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  • richardmitnick 7:40 am on October 12, 2016 Permalink | Reply
    Tags: , , Medicine, ,   

    From SLAC: “X-rays Reveal New Path In Battle Against Mosquito-borne Illness” 

    SLAC Lab

    The mosquito larvicide BinAB is composed of two proteins, BinA (yellow) and BinB (blue). Inside bacterial cells, BinAB naturally forms nanocrystals. Using these crystals and the intense X-ray pulses produced by SLAC’s Linac Coherent Light Source, scientists shed light on the three-dimensional structure of BinAB and its mode of action. (SLAC National Accelerator Laboratory)

    September 28, 2016

    SLAC’s X-ray Laser Provides Clues to Engineering a New Protein to Kill Mosquitos Carrying Dengue, Zika

    Structural biology research conducted at the U.S. Department of Energy’s SLAC National Accelerator Laboratory has uncovered how small insecticidal protein crystals that are naturally produced by bacteria might be tailored to combat dengue fever and the Zika virus.

    SLAC’s X-ray free-electron laser – the Linac Coherent Light Source (LCLS), a DOE Office of Science User Facility – offered unprecedented views of the toxin BinAB, used as a larvicide in public health efforts against mosquito-borne diseases such as malaria, West Nile virus and viral encephalitis.


    The larvicide is currently ineffective against the Aedes mosquitos that transmit Zika and dengue fever, and therefore not used to combat these species of mosquitos at this time. The new information provides clues to how scientists could design a composite toxin that would work against a broader range of mosquito species, including Aedes.

    Today, Nature published the study.

    “A more detailed look at the proteins’ structure provides information fundamental to understanding how the crystals kill mosquito larvae,” said Jacques-Philippe Colletier, a scientist at the Institut de Biologie Structurale in Grenoble, France and lead author on the paper. “This is a prerequisite for modifying the toxin to adapt it to our needs.”

    Selective Mosquito Control, Courtesy of Bacteria

    The BinAB crystals are produced by Lysinibacillus sphaericus bacteria, which release the crystals along with spores at the end of their life cycle. Mosquito larvae eat the crystals along with the spores, and then die.

    BinAB is inactive in the crystalline state and does not work on contact. For the crystals to dissolve, they must be exposed to alkaline conditions, such as those in a mosquito larva’s gut. The binary protein is then activated, recognized by a specific receptor at the surface of cells and internalized.

    Because Aedes larvae can evade one of these steps of intoxication, they are resistant to BinAB. These larvae do not express the correct receptors at the surface of their intestinal cells. Many other insect species, small crustaceans and humans also lack these receptors, as well as alkaline digestive systems.

    “Part of the appeal is that the larvicide’s safe because it’s so specific, but that’s also part of its limitation,” said Michael Sawaya, a scientist at the University of California, Los Angeles-DOE Molecular Biology Institute and co-author on the paper.

    For public health officials who want to prevent mosquito-borne disease, BinAB could also offer an alternative for controlling certain species of mosquitos that have begun to show resistance to other forms of chemical control.

    Creating a Tailored Insecticide

    The research team already knew the larvicide is composed of a pair of proteins, BinA and BinB, that pair together in crystals and are later activated by larval digestive enzymes.

    In the LCLS experiments, they learned the molecular basis for how the two proteins paired with each other – each performing an important, unique function. Previous research had determined that BinA is the toxic part of the complex, while BinB is responsible for binding the toxin to the mosquito’s intestine. BinB ushers BinA into the cells; once inside, BinA kills the cell.

    The scientists also identified four “hot spots” on the proteins that are activated by the alkaline conditions in the larval gut. All together, they trigger a change from a nontoxic form of the protein to a version that is lethal to mosquito larvae.

    Using the information gathered during the crystallography study, the research team has already begun to engineer a form of the BinAB proteins that will work against more species of mosquitos. This is ongoing work at Institut de Biologie Structurale, UCLA, University of California, Riverside and SLAC.

    Solving the Structure

    Only coarse details were known about the unique three-dimensional structure and biological behavior of BinAB prior to the experiment at LCLS.

    “We chose to look at the BinAB larvicide because it is so widely used, yet the structural details were a mystery,” said Brian Federici, professor of entomology at UC Riverside.

    The small size of the crystals made them difficult to study at conventional X-ray sources. So the research team used genetic engineering techniques to increase the size of the crystals, and the bright, fast pulses of light at LCLS allowed the scientists to collect detailed structural data from the tiny crystals before X-rays damaged their samples.

    The researchers used a crystallography technique called de novo phasing. This involves tagging the crystals with heavy metal markers, collecting tens of thousands of X-ray diffraction patterns, and combining the information collected to obtain a three-dimensional map of the electron density of the protein.

    “This is the first time we’ve used de novo phasing on a crystal of great interest at an X-ray free-electron laser,” said Sebastien Boutet, SLAC scientist.

    The technique had so far only been used on test samples where the structure was already known, in order to prove that it would work.

    “The most immediate need is to now expand the spectrum of action of the BinAB toxin to counter the progression of Zika, in particular,” said Colletier. “BinAB is already effective against Culex [carrier of West Nile encephalitis] and Anopheles [carrier of malaria] mosquitos. With the results of the study, we now feel more confident that we can design the protein to target Aedes mosquitos.”

    Additional contributors to the research include scientists from the Howard Hughes Medical Institutes at UCLA, Lawrence Berkeley National Laboratory, and Stanford University. The Institut de Biologie Structurale is a research center for integrated structural biology funded by the Commissariat à l’Énergie Atomique, the Centre National de la Recherche Scientifique and the Université Grenoble Alpes. The Collaborative Innovation Award program of Howard Hughes Medical Institute (HCIA-HHMI), W.M Keck Foundation, National Institutes of Health, National Science Foundation, France Alzheimer Foundation, Agence Nationale de la Recherche, and DOE Office of Science supported the research.

    See the full article here .

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    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.

  • richardmitnick 7:58 am on September 27, 2016 Permalink | Reply
    Tags: , Medicine, , UCLA researchers help design wearable microscope that can measure fluorescent dyes through skin   

    From UCLA: “UCLA researchers help design wearable microscope that can measure fluorescent dyes through skin” 

    UCLA bloc


    September 26, 2016
    Meghan Steele Horan

    Researchers can detect spatial frequencies of a fluorescent image…

    CLA researchers working with a team at Verily Life Sciences have designed a mobile microscope that can detect and monitor fluorescent biomarkers inside the skin with a high level of sensitivity, an important tool in tracking various biochemical reactions for medical diagnostics and therapy.

    This new system weighs less than a one-tenth of a pound, making it small and light enough for a person to wear around their bicep, among other parts of their body. In the future, technology like this could be used for continuous patient monitoring at home or at point-of-care settings.

    The research, which was published in the journal ACS Nano, was led by Aydogan Ozcan, UCLA’s Chancellor’s Professor of Electrical Engineering and Bioengineering and associate director of the California NanoSystems Institute and Vasiliki Demas of Verily Life Sciences (formerly Google Life Sciences).

    Fluorescent biomarkers are routinely used for cancer detection and drug delivery and release among other medical therapies. Recently, biocompatible fluorescent dyes have emerged, creating new opportunities for noninvasive sensing and measuring of biomarkers through the skin.

    However, detecting artificially added fluorescent objects under the skin is challenging. Collagen, melanin and other biological structures emit natural light in a process called autofluorescence. Various methods have been tried to investigate this problem using different sensing systems. Most are quite expensive and difficult to make small and cost-effective enough to be used in a wearable imaging system.

    To test the mobile microscope, researchers first designed a tissue phantom — an artificially created material that mimics human skin optical properties, such as autofluorescence, absorption and scattering. The target fluorescent dye solution was injected into a micro-well with a volume of about one-hundredth of a microliter, thinner than a human hair, and subsequently implanted into the tissue phantom half a millimeter to 2 millimeters from the surface — which would be deep enough to reach blood and other tissue fluids in practice.

    This microscope can monitor fluorescent biomarkers inside the skin. Ozcan Research Group/UCLA

    To measure the fluorescent dye, the wearable microscope created by Ozcan and his team used a laser to hit the skin at an angle. The fluorescent image at the surface of the skin was captured via the wearable microscope. The image was then uploaded to a computer where it was processed using a custom-designed algorithm, digitally separating the target fluorescent signal from the autofluorescence of the skin, at a very sensitive parts-per-billion level of detection.

    “We can place various tiny bio-sensors inside the skin next to each other, and through our imaging system, we can tell them apart,” Ozcan said. “We can monitor all these embedded sensors inside the skin in parallel, even understand potential misalignments of the wearable imager and correct it to continuously quantify a panel of biomarkers.”

    This computational imaging framework might also be used in the future to continuously monitor various chronic diseases through the skin using an implantable or injectable fluorescent dye.

    Other authors of the manuscript include UCLA postdoctoral researchers Zoltan Gorocs, Yair Rivenson, Hatice Koydemir, UCLA development engineer Derek Tseng, and Tamara Troy of Verily Life Sciences.

    This project was supported by Verily Life Sciences. Ozcan’s research group is supported by a Presidential Early Career Award for Scientists and Engineers, and by the Army Research Office Life Sciences Division, the National Science Foundation’s CBET Division Biophotonics Program, a National Science Foundation Emerging Frontiers in Research and Innovation award, an NSF EAGER award, an NSF INSPIRE award, the NSF Partnerships for Innovation: Building Innovation Capacity program, the Office of Naval Research, the Howard Hughes Medical Institute, the Vodaphone Americas Foundation, and King Abdullah University of Science and Technology.

    See the full article here .

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    UC LA Campus

    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

  • richardmitnick 7:23 am on September 27, 2016 Permalink | Reply
    Tags: , , Killing Superbugs with Star-Shaped Polymers instead of Antibiotics, Medicine, Shu Lam, U Melbourne   

    From University of Melbourne via Science Alert: Women in STEM – “Killing Superbugs with Star-Shaped Polymers instead of Antibiotics” Shu Lam 


    University of Melbourne


    Science Alert

    The science world is freaking out over this 25-year-old’s answer to antibiotic resistance

    26 SEP 2016

    Could this be the end of superbugs?

    Shu Lam

    A 25-year-old student has just come up with a way to fight drug-resistant superbugs without antibiotics.

    The new approach has so far only been tested in the lab and on mice, but it could offer a potential solution to antibiotic resistance, which is now getting so bad that the United Nations recently declared it a “fundamental threat” to global health.

    Antibiotic-resistant bacteria already kill around 700,000 people each year, but a recent study suggests that number could rise to around 10 million by 2050.

    In addition to common hospital superbug, methicillin-resistant Staphylococcus aureus (MRSA), scientists are now also concerned that gonorrhoea is about to become resistant to all remaining drugs.

    But Shu Lam, a 25-year-old PhD student at the University of Melbourne in Australia, has developed a star-shaped polymer that can kill six different superbug strains without antibiotics, simply by ripping apart their cell walls.

    “We’ve discovered that [the polymers] actually target the bacteria and kill it in multiple ways,” Lam told Nicola Smith from The Telegraph. “One method is by physically disrupting or breaking apart the cell wall of the bacteria. This creates a lot of stress on the bacteria and causes it to start killing itself.”

    The research has been published in Nature Microbiology, and according to Smith, it’s already being hailed by scientists in the field as “a breakthrough that could change the face of modern medicine”.

    Before we get too carried away, it’s still very early days. So far, Lam has only tested her star-shaped polymers on six strains of drug-resistant bacteria in the lab, and on one superbug in live mice.

    But in all experiments, they’ve been able to kill their targeted bacteria – and generation after generation don’t seem to develop resistance to the polymers.

    The polymers – which they call SNAPPs, or structurally nanoengineered antimicrobial peptide polymers – work by directly attacking, penetrating, and then destabilising the cell membrane of bacteria.

    Unlike antibiotics, which ‘poison’ bacteria, and can also affect healthy cells in the area, the SNAPPs that Lam has designed are so large that they don’t seem to affect healthy cells at all.

    “With this polymerised peptide we are talking the difference in scale between a mouse and an elephant,” Lam’s supervisor, Greg Qiao, told Marcus Strom from the Sydney Morning Herald. “The large peptide molecules can’t enter the [healthy] cells.”

    You can see the SNAPPs (green) surrounding and ripping apart bacterial cells below:


    While the results are positive so far, it’s too early to get excited about what this could mean for humans, says Cyrille Boyer from the University of New South Wales in Australia, who wasn’t involved in the research.

    “The main advantage seems to be they can kill bacteria more effectively and selectively [than other peptides]” Boyer told Strom, before adding that the team is a long way off clinical applications.

    But what’s awesome about the new project is that, while other teams are looking for new antibiotics, Lam has found a completely different approach. And it could make all the different in the coming ‘post-antibiotic world’.

    That’s what she’s hoping, anyway.

    “For a time, I had to come in at 4am in the morning to look after my mice and my cells,” she told The Telegraph. “I wanted to be involved in some kind of research that would help solve problems … I really hope that the polymers we are trying to develop here could eventually be a solution.”

    See the full article here .


    The University of Melbourne (informally Melbourne University) is an Australian public research university located in Melbourne, Victoria. Founded in 1853, it is Australia’s second oldest university and the oldest in Victoria. Times Higher Education ranks Melbourne as 33rd in the world, while the Academic Ranking of World Universities places Melbourne 44th in the world (both first in Australia).

    Melbourne’s main campus is located in Parkville, an inner suburb north of the Melbourne central business district, with several other campuses located across Victoria. Melbourne is a sandstone university and a member of the Group of Eight, Universitas 21 and the Association of Pacific Rim Universities. Since 1872 various residential colleges have become affiliated with the university. There are 12 colleges located on the main campus and in nearby suburbs offering academic, sporting and cultural programs alongside accommodation for Melbourne students and faculty.

    Melbourne comprises 11 separate academic units and is associated with numerous institutes and research centres, including the Walter and Eliza Hall Institute of Medical Research, Florey Institute of Neuroscience and Mental Health, the Melbourne Institute of Applied Economic and Social Research and the Grattan Institute. Amongst Melbourne’s 15 graduate schools the Melbourne Business School, the Melbourne Law School and the Melbourne Medical School are particularly well regarded.

    Four Australian prime ministers and five governors-general have graduated from Melbourne. Nine Nobel laureates have been students or faculty, the most of any Australian university

  • richardmitnick 12:59 pm on September 19, 2016 Permalink | Reply
    Tags: , Medicine, , , Tuberculosis Can Persist in Lungs After Treatment   

    From Rutgers: “Tuberculosis Can Persist in Lungs After Treatment, Study Finds” 

    Rutgers University
    Rutgers University

    September 7, 2016
    Dory Devlin

    A microscopic view of Mycobacterium tuberculosis, the microbe that causes TB. Shutterstock

    Tuberculosis persists in many patients after they receive drug therapies, while others relapse after being successfully cured of symptoms, a study published in Nature Medicine finds.

    Patients with pulmonary tuberculosis (TB) are typically treated with several medications for a period of six months, and some longer. Through PET and CT scans, and by looking for the presence of Mycobacterium tuberculosis mRNA in patients during treatment, researchers discovered that TB lesions and the infecting bacteria can remain in the lungs long after treatment – even if M. tuberculosis can no longer be cultured from a sputum sample.

    “This is very surprising: When we treat people with TB drugs, we don’t seem to always cure the infection, even if patients appear to be clinically cured,” said David Alland, a co-author and director of the Division of Infectious Diseases at Rutgers New Jersey Medical School. “Therefore, the body must do the rest of the job. We need to find ways to stimulate the body’s immune system to find a faster way of killing TB.”


    David Alland, associate dean of clinical research at New Jersey Medical School and director of the Division of Infectious Diseases, says the findings reveal researchers need to finds ways to stimulate immune systems to eradicate M. tuberculosis faster. John Emerson/Rutgers University.

    TB remains one of the leading causes of death worldwide, despite TB mortality rates dropping 45 percent between 1990 and 2012. One third of the world’s population is infected with TB, with more than 9.5 million people a year becoming sick with the disease, according to the Centers for Disease Control.

    As the World Health Organization and the Bill & Melinda Gates Foundation focus on developing shorter, simpler treatment regimens to increase the number of TB patients who complete treatments as prescribed, these findings will help researchers test how new therapies and different drug combinations are working, Alland said. PET/CT scans and mRNA analysis during treatment can measure inflammation, detect lesions and live bacteria in the lungs, and monitor how effectively the treatments are eradicating the disease.

    Studying 99 non-HIV, nondiabetic adult patients with TB in Cape Town, South Africa, researchers found that after six months of treatment, PET/CT scans found lung lesions similar to those found in untreated pulmonary TB patients in 76 of them. A year after treatment ended, 50 patients continued to show lung abnormalities; researchers found that while most lesions decreased in severity and size, only 16 patients with these abnormalities were fully free of TB lesions. The remaining 34 had significant residual lesions and many had detectible M. tuberculosis mRNA in their sputum, indicating the persistent presence of live bacteria, even though these patients were considered cured of the clinical symptoms of TB.

    “It’s kind of a mind-blowing study that tells us we need to refocus on how to kill this persistent-population TB,” Alland said. “There are a range of new drug combinations and new vaccines being worked on, including therapeutic vaccines to stimulate the immune system. With these markers that we’ve developed to look at outcomes, we should be able to get a better line on what works.”

    Alland’s post-doctoral student Subhada Shenai was the second author on the study, to which Alland also contributed. Researchers from Stellenbosch University in Cape Town, South Africa, are the lead authors. Researchers from the National Institute of Allergy and Infectious Disease, National Institutes of Health; Stanford University; the International Tuberculosis Research Center in Seoul, South Korea; and the Catalysis Foundation for Health in California also participated.

    See the full article here .

    The original RutgersResearch post is here .

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    Rutgers, The State University of New Jersey, is a leading national research university and the state’s preeminent, comprehensive public institution of higher education. Rutgers is dedicated to teaching that meets the highest standards of excellence; to conducting research that breaks new ground; and to providing services, solutions, and clinical care that help individuals and the local, national, and global communities where they live.

    Founded in 1766, Rutgers teaches across the full educational spectrum: preschool to precollege; undergraduate to graduate; postdoctoral fellowships to residencies; and continuing education for professional and personal advancement.

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  • richardmitnick 9:32 am on September 19, 2016 Permalink | Reply
    Tags: , Epilepsy, Medicine, ,   

    From Science Node: “Stalking epilepsy” 

    Science Node bloc
    Science Node

    15 Sep, 2016
    Lance Farrell

    Courtesy Enzo Varriale. (CC BY-ND 2.0)

    Scientists in Italy may have found a brain activity marker that forecasts epilepsy development. All it took was some big computers and tiny mice.

    By the time you finish reading this story, an untold number of people will have had a stroke, or have suffered a traumatic brain injury, or perhaps have been exposed to a toxic chemical agent. These events occur every day, millions of times each year. Of these victims, nearly 1 million go on to develop epilepsy.

    These events — stroke, brain injury, toxic exposure, among others — are some of the known causes of epilepsy (also known as epileptogenic events), but not all who suffer from them develop epilepsy. Scientists today struggle to identify people who will develop epilepsy following the exposure to risk factors.

    Even if identification were possible, there are no treatments available to prevent the emergence of epilepsy. The development of such therapeutics is a holy grail of epilepsy research, since this would reduce the incidence of epilepsy by about 40 percent.

    The development of anti-epileptogenic treatments awaits identification of a so-called epileptogenic marker – that is, a measurable event which occurs specifically only during the development of epilepsy, when seizures have yet to become clinically evident.

    An European Grid Infrastructure (EGI) collaboration, led by Massimo Rizzi at the Mario Negri Institute for Pharmacological Research, appears to have pinpointed just such a marker. All it took was some heavy-duty grid computing and a handful of mice.


    Epilepsy comes in many varieties, and is characterized as a seizure-inducing condition of the brain. These seizures result from the simultaneous signaling of multiple neurons. Considered chronic, this neurological disorder afflicts some 65 million people internationally.

    Squadra di calcolo. Scientists credit a recent breakthrough in epilepsy research to the computational power provided by the Italian National Institute of Nuclear Physics (INFN), a key component of the Italian Grid Infrastructure (IGI) and European Grid Infrastructure (EGI). Courtesy INFN.

    Incurable at present, epileptic seizures are controllable to a large extent, typically with pharmacological agents. Changes in diet can lower seizures, as can electrical devices and surgeries. According the US National Institute of Health (NIH), annual US epilepsy-related costs are estimated at $15.5 billion.

    Scientists Rizzi and his colleagues thought an alteration in brain electrical activity following the exposure to a risk factor might be a smart place to look for an epileptogenic marker. If this marker could be located, it then could be exploited to develop treatments that prevent the emergence of epilepsy.

    Of mice and men

    To search for the marker, Rizzi’s team focused their attention on an animal model of epilepsy. Mice developed epilepsy after exposure to a cerebral insult that mimics the effects of risk factors as they would occur in humans.

    Examining the brain electrical activity of these mice, Rizzi’s team combed through 32,000 epidural electrocorticograms (ECoG), 12 seconds/4800 data points at a time, for up to an hour preceding the first epileptic seizure.

    Each swath of ECoGs were run through the recurrence quantification analysis (RQA), a powerful mathematical tool specifically designed for the investigation of non-linear complex dynamics embedded in time-series readings such as the ECoG.

    Thinking of a mouse. Brain activity of a mouse that developed epilepsy following exposure to an infusion of albumin.

    When the dust had settled, nearly 400,000 seconds of ECoGs revealed a telling pattern. The scientists found that high rates of dynamic intermittency accompany the development of epilepsy. In other words, the ECoGs of mice developing epilepsy from the induced trauma would rapidly alter between nearly periodic and then irregular behavior of brain electrical activity.

    Noting this signal, researchers applied an experimental anti-epileptogenic treatment that successfully reduced the rate of occurrence of this complex oscillation pattern. Identification of the complex oscillation and its arrest under treatment led Rizzi and his team to confidently assert that high rates of dynamic intermittency can be considered as a marker of epileptogenesis. Their research was recently published in Scientific Reports.

    Tools of the trade

    Rizzi’s team made good use of the computational and storage resources at the Italian National Institute of Nuclear Physics (INFN). The INFN is a key component in the Italian Grid Infrastructure (IGI), which is integrated into the larger EGI, Europe’s leading grid computing infrastructure.

    “The time required to accomplish calculations of these datasets would have taken more than two months by an ordinary PC, instead of a little more than two days using grid computing,” says Rizzi. “Considering also the preliminary settings of analytical conditions and validation tests of results, almost two years of calculations were collapsed into a couple of months by high throughput computing technology.”

    From here, Rizzi hands off to pre-clinical researchers who can begin to develop interventions that will reduce and hopefully eliminate the emergence of epilepsy after exposure to risk factors. This knowledge holds out promise for use in the development of anti-epileptogenic therapies.

    “This insight will help us reduce the incidence of epilepsy by approximately 40 percent,” Rizzi estimates. “Our future aim is to exploit our finding in order to improve the development of therapeutics. High throughput computer technology will keep on playing a fundamental role by significantly speeding up this field of research.”

    See the full article here .

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    Science Node is an international weekly online publication that covers distributed computing and the research it enables.

    “We report on all aspects of distributed computing technology, such as grids and clouds. We also regularly feature articles on distributed computing-enabled research in a large variety of disciplines, including physics, biology, sociology, earth sciences, archaeology, medicine, disaster management, crime, and art. (Note that we do not cover stories that are purely about commercial technology.)

    In its current incarnation, Science Node is also an online destination where you can host a profile and blog, and find and disseminate announcements and information about events, deadlines, and jobs. In the near future it will also be a place where you can network with colleagues.

    You can read Science Node via our homepage, RSS, or email. For the complete iSGTW experience, sign up for an account or log in with OpenID and manage your email subscription from your account preferences. If you do not wish to access the website’s features, you can just subscribe to the weekly email.”

  • richardmitnick 10:52 am on September 16, 2016 Permalink | Reply
    Tags: , Cipro and its generic version ciprofloxacin, ESBL, Fluoroquinolone, Increase in antibiotic-resistant bacteria hinders treatment of kidney infections, Medicine, Pyelonephritis,   

    From UCLA: “Increase in antibiotic-resistant bacteria hinders treatment of kidney infections” 

    UCLA bloc


    September 15, 2016
    Phil Hampton

    Extended-spectrum ß-lactamase-producing bacteria come from a strain of E. coli and are resistant to several types of antibiotics, severely limiting treatment options.

    The increase in illnesses and deaths linked to medication-resistant bacteria has been well-documented by researchers and received extensive public attention in recent years. Now, UCLA-led research shows how these bacteria are making it more difficult to treat a common but severe kidney infection.

    Pyelonephritis — infection of the kidney usually caused by E. coli bacteria and which can start as a urinary tract infection — causes fever, back pain and vomiting. About half of people infected require hospitalization. If not treated with effective antibiotics, it can cause sepsis and death.

    In a UCLA-led study based on data from 10 large hospital emergency departments around the country, almost 12 percent of people diagnosed with pyelonephritis had infections resistant to the standard class of antibiotic used in treatment — fluoroquinolone. (Cipro and its generic version ciprofloxacin are commonly used medications in this class.) That’s up from 4 percent in a similar study conducted a decade ago. In some cities, and among some people with certain risk factors — such as international travel or recent hospitalization or treatment with an antibiotic — fluoroquinolone resistance rates exceeded 20 percent.

    The new study — published in the September issue of Emerging Infectious Diseases — also documents the emergence of infections caused by a specific strain of E. coli that is resistant to additional types of antibiotics, severely limiting treatment options. That strain, dubbed ESBL for the antibiotic-destroying enzymes it produces (extended-spectrum beta-lactamases), was not detected in the previous study. The enzymes were first detected in 1979 and are most often found in developing nations.

    Currently, there are only a few intravenous antibiotic options to treat ESBL-related infections, and no oral antibiotics that are consistently effective.

    “This is a very real example of the threat posed by the emergence of new antibiotic-resistant strains of bacteria, which greatly complicates treatment of infection,” said Dr. David Talan, the study’s lead author and a professor in the department of emergency medicine at the David Geffen School of Medicine at UCLA. He is also a professor in the department of medicine, division of infectious diseases.

    The study included 453 people diagnosed with kidney infection. The study participants were diagnosed between July 2013 and December 2014 in 10 emergency departments at large hospitals around the country, including Olive View–UCLA Medical Center in Sylmar, which is operated by Los Angeles County.

    Researchers reported that:

    The rates of ESBL-related infections varied from 0 percent to more than 20 percent, depending on the location of the emergency room and patient risk factors.
    About one in three people infected with ESBL-producing E. coli had no traditional risk factors for antibiotic resistance, suggesting the bacterial strain is now endemic in the United States and healthy people are also at risk.
    About three of every four people infected with ESBL-producing E. coli were initially treated with antibiotics ineffective against that particular strain of bacteria, placing them at risk for poor outcomes.

    Talan and his research colleagues recommended the development of new medications and new guidelines calling for treatment with different types and combinations of antibiotics. They also recommended physicians evaluating treatment options pay close attention to antibiotic resistance rates in their regions and quickly test bacteria samples to determine specific strains.

    The research was supported by the U.S. Centers for Disease Control and Prevention and by Merck.

    See the full article here .

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    UC LA Campus

    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

  • richardmitnick 10:09 am on September 16, 2016 Permalink | Reply
    Tags: , , Medicine,   

    From MIT: “High-capacity nanoparticle” 

    MIT News
    MIT News
    MIT Widget

    September 14, 2016
    Anne Trafton | MIT News Office

    Human colorectal cancer cells. Image: NCI Center for Cancer Research

    Particles that carry three or more drugs hold potential for targeted cancer therapy.

    Nanoparticles offer a promising way to deliver cancer drugs in a targeted fashion, helping to kill tumors while sparing healthy tissue. However, most nanoparticles that have been developed so far are limited to carrying only one or two drugs.

    MIT chemists have now shown that they can package three or more drugs into a novel type of nanoparticle, allowing them to design custom combination therapies for cancer. In tests in mice, the researchers showed that the particles could successfully deliver three chemotherapy drugs and shrink tumors.

    In the same study, which appears in the Sept. 14 issue of the Journal of the American Chemical Society, the researchers also showed that when drugs are delivered by nanoparticles, they don’t necessarily work by the same DNA-damaging mechanism as when delivered in their traditional form.

    That is significant because most scientists usually assume that nanoparticle drugs are working the same way as the original drugs, says Jeremiah Johnson, the Firmenich Career Development Associate Professor of Chemistry and the senior author of the paper. Even if the nanoparticle version of the drug still kills cancer cells, it’s important to know the underlying mechanism of action when choosing combination therapies and seeking regulatory approval of new drugs, he says.

    “People tend to take it as a given that when you put a drug into a nanoparticle it’s the same drug, just in a nanoparticle,” Johnson says. “Here, in collaboration with Mike Hemann, we conducted detailed characterization using an RNA interference assay that Mike developed to make sure the drug is still hitting the same target in the cell and doing everything that it would if it weren’t in a nanoparticle.”

    The paper’s lead authors are Jonathan Barnes, a former MIT postdoc; and Peter Bruno, a former MIT graduate student. Other authors are grad students Hung Nguyen and Jenny Liu, former postdoc Longyan Liao, and Michael Hemann, an associate professor of biology and member of MIT’s Koch Institute for Integrative Cancer Research.

    Precise control

    The new nanoparticle production technique, which Johnson’s lab first reported in 2014, differs from other methods that encapsulate drugs or chemically attach them to a particle. Instead, the MIT team creates particles from building blocks that already contain drug molecules. They can join the building blocks together in a specific structure and precisely control how much of each drug is incorporated.

    “We can take any drug, as long as it has a functional group [a group of atoms that allows a molecule to participate in chemical reactions], and we can load it into our particles in exactly the ratio that we want, and have it release under exactly the conditions that we want it to,” Johnson says. “It’s very modular.”

    A key advantage is that this approach can be used to deliver drugs that normally can’t be encapsulated by traditional methods.

    Using the new particles, the researchers delivered doses of three chemotherapy drugs — cisplatin, doxorubicin, and camptothecin — at concentrations that would be toxic if delivered by injection throughout the body, as chemotherapy drugs usually are. In mice that received this treatment, ovarian tumors shrank and the mice survived much longer than untreated mice, with few side effects.

    “Performing combination chemotherapy using these new designer polymer nanoparticles is an exciting new approach to chemotherapeutics, and this polymer platform is particularly promising for its ability to carry a large load of drugs and deliver them in a triggered, controlled manner,” says Todd Emrick, a professor of polymer science and engineering at the University of Massachusetts at Amherst who was not involved in the study.

    Unexpected mechanism

    Using a method developed by Hemann’s lab, the researchers then investigated how their nanoparticle drugs affect cells. The technique measures cancer drugs’ effects on eight genes that are involved in the programmed cell death often triggered by cancer drugs. This allows scientists to classify the drugs based on which clusters of genes they affect.

    “Drugs that damage DNA get clustered into DNA damage-inducing agents, and drugs that inhibit topoisomerases cluster together in another region,” Johnson says. “If you have a drug that you don’t know the mechanism of, you can do this test and see if the drug clusters with other drugs whose actions are known. That lets you make a hypothesis about what the unknown drug is doing.”

    The researchers found that nanoparticle-delivered camptothecin and doxorubicin worked just as expected. However, cisplatin did not. Cisplatin normally acts by linking adjacent strands of DNA, causing damage that is nearly impossible for the cell to repair. When delivered in nanoparticle form, the researchers found that cisplatin acts more like a different platinum-based drug known as oxaliplatin. This drug also kills cells, but by a different mechanism: It binds to DNA but induces a different pattern of DNA damage.

    The researchers hypothesize that after cisplatin is released from the nanoparticle, via a reaction that kicks off a group known as a carboxylate, the carboxylate group then reattaches in a way that makes the drug act more like oxaliplatin. Many other researchers attach cisplatin to nanoparticles the same way, so Johnson suspects this could be a more widespread issue.

    His lab is now working on a new version of the cisplatin nanoparticle that operates according to the same mechanism as regular cisplatin. The team is also developing nanoparticles with different combinations of drugs to test against pancreatic and other types of cancers.

    See the full article here .

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  • richardmitnick 12:25 pm on September 15, 2016 Permalink | Reply
    Tags: Advanced imaging, , Medicine, , Virus studies   

    From U Washington: “Advanced imaging shows how deadly viruses evade defenses” 

    U Washington

    University of Washington

    Michael McCarthy

    Alexandra Walls peers into a transmission electron microscope as part of her molecular structure studies. Michael McCarthy

    A virus that causes severe respiratory infections evades our immune system by concealing proteins on its surface behind sugar “shields,” UW Medicine researchers report in a new study appearing in the journal Nature Structural & Molecular Biology.

    The virus, called human coronavirus NL63, is a major cause of pneumonia in newborns. It also can cause respiratory tract infections in other individuals, especially young children, the elderly, and those with weakened immune systems.

    “Currently, there are no effective vaccines or therapies for human coronavirus infections,” said David Veesler, assistant professor of biochemistry, who led the research. “These findings should help scientists develop vaccines and drugs targeting this virus and related coronaviruses.”

    Three-dimensional structure of a coronavirus spike protein trimer (purple) wtih glycans (light grey) that help the virus evade the immune system. Veesler Lab

    Coronaviruses make up a family of animal viruses that recently have been shown to jump from animals to humans. They have the potential to cause deadly worldwide pandemics. A coronavirus was responsible for the deadly severe acute respiratory syndrome (SARS) outbreak in 2003, in which one in ten people who became infected died. Another coronavirus is responsible for the ongoing outbreak of Middle East respiratory syndrome (MERS) which has a a fatality rate of 40 percent.

    The new study’s lead author is Alexandra C. Walls, a graduate student working with colleagues in the Veesler lab and DiMaio lab as well as with collaborators at the Institute Pasteur in Paris, France, and Utretch University in Utrecht, the Netherlands. Her team used a technique called cryo-electron microscopy to examine spike proteins that are found over the surface of the virus. The look of these spike proteins gives coronaviruses — which means “crown viruses” — their name.

    The coronavirus spikes have two main purposes. First, they grab onto proteins found on the surface of human and animal cells to allow the virus to invade. Once inside the cells, they participate in a process called fusion that releases the viral proteins and its RNA instructions. This enables the the virus to take over the cell and begin copying itself.

    Coronavirus spike proteins are of particular interest to medical researchers. They are virtually the only coronavirus surface protein that can be easily targeted by antibodies, the immune proteins that bind to and help destroy invading viruses and bacteria.

    To visualize the coronavirus spikes, UW Medicine researchers froze the proteins to the temperature of -180 degrees C. This technique fixes the proteins so they can be studied in a near-native state with a transmission electron microscope. Through this technique, the researchers achieved a protein model at a resolution of 3.4 ångström.

    This resolution made it possible to establish the precise position of the individual amino acids that make up the spike proteins. Another technique used, called mass spectrometry, t revealed the chemical composition of the different sugar components of the spikes.

    Using both techniques they were able to create a model that revealed the protein’s structure as well as the location of sugars, called glycans, that extend from the spike protein. The location of the glycans is important to know because our antibodies preferentially target and bind to proteins, not sugars. As a result, viral glycans, if properly placed, can shield proteins from host antibody attack.

    The researchers found that the virus appears to tap into two strategies to elude the attacking antibodies. First, the spike proteins are covered with more than 100 glycan moieties. These protect, among other areas, the part of spike that binds to the target cell. This hides this crucial structure from neutralizing antibodies. Second, the protein flexes so that this binding area is tucked out of sight until it comes into contact with the target cell. With contact, the protein changes shape to expose the binding area so the virus can attach and enter the host cell. This occurs so quickly that there is little time for antibodies to detect the exposed binding area and trigger an immune attack.

    Now, with much more precise understanding of the structure of the spikes, the existence of a glycan shield, and how the proteins flex, it may be possible to create vaccines and drugs that can effectively prevent or combat coronavirus infections, Veesler said.

    The work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award numbers 1R01GM120553-01 and T32GM008268. Support also came from the Netherlands Organization for Scientific Research (NWO Rubicon 019.2015.2.310.006) and the European Molecular Biology Organisation (EMBO ALTF 933-2015) and the Institute Pasteur and the Le Centre National de la Recherche Scientifique.

    See the full article here .

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    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.

    So what defines us — the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

  • richardmitnick 9:36 am on September 15, 2016 Permalink | Reply
    Tags: , How a New Drug Could Treat Both Diabetes and Bone Loss, Medicine, New compound SR10171, , Type II diabetes and bone loss   

    From Scripps: “How a New Drug Could Treat Both Diabetes and Bone Loss” 

    Scripps Research Institute

    September 2016
    No writer credit

    In addition to its more obvious ills, type 2 diabetes is a condition closely associated with bone fractures – increasing the risk of fractures twofold. To make matters worse, certain anti-diabetic drugs further increase this risk, particularly in postmenopausal women, severely limiting their treatment options.

    But now, a team of scientists at on the Florida campus of The Scripps Research Institute (TSRI), co-led by TSRI’s Patrick R. Griffin and B. Lecka-Czernik, a professor at the University of Toledo, has shown that a new class of drug candidates developed at TSRI increase bone mass by expanding bone formation (deposition of new bone) and bone turnover (a normal process of bone replacement). The discovery could lead to new therapies for type 2 diabetes and bone loss. A proper balance of these two processes is critical to healthy bone maintenance, and this balance is frequently negatively affected in diabetic patients.

    The result is a new dual-targeting drug candidate – or, as Dr. Griffin describes it, “one drug addressing multiple therapeutic indications” – which could treat both diabetes and bone disease. The compound has been referenced as “SR10171.”

    Diabetes affects more than 29 million people in the United States, according to a 2012 report from the American Diabetes Association. In 2013, estimated direct medical costs of the disease totaled $176 billion.

    Over the past decade, Dr. Griffin and his colleague, TSRI Associate Professor Theodore Kamenecka, have focused on the details of molecules that increase sensitivity to insulin (a hormone that regulates blood sugar). Using newly discovered information, the researchers made significant advances in developing a family of drug candidates that target a receptor known as peroxisome proliferator-activated receptors gamma (PPARγ), a key regulator of stem cells controlling bone formation and bone resorption and a master regulator of fat.

    Anti-diabetic drugs known as glitazones (TZDs) target the PPARγ protein, but that interaction leads to severe bone loss and increased fractures. Stem cells in the bone marrow can differentiate either into bone cells or fat cells, and the glitazones drive them to fat at the expense of bone.

    But SR10171 is designed to avoid this troubling outcome. In animal models treated with the compound, fat formation in the bone marrow was successfully blocked independent of their metabolic state (healthy or diabetic).

    “Using structural biology techniques and rational design synthetic chemistry, SR10171 was constructed to engage the PPARγ protein in a unique way possessing an optimal balance with the receptor’s other family member, PPARa, to treat diabetes and, at the same time, improve bone health,” Dr. Griffin said. “This targeted polypharmacological approach demonstrates that the target isn’t the problem if you target it correctly.”

    The compound increases bone mass by protecting and increasing the activity of bone cells in various stages of normal bone maintenance, utilizing mechanisms that overlap those that regulate whole-body energy metabolism.

    “SR10171 improves bone mass regardless of body mass index, normal to obese,” Dr. Griffin added. “So you could use such a drug to treat osteoporosis whether patients are diabetic or not.”

    See the full article here .

    Please help promote STEM in your local schools.

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    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

  • richardmitnick 1:26 pm on September 13, 2016 Permalink | Reply
    Tags: , Medicine, , ,   

    From Scripps: “TSRI Scientists Discover Antibodies that Target Holes in HIV’s Defenses” 

    Scripps Research Institute

    September 12, 2016

    New Findings Could Lead to New AIDS Vaccine Candidates

    A new study from scientists at The Scripps Research Institute (TSRI) shows that “holes” in HIV’s defensive sugar shield could be important in designing an HIV vaccine.

    It appears that antibodies can target these holes, which are scattered in HIV’s protective sugar or “glycan” shield, and the question is now whether these holes can be exploited to induce protective antibodies.

    “It’s important now to evaluate future vaccine candidates to more rapidly understand the immune response they induce to particular glycan holes and learn from it,” said TSRI Professor Dennis R. Burton, who is also scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and of the National Institutes of Health’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI.

    The study, published recently in the journal Cell Reports, was co-led by Burton, TSRI Associate Professor Andrew Ward, also of CHAVI-ID, and Rogier W. Sanders of the University of Amsterdam and Cornell University.

    A Clue to Stopping HIV

    Every virus has a signature structure, like the architecture of a building. By solving these structures, scientists can put together a blueprint showing where HIV is vulnerable to infection-blocking antibodies.

    In the 1990s, scientists discovered that HIV can have random holes in its protective outer shell of glycan molecules. Until now, however, scientists weren’t sure if antibodies could recognize and target these holes.

    Researchers at Cornell and TSRI had previously designed a stabilized version of an important HIV protein, called the envelope glycoprotein (Env) trimer, to prompt rabbit models to produce antibodies against the virus. In the new study, the plan was to reveal HIV’s vulnerabilities by examining where the antibodies bound the virus.

    “From work on HIV-positive individuals, we knew that the best way to understand an antibody response is to isolate the individual antibodies and study them in detail,” said Laura McCoy, a TSRI, IAVI and CHAVI-ID researcher now at University College London, who served as co-first author of the study with TSRI Senior Research Associate Gabriel Ozorowski, also of TSRI and CHAVI-ID, and Marit J. van Gils of the University of Amsterdam.

    To their surprise, when the researchers examined the rabbits’ antibodies, they found three rabbits had produced antibodies that targeted the same hole in Env. It appeared that antibodies could indeed target holes in the glycan shield.

    “This opened up a whole new concept,” said Ozorowski.

    If the immune system was targeting this hole—preferring it to other vulnerable spots on Env—maybe holes would be especially important in designing vaccine candidates.

    Toward Better Antibodies

    By analyzing the genetic sequences of thousands of strains of HIV, the researchers found that 89 percent of strains appear to have a targetable hole in the Env. The virus has a defense mechanism though—it quickly mutates to fill in these gaps.

    The researchers speculate that future vaccines might prompt the immune system to create antibodies to target holes. “Targeting a hole could help the immune system get its foot in the door,” Ozorowski said. Alternatively, the holes may prove a distraction and should be filled in so the immune system can focus on targeting better sites for neutralizing the virus.

    Burton said researchers must investigate the different possibilities, but he emphasized that this new understanding of glycan holes could help researchers narrow down the field of molecules needed in potential HIV vaccines.

    Ward added that this same method of “rational” vaccine design—where researchers use a virus’s precise molecular details to prompt the immune system to produce specific antibodies—can also be applied to efforts to fight other viruses, such as influenza and Ebola viruses.

    In addition to Burton, Ward, Sanders, McCoy, Ozorowski and van Gils, authors of the study, “Holes in the glycan shield of the native HIV envelope are a target of trimer-elicited neutralizing antibodies,” were Terrence Messmer, Bryan Briney, James E. Voss, Daniel W. Kulp, Devin Sok, Matthias Pauthner, Sergey Menis and Jessica Hsueh of TSRI, IAVI and CHAVI-ID; Christopher A. Cottrell, Jonathan L. Torres and Ian A. Wilson of TSRI and CHAVI-ID; Matthew S. Macauley of TSRI; and William R. Schief of TSRI, IAVI, CHAVI-ID and the Ragon Institute.

    This study was supported by CHAVI-ID (grant UM1AI100663), the National Institutes of Health’s HIV Vaccine Research and Design (HIVRAD) Program (grant P01 AI110657), the IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD, grants OPP1084519 and OPP1115782), a Marie-Curie Fellowship (FP7-PEOPLE-2013-IOF), the Aids Fonds Netherlands (grant 2012041), EMBO (grant ASTF260-2013), the Netherlands Organization for Scientific Research (grant 917.11.314) and the European Research Council (grant ERC-StG- 2011-280829-SHEV).

    See the full article here .


    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG) From Scripps Research Institute.


    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.




    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

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