unless neither DOJ nor the FTC issues a decision or statement in connection with such merger. Requires the FCC to conclude any review so conducted within 60 days after DOJ or FTC issues such a decision or statement. | 1,870 | 330 | billsum | en |
Summarize: TECHNICAL FIELD This invention relates to aerodynamic toys comprised of an aerodynamic item and a launching mechanism. In particular, this invention relates to a toy comprised of an aerodynamic rotor with an attachable shaft and a hand-held pull-cord launcher assembly, the rotor's shaft and the launcher's connector of which can easily be connected to each other in the dark, by feel, and the rotor of which has means thereon for attachment of a self-contained chemiluminescent light source thereto for the purpose of extending the toy's use into the non-daylight hours, outdoors, in the absence of artificial outdoor lighting, and for the purpose of creating a glowing shape of light which is formed and patterned by the direct light of the luminescent device in motion when the rotor is launched and rotates rapidly. BACKGROUND ART For decades a popular toy for outdoor use has been an item comprised of a rotor with an attachable shaft and a hand-held pull-cord launcher. The typical rotor is made of integrally molded plastic material which forms a system of pitched blades (airfoils) which converge horizontally to an axis to which the top of the rotor's shaft can be attached vertically from the bottom side of the rotor. The converging blades are equal and evenly distributed about the axis. An annular band extending continuously from the extreme outer end of one blade to that of the next forms the perimeter of the rotor and is concentrically positioned about the axis. The typical hand-held pull-cord launcher is an assembly comprised of molded plastic components, a cord, a rubber band, and fasteners. The molded plastic components include two side walls which adjoin to form the side wall and bottom end of a hollow handle with an interconnecting circular compartment atop, referred to as the spool compartment. The spool compartment has an opening through the center of its top, the center of its bottom, and the center of its side wall. The compartment is designed to house a molded plastic spool which is integrally formed with a hook extending from the center of one of its flat circular ends and with a connector extending from the other, which is designed to connect the rotor's shaft to the launcher. The spool sits vertically, on end, inside the compartment with the hook extending through the opening in the bottom of the compartment and into the top portion of the hollow handle. The connector extends through the opening in the top of the spool compartment. One end of the cord attaches to the center of the side of the spool. The remainder of the cord winds clockwise around the spool and the opposite end of the cord exits the compartment through the opening in its side wall and attaches to a pull. The rubber band is attached to the hook, wound counterclockwise, stretched and connected to a rod which protrudes inward from the inner surface of the hollow handle, near its bottom end. The tension created in the rubber band keeps the cord wound onto the spool when the launcher is not in use. The side walls forming the side wall of the launcher are held together by screws or keeper rings. The rotor is launched by grasping the handle with one hand, pointing the connector skyward, and, using the other hand, connecting the shaft attached to the rotor to the connector, grasping the pull, and rapidly pulling the cord, unwinding it from the spool. The unwinding action of the cord rotates the rubber band, the integrally formed hook/spool/connector composite component, and the rotor and its shaft counterclockwise, in unison, and creates lift beneath the horizontal rotating blades of the rotor. When the cord ceases to unwind, the rotating parts of the launcher cease to rotate. Simultaneously, momentum or inertia continues to rotate the rotor and its shaft and this force, combined with the lift created beneath the blades, causes the shaft to be released from the connector and sends the rotor and its shaft flying into the air, rotating about an axis of rotation while traveling generally perpendicular to that axis at the same time. When the cord is released, the increased tension in the wound rubber band is released and the unwinding action of the rubber band rotates the hook/spool/connector composite component clockwise and rewinds the cord onto the spool. The typical aerodynamic rotor with pull-cord launcher toy has proven to be a suitable item for outdoor use during the hours of daylight. However, it is unsuited for outdoor use during non-daylight hours, in the absence of artificial outdoor lighting. The new invention makes the toy suitable for outdoor use during the hours of darkness, without artificial outdoor lighting. The design of the typical aerodynamic rotor with pull-cord launcher toy is such that connecting the rotor's shaft to the launcher's connector is accomplished easily only when the interconnecting areas of the two approach each other at a precise angle, prior to making contact with each other. Such a connection is not easily accomplished in the dark or in insufficient light. The present invention provides a shaft and a connector which can easily be connected by feel, making the connection easily accomplished in the dark. BRIEF DISCLOSURE OF THE INVENTION It is an objective of this invention to provide an aerodynamic rotor with pull-cord launcher toy, the rotor of which has means thereon for attaching a self-contained chemiluminescent light source thereto for the purpose of extending the item's use into the non-daylight hours, outdoors, in the absence of artificial outdoor lighting, making the rotor easy to locate in the dark after it lands. It is an objective of this invention to provide an aerodynamic rotor with pull-cord launcher toy, the rotor of which has means thereon for attaching a self-contained chemiluminescent light source thereto for the purpose of creating a glowing, circular light shape which is not simply an illuminated image of the item to which the luminescent device is attached, but a circular shape of light formed and patterned by the direct light of the luminescent device attached to the rotor in motion. It is a further objective of this invention to provide an aerodynamic rotor with pull-cord launcher toy, the rotor's shaft and the launcher's connector of which can easily be connected in the dark, by feel. Another objective of this invention is to provide an aerodynamic rotor with pull-cord launcher toy, the rotor of which has means thereon for producing a whistling sound when the rotor is launched and rotates rapidly. In recent decades the public has become familiar with self-contained chemiluminescent light sources. The chemiluminescent light source used in conjunction with this toy is not a claim of this invention. However, a brief description of the embodiment of the luminescent device and how it produces light is appropriate U.S. Pat. No. 3,576,987 describes such a device as "a pair of reactant compounds, one of which is positioned in a thin glass tube and the other of which is positioned in a pliable plastic tube which completely surrounds the inner glass tube.... In order to mix the chemicals and provide a reaction which produces light, the outer plastic container is bent until the inner glass container breaks providing mixture of the compounds. The light source produced is non-heat generating and provides a strong light source for at least eight hours, with the source dissipating slowly thereafter." The aerodynamic toy of the present invention is comprised of a molded plastic rotor with an attachable shaft and a pull-cord launcher assembly. In its preferred embodiment, the aerodynamic rotor is made of an integrally molded plastic material which forms a system of pitched blades (airfoils) which converge horizontally to an axis ring. The converging blades are substantially equal and evenly distributed about the axis ring. An annular band extending continuously from the extreme outer end of one blade to that of the next forms the perimeter of the rotor and is concentrically positioned about the axis ring. A holder, incorporated into the manufacture of the rotor, provides means for attaching a self-contained chemiluminescent light source to a blade, making the item suitable for outdoor use in the dark, and for the purpose of creating a glowing, circular shape of light which is formed and patterned by the direct light of the luminescent device in motion, when the rotor is launched and rotates rapidly. The rotor may contain a multiple number of holders and they may be used simultaneously. The rotor has small rectangular openings positioned near the outer end of some of its blades. When the rotor is launched and rotates rapidly, air is compressed through the openings and a whistling sound is produced. A socket extends from the center of the axis ring, on the bottom side of the rotor, providing means for attaching the shaft to the rotor. The rotor's attachable shaft is integrally formed of a moldable plastic material and its column has a tapered cylindrical shape. The top end of the column is substantially larger than the bottom end and has a rectangular prong extending from its center which fits firmly into the socket extending from the center of the rotor's axis ring. Two small cylinders protrude perpendicularly from the center of the column, opposite each other. The pull-cord launcher's connector is a cylindrical shaped hollow tube which has an even number of slots evenly positioned about the circumference of the upper portion of its side wall, at the open end of the tube. The diameter of the connector tube's opening is approximately twice as large as the diameter of the bottom end of the shaft's column. Connecting the rotor's shaft to the launcher's connector tube is easily accomplished by feel due to their size, shape, and interconnecting design. The connection is made by grasping the axis ring with one hand, with the shaft pointing downward, and, with the connector tube pointed skyward, grasping the slotted upper side-end portion of the connector tube between the thumb and forefinger of the other hand, overlapping them slightly across the open end of the tube, and using them as a guide to direct the bottom end of the shaft's column into the open end of the tube. Once accomplished, applying gentle downward twisting pressure to the axis ring will automatically seat the cylinders protruding from the center of the shaft's column to the bottom of two slots in the side wall of the connector tube, thereby readying the toy for launch. In describing the preferred embodiment of the invention, which is illustrated in the drawings, specific terminology will be resorted to for the sake of clarity. However, it is not intended that the invention be limited to the specific terms so selected and it is to be understood that each specific term includes all technical equivalents which operate in a similar manner to accomplish a similar purpose. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view of the toy showing the bottom side of the rotor and the holder for attaching the self-contained chemiluminescent light source to one of the blades thereof; the shaft attached to the rotor thereof; and the pull-cord launcher thereof. FIG. 2 is a perspective view of the top of the rotor showing a top view of the holder for attaching the self-contained chemiluminescent light source to one of the blades thereof. FIG. 3 is a side view of the shaft. FIG. 3a is a sectional view of the axis ring of the rotor taken substantially along line 3--3 of FIG. 1 showing the top of the shaft inside the socket thereof. FIG. 4 is an enlarged perspective view of a portion of the top of the blade of the rotor having the holder integrally formed therein, showing the self-contained chemiluminescent light source used in conjunction therewith and lines indicating the direction by which the light source is inserted into and removed from the holder therein. FIG. 5 is an enlarged detailed view of the side of the holder showing the self-contained chemiluminescent device inserted therein. FIG. 5a is an enlarged sectional view taken substantially along line 4--4 of FIG. 5. FIG. 6 is an exploded view of the pull-cord launcher showing a side view of the parts that combine to form the mechanism. FIG. 7 is a perspective view of the side wall of the launcher, formed when the side walls of the launcher assembly are adjoined, showing the notches on the bottom edge thereof. FIG. 8 is a top view of the keeper ring that holds the bottom of the launcher's side wall together showing the inner surface of the bottom thereof, including the rim, and the arm extending therefrom, that partially closes the bottom thereof. FIG. 8a is a sectional view taken substantially along line 5--5 of FIG. 8. FIG. 9 is a top view of the key-way keeper ring showing the key-way grooves therein. FIG. 10 is a partially exploded view of the side of the pull-cord launcher showing the positioning of the internal parts thereof, the positioning of connector tube thereof, and the interconnecting relationship of the components thereof. FIG. 11 is an enlarged perspective side view of the integrally formed hook/spool/connector tube composite component showing the open end of the tube and the slots in the upper portion of the side wall of the connector tube thereof. FIG. 12 is a top view of the integrally formed hook/spool/connector tube composite component showing the positioning of the slots in the upper portion of the side wall of the connector tube thereof and the hollow of the connector tube thereof. FIG. 13 is a perspective view of the toy prepared for launch, showing the chemiluminescent light source inside the holder of the blade of the rotor thereof. DETAILED DESCRIPTION Referring to FIGS. 1 and 4, the aerodynamic rotor with attachable shaft and pull-cord launcher toy of the invention is indicated by the numeral 10. The toy 10 includes generally a molded plastic rotor 10a with an attachable shaft 10b and a hand-held pull-cord launcher assembly 10c. A holder 30, incorporated into the manufacture of the rotor 10a, provides means for attaching a self-contained chemiluminescent light source 80, used in conjunction with the toy 10, to the rotor 10a. Referring to FIGS. 1 and 2, in its preferred embodiment, the rotor 10a is constructed of integrally molded plastic material, such as polypropylene, which forms a system of pitched blades (airfoils) 21a, 21b, 21c, 21d which converge horizontally to an axis ring 22. The converging blades 21a, 21b, 21c, 21d are substantially equal and evenly positioned about the axis ring 22. An annular band 24 extending continuously from the extreme outer end of one blade 21a or 21b or 21c or 21d to that of the next blade 21a or 21b or 21c or 21d forms the perimeter of the rotor 10a and is concentrically positioned about the axis ring 22. When the rotor 10a is launched and rotates rapidly, air is compressed through the rectangular openings 25a, 25b, 25c near the outer end of some of the blades 21b, 21c, 21d and a whistling sound is produced. A socket 23 with a rectangular shaped inner surface extends perpendicularly from the center of the axis ring 22 and provides means for attaching the shaft 10b to the bottom side of the rotor 10a. Referring to FIGS. 1, 3, and 3a, the shaft 10b is integrally formed of a suitable moldable plastic material, such as delrin. The column 41 of the shaft 10b has a tapered cylindrical shape. The top half of the column 41 has a circumference that is constant and terminates with a flat circular end 41a which has a rectangular prong 43 extending from its center. The bottom half of the column 41 has a circumference that tapers and terminates with a flat circular end 41b. The diameter of the top end 41a is approximately twice as large as the diameter of the bottom end 41b. Two small cylinders 42a, 42b protrude perpendicularly from the center of the column 41, opposite each other. The prong 43 fits into the socket 23 protruding perpendicularly from the axis ring 22, thereby attaching the shaft 10b to the bottom side of the rotor 10a in tight friction-fit fashion. FIGS. 1, 4, 5, and 5a illustrate the preferred embodiment of the new holder 30 for attaching the self-contained chemiluminescent light source 80, used in conjunction with the toy 10, to a blade 21a of the rotor 10a. The holder 30, integrally formed with the rotor 10a, is comprised of a border of material 31 framing an opening 32 through the center of the blade 21a and two "U-shaped" receptacles 33, 34 on the bottom side of the blade 21a positioned opposite each other, at opposing ends of the opening 32. The sides of the opening 32 run parallel to the side edges of the blade 21a. The length of the opening 32 is slightly longer than the length of the luminescent device 80. The width of the opening 32 is minutely smaller than the diameter of the device 80. Each receptacle 33, 34 has a closed end 33a, 34a, respectively, and an open end 33b, 34b, respectively. The inner surface 33c, 34c of each closed end 33a, 34 a, respectively, is an extension of the border of material 31 framing an end of the opening 32. The open ends 33b, 34b of the receptacles 33, 34, respectively, face each other and are positioned in slightly closer spatial relationship to each other than the spatial relation of the distal ends of the luminescent device 80. The concave inner surface of each receptacle 33, 34 faces the opening 32, spanning the width of the opening 32. The luminescent device 80 is inserted into the holder 30 from the top side of the rotor 10a by placing the device 80 on its side onto the border of material 31 framing the opening 32 and pressing on the side-end portions of the device 80 until it snaps through the opening 32 and the side-end portions of the device 80 seat to the bottom of the receptacles 33, 34. Each receptacle 33, 34 holds a side-end portion of the device 80 and coacts with the border of material 31 framing the opening 32 to confine the majority of the device 80 beneath the bottom surface of the blade 21a, with the remainder of the device 80 being contained within the opening 32. Due to the design of the holder 30 only a small portion of the device 80 is concealed by confining material, allowing the direct light emitted by the device 80 to clearly be seen from the top, the side, and the bottom of the rotor 10a. When the rotor 10a is launched in the dark and rotates rapidly, the luminescent device 80 creates a glowing circle of light which is formed and patterned by the direct light emitted from the device 80 attached to the rotor 10a in motion. When the rotor 10a lands and ceases to rotate, the light from the device 80 makes the rotor 10a easy to locate in the dark. Neither the holder 30 nor the luminescent device 80 produces a substantial effect on the aerodynamic qualities of the rotor 10a. A multiple number of holders 30 may be incorporated into the manufacture of the rotor 10a and they may be utilized simultaneously. Referring to FIGS. 1, 6, 7, 8, 8a, and 9, the pull-cord launcher assembly 10c is comprised of a cord 70, a rubber band 90, and components formed of a suitable moldable plastic material, such as ABS plastic material. The molded plastic components include two elongated side walls 50a, 50b which adjoin at their side edges to form the side wall 50 of a hollow housing 51 for the internal components of the launcher assembly 10c. Another molded plastic component of the launcher assembly 10c is an integrally formed component which is a composite consisting of a spool 60 having a cylindrical shaped tube extension 64 with a slotted connector tube 65 atop extending, in sequence, from the center of one of its flat circular ends 60a and having a flat circular riser 61, a cylindrical shaped hook extension 62 with a rim 62a, and a hook 63 extending, in sequence, from the center of its other flat circular end 60b. The spool 60 has an opening 67 extending through the center of its side. Another plastic component is a hollow cone-shaped pull 54 with a sizeable rim 54b at its larger end and which has an opening 54a extending from end-to-end. The remaining plastic components include a key-way keeper ring 53 with two key-way grooves 53a, 53b and a keeper ring 55, one end of which is partially closed by a flat circular rim 56 which has a flat arm 57 with a flat bulbous end 57a extending into the diameter of its center. The rim 56 has protrusions 56a, 56b extending toward the opposite end of the keeper ring 55, angled in a counterclockwise direction. Referring to FIGS. 1, 6, 7, 8, 8a, 9, and 10, the components forming the pull-cord launcher 10c are assembled in a systematic manner. The rubber band 90 is attached to the arm 57 of the keeper ring 55. One end of the cord 70 is inserted through the opening 67 in the center of the spool 60 and a knot is tied in it to keep it from passing back through the opening 67. The opposite end of the cord 70 is inserted through the chase 52 in the cavity 17b of side wall 50b and then through the opening 54a extending through the pull 54 and a knot is tied in it to keep it from passing back through the opening 54a. The cord 70 is then wound clockwise onto the spool 60 until it can no longer be wound and half of the riser 61, half of the spool 60 and half of its ends 60a, 60b, and half of a small portion of the tube extension 64 are drawn into cavity 17b, thereby positioning half of the hook 63 and half of the hook extension's rim 62a into cavity 15b; half of the hook extension 62 into cavity 16b; half of the remainder of the tube extension 64 into cavity 18b; and half of the connector tube 65 directly above cavity 18b. The rubber band 90, which is already attached to the keeper ring 55, is attached to the hook 63; the keeper ring 55 is grasped and pulled, thereby stretching the rubber band 90 and creating tension in it; the bottom end 68b of the side wall 50b is placed inside the keeper ring 55, and the keeper ring 55 is released. The tension in the stretched rubber band 90 butts the inner surface of the rim 56 against the bottom end 68b of side wall 50b, thereby adjoining the two and holding the integrally molded composite component, consisting generally of the connector tube 65, the spool 60, and the hook 63, in place. Beginning with cavities 18a, 18b, side walls 50a, 50b are adjoined, including fitting the positioning pins 58a, 58b, 58c, 58d into their corresponding receptacles 59a, 59b, 59c, 59d and the bottom end 68a of side wall 50a inside the keeper ring 55. The key-way keeper ring 53 is passed over the connector tube 65, over the key-way tabs 53c, 53d and turned one-quarter of a turn, to disalign the key-way tabs 53c, 53d and the key way grooves 53a, 53b, thereby holding the top of the side wall 50 together. The bottom edge 68a, 68b of the side walls 50a, 50b are angled. When the side walls 50a, 50b are adjoined to form the side wall 50 of the launcher 10c the bottom edge 68 of the side wall 50 forms notches 69a, 69b. The protrusions 56a, 56b rising from the inner surface of the rim 56 of the keeper ring 55 and the notches 69a, 69b on the bottom edge 68 of the side wall 50 allow the keeper ring 55 to be turned only counterclockwise. Once assemblage of the launcher assembly 10c is completed, the keeper ring 55 is turned a few turns for the purpose of increasing the tension in the rubber band 90. Referring to FIGS. 1, 6, and 10, when adjoined as described, the side walls 50a, 50b and the keeper rings 53, 55 form an elongated housing 51 containing a series of interconnecting chases 51a, 51b, 51c, 51d, formed when the cavities 15a, 16a, 17a, 18a of side wall 50a are adjoined to the cavities 15b, 16b, 17b, 18b of side wall 50b and their locations of which are indicated by the major changes in the contour of the outer surface of the housing 51. The mass of material encircling chase 51a serves as a handle and houses the rubber band 90, the hook 63, and the hook extension's rim 62a. The mass of material encircling chase 51b houses the hook extension 62. The mass of material encircling chase 51c houses the riser 61, the spool 60, the spool's ends 60a, 60b, and a small portion of the tube extension 64. The mass of material encircling chase 51d houses the remainder of the tube extension 64. The connector tube 65 sits atop the housing 51. The inner surface of the material encircling chases 51d and 51b and the hook extension's rim 62a limit the lateral movement and the list of the tube extension 64 and the hook extension 62 to such degree that they do not stray significantly from the center of the housing 51, thereby limiting the lateral movement and the list of the spool 60 to such degree that its ends 60a, 60b do not rub against the inner surface of material encircling and framing chase 51c, when the cord 70 is pulled and the spool 60 rotates inside the chase 51c. The tension in the stretched rubber band 90 keeps the riser 61 butted against the surface of the material differentiating chase 51c from chase 51 b and also keeps the cord 70 wound onto the spool 60 when the pull-cord launcher 10c is not in use. FIGS. 1, 6, 11, 12, and 13, illustrate the preferred embodiment of the new connector tube 65 of the launcher 10c. The cylindrical shaped tube 65 has an even number of slots 66a, 66b, 66c, 66d evenly distributed about the circumference of the upper portion of its side wall, at the open end of the tube 65. The bottom of each slot 66a, 66b, 66c, 66d is angled and curved and is designed to partially encircle the circumference of one of the small cylinders 42a, 42b protruding from the column 41 of the shaft 10b. The diameter of the hollow 65a of the connector tube 65 is approximately twice as large as the diameter of the bottom end 41b of the shaft 10b. The shaft 10b is easily connected to the connector tube 65 by feel due to their size, shape and interconnecting design. The connection is made by placing the launcher 10c diagonally across the fingers of one hand in such fashion that the pad of the thumb and the pad of the forefinger can grasp the slotted upper side-edge of the connector tube 65 and partially overlap the open end of the tube 65, then, using the other hand, grasping the axis ring 22 from the top side of the rotor 10a, then placing the bottom end 41b of the shaft 10b between the pad of the thumb and the pad of the finger overlapping the open end of the tube 65, using them to guide the bottom end 41b of the shaft 10b into the top of the hollow 65a of the tube 65, and then applying gentle downward twisting pressure to the axis ring 22 until the small cylinders 42a, 42b protruding opposite each other from the center of the column 41 of the shaft 10b seat into two oppositely positioned slots 66a, 66c, or 66b, 66d of the connector tube 65. Once accomplished, the toy 10 is ready for launch. Referring to FIGS. 1, 10 and 13, the rotor 10a and its shaft 10b are launched by grasping the handle 51a with one hand, pointing the connector tube 65 skyward, grasping the pull 54 with the other hand, and pulling the cord 70 rapidly, unwinding it from the spool 60. The unwinding action of the cord 70 rotates the rubber band 90, the hook 63/spool 60/connector tube 65 composite component, and the rotor 10a and its shaft 10b counterclockwise, in unison, and creates lift beneath the horizontal rotating blades 21a, 21b, 21c, 21d. When the cord 70 ceases to unwind, the rotating parts of the launcher 10c cease to rotate. Simultaneously, centrifugal force continues to rotate the rotor 10a and its shaft 10b and this force, combined with the lift created beneath the blades 21a, 21b, 21c, 21d, causes the shaft 10b to be released from the connector tube 65 and sends the rotor 10a and its shaft 10b flying into the air, rotating about an axis of rotation while traveling generally perpendicular to that axis at the same time. When the pull 54 is released, the increased tension in the wound rubber band 90 is released and the unwinding action of the rubber band 90 rewinds the cord 70 onto the spool 60. While certain preferred embodiments of the present invention have been disclosed in detail, it is to be understood that various modifications in its structure may be adopted without departing from the spirit of the invention or the scope of the following claims. The present application is intended to cover all such modifications that fall within the basic underlying principles disclosed and claimed herein. | Summary: An aerodynamic rotor with pull-cord launcher toy adapted to attach a self-contained chemiluminescent light source to the rotor thereof, making the toy suited for use in the dark. The rotor includes one or more holders integrally formed into the blade(s) thereof for confining the light source therein. The light source is non-heat generating and creates a glowing shape of light when the rotor is launched and provides a source for locating the rotor when it lands. The rotor's shaft and the launcher's connector tube have an interconnecting design which enables them to easily be connected in the dark by feel. Some blades of the rotor have a small opening near their outer end to produce a whistling sound when the rotor is launched and rotates rapidly. | 7,619 | 175 | big_patent | en |
Summarize: CLOSE Take a trip back to your younger days with one of the nation's best-known retail chains. USA TODAY Geoffrey's Toy Box will make its debut this holiday season at Kroger-owned grocery stores (Photo: Kroger, Geoffrey's Toy Box) Geoffrey's back. The Toys R Us mascot is the face of Geoffrey's Toy Box, a collection of brands that will be featured at nearly 600 Kroger-owned grocery stores this holiday season. That means shoppers wanting Imaginarium play sets or You & Me dolls will be able to get them to tuck under the tree even though Toys R Us closed up shop in June after failing to restructure under bankruptcy protection. “We’re excited to offer Geoffrey’s Toy Box this holiday season to provide our customers with the opportunity to purchase a selection of toys once exclusive to Toys R Us,” Robert Clark, Kroger’s senior vice president of merchandising, said in a statement. This marks the debut of Geoffrey's Toy Box, a venture by Toys R Us' one-time lenders who held onto the toy giant's corporate brand names and intellectual properties, including its iconic mascot, Geoffrey the giraffe. A mix of 35 toys, costing from $19.99 to $49.99, will be for sale at various Kroger-owned grocery stores, including Ralphs, Smith's and Fred Meyer, as well as the Kroger namesake chain. More Money: Toy wars: Target, Party City prepare to battle for shoppers now that Toys R Us is gone More Money: A Toys R Us comeback? New name, same mascot Geoffrey emerge in post-bankruptcy plan More Money: Toys R Us may be out, but FAO Schwarz is back in – making a comeback in time for holidays Retailers of all stripes are doubling down on toys this year to grab a larger slice of the $27-billion toy industry in the wake of Toys R Us' demise. Target and Walmart are expanding their toy aisles, Party City is unveiling dozens of Toy City seasonal shops, and this month, iconic toy emporium FAO Schwarz will open its first store in three years. CLOSE Love or hate those seasonal Starbucks cups, they're coming and here's how to get a free reusable one. Buzz60's Tony Spitz has the cheery details. Buzz60 Read or Share this story: https://www.usatoday.com/story/money/2018/11/02/toys-r-us-geoffrey-back-his-toy-box-debuting-kroger/1857111002/ Geoffrey has risen from the grave. The company formerly known as Toy R Us announced in early October that it had cancelled an auction to sell off all of its assets. Instead, its controlling interests reorganized as Geoffrey, LLC and later announced during a toy-industry event that it would launch a new retail brand for in-store pop-ups, called Geoffrey's Toy Box, the New York Post reported. Details were scarce at the time, but displays with the new brand have recently popped up in Kroger and Fred Meyer stores, according to shoppers posting on social media. On Friday, Kroger announced that the Geoffrey's Toy Box pop-up displays would roll out to 600 Kroger mainline and subsidiary stores across the United States. They will sell toys from Toys R Us' former private labels, like Animal Zone, Imaginarium, Journey Girls, Edu Science, You & Me, and Just Like Home. "Geoffrey's Toy Box delivers a unique shopping destination within Kroger stores," Robert Clark, Kroger's head of merchandising, said in a statement. "We're excited to offer Geoffrey's Toy Box this holiday season to provide our customers with the opportunity to purchase a selection of toys once exclusive to Toys R Us." All toys will cost between $19.99 and $49.99, and the displays will last throughout the holiday season. Instagram/exclusivebenji Instagram/exclusivebenji According to its October 2 press release, Geoffrey, LLC still owns the rights to Toys R Us' giraffe mascot, Geoffrey, and the defunct retailer's 20 proprietary toy brands. It also owns the right to use the Toys R Us and Babies R Us brand names globally, except in Canada. Geoffrey's Toy Box makes use of this by incorporating Geoffrey as well as the classic style of the Toys R Us bubble logo. Read more: Best Buy is making a bold move to capture a piece of over $10 billion in sales up for grabs Instagram user @exclusivebenji told Business Insider he spotted the displays in a Fred Meyer store in Lacey, Washington, in late October. Fred Meyer is a subsidiary of Kroger. Other social media users have posted about seeing the displays in Kroger stores. The future of Toys R Us' brand had been in doubt since it filed a motion to liquidate its US business earlier this year. In a press release announcing the formation of the new company, Geoffrey, LLC said: "The new owners are actively working with potential partners to develop ideas for new Toys R Us and Babies R Us stores in the United States and abroad that could bring back these iconic brands in a new and re-imagined way." There are nearly 600 Geoffrey's Toy Box pop-ups in Kroger grocery stores nationwide. AMELIA, Ohio — The giraffe was supposed to be long gone, but here he is, beaming on the cardboard displays inside a Kroger. He’s right at home, surrounded by unblinking baby dolls and drones that are liable to break when little hands inevitably pilot them straight into the ceiling fan. Buckets of little green Army men, waiting to be unleashed and eventually stepped on. Kids, bundled up and rosy-cheeked, bound toward the toys and circle the displays like predators. They paw at the boxes, leaving fingerprints on the plastic. Some clutch toys to their chests before they begin pretty-pleasing. “Mom,” one boy with a buzz cut yells, lofting an action figure. “Look, they have Venom!” “I am not talking about this right now,” his mother says, but she mouths the name on the box and nods, before whisking her son toward the pharmacy. [Welcome to the first holiday season without the big-box Toys R Us] Parents pushing shopping carts rubberneck as they walk by the menagerie. Some smile in recognition. Others squint, eyeing the giraffe and his toys skeptically. That couldn’t be, could it? It is. The beloved mascot, the array of toys, the bright, blocky lettering spelling out “Geoffrey’s Toy Box” are all seeds of the complicated comeback of Toys R Us. *** Toys R Us’s fall was a long one, marked by a botched buyout, mountainous debt and a losing battle with big-box and online competitors. After filing for bankruptcy in September 2017, the toy store that had delighted kids for six decades announced in March it would be closing its doors, leaving 33,000 employees jobless. Then, as retailers geared up for the lucrative first holiday without Toys R Us, the company rose from the grave. The hedge funds that own its assets filed paperwork in October to hang on to the Toys R Us and Babies R Us brand names, Web domains and mascot Geoffrey the Giraffe while considering “a new, operating Toys R Us and Babies R Us branding company.” A month later, Kroger announced it would partner with Geoffrey, the subsidiary for Toys R Us intellectual property, to bring pop-up toy shops to 600 of its stores through the holidays. The pop-ups carry 35 toys from six brands that were once exclusive to Toys R Us, including Imaginarium, Just Like Home and Journey Girls. “I’ve never seen something in our stores that our customers are so excited about,” said Erin Rolfes, a corporate affairs manager for Kroger. “It was disappointing for everyone to hear Toys R Us went bankrupt. And the idea of bringing it back in a hometown store like Kroger, well it gives a great sense of nostalgia and it’s a good opportunity to introduce Geoffrey’s Toy Box.” [Why Black Friday might be the worst day to buy sneakers] But while some customers revel in this return, the news was far less welcome for legions of former employees. Seeing the brand resurrected while so many families struggle after losing their jobs is gutting, said Carrie Gleason, campaign manager for the worker advocacy group Rise Up Retail, which works with ex-Toys R Us employees. “It’s hard to explain how it feels that the people responsible for liquidating the company are the ones that are doing this,” said Anthony Kittleson, who was laid off, along with his fiancee, after years of working at Toys R Us. “It feels like a slap in the face.” After he found out about the Geoffrey’s Toy Box pop-ups, Kittleson and his family went to their local Kroger in Rancho Cucamonga, Calif., to protest. Families in Arizona, Washington, Ohio and elsewhere in California have done the same, Gleason said. [5 things to know before Black Friday shopping] Kittleson propped his 7-month-old daughter Gemma up on the toy display with a sign that said, “I’ll never get to be a Toys R Us kid because of Solus and Angelo Gordon,” two of the hedge funds that now own the company. Solus Alternative Asset Management and Angelo Gordon & Company did not respond to a request for comment from The Washington Post. “Putting my daughter’s face in front of that display was kind of our way of saying, ‘Hey, these are the people you hurt,’” Kittleson said. *** While Geoffrey’s Toy Box is notable for marking the possible comeback of Toys R Us, it’s unlikely that it’ll capture much of the holiday toy market because of its limited offerings, according to Linda Bolton Weiser, an analyst with D.A. Davidson. Kids are rigid about their Christmas lists and aren’t usually interested in products they don’t recognize. The brands Geoffrey’s Toy Box is offering don’t have much name recognition, Bolton Weiser said. “Kids are gonna want the Hot Wheels and Barbies and Nerf and other licensed products,” Bolton Weiser said. Geoffrey’s Toy Box “isn’t carrying the products that would let them compete with the diversified retailers. It’s immaterial in the whole retail landscape.” [Hot toys 2018: Pooping unicorns, matted furballs and endless unboxing] The primary customer for the pop-ups will be “convenience buyers," Bolton Weiser said, who need something fast and aren’t sure what to get. Sure, some customers will feel warm and fuzzy when they lay eyes on Geoffrey, but that probably won’t be enough to drive significant sales. “Nostalgia only goes so far,” Bolton Weiser said. “It wasn’t enough to keep Toys R Us in business.” Tuesday night, in an eastern Cincinnati Kroger, Rosemary Voyles rifled through boxes of Journey Girls dolls. The 73-year-old didn’t particularly care that the pop-up was Toys R Us-related (she had avoided it before because of the crowds and chaos). Now, she was on the hunt for a cheaper substitute to the pricey American Girl doll her granddaughter wanted. “I’m hoping she’ll be satisfied if they have a doll named Amy," Voyles said. "That’s her name.” All the dolls were named Dana and Meredith, so she moved on. She wasn’t looking for gifts for her older grandson, because she knew he wanted a particular name-brand model car that wasn’t on the shelves here. But her 3-year-old grandson would be satisfied with anything that buzzed or moved, she reasoned. She picked up a blue plastic saw that boasted “realistic blade action” on the box. “This’ll work well enough," she mused, and tossed it in her cart along with the fixings for Thanksgiving dinner. The hedge funds that now own the Toys R Us brand plan to relaunch the toy retailer as a standalone operation next year, according to people familiar with the matter. Solus Alternative Asset Management and Angelo Gordon will look to raise capital to help revive the retailer, which closed its last stores at the end of June, and are making plans that include brick-and-mortar locations for the chain, the people said. Before opening their own establishments, the funds are partnering with Kroger, the largest grocery store operator in the U.S., to create pop-up sections named Geoffrey's Toy Box in about 600 stores, according to two of the people. The areas inside the supermarkets will operate this holiday season, selling a selection of toys from brands like Imaginarium and Journey Girls. The bigger plan is still in the works, the people said, and could change depending on various factors including financing. Representatives for Angelo Gordon and Solus Alternative Asset Management did not comment. Rebuilding the Toys R Us brand remains a daunting task, especially since the chain's leases and distribution centers were sold in the liquidation. While a few retailers have found a second life after liquidating, it's usually been online only or as a section in another store. Solus and its cohorts didn't set out to be merchants. The lenders assumed control of the Toys R Us and Babies R Us brands because the intellectual property served as collateral on their loans, which the troubled retailer defaulted on after filing for bankruptcy. The funds initially put the IP rights up for auction, but canceled the sale, arguing that holding on to them was better than the offers it received. The process, however, prevented them from formulating a plan in time for the critical holiday shopping season. Many toy vendors now say they've simply moved on. The plans for a relaunch of the brand, first reported by Bloomberg last month, don't sit well with former workers, who blame the funds for the company's liquidation and the loss of 33,000 jobs. "I'm just sick over this," said Cheryl Claude, a former assistant store manager who traveled from New Jersey to protest last month outside the Manhattan offices of Solus and Angelo Gordon. It's not just the workers that have been hurt by the company's absence. Hasbro said on its October earnings call that the impact of the retailer's demise could persist for a few quarters. Mattel has also been hurt by the liquidation of its biggest customer. | Summary: In March Toys R Us announced it was closing for good and leaving 33,000 people out of work. But the Washington Post reports on the toy retailer's "complicated comeback," saying it has come "crawling back" from what looked to be a certain demise. Geoffrey (the chain's giraffe mascot) has "risen from the grave," as Business Insider puts it, with the chain setting up a presence for holiday shopping via Geoffrey's Toy Box pop-up shops in almost 600 Kroger and Kroger-owned stores around the country. "I've never seen something in our stores that our customers are so excited about," a Kroger rep says. Who isn't so excited: Ex-Toys R Us employees, one of whom says the pop-ups feel like "a slap in the face." "It's hard to explain how it feels that the people responsible for liquidating the company are the ones that are doing this," a California man who was a Toys R Us employee for years tells the Post of the hedge funds that now own the company. An analyst also points out that, even though the crowds seem receptive to the idea of the Toys R Us pop-ups, "nostalgia only goes so far"-Geoffrey's Toy Box offers only limited, private-label brands (e.g., Imaginarium) that people may only buy in a pinch, not the hot brands people usually want around the holidays. "It's immaterial in the whole retail landscape," she notes. The 35 toys offered in the pop-up displays will cost between $20 and $50, per USA Today. As for what happens after the holidays: Sources tell the Chicago Tribune that the hedge funds may be planning a stand-alone relaunch next year. | 3,271 | 387 | multi_news | en |
Summarize: By. Ryan Gorman and David Mccormack. PUBLISHED:. 01:03 EST, 12 December 2013. |. UPDATED:. 05:48 EST, 12 December 2013. The 16-year-old boy who died after suffering a medical emergency on a Delta flight on Saturday has been identified as Zachary Bisiar. The teenager, who suffered from cerebral palsy, went into cardiac arrest after a medical emergency 30 minutes after take-off from Seattle on a flight bound for Atlanta. The boy was flying with his mother, grandmother and younger brother to visit his father, who is stationed at McChord Air Force Base, for Christmas. Zachary Bisiar, 16, who suffered from cerebral palsy, went into cardiac arrest 30 minutes after take-off from Seattle on a flight bound for Atlanta. The medical examiner's office in Washington's Spokane County said on Monday that the autopsy results for Zachary were still pending further tests. Forensic pathologist Sally S. Aiken, with Spokane's Medical Examiner office, noted that the cause of the boy's death is currently 'pending' further microscopic and other studies. In a statement, Dr. Aiken said that it was 'thought to be a rare complication of a rare disease process. The manner of death is natural.' The plane was diverted to an airport in Spokane, Washington, after the boy suffered a medical emergency and died on board. 'It was a complete surprise - they were completely devastated,' said Spokane Fire Department spokesperson Brian Schaeffer. Zachary's uncle Steven Leahy has launched a fundraising page to help his sister and her husband cover the expenses involved in funeral which is scheduled for December 22. He hopes to raise $15,000. The medical examiner's office in Washington's Spokane County believe Zachary's death was due to 'a rare complication of a rare disease process. The manner of death is natural' ‘Please help my sister and her husband who lost their son, Zachary Bisiar, on flight 128 from Seattle to Atlanta,’ he writes on the GoFundMe.com page he has launched. ‘All proceeds will go towards laying him to rest and aiding the family with the difficult time they are having now with the loss of their child.’ The incident happened aboard Delta Flight 128, which departed Seattle around 9 a.m. local time on Saturday. Washington State patient-confidentiality rules prohibit local officials from divulging such information outside of a coroner’s report, but Schaeffer did say there was nothing in his medical history to suggest such an incident was to be expected. The boy and his family were sitting at the back of the plane when they began calling for help, passenger Joe Ryan, of Atlanta, told MailOnline. Zachary's uncle Steven Leahy has launched a fundraising page to help his sister and her husband cover the expenses involved in funeral which is scheduled for December 22. The flight crew immediately sprung into action. Despite the dire circumstances, everyone – including passengers – remained calm and collected throughout. ‘It was calm and the male flight attendants rushed to his aid at the back of the plane,’ said Ryan. ‘They started performing CPR on him… the pilot got on the air and said we are going to have an emergency landing.’ ‘We were on the ground in five minutes... I think that they did everything they could to save that boy’s life,' Ryan added. A registered nurse aboard a flight, Dan Goslin, told WSBTV that he and two other passengers, a doctor and a midwife, did everything they could to revive the boy. Medical aid: Dan Goslin, a nurse, along with a doctor and a midwife all tried desperately to save the 16-year-old boy during Saturday's flight. 'He was having trouble breathing. We tried oxygen. That didn't work. We tried to move him out of the chair and get him to another position. That didn't work and everything we tried just really didn't work,' Goslin said. Emergency personnel were already on their way when the plane touched down. ‘We met them on the ground with our fire fighter paramedics and attempted resuscitate him for well over 30 minutes,’ Schaeffer said. ‘Paramedics rushed on to the plane, you could tell there was a lot of urgency… then everything calmed down and you could put two and two together,’ Ryan lamented. The boy was pronounced dead on the plane. On the ground: Emergency personnel with the Tacoma Fire Department race to the plane to try to try and save the boy's life | Summary: Zachary Bisiar, who suffered from cerebral palsy, went into cardiac arrest 30 minutes after takeoff, causing the plane to be diverted. A flight attendant performed CPR as the plane made an emergency landing, but the boy had already died. Autopsy results are pending further tests. Medical examiner believe it was 'a rare complication of a rare disease process. The manner of death is natural' The boy's uncle has launched a fundraising page to help pay for the funeral. | 1,053 | 108 | cnn_dailymail | en |
Summarize: By. Daniel Bates. PUBLISHED:. 11:48 EST, 1 October 2012. |. UPDATED:. 12:41 EST, 1 October 2012. Military chiefs have been accused of dishonoring the war dead over plans to put 60,000 solar panels on the famous runway at Pearl Harbor's Ford Island. The Navy wants to erect a 7ft tall fence on the site and turn it into what critics claim will be a'monstrosity' in a bid to make itself more green. It has chosen the site because it claims the airfield is not in use - even though the memory of events still lingers on. Outrage: The Navy plans to install 60,000 blue solar panels on the runway at Pearl Harbour's Ford Island. Critics say the panels (pictured in a mockup for the project) will make it look like the runway's made of Legos. Never forget: Airmen at the Ford Island Naval Air Station watch smoke billow from the USS Shaw which had just been blown up by Japanese bombers during the attack on Pearl Harbor on Dec. 7, 1941. The runway at Ford Island was where the US military tried to launch planes to try and counter attack during the Pearl Harbor raid on December 7, 1941. Some 33 of the 70 craft stationed there were destroyed as Japanese aircraft slaughtered 2,402 Americans and wounded 1,282 during the surprise offensive. In 1964 the runway was designated a National Historic Landmark and its iconic red and white control tower has featured in films such as ‘Pearl Harbor’. Now, however, the Navy wants to disregard all that and turn it into a solar farm. Going green: Solar panels (like those at the Solarmine facility in Taft, California) will help the Navy reach its goal to get 50 per cent of its energy from renewables by 2020. Ken DeHoff, director of the Pacific Aviation Museum on Ford Island, called for other sites to be considered. He said: 'We totally agree with (the Navy) being green, but we don't think they should do it where Americans spilled their red blood. 'There's plenty of room for them to create this project off to the west, which is just scrub oak and abandoned land.' He added that even though the site has not been maintained since 1999, it was still used by the local community. He said: 'This is an area that the kids play in, and they're going to cover it up and put a 7-foot high fence around it and basically make the place a monstrosity'. In Memoriam: The USS Arizona Memorial that remembers those who lost their lives on December 7, 1941 during the Japanese bombing of Pearl Harbor. In remembrance: 2,402 Americans died in the Pearl Harbor attacks by the Japanese on December 7, 1941. Edward Boruki, 83, of Massachusetts, a Pearl Harbor survivor, remembers the dead at an event in 2004. Under the Navy's plan 60,000 of the blue solar panels, which are 4ft by 6ft in size, would be arranged so that they still looked like the runway does now. There would also be a white cross every 1,000ft along the 4,000ft runway to create the effect. Some 14 acres of land adjoining the runway would be developed as part of the $500 million project as the Navy seeks to get 50 per cent of its energy from renewables by 2020. Museum spokeswoman Barbara Bloom said that the new design was awful and claimed 'it's going to look like the runway's made of Lego'. But according to the Navy, the runway is actually an 'inactive space that is ideally located and sized' for a solar farm. Spokeswoman Agnes Tauyan told USA Today that the Navy'remains committed to balancing our responsibility towards environmental stewardship, energy security and the preservation of historically significant facilities and structures.' | Summary: U.S. Navy plans to install 60,000 of the blue solar panels on runway at Pearl Harbor's Ford Island. Panels are 4ft by 6ft in size - part of a $500 million project. 2,402 Americans died and 1,282 were wounded in the Pearl Harbor attack on December 7, 1941. 'We don't think they should do it where Americans spilled their red blood,' the director of the memorial's museum said of the Navy's plan to 'go green' | 964 | 129 | cnn_dailymail | en |
Summarize: A 15-year-old accused of stabbing her 12-year-old brother and attempting to stab her younger sister as part of a plot to kill her family and run away with her 23-year-old boyfriend appeared in court in Detroit on Thursday. Roksana Sikorski has had her bail set at $1 million and has been charged as an adult with four counts of conspiracy to commit murder and one count of assault after putting in action her plot, encouraged by boyfriend, Michael Rivera. The 'truly haunting' attack began at 2am last Friday at the family's Detroit home when Sikorski attacked her younger sibling's first and then allegedly planned to kill her parents while Rivera sat outside in his car giving instructions via text. Charged: Roksana Sikorski and Michael Rivera both face charges of conspiracy to murder after Sikorski attacked her family at their Detroit home early on Friday morning. Rivera, who wore a red jumpsuit in court, faces the same charges as well as a felonious assault charge. He was ordered held on $1 million bond Sunday. The girl's parents said she and Rivera were in a sexual relationship. The Detroit prosecutor's office said that after Sikorski stabbed her brother in the throat his screams alerted her parents, who rushed to his aid. He was taken to the Mott Children's Hospital in Ann Arbor and is expected to recover after surgery. Sikorski and Rivera fled the scene and police found them at a home in Detroit's southwest side and took them into custody at 8am on Friday morning. Concerned: Sikorski's parents Laurene and Jeff believe their daughter was heavily influence by Rivera and told the court in Detroit as much. 'He was using her to do his dirty work. She was under this man's spell,' the girl's mother told reporters after the hearing. The parents said the girl met Rivera earlier this year through social media. They said they first learned about the relationship after their daughter ran away from home this summer. 'I think it was a big secret. I didn't know about him,' her mother said. According to ClickDetroit, Sikorski's parents, Laurene and Jeff, told the court they have a'strong bond' with their daughter and want to be there for her through these 'difficult times. 'I think she just thought this guy loved her and she wanted to do whatever he told her, and she was very vulnerable and she has a mental disorder and she needs help,' said Laurene Sikorski. 'I want to make sure she gets help.' Shocked: Sikorski appeared dazed and confused in the courtroom and is being held on $1 million bail. The couple said they adopted the girl and her two younger siblings from Poland when she was 4½ years old. They said she had been receiving treatment for depression and ADHD. 'She's never been violent in the past. We had no clue this was going to happen,' her mother said. 'She's getting psychiatric counseling. She's on medications. We've done everything in our power to help her.' Defense attorney Leslie Posner told reporters that the girl and her siblings were physically abused in Poland, eventually removed from their home in that country and later adopted by the Michigan family. 'They came from a very, very, very bad background,' the lawyer said, referring to the abuse that allegedly came from the children's biological parents. 'They were locked in closets. They were beaten.' The parents in Michigan said they are supporting their daughter despite the charges. If released on bond, the judge said the girl can't have any contact with her siblings and must wear a GPS monitor. She made eye contact with her parents several times during the hearing. 'Your honor, we have a very strong bond with our daughter,' her mother said. Court records did not list a lawyer for Rivera on Thursday. Preliminary hearings for both him and the girl are scheduled for Oct. 31 | Summary: Roksana Sikorski set in motion her 'horrifying plan' on Friday. Was encouraged by Michael Rivera, 23, in texts messages beforehand. She stabbed her 12-year-old brother and tried to attack her younger sister. Escaped with Rivera and both were arrested early on Friday morning. They have both been charged and had their bail set at $1 million. Parents adopted the girl and her two younger siblings from Poland when she was 4½ years old. They said she had been receiving treatment for depression and ADHD. | 882 | 117 | cnn_dailymail | en |
Summarize: By. Meghan Keneally. PUBLISHED:. 08:34 EST, 21 October 2013. |. UPDATED:. 09:52 EST, 21 October 2013. Former Vice President Dick Cheney has revealed that he had a signed resignation letter ready for much of his time in President George W. Bush’s administration in case he became incapacitated by a heart attack. Cheney has had five heart attacks- including one during the month of Bush’s first election- and felt that he had to prepare in case something happened while in office. During an interview on The Today Show, he said that one of his motivations in drawing up the unusual letter was because he looked back at the medical problems of Woodrow Wilson who had a stroke that incapacitated him but kept him in office due to the constraints of the Constitution. SCROLL DOWN FOR VIDEO. Medical marvel: Dick Cheney has written about the technological advancements that have made it possible for him to survive five heart attacks and a transplant. In case of emergency: Cheney revealed that he wrote this letter of resignation and had it ready in case something happened, adding that George W. Bush was surprised by the move but saw its purpose. Cheney said that because there are no such altered provisions in the Constitution regarding the Vice President, he felt he needed to take his own action. In spite of this awareness, Cheney got defensive when questioned about whether or not his three prior heart attacks should have ruled him out from being elected Vice President in the first place. ‘I didn't seek the job, the president came to me, the party nominated me, the doctors that consulted on it reached a conclusion, the people elected me,’ he said during an interview with Sanjay Gupta on 60 Minutes on Sunday night. ‘At what basis do you want to override that decision making process? Do you want to have an offshoot where we come check with Sanjay Gupta and say “Gee, is he up to the task?” That's not the way it works.’ Opening up: Cheney is promoting a book he co-wrote alongside his cardiologist. Gupta went on to question a campaign doctor’s report who gave Cheney the all-clear, writing that at the time he had ‘normal cardiac function’ in spite of having had three heart attacks and having smoked three packs of cigarettes a day for more than two decades. ‘I'm not responsible for that. I don't know what took place between the doctors,’ he said. ‘There's no question I think based upon the fact that I did it for eight years that they were right.’ The 72-year-old Republican is promoting a book he co-wrote alongside his cardiologist about the ways in which medical advancements have dramatically improved conditions for patients with heart disease like himself. Way too big: Because his heart was too big (left), it made it harder for the organ to effectively pump blood throughout the body, and that problem was fixed with the new transplant organ. Unusual: This picture shows Cheney's old heart immediately after it was removed, and it was noticeably bigger than it should be. They also revealed that they debated. putting in a defibrilltor to help regulate the then-Vice President’s. blood flow, but they were concerned that a terrorist may be able to. remotely gain control of the heart and kill him. The scheme seems outrageous, but it resonates now as it was used as a plotline in the hit television series Homeland where a terrorist used that exact trick to kill the Vice President. ‘I was aware of the dangers that existed,’ Cheney said when asked about the parallels between his life and the fictitious show. ‘I know from the experience we had. and the necessity for adjusting my own device that it was an accurate. portrayal of what was possible.’ Art imitating life: Cheney's fears of a terror attack on a prospective defibrillator were played out in this episode of Homeland where the Vice President is killed by a terrorist remotely operating his heart mechanism. During his 60 Minutes appearance, Cheney and his doctor Jonathan Reiner showed pictures of Cheney’s old heart that was replaced with a transplant in March of last year and the size of the old heart showed just how damaged it was. According to the doctor, a healthy heart is typically the size of two hands clamped together; the heart that was removed from Cheney’s chest was half-a-foot wide. ‘It's one of those situations where bigger is not necessarily better,’ Cheney joked. WATCH THE VIDEO HERE | Summary: Former Vice President has had five heart attacks and a heart transplant. Cheney is now promoting a book he wrote with his cardiologist. Revealed that he feared he would be incapacitated in office and the Constitution had no parameters to replace him so he wrote a letter removing him from office that could be used if he was unable to write. Also said his doctor warned against a terrorist attack using a defibrillator like Homeland showed in a recent episode. | 1,032 | 97 | cnn_dailymail | en |
Summarize: Police in Maryland are looking for a pregnant teacher who didn't show up for the first day of class. (Published Thursday, Sept. 7, 2017) Police in Maryland are looking for a pregnant teacher who didn't show up for the first day of class. Laura Elizabeth Wallen, 31, was last seen at the Olney condo where she lives alone about 8:30 a.m. Monday. Her family said they received a "troubling" text message from her about an hour later, but attempts to reach her have failed. Police don't want to release the contents of the text message she sent. Her father said he went to her condo but didn't find her. She also failed to show up for the first day of classes Tuesday at Wilde Lake High School in Columbia, where she teaches history and law. Her father, Mark Wallen, said that set off alarms for him. Pregnant Maryland Teacher Missing as School Year Starts Police in Maryland are looking for a pregnant teacher who didn't show up for the first day of class. Pat Collins reports. (Published Wednesday, Sept. 6, 2017) "You feel so helpless at that point because you don't know where your child is," he said. He suspects someone is responsible for his daughter's disappearance. "Well we're reaching out to, of course, family, friends, coworkers, neighbors and also other strategies I don't want to get into at this time," Montgomery County Police Capt. Paul Starks said. "This is like an alternate universe," said Wallen's sister, Jennifer Kadi. "It just doesn't seem real." Wallen is four months pregnant, and her family said she was excited about it and posted her sonogram on her refrigerator. "That obviously puts an enormous amount of worry on us because she is out there somewhere and she has a baby, so that's a really scary thing," Kadi said. "It's like a TV drama you wish you could shut off but you can't," Mark Wallen said. Wallen is 5-foot-5-inches tall, weighs 200 pounds and has blonde hair and blue eyes. Police are also looking for her car, a black 2011 Ford Escape with Maryland license plate M522473. Anyone with information about Wallen's location or the location of her car should call police at 301-279-8000. Columbia, Md. (WJZ)– Montgomery County police in Maryland continue to look for a pregnant teacher who didn’t show up for the first day of class. Police say Olney resident, Laura Elizabeth Wallen, 31, last contacted family members by text message on Monday. Wallen failed to show up for the first day of classes Tuesday at Wilde Lake High School in Columbia, where she teaches history and law. “She was a favorite amongst the students. She was really nice and this is really sad, what’s happening, you see it’s really taking a toll on people,” said student Paris Cooper. Relatives of Wallen confirmed that she was excited about her pregnancy, never gave signs that anything was bothering her and left her dog behind. “I’m hoping they find her and I’m hoping that she’ll be alive and well,” said neighbor Joyce Robinson. Police won’t reveal the context of the text message she sent the family. “That was alarming enough that the family said ‘we need to call police,'” Sgt. Rebecca Innocenti said. Wallen spent days preparing her classroom, which makes it unusual that she didn’t show up. She earned honors as senior class teacher last year. “People are concerned for her safety,” said Brian Bassett of Howard County Schools. “I know she’s really highly regarded at Wilde Lake High School.” Students flooded social media using the hashtag #BringWallenHome. Wallen is 5-foot-5-inches tall, weighs 200 pounds and has blonde hair and blue eyes. Police are also looking for her car, a black 2011 Ford Escape with Maryland license plate M522473. Anyone with information about Wallen’s location or the location of her car should call police at 301-279-8000. Follow @CBSBaltimore on Twitter and like WJZ-TV CBS Baltimore on Facebook | Summary: The mysterious disappearance of a pregnant high school teacher has prompted a police search in Olney, Maryland. Montgomery County police say Laura Elizabeth Wallen, a 31-year-old history and law teacher, failed to show up for the first day of class Tuesday at Wilde Lake High School, NBC Washington reports. The day before, her family received what they say was a "troubling" text from Wallen about an hour after she was last seen, at 8:30am Monday at her condo complex. Police aren't sharing that text message, but Sgt. Rebecca Innocenti told CBS Baltimore the message was "alarming enough that the family said, 'We need to call police.'" Witnesses say Wallen, who is four months pregnant, spent several days before the new school year began preparing her classroom. She is five-foot-five inches tall, weighs 200 pounds, and has blonde hair and blue eyes. Police are also searching for her car, a black 2011 Ford Escape with Maryland tag M522473. | 968 | 231 | multi_news | en |
Summarize: By. Julie-anne Barnes. Distraught: Gary Wells, 36, was left 'unable to cope' when long-term girlfriend Diane left him last month. A jilted lover killed himself by standing in front of a train driven by his ex-girlfriend, it emerged last night. Gary Wells, 36, was said to be distraught after splitting from Diane MacDonald three weeks ago. Miss MacDonald, 29, was powerless to prevent a collision after he stepped on to the track in front of the train she was driving on one of Britain’s most scenic rail routes. Mr Wells died instantly as he was hit by the train. Miss MacDonald, the first woman train driver on the West Highland Line in Scotland, was left so distressed that she required sedation after the tragedy, which happened at Inverlochy, near Fort William, on Tuesday morning. Mr Wells had been in a long-term relationship with Miss MacDonald but friends said their relationship ended around three weeks ago. Sources said the break-up had left Mr Wells struggling to cope. Last night, a school friend told how Mr Wells was a devoted father whose weekends were spent with his son Lewis, who was from a previous relationship. The friend, who did not wish to be named, said: ‘Gary was a nice guy. ‘He and Diane were like peas in a pod. They were together for eight or nine years and split up a few weeks ago. I can’t believe he did this. I heard Diane had to be sedated. ‘It’s so sad. He loved spending time with his son Lewis. His weekends were devoted to him.’ Mr Wells is thought to have been working at a local engineering company and had previously worked some evenings and weekends as a pub bouncer. His family was too distressed yesterday to talk about what happened. In a statement, Miss MacDonald said last night: ‘The circumstances are extremely upsetting for everyone involved. We would ask the media to please respect our privacy while we come to terms with what has happened.’ British Transport Police confirmed they are investigating the incident. A spokesman said: ‘We were called to a rail crossing in Inverlochy, Fort William, shortly before 8am on Tuesday, August 19, to a report that a man had been struck by a train. Colleagues from Police Scotland and Scottish Ambulance Service also attended, but a 36-year-old man from the Fort William area was pronounced dead at the scene. ‘His death is currently not being treated as suspicious. ‘The man’s family have been informed. A report will be sent to the Procurator Fiscal.’ Shock: Diane MacDonald, the first woman driver for West Highland Line, was sedated at the scene. No one was available for comment last night at MacPherson Welding and Engineering in Fort William, where Mr Wells is understood to have worked. Miss MacDonald became the first female train driver on the West Highland Line – and the youngest qualified driver working for First ScotRail – in 2009. She started her railway career when she was 19, working part-time at Fort William station, then became a conductor on the West Highland Line, working out of Mallaig, before applying to become a driver. At the time, she said: ‘I’m excited and proud to have qualified as a train driver. The training was intense but worth it. ‘The West Highland Line is one of the best routes to work because of the amazing scenery.’ | Summary: Gary Wells, 36, 'distraught' when Diane MacDonald, 29, left him in July. Killed instantly when he stepped in front of train near Fort William. Tributes paid to father-of-one who loved spending time with his son, Lewis. Miss MacDonald so distressed that she required sedation at the scene. She was the first woman driver of West Highland Line in Scotland. For confidential support call the Samaritans on 08457 90 90 90, visit a local Samaritans branch or go to www.samaritans.org. | 762 | 134 | cnn_dailymail | en |
Summarize: Donald J. Sobol, the creator of Encyclopedia Brown, the clever boy detective who made bookworms of many a reluctant young reader, died on Wednesday in South Miami. He was 87. The cause was gastric lymphoma, his son John said. Mr. Sobol’s books have been translated into 12 languages and have sold millions of copies worldwide, according to his publisher, Penguin Young Readers Group. He continued to write every day until a month or so before his death, his son said. The 28th book in the series, “Encyclopedia Brown and the Case of the Soccer Scheme,” is to be published in October. The first Encyclopedia Brown book came out in 1963 (after being rejected by two dozen publishers, something Mr. Sobol liked to tell aspiring writers to encourage them not to lose faith in their work). Mr. Sobol found a winning formula and stuck to it. Each book holds 10 stories, each involving a mystery that 10-year-old Leroy (Encyclopedia) Brown solves by keen observation and deduction. He notices that the culprit has his sweater on inside out, or claims to smell flowers that are fake. The rest is self-evident. The solution is not spelled out in the story; readers are challenged to figure it out for themselves — or to flip to the back for the answer, as Jack Nicholson’s character in the movie “About Schmidt” does as he lies in bed, engrossed in “Encyclopedia Brown Gets His Man.” Photo Encyclopedia never ages and never charges more than 25 cents an hour for his detective services. Mr. Sobol wanted each book to stand alone, so that children could start with any one in the series and read the books in any order. The first story in each book always explains that his father is the chief of police in their hometown, Idaville — named, unbeknown to most readers, for Mr. Sobol’s mother. (The books also included characters named for Mr. Sobol’s children and their friends, as well as another town, Glennville, named for a son, Glenn, who died in a car accident in 1983 at the age of 23.) Advertisement Continue reading the main story The 28th book begins: “Idaville looked like many seaside towns on the outside. On the inside, however, Idaville was different. Very different. We at GeekDad are sorry to hear of the death of author Donald J. Sobol who, according to Reuters, passed away on July 11 at age 87, of natural causes. Sobol was best known for his Encyclopedia Brown series, featuring a boy detective named Leroy “Encyclopedia” Brown (so nicknamed because he was a genius). The boy Sherlock Holmes appeared in some 30 books from 1963 to 2011. Each Encyclopedia Brown book contained around 10 mysteries that Encyclopedia would solve — either a kid-centered minor crime (often involving local bully Bugs Meany, the leader of a local gang called the Tigers), or a real case that vexed his father, the police chief of the fictional town of Idaville, Florida. Encyclopedia set up his detective agency’s office in the Brown family garage on Rover Avenue. His slogan was: “25 cents per day plus expenses: No case too small.” At the end of each case, Sobol showed “Encyclopedia” Brown in the process of solving the case. But before the boy detective would give the answer, Sobol cleverly gave the reader a chance to also solve the case. (See image.) You could flip to the end of the book to see if you, too, solved the crime correctly, which often involved catching a petty criminal in a lie. That was a smart move by Sobol — to let youthful, aspiring detectives participate in solving each crime story. Those same bookish types who might have otherwise felt disempowered, ostracized or bullied. For me, these books taught me to be curious, to investigate, to be entrepreneurial — and to fight the bullies like Bugs Meany, real or metaphorical, in my young life. The series suggested to me that a kid could have real power. He could defeat injustice and outsmart the brawny brutes of the world using his brains. A classic “revenge of the nerds” scenario. I wasn’t actually all that great at solving the mysteries. No matter. I lived vicariously through Encyclopedia Brown. And I came up with a hundred schemes a summer to make money, trick the bully, or otherwise engineer a scenario to be the smart one who would sweep in to save the day. But Encyclopedia’s success wasn’t only due to his problem-solving prowess. Credit his best pal (and girl Friday) Sally Kimball: older, stronger and sometimes smarter. She also could stand up to Bugs, and was Encyclopedia’s bodyguard. That was a novel premise, to give that role of “the muscle” to a girl. Hearing about Sobol’s death, I was reminded of other books about boy or girl protagonists solving mysteries and scheming to do cool things. One that came to mind is the wonderful Great Brain series, about a mischievous older brother named “The Great Brain,” who exploits in small Utah town at the turn of the century are told by his younger brother. Another series I loved was Bertrand R. Brinley’s Mad Scientists’ Club. Can you think of any others? The Encyclopedia Brown series was translated into 12 languages, and has sold millions of copies worldwide, according to Penguin. It was adapted as a newspaper comic strip and a TV series. Sobol also wrote a series called Two-Minute Mysteries. The latest (and last Sobol-written) installment, Encyclopedia Brown and the Case of the Soccer Scheme, will be released in October. In 1976, The Mystery Writers of America gave Sobol a special Edgar Award. | Summary: Donald J. Sobol, creator of the enduring popular Encyclopedia Brown children's detective series, has written his last case. Sobol, who has died at the age of 87, wrote a total of 28 books in the best-selling series, starting in 1963 and finishing with Encyclopedia Brown and the Case of the Soccer Scheme, which will be published this fall. The books, starring 10-year-old Leroy Brown and his sidekick Sally Kimball, gave readers a chance to crack the case before Brown did, "which was a smart move by Sobol to let youthful, aspiring detectives participate in solving each crime story," writes Ethan Gilsdorf at Wired. Sokol, a native of New York City, became a reporter at the New York Sun after serving in a combat engineer battalion in the Pacific in World War II. His first book was rejected more than two dozen times but he went on to write more than 80, including many nonfiction works. The Brown books sold millions of copies worldwide and were translated into 12 languages but Sobol, who kept writing until the end, never grew rich from his creation, his son says. "My father was not a businessman," he tells the New York Times. "His contribution was sort of inversely proportional to his financial compensation. He lived a comfortable middle-class life." | 1,321 | 299 | multi_news | en |
Summarize: This application is a continuation-in-part of U.S. application Ser. No. 07/974,028, now abandoned, filed on Nov. 20, 1992. FIELD OF THE INVENTION This invention relates to the field of protective covers for bags which may be carried by means of a harness. BACKGROUND OF THE INVENTION Many types of bags have been designed for specific uses. Photographers, in particular, require bags which are adapted to carry photographic equipment and supplies in a manner that will protect that equipment and supplies. In some cases, particularly in the field of nature photography and the like, rather large amounts of equipment are carried in significantly large bags. In view of the size of the bags and the amount of the equipment carried, such bags are often fitted with harnesses so that the bags may be carried like a backpack. In other cases, where relatively smaller amounts of equipment are carried, the bag may be of a more convenient size but is often equipped with a strap or harness in order that the bag may be carried by means of a strap which would be looped over one shoulder of the photographer or passed around the waist. Quite apart from the photography field, there are other specialized bags of a similar nature. Outdoors persons generally are familiar with backpacks which may be used to carry all manner of camping supplies or other supplies. There is also a wide range of smaller bags carried in shoulder straps and the like for carrying other than photographic supplies. One common feature of these types of bags is that they are carried in all kinds of weather. Such bags during good weather conditions provide sufficient protection for the goods carried within the bags. However, in inclement weather such bags may leak water or admit fine dust. Most bags are arranged with some type of openable flap having closure means which extend around the upper portion of the bag. In addition, the bag may have one or more compartments each of which is accessible through a hinged flap having closure means. The usual type of closure is a zipper. Other types of closures such as hook-and-loop materials such as that sold under the trade mark VELCRO may be used. Snap fasteners and the like may also be used as appropriate. It is usually desired that the bags be manufactured from lightweight but strong material. To this end, many bags are now manufactured from nylon products which are soft sided but still give the required protection by means of inserts or the like which provide against crushing of the equipment carried in the bag. When the traditional bag is carried in inclement weather there arises the danger of leakage through the bag material itself or through the closures. As the bags are often equipped with a number of different pockets for various size articles, there are often a number of such closures, and some or all of those closures may leak. SUMMARY OF THE INVENTION In accordance with this invention, additional protection for the bag and its contents in inclement weather is provided by an encompassing cover. The cover is intended for use with a bag that can be carried by a human being and which is equipped with a harness. In this specification and claims, the word harness is used to encompass any type of strap which may be used to support the bag on one or both shoulders of a person carrying the bag or which may encircle the waist of the wearer. The bag will comprise a housing which may be divided into one or more compartments. The cover for the bag is constructed from a flexible water resistant material. The cover has a hinged portion and a free edge portion. The bag comprises a closable pocket which is adapted to contain the cover when it is in its folded condition and in which the cover is stored when not required. The pocket thus contains the hinge which attaches the cover to the bag. The cover is large enough to substantially enclose the bag to protect the surfaces of the bag that would be subject to inclement weather when the bag is carried by means of the harness or when resting on the ground. In particular, the cover is large enough to extend over all openable flaps of the bag to protect against leakage through the closures of the flaps. dr DESCRIPTION OF THE DRAWINGS Further and other features of the invention will be more clear from reference to the enclosed drawings which illustrate preferred embodiments and in which: FIG. 1 is perspective view of a shoulder bag in accordance with the invention showing the top, back and right surfaces of the shoulder bag; FIG. 2 is a perspective view of the bag of FIG. 1 but showing the inner surface of the cover unfurled from its pocket; FIG. 3 shows the bag of FIGS. 1 and 2 with the cover in place on the bag; FIG. 4 is a perspective view of a fanny pack in accordance with the invention showing the top, front and right surfaces of the pack and a cover unfurled from its pocket in an inverted orientation; FIG. 5 shows the pack of FIG. 4 with the cover in a proper orientation for installation over the pack; FIG. 6 shows the pack of FIGS. 4 and 5 with the cover partially installation over the pack; and FIG. 7 shows an alternate embodiment of the cover with a system of buckles to transfer load from a pack or bag to a harness. DESCRIPTION OF THE PREFERRED EMBODIMENTS FIG. 1 illustrates a bag, generally indicated by the reference numeral 10, which is sometimes referred to as a "shoulder bag". The shoulder bag 10 may be used by photographers, campers and outdoorsmen generally, typically on short duration excursions outdoors. The shoulder bag may be fitted with impact resistant padding to protect the bag's contents, such as fragile camera lenses or the like. The shoulder bag 10 has a harness 14 which is adapted to be looped over one shoulder of the person carrying the bag. The shoulder bag 10 comprises an upper surface 20, a lower surface 21, right and left side surfaces 22 and 24, and front 26 and back 28 surfaces. The back surface 28 will be adjacent the hip or side of the person carrying the bag. However, the back surface 28 may also be equipped with two or more rectangular pieces of webbing 30, sewn at either end to the back surface 28, to allow a waist belt or a comparable harness (not shown) to be slid through the openings formed by the webbings 30. The shoulder bag 10 may therefore be worn about the wearer's waist with the back surface 28 bearing against the wearer's lower back, for example. The shoulder bag 10 illustrated in FIGS. 1-3 will have a number of compartments 40 on the right, left and front surfaces 22,24 and 26 to hold various pieces of equipment and supplies. A closure means 42 (a zipper, for example) provides access to each of the compartments 40. A lid 44 and a corresponding closure means 42 extending around the right, left and front surfaces 22, 24 and 26 provides access to the interior of the bag 10. The top of lid 44 may also include, if desired, a small pouch and/or a handle (not shown) for carrying the bag 10. It will be appreciated by those skilled in the art that the closure means 42 and any seams in the bag are subject to leakage in inclement weather. The back surface 28 of shoulder bag 10 also has a pocket 46 and associated closure means. Pocket 46 is large enough to accommodate a cover 50 shown in FIG. 2 in its unfurled position out of the pocket. The cover 50 has a hinged portion 52 within the pocket 46 and a free edge portion 54 having a first portion 55 and a second portion 56. In order to install the unfurled cover 50 on the bag 10 to provide protection in inclement weather, the cover 50 is first drawn upwardly and sideways over the lid 44, then downwardly over the front surface 26, and then across the lower surface 21 until a part of the free edge portion 54 extends across the back surface 28 on either side of the webbings 30, as shown in FIG. 3. As this is being done, part of the cover 50 is also extended over the right and left side surfaces 22, 24. It is therefore understood that the cover 50 should be large enough that it can be wrapped about the bag 10 on all sides on which compartments 40 are situated, as shown in FIG. 3 (note that FIG. 3 shows the bag 10 from the back surface 28 with a view similar to that in FIG. 1). FIG. 3 therefore illustrates the bag 10 with the cover 50 in place. To ensure that the shoulder harness 14 remains accessible, the cover 50 is provided with appropriate slits or reliefs 60 in the second portion 56 of the free edge 54 so that the shoulder harness fixation points remain accessible, thus allowing use of the harness 14 when the bag 10 is covered. The slits 60 are formed (ie. "closed") about the fixation points of the harness by a closure means 62 (illustrated as 62', 62", 62'" and 62"" in FIG. 2 and FIG. 3), such as hook-and-loop fasteners, as illustrated in FIGS. 2 and 3. The first portion 55 of the free edge 54 of the cover 50 may be provided with an elasticized band 57, draw-string, or the like, if desired, to help hold the cover in place on the bag. It will be observed that the free edge portion 54 leaves a panel which includes most of the back surface 28, exposed. In particular, the webbings 30 should remain exposed on the panel so that the bag 10 may be worn on the waist belt when the cover 50 is in place. The waist belt can be passed under the webbings 30 to affix the waist belt to the pack. Even if moisture or other inclement weather comes into contact with the panel of the back surface 28, there is very little danger of leakage since there are no openings or compartments on that panel. Another version of both the bag 10 and the cover 50, indicated by the reference numerals 110 and 150, respectively, is shown in FIGS. 4 to 6. For ease of reference, those features on the bag 110 and the cover 150 which are similar to those on the bag 10 and the cover 50 will share the same reference numerals, with the addition of a prefix "1". The bag 110 illustrated is often referred to as a "fanny pack" since a waist belt 116 is attached to the pack 110 and is worn about the wearer's waist, with the body of the pack 110 located near the base of the wearer's back. The waist belt 116 has a buckle 117 with a male potion 117a and a female portion 117b, and cushioned portions 118 adjacent each side of the pack 110 for a more comfortable fit about the wearer's waist. The pack 110 also has a shoulder harness 114 detachably connected to the pack 110 with buckles 119 (of similar construction to buckle 117) on either end to provide the user with the option of carrying the pack on one shoulder. The pack 110 has an upper surface 120, a lower surface 121, a generally rounded back surface 128 and a front surface 126. The front surface 126 is preferably padded for a comfortable fit against the wearer's back when the waist belt 116 is used. The waist belt 116 may be buckled around the other side of the pack 110 (ie. opposite to that shown in FIG. 4) and the front surface will be adjacent the wearer's hip when the harness 114 is used. The pack 110 has a compartment 140 on the back surface 128, and a closure means 142 provides access to the compartment 140. A lid 144 and a corresponding closure means 142 extending around the top of the pack 110 from one side of the compartment 140 to the other side as shown provides access to the interior of the bag 110. A lower pocket 145 of the compartment 140 has a closure means underneath (not shown) and is large enough to accommodate a cover 150. The cover 150 has a hinged end 152 within the lower pocket 146 and a free edge portion 154. A short, elongate elastomeric band 156 is connected at each of its ends to the free edge portion 154. The entire free edge portion 154 in this embodiment should have an elasticized band 157. When the cover 150 is withdrawn from the pocket 146, it will look like either that shown in FIG. 4 or 5. If it looks like that shown in FIG. 4, then it should be inverted (by moving the free edge portion 154 which is furthest from the pocket 146 underneath the band 156 in the direction of arrows 158) to resemble the orientation of the cover 150 in FIG. 5. In the FIG. 5 orientation, the cover 150 has an inner surface 159 and an outer surface 160. The terms "inner" and "outer" are used to indicate the location of these surfaces once the pack 110 is covered. In order to install the unfurled cover 150 of FIG. 5 to provide protection in inclement weather, the inner surface 159 of the cover 150 is first drawn over the upper surface 120 and toward the waist belt 116 (as indicated by arrow 170 in FIGS. 5 and 6) until the elasticized band 157 of the cover 150 is located at about the level of the closure means 142 of the lid 144 along the front panel 126. Then the remaining (unstretched) part of the elasticized band 157 of the cover 150 is pulled underneath the pack 110 toward the waist belt 116 (following the arrow 171 in FIGS. 5 and 6). Once the cover 150 is securely fitted, the buckles 119 (unclipped from the harness 114) may be pushed through apertures 161 so as to be accessible to the harness 114. With the cover 150 installed over the pack 110, the upper surface 120 and the back surface 128, including any compartments 140 and closure means 142, should be covered by the cover 150 to ensure full protection against inclement weather. A part of the lower surface 121 in this embodiment remains uncovered by the cover 150 since it is bereft of compartments and closure means, and a panel on the front surface 126, remains substantially exposed to retain access to the waist belt 116. The covers 50 and 150 as illustrated and discussed above provide complete encapsulating protection for the bag at least on all sides wherein there is an openable compartment and can extend over all sides of the bag or pack if desired. In order to do so, it is only necessary to provide a cover of a complimentary shape so that it can completely enclose the outside surface of the bag or pack. The cover 50 and 150 may advantageously be manufactured from a single sheet of flexible water resistant material such as treated ripstop nylon or the like. The cover must itself be water resistant so that rain, snow, sand, dust and the like cannot enter into the bag when the cover is in place. While advantageously the covers 50 and 150 are one piece covers, it is not necessary that the covers be manufactured from a single sheet of water resistant material. While the location of the pockets 46 and 146 containing the covers 50 and 150, respectively, have been illustrated in the specific examples discussed herein, it will be apparent that the pocket into which the cover is folded when not in use may be located on any portion of the bag. Advantageously, the cover pocket is so arranged so that the pocket will not itself become accessible to inclement weather conditions. This may normally be accomplished by arranging the pocket either in the bottom surface of the pack or bag as carried or in a surface which is adjacent to the body of the wearer so that the portion of the surface, if any, which is not completely enclosed by the cover is adjacent the body of the wearer and thus is protected for inclement weather conditions. As an added measure of protection against the invasion of any inclement weather into the pack 110, for example, the apertures 161 for the buckles 119 may be omitted entirely and substituted by a direct load transfer arrangement on the cover as illustrated in FIG. 7. FIG. 7 shows a portion of the pack 110, closest to the viewer in FIG. 5, enclosed by the cover 150. The female portion of the buckle 119 (indicated by 119a) attached to the pack 110 is underneath the cover 150, as indicated in dotted outline. A complimentary male buckle 165, attached to the inner surface 159 of the cover 150, is joined to the female portion 119a of the pack's buckle 119. Another female buckle 166 is attached to the outer surface 160 of the cover 150 along attachment line 167 adjacent the cover's inner male buckle 165. This female buckle 166 is in turn used to connect to the male portion of buckle 119 (indicated by reference number 119b) on harness 114. It will therefore be appreciated that load from the pack 110 is transferred directly to the harness 114 and the wearer' s shoulder through the female portion of buckle 119, to the male buckle 165, through the attachment line 167 of cover 150, to the female buckle 166 and into the male portion 119b of buckle 119. The above description is intended in an illustrative rather than a restrictive sense and variations to the specific configuration and materials described may be apparent to skilled persons in adapting the present invention to specific applications. Such variations are intended to form part of the present invention insofar as they are within the spirit and scope of the claims below. | Summary: A protective cover for bags which may be carried by means of a harness or waist belt such as shoulder bags, fanny packs and the like is described. In order to provide additional protection against inclement weather, the bag comprises a pocket having a fastener and into which a cover of flexible water resistant material may be folded when the cover is stored. When additional protection for the bag is desired the pocket is opened and the cover unfolded from the pocket. The pocket contains the hinge joining the cover to the bag. The cover then extends around the bag to provide a water resistant covering extending over at least those sides of the bag which have openable flaps through which leakage may occur. The cover extends around but does not cover the harness so that the harness is still available for its intended use. | 4,425 | 172 | big_patent | en |
Summarize: The Liberal government announced new measures during the release of the 2016 budget to help assist with the debt load recent post-secondary graduates face before joining the workforce. They will take effect starting Tuesday. As of Nov. 1, students who have taken out a Canada Student Loan will not have to repay their debt until he or she is earning at least $25,000 per year, Employment and Social Development Canada announced in a press release. Students who are having difficulty meeting their monthly loan payments can apply for assistance through the Repayment Assistance Plan, the government said. READ MORE: Canada student loan program mistakenly forgives $113K to doctors, nurses Based on the individual’s financial situation, a borrower can apply for a reduced Canada Student Loan monthly payment, or for no payment at all, the government said in the statement. “The future prosperity of our country depends on young Canadians getting the education and training needed to succeed in the job market,” Employment Minister MaryAnn Mihychuk said in a statement. “As a result of this new measure, students will be better positioned to transition into the workforce after graduation.” The announcement follows increased support for students through the Canada Student Grants. On Aug. 1, the federal government announced a 50 per cent financial increase in Canada Student Grant amounts. READ MORE: Federal government may allow students to use travel points to repay loans As of late summer, full-time students from low-income families can receive from $2,000 to $3,000 per year, while part-time students from low-income families can receive anywhere from $1,200 to $1,800 per year. Students from middle-income families can receive $800 to $1,200 per year. According to Employment and Social Development Canada, about 750,000 Canadians were repaying their Canada Student Loans in 2013 and 2014, and about 234,000 of those used the Repayment Assistance Plan. TORONTO — Many of this year’s new post-secondary graduates have left the academic world carrying tens of thousands of dollars in debt. Meantime, those heading to college and university this fall will soon contend with steep tuition rates that often result in a similar burden. While schools attempt to lessen the load by offering financial aid, average student debt appears to be climbing. So some institutions are also responding by beefing up their mental health services to help students cope with life in the red. “We’re worried about one type of debt — student debt — and we want to know how to pay it off as quickly as possible,” said Dillon Collet, who is about to enter his final year at the University of Toronto’s faculty of law and sat on the dean’s advisory committee on financial aid. The committee organized a financial aid workshop that discussed the psychology of debt. It was well-attended, Collet said, with about 60 students in the room and a lineup outside. The committee’s student representatives also pushed to have tuition fees — and their connection to student stress — to be discussed at the faculty council’s meeting each year, Collet said. “A lot of students suffer silently.” Estimates suggest average student debt in Canada is past the $25,000 mark. In 2013-14, graduates finished school with an average of $12,480 in federal loan debt, according to numbers from the Canada Student Loans Program. However, that figure doesn’t include provincial or private loans. An Ontario student graduating from a four-year university program, for example, shouldered an average of $22,207 in provincial debt in 2012-2013. That makes for a total debt load of more than $34,000 if they also borrowed the average sum from the federal government. The Canadian University Survey Consortium surveyed more than 18,000 graduating university students from 36 Canadian universities for its 2015 annual report. The average debt-ridden student owed $26,819. Such a debt load can have an impact on a student or graduate’s mental health, though only a small amount of published research exists on the apparent link. A 2015 journal paper analyzed data from a U.S. Bureau of Labour Statistics survey of more than 8,000 youth in the United States — where tuition fees are significantly higher than in Canada — to determine if debt load and psychological well-being were connected. “Students who took out more student loans were more likely to report poor mental health in early adulthood,” said one of the paper’s authors, Katrina M. Walsemann, an associate professor at the University of South Carolina. Canadian experts have also noticed a link, even though Canadian students don’t generally go into as much debt as their American cohorts. Jillian Yeung Do, York University’s director of student financial services, witnessed it while working with a student. While she couldn’t provide much detail for privacy reasons, she said she became really concerned about a student. “After that encounter, I decided that it would be a good idea to — for myself, personally, and as well for the entire team — to be trained in having these conversations with students,” she said. Students who took out more student loans were more likely to report poor mental health in early adulthood The university’s health educator taught the financial services staff how to identify students in distress, listen to them and provide proper referrals. York University also plans to launch a new financial literacy campaign soon, she said. The University of Toronto’s faculty of law staff, including its financial aid workers, will also have training on mental health issues next month, said Alexis Archbold, the assistant dean of the JD (juris doctor) program. She’s also the chair of the dean’s advisory committee on mental health and wellness, formed this past academic year. Archbold and the committee spent the year listening to students’ primary concerns. Unsurprisingly for a professional program, she said, high tuition and the anxiety of the corresponding debt load emerged as one of the common themes. The school’s new academic, personal and wellness co-ordinator will work with Archbold this summer to develop a wellness strategy, she said. The committee will continue to hear from students on how to improve the strategy, which seems to fall in line with at least some of what the students want. “We want a platform in which we can engage with the faculty and the administration,” said Collett, “and we can really talk about the nuts and bolts.” Being a college student in Canada is about to get a whole lot easier. Starting Tuesday, people who borrowed money to finance their higher education will not have to pay back their government loans until their yearly earnings exceed $25,000, CTV News reported. It's part of the Canada Student Loans Program's Repayment Assistance Plan. "The future prosperity of our country depends on young Canadians getting the education and training needed to succeed in the job market," MaryAnn Mihychuk, the minister of employment, workforce development and labor, said in a news release published Sunday. "As a result of this new measure, students will be better positioned to transition into the workforce after graduation." In addition to the $25,000 rule, the government announced that people who are having trouble paying off their debt can also request smaller monthly payments — or have them suspended entirely. The developments came just months after Canada moved in August to increase the amount of grant money it gave to low- and middle-income students. The measures will apply to the roughly 750,000 people making payments on their Canada Student Loans, according to the release. Last year, the average student graduating with loans was on the hook for $26,819, according to the Canadian University Survey Consortium, a group of institutions that regularly polls students. About half of respondents said they were in debt upon leaving university, and 40 percent of them said they had government student loans. Canada's tuition averages about $4,800 a year to the United States' $8,200, the Huffington Post reported. But students were still concerned. "We're worried about one type of debt — student debt — and we want to know how to pay it off as quickly as possible," Dillon Collet, who attended the University of Toronto, told the National Post earlier this year. "A lot of students suffer silently." | Summary: Canada's about to make it a lot easier for low-earning graduates to repay their college debt, Global News reports. A new plan allows those earning less than CAD $25,000 (USD $18,650) per year to defer payment on government loans until they secure a higher-paying job. Almost 750,000 young Canadians have some sort of student debt to deal with, Quartz reports. The new program will only apply to government-issued Canada Student Loans. The average Canadian student graduating college with student debt owes CAD $26,819 (approximately $20,000 in US dollars), according to the International Business Times. That's not bad compared to US students, who are graduating with an average debt of $35,000 these days. Canadians also pay about half as much in tuition costs as Americans do, on average. But that doesn't mean student debt isn't a burden to young Canadians-the National Post reports that universities are increasing mental-health services on campus, as the stress can silently eat away at some students. | 1,869 | 254 | multi_news | en |
Summarize: "I lay on my straw, but I could not sleep. I thought of the occurrences of the day. What chiefly struck me was the gentle manners of these people; and I longed to join them, but dared not. I remembered too well the treatment I had suffered the night before from the barbarous villagers, and resolved, whatever course of conduct I might hereafter think it right to pursue, that for the present I would remain quietly in my hovel, watching, and endeavouring to discover the motives which influenced their actions. "The cottagers arose the next morning before the sun. The young woman arranged the cottage, and prepared the food; and the youth departed after the first meal. "This day was passed in the same routine as that which preceded it. The young man was constantly employed out of doors, and the girl in various laborious occupations within. The old man, whom I soon perceived to be blind, employed his leisure hours on his instrument, or in contemplation. Nothing could exceed the love and respect which the younger cottagers exhibited towards their venerable companion. They performed towards him every little office of affection and duty with gentleness; and he rewarded them by his benevolent smiles. "They were not entirely happy. The young man and his companion often went apart, and appeared to weep. I saw no cause for their unhappiness; but I was deeply affected by it. If such lovely creatures were miserable, it was less strange that I, an imperfect and solitary being, should be wretched. Yet why were these gentle beings unhappy? They possessed a delightful house (for such it was in my eyes), and every luxury; they had a fire to warm them when chill, and delicious viands when hungry; they were dressed in excellent clothes; and, still more, they enjoyed one another's company and speech, interchanging each day looks of affection and kindness. What did their tears imply? Did they really express pain? I was at first unable to solve these questions; but perpetual attention, and time, explained to me many appearances which were at first enigmatic. "A considerable period elapsed before I discovered one of the causes of the uneasiness of this amiable family; it was poverty: and they suffered that evil in a very distressing degree. Their nourishment consisted entirely of the vegetables of their garden, and the milk of one cow, who gave very little during the winter, when its masters could scarcely procure food to support it. They often, I believe, suffered the pangs of hunger very poignantly, especially the two younger cottagers; for several times they placed food before the old man, when they reserved none for themselves. "This trait of kindness moved me sensibly. I had been accustomed, during the night, to steal a part of their store for my own consumption; but when I found that in doing this I inflicted pain on the cottagers, I abstained, and satisfied myself with berries, nuts, and roots, which I gathered from a neighbouring wood. "I discovered also another means through which I was enabled to assist their labours. I found that the youth spent a great part of each day in collecting wood for the family fire; and, during the night, I often took his tools, the use of which I quickly discovered, and brought home firing sufficient for the consumption of several days. "I remember, the first time that I did this, the young woman, when she opened the door in the morning, appeared greatly astonished on seeing a great pile of wood on the outside. She uttered some words in a loud voice, and the youth joined her, who also expressed surprise. I observed, with pleasure, that he did not go to the forest that day, but spent it in repairing the cottage, and cultivating the garden. "By degrees I made a discovery of still greater moment. I found that these people possessed a method of communicating their experience and feelings to one another by articulate sounds. I perceived that the words they spoke sometimes produced pleasure or pain, smiles or sadness, in the minds and countenances of the hearers. This was indeed a godlike science, and I ardently desired to become acquainted with it. But I was baffled in every attempt I made for this purpose. Their pronunciation was quick; and the words they uttered, not having any apparent connexion with visible objects, I was unable to discover any clue by which I could unravel the mystery of their reference. By great application, however, and after having remained during the space of several revolutions of the moon in my hovel, I discovered the names that were given to some of the most familiar objects of discourse: I learned and applied the words _fire_, _milk_, _bread_, and _wood_. I learned also the names of the cottagers themselves. The youth and his companion had each of them several names, but the old man had only one, which was _father_. The girl was called _sister_, or _Agatha_; and the youth _Felix_, _brother_, or _son_. I cannot describe the delight I felt when I learned the ideas appropriated to each of these sounds, and was able to pronounce them. I distinguished several other words, without being able as yet to understand or apply them; such as _good_, _dearest_, _unhappy_. "I spent the winter in this manner. The gentle manners and beauty of the cottagers greatly endeared them to me: when they were unhappy, I felt depressed; when they rejoiced, I sympathized in their joys. I saw few human beings beside them; and if any other happened to enter the cottage, their harsh manners and rude gait only enhanced to me the superior accomplishments of my friends. The old man, I could perceive, often endeavoured to encourage his children, as sometimes I found that he called them, to cast off their melancholy. He would talk in a cheerful accent, with an expression of goodness that bestowed pleasure even upon me. Agatha listened with respect, her eyes sometimes filled with tears, which she endeavoured to wipe away unperceived; but I generally found that her countenance and tone were more cheerful after having listened to the exhortations of her father. It was not thus with Felix. He was always the saddest of the groupe; and, even to my unpractised senses, he appeared to have suffered more deeply than his friends. But if his countenance was more sorrowful, his voice was more cheerful than that of his sister, especially when he addressed the old man. "I could mention innumerable instances, which, although slight, marked the dispositions of these amiable cottagers. In the midst of poverty and want, Felix carried with pleasure to his sister the first little white flower that peeped out from beneath the snowy ground. Early in the morning before she had risen, he cleared away the snow that obstructed her path to the milk-house, drew water from the well, and brought the wood from the out-house, where, to his perpetual astonishment, he found his store always replenished by an invisible hand. In the day, I believe, he worked sometimes for a neighbouring farmer, because he often went forth, and did not return until dinner, yet brought no wood with him. At other times he worked in the garden; but, as there was little to do in the frosty season, he read to the old man and Agatha. "This reading had puzzled me extremely at first; but, by degrees, I discovered that he uttered many of the same sounds when he read as when he talked. I conjectured, therefore, that he found on the paper signs for speech which he understood, and I ardently longed to comprehend these also; but how was that possible, when I did not even understand the sounds for which they stood as signs? I improved, however, sensibly in this science, but not sufficiently to follow up any kind of conversation, although I applied my whole mind to the endeavour: for I easily perceived that, although I eagerly longed to discover myself to the cottagers, I ought not to make the attempt until I had first become master of their language; which knowledge might enable me to make them overlook the deformity of my figure; for with this also the contrast perpetually presented to my eyes had made me acquainted. "I had admired the perfect forms of my cottagers--their grace, beauty, and delicate complexions: but how was I terrified, when I viewed myself in a transparent pool! At first I started back, unable to believe that it was indeed I who was reflected in the mirror; and when I became fully convinced that I was in reality the monster that I am, I was filled with the bitterest sensations of despondence and mortification. Alas! I did not yet entirely know the fatal effects of this miserable deformity. "As the sun became warmer, and the light of day longer, the snow vanished, and I beheld the bare trees and the black earth. From this time Felix was more employed; and the heart-moving indications of impending famine disappeared. Their food, as I afterwards found, was coarse, but it was wholesome; and they procured a sufficiency of it. Several new kinds of plants sprung up in the garden, which they dressed; and these signs of comfort increased daily as the season advanced. "The old man, leaning on his son, walked each day at noon, when it did not rain, as I found it was called when the heavens poured forth its waters. This frequently took place; but a high wind quickly dried the earth, and the season became far more pleasant than it had been. "My mode of life in my hovel was uniform. During the morning I attended the motions of the cottagers; and when they were dispersed in various occupations, I slept: the remainder of the day was spent in observing my friends. When they had retired to rest, if there was any moon, or the night was star-light, I went into the woods, and collected my own food and fuel for the cottage. When I returned, as often as it was necessary, I cleared their path from the snow, and performed those offices that I had seen done by Felix. I afterwards found that these labours, performed by an invisible hand, greatly astonished them; and once or twice I heard them, on these occasions, utter the words _good spirit_, _wonderful_; but I did not then understand the signification of these terms. "My thoughts now became more active, and I longed to discover the motives and feelings of these lovely creatures; I was inquisitive to know why Felix appeared so miserable, and Agatha so sad. I thought (foolish wretch!) that it might be in my power to restore happiness to these deserving people. When I slept, or was absent, the forms of the venerable blind father, the gentle Agatha, and the excellent Felix, flitted before me. I looked upon them as superior beings, who would be the arbiters of my future destiny. I formed in my imagination a thousand pictures of presenting myself to them, and their reception of me. I imagined that they would be disgusted, until, by my gentle demeanour and conciliating words, I should first win their favour, and afterwards their love. "These thoughts exhilarated me, and led me to apply with fresh ardour to the acquiring the art of language. My organs were indeed harsh, but supple; and although my voice was very unlike the soft music of their tones, yet I pronounced such words as I understood with tolerable ease. It was as the ass and the lap-dog; yet surely the gentle ass, whose intentions were affectionate, although his manners were rude, deserved better treatment than blows and execration. "The pleasant showers and genial warmth of spring greatly altered the aspect of the earth. Men, who before this change seemed to have been hid in caves, dispersed themselves, and were employed in various arts of cultivation. The birds sang in more cheerful notes, and the leaves began to bud forth on the trees. Happy, happy earth! fit habitation for gods, which, so short a time before, was bleak, damp, and unwholesome. My spirits were elevated by the enchanting appearance of nature; the past was blotted from my memory, the present was tranquil, and the future gilded by bright rays of hope, and anticipations of joy." | Summary: The creature begins by recalling his deep and tormenting desire to speak to the cottagers, who impress him with their gentleness and simplicity. He hesitates, however, as he is fearful of incurring the same kind of disgust and cruelty that he experienced at the hands of the villagers. In observing the family, he discovers that they suffer from great poverty. The two young people are very generous with the old man, and often go hungry so that he might eat. The creature, greatly touched by this, ceases to take from their store of food, even though he is terribly hungry himself. He begins to cut their firewood for them, so that the young man, whose name is Felix, will no longer have to. The creature spends the entire winter watching the cottagers, and grows to love each of them passionately. He attempts to learn their language, which he regards as "a godlike science. At first, he makes little progress. Every act of the cottagers, however banal, strikes him as miraculous: to watch them read aloud, or play music, or simply speak to one another, delights him immeasurably. Though he realizes that they are terribly unhappy, he cannot understand why: to him, the family seems to possess everything one could want: a roof, a fire, and the glories of human companionship. Upon seeing his own reflection in a pool of water, the creature becomes even more certain that he will never know such happiness; he finds his own face to be monstrous, capable of inspiring only fear or disgust. Nonetheless, he dreams of winning the love of the cottagers by mastering their language; in this way, he hopes, he can reveal to them the beauty and gentleness of his soul. | 2,816 | 386 | booksum | en |
Summarize: New York police fear that a crazed hatchet attack on four police officers in Jamaica, Queens, today could be linked to terrorism. Suspect Zale Thompson, 32, pictured in surveillance footage, was shot dead on the scene after slashing one cop in the arm and the other in the head at around without warning about 2pm. The officer struck in the head was critically injured. A 29-year-old female bystander a half-a-block away from the attack was critically injured after being shot by an errant police round. She is currently recovering from surgery at Jamaica Hospital and is listed in 'grave' condition. SCROLL DOWN FOR VIDEO. Act if terror?: Suspect Zale Thompson can be seen swinging a hatchet towards police officers at 2 p.m. on Thursday afternoon in Jamaica, Queens. Without warning: Zale Thompson attacked officers without warning or uttering a single word. Bloodied hatchet: The 18 and 1/2 inch hatchet is dripping with blood after Zale Thompson used it to slash a police officer in the head and the other in the arm. Police say they were investigating whether Thompson's attack on the cops was linked to Islamic terrorism. ISIS has urged fighters to launch lone wolf attacks in the United States. Thompson's Facebook page features a photograph of a man dressed in Middle Eastern garb and a cover photo displaying Arabic writing. Two attacks in Canada this week by radicalized converts to Islam have killed two Canadian soldiers. In one, a man ran down two soldiers in his car in Quebec, killing one, before being shot dead. On Wednesday a convicted felon ambushed a soldier outside Canadian Parliament, fatally wounding him, before running the Parliament building and opening fire. DNA Info reports that on Thursday afternoon a freelance photographer approached the group of rookie cops and asked to take their photograph. As the officers were posing for the camera, Thompson charged towards them swinging an 18.5 inch hatchet without uttering a single word. One 24-year-old officer was slashed in the arm. Another 25-year-old officer was slashed in the back of head and taken to Jamaica Hospital where he is being treated in critical condition, reports CBS. The two remaining police shot at Thompson who dropped his hatchet then died at the scene. Police Commissioner Bill Bratton said he's not ruling out terrorism especially in the wake of recent terror attacks in Canada, reports CNN. 'There is nothing we know as of this time that would indicate that were the case. I think certainly the heightened concern is relative to that type of assault based on what just happened in Canada,' said Bratton. CNN reports that Thompson has a criminal record in California and that he was discharged from the U.S. Navy for misconduct. Details of his criminal record and his misconduct are not known at this time. His Facebook page says that Thompson graduated from Columbia Teacher's College and that he resides in Queens. CNN reports that New York police were alerted to be on the lookout for random attacks following Thursday's incident. DNA Info spoke with witnesses on the scene. The scene: NYPD officers shot dead a man armed with a hatchet who attacked them Thursday afternoon and critically injured a 29-year-old female bystander in the process. Innocent bystander: Police gather around a woman who was struck by an errant bullet discharged by a cop. Praise: Police Commissioner Bill Bratton hold up a photo of the scene on Thursday and says that the group of recent Police Academy graduates handled the situation as best they could. 'We heard pop, pop, pop, pop,' said Rafael, 44, who works at Overseas Travel nearby where the incident occurred. 'She was screaming,"'Help me." She couldn't get up,' said Ericka Babb, a medical assistant at Priority Medical Center in Queens. 'We were way too scared,' said Rafael. Officers say they shot the hatchet-yielding suspect but it’s not clear how many rounds were fired. 'It was a completely unprovoked attack,' said NYPD Chief Kim Royster, a department spokeswoman. Police Commissioner Bill Bratton said during a news conference that all of the police involved are recent graduates of this summer's Police Academy class. 'Three rookie cops, absolutely modest about what happened today and what they did,' de Blasio said. During the conference Bill De Blasio lauded the officers' training and their fast response to the unprovoked attack. Dead:The body of the attacker lays covered on Jamaica Avenue near 162nd street in the borough of Queens in New York where the fight occurred on Thursday | Summary: The suspect, identified as Zale Thompson, lunged at police with a hatchet in Queens. Authorities are investigating whether Thompson was motivated by Islamic terrorists calling for attacks in the US. An officer was slashed in the head and another one was slashed in the arm before one officer was able to fatally shoot the attacker. A 29-year-old female bystander was critically injured after being shot by an errant police round and is listed in 'grave' condition. Both officers are being treated and one was listed in critical condition. Thompson has a criminal record in California and was discharged from the U.S. Navy for misconduct but authorities have not revealed his record nor have they detailed his Naval discharge. | 1,048 | 153 | cnn_dailymail | en |
Summarize: By. Rob Cooper, Graham Smith and Daniel Martin. PUBLISHED:. 03:50 EST, 18 April 2012. |. UPDATED:. 18:42 EST, 18 April 2012. Companies were yesterday urged to ‘hire a hoodie’ in an attempt to get more young Britons off the dole queue. Employment Minister Chris Grayling called on bosses to give local youths a chance instead of hiring experienced Eastern Europeans. He claimed that despite their lack of experience, ‘surly young men can turn into excited and motivated employees’. 'Hire a hoodie': Employment Minister Chris Grayling (left) today called on firms to hire local youths instead of Eastern Europeans. His comments echoed David Cameron's 2007 'hug a hoodie' remark, which was infamously ridiculed by Manchester teen Ryan Florence (right) The minister spoke on the day figures revealed that unemployment had. fallen slightly across the country. But many of the new jobs are being. taken by migrants. The figures also showed that record numbers of men are being forced to. accept part-time work because they can’t find full-time jobs. Mr Grayling said it was ‘easy’ for companies to hire Eastern Europeans,. who tended to be older and more experienced than many Britons seeking. work. Speaking to the Policy Exchange think-tank in London, he said: ‘But. those who look closer to home can find gems too. Falling: The number of people out of work dropped by 35,000 in the last quarter - yet the number of people claiming Jobseeker's Allowance actually increased. Often the surly young. man in a hoodie who turns up looking unwilling to work can turn into an. exciting and motivated employee. ‘It’s all about the explanations that they have, and the place they come. from. And employers who give them that chance find it enormously. rewarding. ‘So I stand foursquare behind my hope that British employers will put local recruits first.’ In a wide-ranging speech on employment issues, Mr Grayling - whose. comments echoed David Cameron’s call for people to ‘hug a hoodie’ while. in Opposition - also criticised companies who set up call centres. abroad, calling them ‘mad’. He said: ‘We all know how frustrating it can. be speaking to a call centre operator overseas who works from a set. script, but doesn’t get what your problem is.’ The figures, from the Office for National Statistics, also revealed that. the number of full-time workers actually fell 27,000 to 21.2million,. showing how the unemployment drop is being fuelled by the ballooning. ‘Part-Time Britain’ trend. There were 80,000 more part-time workers between December and February, taking the total to 7.9million. Of those, the ONS figures revealed that 1.4million have only taken. part-time work after failing to get a full-time job - with the most. dramatic increase in this category among men. The army of men working part-time following a fruitless search for. full-time employment has increased to 626,000, the largest number since. records began 20 years ago. It has more than doubled since the credit. crunch struck in 2007, and there are fears it will keep on climbing. John Philpott, of the Chartered Institute of Personnel and Development,. said: ‘For these men, it is a choice between a part-time job and being. unemployed.’ Jobs crisis: There will be almost one million people who are 'long-term unemployed' by the end of the year. Almost a million people will have been out of work for more than a year by the end of 2012, according to new research. The IPPR think tank said another 107,000 people will join the ranks of the long-term unemployed in the coming months, taking the total to its highest level since 1995. The report, said long-term unemployment was the 'hidden crisis' facing the UK economy. Tony Dolphin, the IPPR's chief economist, said: 'Long-term unemployment is the hidden crisis of the slowest ever economic recovery in the UK. 'While the youth contract is designed to help young people out of work for more than a year, the Work Programme has only been able to secure employment for about a third of jobseekers on the programme. 'On current progress, just two-thirds of people out of work for a year will not get work in the following two years. Government policy is not keeping pace with joblessness. 'Unemployment is not going to fall until the middle of 2013 and the number of people out of work for more than a year is going to grow to almost a million the end of this year. The longer someone is unemployed, the less likely they are to ever return to work. 'The government should guarantee everyone who has been unemployed for more than a year a job at the minimum wage in local government or the voluntary sector. But with that right should come the responsibility to take that job or risk losing their benefits.' The reports follow news that almost 500 jobs are under threat after supermarket milk supplier Dairy Crest announced plans to close two dairies. The proposed closures involve a glass bottling dairy at Aintree, where 220 people work, and a site at Fenstanton in Cambridgeshire employing 250 people. The Unite union described it as 'devastating news.' Aquascutum, the 160-year-old British clothing retailer which has dressed Winston Churchill and the Queen Mother, collapsed into administration yesterday, jeopardising 250 jobs. The business was bought by Jaeger's owner Harold Tillman and its chief executive Belinda Earl in 2009 but it continued to make'significant losses' despite their efforts to turn it around, according to administrators at FRP Advisory | Summary: Employment Minister Chris Grayling said hiring Eastern Europeans over local youths was 'easy' option. Figures reveal 35,000 fall in unemployment. Overall jobless rate now stands at 8.3%. 1.4million people only work part-time as people struggle to find full-time jobs. Number of part-time employees soared by 89,000 in the last three months. 8,000 more women out of work than three months ago. | 1,377 | 109 | cnn_dailymail | en |
Summarize: TECHNICAL FIELD This invention relates to the harvesting arts and, more particularly, to a harvesting header of a combine or the like which can be tilted laterally with respect to a generally fore-and-aft axis so that the header can accommodate changes in ground contours experienced between opposite lateral ends of the header. BACKGROUND ART Harvesting headers such as those utilized on combines have become increasingly large in recent years in order to promote harvesting efficiencies by diminishing the number of passes the operator must make across a field. By increasing the length of such headers, the width of swath taken by the combine as it moves across the field is correspondingly increased. At the same time, however, the increased length of such headers increases the likelihood that the ground contour adjacent one end of the header will not be the same as that at the opposite end. Moreover, the wheels on one side of the tractor of the combine may run in a furrow while the wheels on the opposite side may run along a ridge, for example. If the header cannot be tilted transversely about a fore-and-aft axis under such circumstances, one lateral end of the header will be dropped down while the opposite lateral end will be raised up as the tractor tilts down on one side. This type of action can be particularly unacceptable where a crop such as soybeans is being harvested since, in that circumstance, the plants must be severed virtually directly at ground level in order to be assured that a maximum harvesting of the ground-level bean pods is obtained. As is apparent, if one end of the header is raised up because the opposite side of the combine is traveling in a furrow, many beans will be missed at the raised end because the plants will simply be severed too high off the ground. Various so-called "sidehill combines" are presently available on the market in which the headers can be tilted relative to the throat portions of the machines. However, to be best of my knowledge, all of such sidehill machines are arranged so that the header swings about a pivot that is located along the top of the throat as opposed to the bottom thereof as in the present invention. Moreover, to my knowledge there is no present arrangement for converting machines with non-tilting headers into tilting header machines according to the concepts of the present invention. SUMMARY OF THE PRESENT INVENTION Accordingly, one important object of the present invention is to provide a combine or the like in which the header thereof may be tilted in either of two lateral directions about a generally fore-and-aft pivot located adjacent the lowermost section of the receiving throat of the combine so as to obtain the significant benefits flowing from such a lower pivoting arrangement. As will be elaborated upon hereinafter, one such benefit resides in the fact that most crop material being transferred from the header to the combine throat travels along the lower extremity of that region. Because the pivot is located closely adjacent the primary crop flow, disalignment of the relatively rotatable, tubular components through which the crop flows during header tilting does not detract from smooth, even crop flow. In further accordance with the concepts of the present invention, a pair of tubular adapter components are provided, one of which is adapted for quick detachable mounting onto the throat and the other of which is adapted for quick detachable mounting onto the header. The two components are rockably interconnected by a pivot adjacent their lower extremities which establishes general axial registration between the two components and provides for relative rocking movement therebetween so as to in turn permit the header to tilt laterally with respect to the throat. Special retaining means remote from the pivot adjacent the upper extremity of the throat assists in preventing axial separation of the components during rocking movement of the header to its tilted positions, and an auxiliary feeder is located within the passage defined by the two aligned components to augment feeding of crop material from the header into the throat. A flexible flap covers the joint adjacent the pivot point between the two components so as to additionally facilitate crop flow even during those times that the components are in a rocked condition relative to each other. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic top plan view of a combine or like harvesting machine employing the principles of the present invention; FIG. 2 is a fragmentary, enlarged side elevational view of the combine showing in particular the adapter assembly located between the header and the throat portions thereof; FIG. 3 is a fragmentary, transverse, cross-sectional view through the throat portion of the combine taken substantially along line 3--3 of FIG. 2 but showing the header in one laterally tilted extreme position thereof; FIG. 4 is an end elevational view of the adapter assembly of the present invention from the front thereof with the header of the combine removed; FIG. 5 is a top plan view thereof; FIG. 6 is a cross-sectional view through the adapter assembly taken substantially along line 6--6 of FIG. 4; FIG. 7 is a fragmentary, enlarged, cross-sectional view of one of the retainers for the two components of the adapter assembly, said view being taken along line 7--7 of FIG. 3; and FIG. 8 is a fragmentary, enlarged, cross-sectional view of the other retainer taken substantially along line 8--8 of FIG. 3. DETAILED DESCRIPTION The harvesting machine 10 such as a combine includes a prime mover or tractor 12 adapted to receive harvested crop materials such as, for example, soybeans, to separate the stalks or "chaff" from the beans themselves, to discharge the chaff onto the ground, and to retain the beans in a suitable reservoir until such time as it is appropriate to unload the beans into an awaiting truck or the like. The harvesting header 14 comprising another portion of the combine 10 is spaced forwardly from the tractor 12 and is adapted for severing the crop materials from the ground, collecting such severed materials, and delivering the same rearwardly into a throat portion 16 of the combine 10 for conveyance through the latter into the tractor 12. Details of the tractor 12, the header 14, and the throat 16 will not be set forth herein in view of the fact that such structures may take several different forms, and such details are not germane per se to the principles of the present invention. In accordance with the principles of the present invention, the combine 10 is provided with an adapter assembly broadly denoted by the numeral 18 located between the header 14 and the throat 16 and adapting the header 14 for lateral tilting movement in either of two opposite directions about a generally fore-and-aft axis relative to the normal path of travel of the combine 10. The adapter assembly 18 includes a first tubular component 20 having a rectangular, cross-sectional configuration. Opposite side members 22 of the component 20 are provided with upwardly and rearwardly projecting hooks 24 having downwardly opening notches 26 adapted to receive corresponding, laterally outwardly projecting pins 28 on the throat 16 such as to detachably mount the component 20 onto the throat 16. Sockets 30 at the bottom of the component 20 releasably receive forwardly projecting studs 32 on the throat 16 so as to further attach the component 20 to the throat 16, there being mechanism (not shown) in association with the sockets 30 and the studs 32 for locking the latter in place. The cooperating mounting means thus defined by the hooks 24, pins 28, sockets 30 and studs 32 are so disposed as to retain the component 20 in substantial axial registration with the throat 16 and to hold the component 20 against movement relative to the throat 16. The adapter assembly 18 further includes a second tubular component 34 of transversely rectangular configuration. Components 20 and 34 are virtually identical, except for the fact that component 34 is wider, as seen from the side thereof, than the component 20. Coupling means 36 in the nature of a pivot 38 is provided adjacent the lower extremities of the components 20 and 34 to pivotally interconnect those two structures for relative rocking movement about a generally fore-and-aft axis defined by the pivot 38. As illustrated in FIGS. 3 and 4, the pivot 38 is located in a symmetrical position with respect to the opposite sides of the adapter assembly 18 and, because of its low disposition, is positioned below the crop delivery passage 40 defined interiorally of the components 20 and 34 as a result of their tubular natures. The coupling means 36 is operable to locate the components 20 and 34 in general axial registration with one another and is also operable to retain such components against axial separation along the lower extremities thereof. Additional retaining means denoted broadly by the numeral 42 is located remote from the coupling means 36 along the top extremities of the components 20,34 for assisting in holding the latter against axial separation without adversely affecting the ability of the component 34 to rock about the pivot 38 relative to the component 20. In this regard, the retaining means 42 includes a pair of laterally spaced, upstanding plates 44 on the top, transverse member 46 of the component 20, such plates 44 being edgewise aligned in the same transverse plane across the adapter assembly 18. Each of the plates 44 is clamped between a pair of corresponding roller wheels 48 that are in turn carried by the other component 34 such that, in effect, the component 34 is attached at the top to the component 20 via the plates 44 and the roller wheels 48. One of the roller wheels 48 of each plate 44 is carried by an upstanding, generally L-shaped lug 50 on the top member 52 of the component 34, said arrangement being illustrated in detail in FIG. 8. As seen in that figure, the lug 50 has a generally upright pivot unit 54 for the roller wheel 48 attached via screws 56 to one side thereof such that the axis of rotation of the roller wheel 48 is similarly located on the front side of the lug 50, the latter also having a slot 58 through which the roller wheel 48 may project into abutting contact with the proximal face of the plate 44. The other roller wheel 48 of each pair thereof is somewhat similarly mounted on inverted, generally U-shaped bracket 60 having one leg 62 thereof rigid to the top member 52 of component 34 and a depending, opposite leg 64 thereof positioned rearwardly of the corresponding, proximal plate 44. A pivot unit 66 on the leg 64 adapts the corresponding roller wheel 48 for rotation about a generally upright axis, the unit 66 being attached to the rear side of the leg 64 by screws 68 such that the axis of rotation of the corresponding roller wheel 48 is correspondingly so located. A slot 70 in the leg 64 permits the roller wheel 48 to project through the leg 64 into abutting relationship with the proximal rear face of the corresponding plate 44. Note in FIG. 2 that the bight 72 of the U-shaped bracket 60 may be adjusted in length via a slot-and-bolt assembly 74 so as to permit adjustment of the clamping pressure applied by the roller wheels 48 against opposite faces of the corresponding plate 44. The header 14 is provided with rearwardly projecting hooks 76 on opposite sides thereof which would normally be adapted to receive the pins 28 on the throat 16 but which, in accordance with the principles of the present invention, are instead adapted to receive cooperatingly disposed, laterally outwardly projecting pins 78 on the component 34 adjacent the upper extremities thereof. A notch 80 in each of the hooks 76 opens downwardly so as to readily receive the corresponding pin 78. Rearwardly facing sockets 82 adjacent the lower extremities of the header 14 on opposite sides thereof are disposed to normally receive the forwardly projecting studs 32 of the throat 16 but, in accordance with the present invention, they are also adapted to receive similarly located, forwardly projecting studs 84 on the component 34. Suitable locking mechanism (not shown) may be utilized in connection with the sockets 82 and the studs 84 for releasably latching the two in interlocked engagement with one another. By virtue of this arrangement, it should be clearly apparent that the header 14 is firmly secured to the component 34 in such a way that there is no relative movement between the two. As illustrated in particular in FIGS. 3, 4 and 6, a rotary feeder 86 is positioned within the passage 40 for the purpose of assisting in conveyance of crop materials from the header 14 through the adapter assembly 18 and into the throat 16. Preferably, the feeder 86 includes a transverse shaft 88 spaced above the bottom transverse member 90 of the component 34 and a plurality of circumferentially spaced paddles 92 rigidly affixed to the shaft 88 for rotation with the latter. As illustrated in FIG. 4 and also in FIG. 3, the shaft 88 projects outwardly beyond one side of the component 34 for connection to driving apparatus as will now be explained. As illustrated in FIGS. 1 and 3, the projecting end of the shaft 88 of feeder 86 is provided with a U-joint 94 that is in turn connected to a drive shaft 96 extending along the backside of the header 14. At the outboard end of the shaft 96, a second U-joint 98 connects the latter to a driven sheave 100 drivingly coupled with an upwardly disposed sheave 102 via a belt 104. Sheave 102 is fixed to a short, transverse stub shaft 106 projecting in an outboard direction to an additional sheave 108 entrained by a belt 110 leading to driven parts of the header 14, i.e., the reel 112 shown in FIG. 1, a sickle (not shown) disposed beneath the reel 112, and a center-gathering auger 114. At its inboard end, the stub shaft 106 is provided with a U-joint 116 that is in turn connected to a telescoping drive shaft 118 having a U-joint 120 at its inboardmost end located rearwardly adjacent the upper regions of the component 20. The U-joint 120 is in turn connected to a laterally outwardly projecting shaft 122 of the throat 16 which is driven by apparatus not shown. Power for tilting the header 14 in either lateral direction about the axis of pivot 38 is provided by a hydraulic piston-and-cylinder unit 124 forming a further part of the adapter assembly 18 and situated on top of the components 20,34. In the illustrated embodiment, the ram end 126 of the unit 124 is attached to an upstanding lug 128 on the top member 52 of component 34, while the opposite cylinder end 130 of the unit 124 is attached to a downturned ear 132 of the proximal plate 44, said ear 132 extending transversely forwardly from the plate 44 across the line of intersection between the two components 20,34 such as to permit the unit 124 to interconnect components 20,34 without extending in an oblique disposition across such intersection between the components. As illustrated perhaps most clearly in FIG. 6, the rearward component 20 has a stepped down, forwardmost edge 134 with respect to the proximal rearward edge 136 of the component 34. An elastomeric flap 138 spans the component 34 along said rear edge 136 thereof and projects beyond the same into overhanging relationship to the edge 134 of component 20 such as to provide a relatively smooth transition between components 20 and 34 in that location notwithstanding the angular disalignment of the two components during tilting of the header 14 relative to the throat 16. OPERATION Operation of the combine 10, and in particular the adapter assembly 18, should be apparent from the foregoing detailed description. Certain aspects may be elaborated upon, however, as follows. As above explained, the harvesting parts of the header 14 are provided with driving power from the throat 16 via the telescoping drive shaft 118. Additionally, the feeder 86 within the component 34 of adapter assembly 18 is rotated in a counterclockwise direction viewing FIG. 6 by the drive shaft 96 which takes off power from the shaft 118 in the manner above described and as shown in FIG. 3. Consequently, crop materials that are gathered to the center of the header 14 by the auger 114 and are then delivered rearwardly to the passage 40 of adapter assembly 18 are acted upon by the feeder 86 to the extent necessary to insure continued flow of the crop materials into the throat 16, at which location additional conveying mechanism not shown takes over and moves the materials rearwardly into the tractor portion 12 of the combine for further processing. Normally, the header 14 will be maintained in a level condition, substantially perpendicular to an upright plane through the tractor 12 and throat 16. However, if, for example, it is necessary or desirable for any reason to tilt the header 14, such may be immediately accomplished by actuating the piston-and-cylinder unit 124 to either extend or retract the same from its nominal position illustrated in FIGS. 4 and 5. If the unit 124 is contracted, the header 14, together with the front component 34, will swing in a counterclockwise direction viewing FIG. 3 about the axis of pivot 38. This attitude may be maintained along the full length of a crop row if necessary without adversely affecting the smooth flow of material from the header 14 into the throat 16. This is particularly well shown by FIG. 3 wherein it may be seen that because the pivot 38 is disposed centrally along the bottom of the components 20,34 instead of along the top thereof, the corresponding lower regions of components 20,34 remain substantially registered with one another even though the components 20,34 are rotated with respect to each other. Since the bulk of crop material flow is indeed along the lower portion of the passage 40 as opposed to the top thereof, this becomes a significant feature insofar as promoting the smooth and uninterrupted flow of materials from the header 14 to the throat 16 is concerned. Furthermore, the flap 138 is of assistance, as well as is the fact that the forwardmost edge 134 of the component 20 is stepped down with respect to the corresponding rearmost edge 136 of the component 34. Consequently, even during rather severe tilting of the header 14, no impediment to smooth crop flow is presented at the interface of the components 20 and 34. It is also important to point out that the quick attach and quick detach nature of the header 14 is not sacrificed by the present invention. In this regard, note that the pins 78 and studs 84 associated with the front component 34 still permit the header 14 to be quickly installed and removed as may be necessary or desirable. | Summary: The header or platform of a harvesting machine such as a combine is tiltable laterally relative to the throat of the combine about a lower, fore-and-aft extending pivot located adjacent a normally lower, forwardmost section of the throat so that variations in ground contour between opposite lateral ends of the header can be accommodated. A hydraulic piston-and-cylinder unit provides remotely operable, powered tilting, and a special adapter assembly renders existing combines having non-tilting headers capable of achieving the aforementioned header tilt. One tubular component of the assembly is adapted to be detachably mounted onto the throat while the other tubular component of the assembly is adapted to be detachably mounted onto the header, there being a lower pivot between the two components providing the relative rocking therebetween to present the desired tiltability of the header relative to the throat. | 4,647 | 197 | big_patent | en |
Summarize: A father and son were facing child porn charges after sordid material was found at their home during a separate sexual assault investigation involving a 14-year-old girl. Police had executed a search warrant at the Midland Park, New Jersey home of Richard Stoldt, 58, while investigating his 19-year-old son James on Tuesday. According to prosecutors, the 14-year-old girl recently told a friend that James assaulted her when she was 13. Richard Stoldt (right), 58, and his son James (left), 19, were arrested for possessing child pornography that was discovered during a sexual assault investigation allegedly involving James and a 14-year-old girl. The girl was interviewed by police after the friend contacted authorities and James Stoldt was subsequently arrested, according to NBC 4. Computers that were seized from the father and son's home revealed that they were each independently accessing child pornography, according to Bergen County Prosecutor John L. Molinelli. 'Computer media used by each, separate and distinct from one another, were found to contain images depicting the sexual exploitation of children,' Molinelli said in a statement, according to NJ.com. Richard Stoldt, a software engineer, was arrested on a charge of child endangerment and was released on his own recognizance, meaning he did not need to pay bail after agreeing in writing to appear for all of his court proceedings. His son was arrested on sexual assault and child endangerment charges and is in custody at Bergen County Jail, where his bail was set at $125,000. According to prosecutors, computers seized from the home revealed that father (right) and son were each independently accessing child pornography. James Stoldt (left) has also been charged with sexual assault | Summary: Police executed a search warrant at Midland Park home of Richard Stoldt, 58, after arresting his 19-year-old son James. Alleged victim recently told a friend that James assaulted her when she was 13, according to prosecutors. The 14-year-old girl was interviewed by police after the friend told authorities. Computers seized from the father and son's home allegedly revealed they were both independently accessing child porn. Both were charged with child endangerment and James Stoldt was also charged with sexual assault. | 409 | 124 | cnn_dailymail | en |
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