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  • richardmitnick 3:40 pm on February 20, 2015 Permalink | Reply
    Tags: , , , Medicine   

    From FightAIDS@Home at WCG: “The end of the beginning is near for FightAIDS@Home” 

    WCGLarge
    WCG new
    World Community Grid

    FAAH
    FightAIDS@home

    20 Feb 2015
    The FightAIDS@Home research team

    Summary
    Thanks to the incredible generosity of World Community Grid volunteers, the FightAIDS@Home project team has finished with an important stage of their project. The research team has refocused on analyzing their existing results and preparing for the end of this historic grid computing stage.

    ________________________________________________________________

    FightAIDS@Home has been running on World Community Grid in some form almost since the beginning of World Community Grid itself: our project launched in 2005. Thanks to the enormous and ongoing support of our worldwide community of volunteers, we have expanded the scope of our research and explored new targets and drug candidates that we simply could not imagine at the outset. It hardly seems sufficient to say thank you for donating over 330,000 years of processing time to support our research, but once again, from all of us to all of you: thank you. Clearly we could not do this research without you.

    With your help, we have reached a new milestone: no new AutoDock (AD) or AD Vina docking experiments are currently being generated. Put another way: we’re done creating new work tasks. The AutoDock queue is now empty, and the AD Vina queue has more than a year’s worth of jobs left. Most of our efforts have shifted towards analysis.

    The analysis of the FightAIDS@Home data has several levels of difficulty due to the sheer amounts of data, which are comprised of several structures of any drug target as well as millions of small molecules, resulting in hundreds of millions of data points. We are attempting to use a couple of approaches to mine this data, one of which includes examining amino-acids involved in top-ranked dockings. Another approach is to investigate the atomic coordinates of important interactions (pharmacophore) between the protein and the small molecule that was docked. Figures 1 and 2 (below) illustrate a simple example of inhibitor TL3 (Figure 1) and the predictions of 1 experiment (Figure 2, ~5.5 million dockings on 1 protein structure). Of course, these evaluations must be done with a large set of known inhibitors and across myriad protein structures. Once these methods pass a high level of confidence, molecules will be bought and sent to collaborators to be tested.

    1
    Figure 1. Docked pose of known HIV-1 protease inhibitor TL3 in an HIV-1 protease structure (not shown). Spherical representations (accompanied with dots, orange for TL3, green for a water molecule) represent important locations for protein-ligand interactions that are used to evaluate if a molecule may be a good drug candidate. The green sphere represents the location of an important (“flap”) water molecule often observed in HIV-1 protease co-crystal structures. The 2 orange spheres directly below the green sphere represent two locations of an interaction with significant amino acids (Asp25) of HIV-1 protease.

    3
    Figure 2. Same docked pose of TL3 in HIV-1 protease as Figure 1 with top percentage of interactions from 1 experiment (pink spheres) and several predictions (transparent surfaces) for important protein-ligand interactions. Note that the water molecule (green) and the 2 orange interactions below it are always predicted.

    See the full article here.

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    FightAIDS@Home is a project run by the Olson Laboratory that uses distributed computing to contribute your computer’s idle resources to accelerate research into new drug therapies for HIV, the virus that causes AIDS. FightAIDS@Home made history in September 2000 when it became the first biomedical Internet-based grid computing project. FightAIDS@Home was started with Scott Kurowski, founder of Entropia. People all around the World continue to donate their home computer’s idle cycles to running our AutoDock software on HIV-1 protease inhibitor docking problems. With the generous assistance of IBM, we joined World Community Grid in late 2005, and launched FightAIDS@Home on World Community Grid on 21 November, 2005.

    How do I join the FightAIDS@Home Project?

    All you need to do is download and install the free client software. Once you have done this, your computer is then automatically put to work and you can continue using your computer as usual.

     
  • richardmitnick 9:04 am on February 19, 2015 Permalink | Reply
    Tags: , Medicine, ,   

    From MIT: “New nanogel for drug delivery” 


    MIT News

    February 19, 2015
    Anne Trafton | MIT News Office

    1

    Self-healing gel can be injected into the body and act as a long-term drug depot.

    Scientists are interested in using gels to deliver drugs because they can be molded into specific shapes and designed to release their payload over a specified time period. However, current versions aren’t always practical because must be implanted surgically.

    To help overcome that obstacle, MIT chemical engineers have designed a new type of self-healing hydrogel that could be injected through a syringe. Such gels, which can carry one or two drugs at a time, could be useful for treating cancer, macular degeneration, or heart disease, among other diseases, the researchers say.

    The new gel consists of a mesh network made of two components: nanoparticles made of polymers entwined within strands of another polymer, such as cellulose.

    “Now you have a gel that can change shape when you apply stress to it, and then, importantly, it can re-heal when you relax those forces. That allows you to squeeze it through a syringe or a needle and get it into the body without surgery,” says Mark Tibbitt, a postdoc at MIT’s Koch Institute for Integrative Cancer Research and one of the lead authors of a paper describing the gel in Nature Communications on Feb. 19.

    Koch Institute postdoc Eric Appel is also a lead author of the paper, and the paper’s senior author is Robert Langer, the David H. Koch Institute Professor at MIT. Other authors are postdoc Matthew Webber, undergraduate Bradley Mattix, and postdoc Omid Veiseh.

    Heal thyself

    Scientists have previously constructed hydrogels for biomedical uses by forming irreversible chemical linkages between polymers. These gels, used to make soft contact lenses, among other applications, are tough and sturdy, but once they are formed their shape cannot easily be altered.

    The MIT team set out to create a gel that could survive strong mechanical forces, known as shear forces, and then reform itself. Other researchers have created such gels by engineering proteins that self-assemble into hydrogels, but this approach requires complex biochemical processes. The MIT team wanted to design something simpler.

    “We’re working with really simple materials,” Tibbitt says. “They don’t require any advanced chemical functionalization.”

    The MIT approach relies on a combination of two readily available components. One is a type of nanoparticle formed of PEG-PLA copolymers, first developed in Langer’s lab decades ago and now commonly used to package and deliver drugs. To form a hydrogel, the researchers mixed these particles with a polymer — in this case, cellulose.

    Each polymer chain forms weak bonds with many nanoparticles, producing a loosely woven lattice of polymers and nanoparticles. Because each attachment point is fairly weak, the bonds break apart under mechanical stress, such as when injected through a syringe. When the shear forces are over, the polymers and nanoparticles form new attachments with different partners, healing the gel.

    Using two components to form the gel also gives the researchers the opportunity to deliver two different drugs at the same time. PEG-PLA nanoparticles have an inner core that is ideally suited to carry hydrophobic small-molecule drugs, which include many chemotherapy drugs. Meanwhile, the polymers, which exist in a watery solution, can carry hydrophilic molecules such as proteins, including antibodies and growth factors.

    Long-term drug delivery

    In this study, the researchers showed that the gels survived injection under the skin of mice and successfully released two drugs, one hydrophobic and one hydrophilic, over several days.

    This type of gel offers an important advantage over injecting a liquid solution of drug-delivery nanoparticles: While a solution will immediately disperse throughout the body, the gel stays in place after injection, allowing the drug to be targeted to a specific tissue. Furthermore, the properties of each gel component can be tuned so the drugs they carry are released at different rates, allowing them to be tailored for different uses.

    The researchers are now looking into using the gel to deliver anti-angiogenesis drugs to treat macular degeneration. Currently, patients receive these drugs, which cut off the growth of blood vessels that interfere with sight, as an injection into the eye once a month. The MIT team envisions that the new gel could be programmed to deliver these drugs over several months, reducing the frequency of injections.

    Another potential application for the gels is delivering drugs, such as growth factors, that could help repair damaged heart tissue after a heart attack. The researchers are also pursuing the possibility of using this gel to deliver cancer drugs to kill tumor cells that get left behind after surgery. In that case, the gel would be loaded with a chemical that lures cancer cells toward the gel, as well as a chemotherapy drug that would kill them. This could help eliminate the residual cancer cells that often form new tumors following surgery.

    “Removing the tumor leaves behind a cavity that you could fill with our material, which would provide some therapeutic benefit over the long term in recruiting and killing those cells,” Appel says. “We can tailor the materials to provide us with the drug-release profile that makes it the most effective at actually recruiting the cells.”

    The research was funded by the Wellcome Trust, the Misrock Foundation, the Department of Defense, and the National Institutes of Health.

    See the full article here.

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  • richardmitnick 5:30 pm on February 18, 2015 Permalink | Reply
    Tags: , Enzyme studies, Medicine, ,   

    From UCSD: “3D Enzyme Model Provides New Tool for Anti-Inflammatory Drug Development” 

    UC San Diego bloc

    UC San Diego

    January 26, 2015
    Heather Buschman

    Researchers develop first computer models of phospholipase A2 enzymes extracting their substrates out of the cell membrane, an early step in inflammation

    Phospholipase A2 (PLA2) enzymes are known to play a role in many inflammatory diseases, including asthma, arthritis and atherosclerosis. It then stands to reason that PLA2 inhibitors could represent a new class of anti-inflammatory medication. To better understand PLA2 enzymes and help drive therapeutic drug development, researchers at University of California, San Diego School of Medicine developed 3D computer models that show exactly how two PLA2 enzymes extract their substrates from cellular membranes. The new tool is described in a paper published online the week of Jan. 26 by the Proceedings of the National Academy of Sciences.

    1
    Phospholipase Cleavage Sites. Note that an enzyme that displays both PLA1 and PLA2 activities is called a Phospholipase B

    “This is the first time experimental data and supercomputing technology have been used to visualize an enzyme interacting with a membrane,” said Edward A. Dennis, PhD, Distinguished Professor of Pharmacology, chemistry and biochemistry and senior author of the study. “In doing so, we discovered that binding the membrane triggers a conformational change in PLA2 enzymes and activates them. We also saw several important differences between the two PLA2 enzymes we studied — findings that could influence the design and development of specific PLA2 inhibitor drugs for each enzyme.”

    The computer simulations of PLA2 enzymes developed by Dennis and his team, including first author Varnavas D. Mouchlis, PhD, show the specific molecular interactions between PLA2 enzymes and their substrate, arachidonic acid, as the enzymes suck it up from cellular membranes.

    Make no mistake, though — the animations of PLA2 in action are not mere cartoons. They are sophisticated molecular dynamics simulations based upon previously published deuterium exchange mass spectrometry (DXMS) data on PLA2. DXMS is an experimental laboratory technique that provides molecular information about the interactions of these enzymes with membranes.

    “The combination of rigorous experimental data and in silico [computer] models is a very powerful tool — the experimental data guided the development of accurate 3D models, demonstrating that these two scientific fields can inform one another,” Mouchlis said.

    The liberation of arachidonic acid by PLA2 enzymes, as shown in these simulations, sets off a cascade of molecular events that result in inflammation. Aspirin and many other anti-inflammatory drugs work by inhibiting enzymes in this cascade that rely on PLA2 enzymes to provide them with arachidonic acid. That means PLA2 enzymes could potentially also be targeted to dampen inflammation at an earlier point in the process.

    Co-authors include Denis Bucher, UC San Diego, and J. Andrew McCammon, UC San Diego and Howard Hughes Medical Institute.

    This research was funded, in part, by the National Institute of General Medical Sciences at the National Institutes of Health (grants GM20501 and P41GM103712-S1), National Science Foundation (grant ACI-1053575) and Howard Hughes Medical Institute.

    See the full article here.

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    UC San Diego Campus

    The University of California, San Diego (also referred to as UC San Diego or UCSD), is a public research university located in the La Jolla area of San Diego, California, in the United States.[12] The university occupies 2,141 acres (866 ha) near the coast of the Pacific Ocean with the main campus resting on approximately 1,152 acres (466 ha).[13] Established in 1960 near the pre-existing Scripps Institution of Oceanography, UC San Diego is the seventh oldest of the 10 University of California campuses and offers over 200 undergraduate and graduate degree programs, enrolling about 22,700 undergraduate and 6,300 graduate students. UC San Diego is one of America’s Public Ivy universities, which recognizes top public research universities in the United States. UC San Diego was ranked 8th among public universities and 37th among all universities in the United States, and rated the 18th Top World University by U.S. News & World Report ‘s 2015 rankings.

     
  • richardmitnick 9:42 am on February 13, 2015 Permalink | Reply
    Tags: , Medicine, , ,   

    From phys.org: “Scientists discover viral ‘Enigma machine'” 

    physdotorg
    phys.org

    Feb 04, 2015

    1
    A code hidden in the arrangement of the genetic information of single-stranded RNA viruses tells the virus how to pack itself within its outer shell of proteins.

    Researchers have cracked a code that governs infections by a major group of viruses including the common cold and polio.

    Until now, scientists had not noticed the code, which had been hidden in plain sight in the sequence of the ribonucleic acid (RNA) that makes up this type of viral genome.

    But a paper published in the Proceedings of the National Academy of Sciences (PNAS) Early Edition by a group from the University of Leeds and University of York unlocks its meaning and demonstrates that jamming the code can disrupt virus assembly. Stopping a virus assembling can stop it functioning and therefore prevent disease.

    Professor Peter Stockley, Professor of Biological Chemistry in the University of Leeds’ Faculty of Biological Sciences, who led the study, said: “If you think of this as molecular warfare, these are the encrypted signals that allow a virus to deploy itself effectively.”

    “Now, for this whole class of viruses, we have found the ‘Enigma machine’—the coding system that was hiding these signals from us. We have shown that not only can we read these messages but we can jam them and stop the virus’ deployment.”

    Single-stranded RNA viruses are the simplest type of virus and were probably one of the earliest to evolve. However, they are still among the most potent and damaging of infectious pathogens.

    Rhinovirus (which causes the common cold) accounts for more infections every year than all other infectious agents put together (about 1 billion cases), while emergent infections such as chikungunya and tick-borne encephalitis are from the same ancient family.

    Other single-stranded RNA viruses include the hepatitis C virus, HIV and the winter vomiting bug norovirus.

    This breakthrough was the result of three stages of research

    •In 2012, researchers at the University of Leeds published the first observations at a single-molecule level of how the core of a single-stranded RNA virus packs itself into its outer shell—a remarkable process because the core must first be correctly folded to fit into the protective viral protein coat. The viruses solve this fiendish problem in milliseconds. The next challenge for researchers was to find out how the viruses did this.
    •University of York mathematicians Dr Eric Dykeman and Professor Reidun Twarock, working with the Leeds group, then devised mathematical algorithms to crack the code governing the process and built computer-based models of the coding system.
    •In this latest study, the two groups have unlocked the code. The group used single-molecule fluorescence spectroscopy to watch the codes being used by the satellite tobacco necrosis virus, a single stranded RNA plant virus.

    Dr Roman Tuma, Reader in Biophysics at the University of Leeds, said: “We have understood for decades that the RNA carries the genetic messages that create viral proteins, but we didn’t know that, hidden within the stream of letters we use to denote the genetic information, is a second code governing virus assembly. It is like finding a secret message within an ordinary news report and then being able to crack the whole coding system behind it.

    “This paper goes further: it also demonstrates that we could design molecules to interfere with the code, making it uninterpretable and effectively stopping the virus in its tracks.”

    Professor Reidun Twarock, of the University of York’s Department of Mathematics, said: “The Enigma machine metaphor is apt. The first observations pointed to the existence of some sort of a coding system, so we set about deciphering the cryptic patterns underpinning it using novel, purpose designed computational approaches. We found multiple dispersed patterns working together in an incredibly intricate mechanism and we were eventually able to unpick those messages. We have now proved that those computer models work in real viral messages.”

    The next step will be to widen the study into animal viruses. The researchers believe that their combination of single-molecule detection capabilities and their computational models offers a novel route for drug discovery.

    See the full article here.

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    About Phys.org in 100 Words

    Phys.org™ (formerly Physorg.com) is a leading web-based science, research and technology news service which covers a full range of topics. These include physics, earth science, medicine, nanotechnology, electronics, space, biology, chemistry, computer sciences, engineering, mathematics and other sciences and technologies. Launched in 2004, Phys.org’s readership has grown steadily to include 1.75 million scientists, researchers, and engineers every month. Phys.org publishes approximately 100 quality articles every day, offering some of the most comprehensive coverage of sci-tech developments world-wide. Quancast 2009 includes Phys.org in its list of the Global Top 2,000 Websites. Phys.org community members enjoy access to many personalized features such as social networking, a personal home page set-up, RSS/XML feeds, article comments and ranking, the ability to save favorite articles, a daily newsletter, and other options.

     
  • richardmitnick 5:59 am on February 13, 2015 Permalink | Reply
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    From Rock U: “Key to blocking influenza virus may lie in a cell’s own machinery” 

    Rockefeller U bloc

    Rockefeller University

    February 12, 2015
    Zach Veilleux | 212-327-8982
    newswire@rockefeller.edu

    1
    Going viral: To test which virus-fighting proteins could interfere with the spread of an infection, the researchers introduced immune genes individually into cells, before infecting them with Influenza A. Above, all cells’ nuclei appear in blue, infected cells in green.
    Viruses are masters of outsourcing, entrusting their fundamental function – reproduction – to the host cells they infect. But it turns out this highly economical approach also creates vulnerability.

    Researchers at Rockefeller University and their collaborators have found an unexpected way the immune system exploits the flu virus’ dependence on its host’s machinery to create new viruses capable of spreading infection. This discovery suggests a new approach to combating winter’s most unpleasant, and sometimes, deadly curse: the seasonal flu.

    “Influenza A, the virus we studied, relies on a host’s protein-cutting machinery to put the final touches on new viral particles. Our research has shown that the host immune system fights back by turning off this machinery,” says study researcher Charles Rice, Maurice R. and Corinne P. Greenberg Professor in Virology Professor and head of the Laboratory of Virology and Infectious Disease. “This concept, that a host would inhibit its own protein-cutting enzymes in order to fight off a virus, is entirely new.”

    Experiments described today (February 12) in Cell reveal a new function for the well-studied protein known as PAI-1 (plasminogen activator inhibitor 1) as the key to this defensive strategy. PAI-1 shuts down proteases, which are enzymes that break the chemical bonds within protein molecules. PAI-1 is best known for inhibiting proteases involved in the break down of blood clots. After seeing evidence of a new role for PAI-1, the researchers found that human and mouse cells unable to properly produce it appeared more vulnerable to infection by influenza A. In experiments, they used the subtype H1N1, a derivative of the 1918 pandemic flu and a member of a large family of flu viruses that include seasonal flu.

    A cell infected by a virus releases chemical signals known as interferons, which turn up the volume on a legion of defensive genes. “The hundreds of host proteins produced by these interferon-stimulated genes are like an army. We know that, together, they can effectively defend against a viral infection, but we don’t know how the individual soldiers fight back, particularly those that interfere with later stages of viral replication, when the virus exits the cell and spreads the infection,” says first author Meike Dittmann, a postdoc in the lab. Previous work here and elsewhere has explored inhibitors of the early stages of viral replication.

    They started out by testing a large suite of genes activated by interferon. With help from Paul Bieniasz’s Laboratory of Retrovirology at The Rockefeller University and the Aaron Diamond AIDS Research Center, they introduced these individual genes into cells, then infected the cells with the flu. With the knowledge that influenza A’s replication cycle takes about eight hours, they watched to see which genes blocked the ability of influenza to spread. As expected, numerous genes inhibited late stages infection, but one stood out: SERPINE1, the gene that codes for PAI-1.

    Given what was already known about PAI-1, Dittmann suspected how it might help cells fight flu.

    “A virus attacks a cell using fusion proteins, and if these don’t work properly, new virus particles get out of an infected cell just fine, but they cannot spread the infection to other cells. Proteases activate fusion proteins by clipping them, but on its own influenza A doesn’t have the gene for the protease it needs. As a result, the virus relies on the host proteases to do the job,” Dittmann says.

    Subsequent experiments confirmed PAI-1 did indeed prevent the cutting of the fusion protein, known as hemagglutinin, and that high levels of PAI-1 prevented the virus from producing particles capable of spreading the infection. Furthermore, mice that lacked the gene for PAI-1 generally fared worse than their peers when infected with the influenza A virus. Experiments conducted by the team’s collaborators at the MRC National Institute for Medical Research in London used infected tissues cultured from mice’s tracheae to confirm PAI-1’s role in fighting off the infection.

    Human cells were the final step. Researchers in Senior Attending Physician and Professor Jean-Laurent Casanova’s St. Giles Laboratory of Human Genetics combed through a database containing genetic information on patients who had suffered from severe infectious disease to find those with genetic changes that reduced PAI-1. Biopsies taken from these patients had been used to create cell lines, and when cells derived from patients with mutations in SERPINE1 were infected, they accumulated higher loads of the virus than cells derived from people without mutations in the gene.

    “While this study was conducted with Influenza A, our results may have broader implications,” Rice says. “PAI-1 is part of a large family of protease inhibitors, and it’s possible that it, or its close relatives, may interfere with the replication of other viruses that don’t carry genes for their own proteases. This suggests that it may be possible to use a PAI-1-like strategy as a treatment for flu, and possibly other viral infections.”

    See the full article here.

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    Rockefeller U Campus

    The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, bioinformatics and physics. The university’s 76 laboratories conduct both clinical and basic research and study a diverse range of biological and biomedical problems with the mission of improving the understanding of life for the benefit of humanity.

    Founded in 1901 by John D. Rockefeller, the Rockefeller Institute for Medical Research was the country’s first institution devoted exclusively to biomedical research. The Rockefeller University Hospital was founded in 1910 as the first hospital devoted exclusively to clinical research. In the 1950s, the institute expanded its mission to include graduate education and began training new generations of scientists to become research leaders around the world. In 1965, it was renamed The Rockefeller University.

     
  • richardmitnick 5:49 am on February 12, 2015 Permalink | Reply
    Tags: , , Medicine,   

    From Rutgers: “Ingredient in Olive Oil Looks Promising in the Fight Against Cancer” 

    Rutgers University
    Rutgers University

    February 12, 2015
    Ken Branson

    1
    Extra-virgin olive oil contains an ingredient, oleocanthal, that kills cancer cells without harming healthy cells, researchers have found.

    A Rutgers nutritional scientist and two cancer biologists at New York City’s Hunter College have found that an ingredient in extra-virgin olive oil kills a variety of human cancer cells without harming healthy cells.

    The ingredient is oleocanthal, a compound that ruptures a part of the cancerous cell, releasing enzymes that cause cell death.

    Paul Breslin, professor of nutritional sciences in the School of Environmental and Biological Sciences, and David Foster and Onica LeGendre of Hunter College, report that oleocanthal kills cancerous cells in the laboratory by rupturing vesicles that store the cell’s waste. LeGendre, the first author, Foster, the senior author, and Breslin have published their findings in Molecular and Cellular Oncology.

    According to the World Health Organization’s World Cancer Report 2014, there were more than 14 million new cases of cancer in 2012 and more than 8 million deaths.

    Scientists knew that oleocanthal killed some cancer cells, but no one really understood how this occurred. Breslin believed that oleocanthal might be targeting a key protein in cancer cells that triggers a programmed cell death, known as apoptosis, and worked with Foster and Legendre to test his hypothesis after meeting David Foster at a seminar he gave at Rutgers.

    “We needed to determine if oleocanthal was targeting that protein and causing the cells to die,” Breslin said.

    After applying oleocanthal to the cancer cells, Foster and LeGendre discovered that the cancer cells were dying very quickly – within 30 minutes to an hour. Since programmed cell death takes between 16 and 24 hours, the scientists realized that something else had to be causing the cancer cells to break down and die.

    LeGendre, a chemist, provided the answer: The cancer cells were being killed by their own enzymes. The oleocanthal was puncturing the vesicles inside the cancer cells that store the cell’s waste – the cell’s “dumpster,” as Breslin called it, or “recycling center,” as Foster refers to it. These vesicles, known as lysosomes are larger in cancer cells than in healthy cells, and they contain a lot of waste. “Once you open one of those things, all hell breaks loose,” Breslin said.

    But oleocanthal didn’t harm healthy cells, the researchers found. It merely stopped their life cycles temporarily – “put them to sleep,” Breslin said. After a day, the healthy cells resumed their cycles.

    The researchers say the logical next step is to go beyond laboratory conditions and show that oleocanthal can kill cancer cells and shrink tumors in living animals. “We also need to understand why it is that cancerous cells are more sensitive to oleocanthal than non-cancerous cells,” Foster said.

    See the full article 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 9:22 pm on February 9, 2015 Permalink | Reply
    Tags: , Medicine,   

    From MIT: “Engineered insulin could offer better diabetes control” 


    MIT News

    February 9, 2015
    Anne Trafton | MIT News Office

    Temp 1

    For patients with diabetes, insulin is critical to maintaining good health and normal blood-sugar levels. However, it’s not an ideal solution because it can be difficult for patients to determine exactly how much insulin they need to prevent their blood sugar from swinging too high or too low.

    MIT engineers hope to improve treatment for diabetes patients with a new type of engineered insulin. In tests in mice, the researchers showed that their modified insulin can circulate in the bloodstream for at least 10 hours, and that it responds rapidly to changes in blood-sugar levels. This could eliminate the need for patients to repeatedly monitor their blood sugar levels and inject insulin throughout the day.

    “The real challenge is getting the right amount of insulin available when you need it, because if you have too little insulin your blood sugar goes up, and if you have too much, it can go dangerously low,” says Daniel Anderson, the Samuel A. Goldblith Associate Professor in MIT’s Department of Chemical Engineering, and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science. “Currently available insulins act independent of the sugar levels in the patient.”

    Anderson and Robert Langer, the David H. Koch Institute Professor at MIT, are the senior authors of a paper describing the engineered insulin in this week’s Proceedings of the National Academy of Sciences. The paper’s lead authors are Hung-Chieh (Danny) Chou, former postdoc Matthew Webber, and postdoc Benjamin Tang. Other authors are technical assistants Amy Lin and Lavanya Thapa, David Deng, Jonathan Truong, and Abel Cortinas.

    Glucose-responsive insulin

    Patients with Type I diabetes lack insulin, which is normally produced by the pancreas and regulates metabolism by stimulating muscle and fat tissue to absorb glucose from the bloodstream. Insulin injections, which form the backbone of treatment for diabetes patients, can be deployed in different ways. Some people take a modified form called long-acting insulin, which stays in the bloodstream for up to 24 hours, to ensure there is always some present when needed. Other patients calculate how much they should inject based on how many calories they consume or how much sugar is present in their blood.

    The MIT team set out to create a new form of insulin that would not only circulate for a long time, but would be activated only when needed — that is, when blood-sugar levels are too high. This would prevent patients’ blood-sugar levels from becoming dangerously low, a condition known as hypoglycemia that can lead to shock and even death.

    To create this glucose-responsive insulin, the researchers first added a hydrophobic molecule called an aliphatic domain, which is a long chain of fatty molecules dangling from the insulin molecule. This helps the insulin circulate in the bloodstream longer, although the researchers do not yet know exactly why that is. One theory is that the fatty tail may bind to albumin, a protein found in the bloodstream, sequestering the insulin and preventing it from latching onto sugar molecules.

    The researchers also attached a chemical group called PBA, which can reversibly bind to glucose. When blood-glucose levels are high, the sugar binds to insulin and activates it, allowing the insulin to stimulate cells to absorb the excess sugar.

    The research team created four variants of the engineered molecule, each of which contained a PBA molecule with a different chemical modification, such as an atom of fluorine and nitrogen. They then tested these variants, along with regular insulin and long-acting insulin, in mice engineered to have an insulin deficiency.

    To compare each type of insulin, the researchers measured how the mice’s blood-sugar levels responded to surges of glucose every few hours for 10 hours. They found that the engineered insulin containing PBA with fluorine worked the best: Mice that received that form of insulin showed the fastest response to blood-glucose spikes.

    “The modified insulin was able to give more appropriate control of blood sugar than the unmodified insulin or the long-acting insulin,” Anderson says.

    The new molecule represents a significant conceptual advance that could help scientists realize the decades-old goal of better controlling diabetes with a glucose-responsive insulin, says Michael Weiss, a professor of biochemistry and medicine at Case Western Reserve University.

    “It would be a breathtaking advance in diabetes treatment if the Anderson/Langer technology could accomplish the translation of this idea into a routine treatment of diabetes,” says Weiss, who was not part of the research team.

    New alternative

    Giving this type of insulin once a day instead of long-acting insulin could offer patients a better alternative that reduces their blood-sugar swings, which can cause health problems when they continue for years and decades, Anderson says. The researchers now plan to test this type of insulin in other animal models and are also working on tweaking the chemical composition of the insulin to make it even more responsive to blood-glucose levels.

    “We’re continuing to think about how we might further tune this to give improved performance so it’s even safer and more efficacious,” Anderson says.

    The research was funded by the Leona M. and Harry B. Helmsley Charitable Trust, the Tayebati Family Foundation, the National Institutes of Health, and the Juvenile Diabetes Research Foundation.

    See the full article here.

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  • richardmitnick 7:26 pm on February 9, 2015 Permalink | Reply
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    From Rice: “Nano-antioxidants prove their potential” 

    Rice U bloc

    Rice University

    February 9, 2015
    Mike Williams

    Rice-led study shows how particles quench damaging superoxides

    Injectable nanoparticles that could protect an injured person from further damage due to oxidative stress have proven to be astoundingly effective in tests to study their mechanism.

    Scientists at Rice University, Baylor College of Medicine and the University of Texas Health Science Center at Houston (UTHealth) Medical School designed methods to validate their 2012 discovery that combined polyethylene glycol-hydrophilic carbon clusters — known as PEG-HCCs — could quickly stem the process of overoxidation that can cause damage in the minutes and hours after an injury.

    1
    A polyethylene glycol-hydrophilic carbon cluster developed at Rice University has the potential to quench the overexpression of damaging superoxides through the catalytic turnover of reactive oxygen species that can harm biological functions. Illustration by Errol Samuel

    The tests revealed a single nanoparticle can quickly catalyze the neutralization of thousands of damaging reactive oxygen species molecules that are overexpressed by the body’s cells in response to an injury and turn the molecules into oxygen. These reactive species can damage cells and cause mutations, but PEG-HCCs appear to have an enormous capacity to turn them into less-reactive substances.

    The researchers hope an injection of PEG-HCCs as soon as possible after an injury, such as traumatic brain injury or stroke, can mitigate further brain damage by restoring normal oxygen levels to the brain’s sensitive circulatory system.

    The results were reported today in the Proceedings of the National Academy of Sciences.

    “Effectively, they bring the level of reactive oxygen species back to normal almost instantly,” said Rice chemist James Tour. “This could be a useful tool for emergency responders who need to quickly stabilize an accident or heart attack victim or to treat soldiers in the field of battle.” Tour led the new study with neurologist Thomas Kent of Baylor College of Medicine and biochemist Ah-Lim Tsai of UTHealth.

    PEG-HCCs are about 3 nanometers wide and 30 to 40 nanometers long and contain from 2,000 to 5,000 carbon atoms. In tests, an individual PEG-HCC nanoparticle can catalyze the conversion of 20,000 to a million reactive oxygen species molecules per second into molecular oxygen, which damaged tissues need, and hydrogen peroxide while quenching reactive intermediates.

    Tour and Kent led the earlier research that determined an infusion of nontoxic PEG-HCCs may quickly stabilize blood flow in the brain and protect against reactive oxygen species molecules overexpressed by cells during a medical trauma, especially when accompanied by massive blood loss.

    Their research targeted traumatic brain injuries, after which cells release an excessive amount of the reactive oxygen species known as a superoxide into the blood. These toxic free radicals are molecules with one unpaired electron that the immune system uses to kill invading microorganisms. In small concentrations, they contribute to a cell’s normal energy regulation. Generally, they are kept in check by superoxide dismutase, an enzyme that neutralizes superoxides.

    But even mild traumas can release enough superoxides to overwhelm the brain’s natural defenses. In turn, superoxides can form such other reactive oxygen species as peroxynitrite that cause further damage.

    “The current research shows PEG-HCCs work catalytically, extremely rapidly and with an enormous capacity to neutralize thousands upon thousands of the deleterious molecules, particularly superoxide and hydroxyl radicals that destroy normal tissue when left unregulated,” Tour said.

    “This will be important not only in traumatic brain injury and stroke treatment, but for many acute injuries of any organ or tissue and in medical procedures such as organ transplantation,” he said. “Anytime tissue is stressed and thereby oxygen-starved, superoxide can form to further attack the surrounding good tissue.”

    The researchers used an electron paramagnetic resonance spectroscopy technique that gets direct structure and rate information for superoxide radicals by counting unpaired electrons in the presence or absence of PEG-HCC antioxidants. Another test with an oxygen-sensing electrode, peroxidase and a red dye confirmed the particles’ ability to catalyze superoxide conversion.

    “In sharp contrast to the well-known superoxide dismutase, PEG-HCC is not a protein and does not have metal to serve the catalytic role,” Tsai said. “The efficient catalytic turnover could be due to its more ‘planar,’ highly conjugated carbon core.”

    The tests showed the number of superoxides consumed far surpassed the number of possible PEG-HCC bonding sites. The researchers found the particles have no effect on important nitric oxides that keep blood vessels dilated and aid neurotransmission and cell protection, nor was the efficiency sensitive to pH changes.

    “PEG-HCCs have enormous capacity to convert superoxide to oxygen and the ability to quench reactive intermediates while not affecting nitric oxide molecules that are beneficial in normal amounts,” Kent said. “So they hold a unique place in our potential armamentarium against a range of diseases that involve loss of oxygen and damaging levels of free radicals.”

    The study also determined PEG-HCCs remain stable, as batches up to 3 months old performed as good as new.

    Graduate student Errol Samuel and alumna Daniela Marcano, both of Rice, and Vladimir Berka, a senior research scientist at UTHealth, are lead authors of the study. Co-authors are Rice alumnus Austin Potter; alumnus Brittany Bitner and associate professor Robia Pautler of Baylor College of Medicine; instructor Gang Wu of UTHealth and Roderic Fabian of Baylor College of Medicine and the Michael E. DeBakey Veterans Affairs Medical Center.

    Kent is a professor of neurology and director of stroke research and education at Baylor College of Medicine and chief of neurology and a member of the Center for Translational Research on Inflammatory Diseases at the DeBakey Center. Tour is the T.T. and W.F. Chao Chair in Chemistry as well as a professor of materials science and nanoengineering and of computer science and a member of Rice’s Richard E. Smalley Institute for Nanoscale Science and Technology. Tsai is a professor of hematology at UTHealth and adjunct professor of biochemistry and cell biology at Rice.

    The Mission Connect Mild Traumatic Brain Injury Consortium from the Department of Defense and the National Institutes of Health, the Alliance for NanoHealth and UTHealth supported the research.

    See the full article here.

    Please help promote STEM in your local schools.

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    Stem Education Coalition

    Rice U campus

    In his 1912 inaugural address, Rice University president Edgar Odell Lovett set forth an ambitious vision for a great research university in Houston, Texas; one dedicated to excellence across the range of human endeavor. With this bold beginning in mind, and with Rice’s centennial approaching, it is time to ask again what we aspire to in a dynamic and shrinking world in which education and the production of knowledge will play an even greater role. What shall our vision be for Rice as we prepare for its second century, and how ought we to advance over the next decade?

    This was the fundamental question posed in the Call to Conversation, a document released to the Rice community in summer 2005. The Call to Conversation asked us to reexamine many aspects of our enterprise, from our fundamental mission and aspirations to the manner in which we define and achieve excellence. It identified the pressures of a constantly changing and increasingly competitive landscape; it asked us to assess honestly Rice’s comparative strengths and weaknesses; and it called on us to define strategic priorities for the future, an effort that will be a focus of the next phase of this process.

     
  • richardmitnick 3:10 pm on February 5, 2015 Permalink | Reply
    Tags: , , Medicine,   

    From NOVA: “Electric Fields Carrying Chemo Could Destroy Intractable Tumors” 

    PBS NOVA

    NOVA

    05 Feb 2015
    Tim De Chant

    There’s no “good” cancer, but some are certainly worse than others when it comes to prognosis. Pancreatic cancer, for example, has a dismal survival rate. It’s inoperable in many cases, and in general it’s hard to deliver chemo to the tumor because its internal pressure keeps drugs at bay.

    Researchers have been devising strategies to concentrate chemo in the most recalcitrant tumors, from injecting drugs directly into tumors themselves to directing chemo-coated magnetic particles to the site. The latest takes some of these ideas a step further while using existing drugs, a time-saving step. It comes in the form of a device that stores chemo and produces electric fields that carry the drugs directly into the tumor. Because many existing drugs are polar molecules, they are carried along with the electric current.

    1
    Pancreatic cancer cells, seen here through a powerful microscope, are targeted by the new treatment.

    Inventors Joseph DeSimone, a professor of chemistry at the University of North Carolina, Chapel Hill, and his team have tested their device on mice and dogs, and the approach shows promise. Here’s Robert F. Service, reporting for Science:

    The team got several promising results. In one experiment, the researchers started with mice that had been implanted with human pancreatic cancer tumors. One group of mice was then implanted with the electrode setup and administered an anticancer drug called gemcitabine twice a week for 7 weeks. Control animals received either saline through the same electrode setup or intravenous (IV) doses of saline or gemcitabine. The researchers report online today in Science Translational Medicine that the animals in the experimental group had far higher gemcitabine concentrations in their tumors compared with mice that received the IV drug. That caused the tumors to shrink dramatically in the experimental animals, whereas tumors in mice that received IV gemcitabine or saline continued to grow.

    Another advantage of the approach is that it limits the distribution of chemo within the body. Though the drugs are highly toxic to cancer cells, they also are taxing to healthy cells, making treatment regimens grueling affairs.

    DeSimone and his team have yet to move the device into clinical trials involving humans, an often unsuccessful transition for many would-be cancer treatments. Still, the fact that the device relies on delivering known, existing drugs more directly to a tumor site should reduce some uncertainty.

    See the full article here.

    Please help promote STEM in your local schools.

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    Stem Education Coalition

    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

     
  • richardmitnick 5:18 am on February 4, 2015 Permalink | Reply
    Tags: , , Medicine,   

    From SLAC: “Record Keeping Helps Bacteria’s Immune System Fight Invaders” 


    SLAC Lab

    February 3, 2015

    Bacteria have a sophisticated means of defending themselves, and they need it: more viruses infect bacteria than any other biological entity.

    Two experiments undertaken at the Department of Energy’s SLAC National Accelerator Laboratory provide new insight at the heart of bacterial adaptive defenses in a system called CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeat.

    This portion of bacteria’s immune system works as a record keeper, taking note of attacking viruses’ identities and storing that information by integrating fragments of the virus’ DNA into its own DNA. In this way, CRISPRs maintain genetic records of previously encountered viruses, making it easier for the bacteria’s immune system to send out complexes that destroy viral invaders by identifying and cutting up the recognized DNA sequences.

    The studies published last year in Science not only reveal important information about how bacteria repel attacking viruses, but also could potentially improve the prevention of disease in humans. Researchers are currently studying ways of preventing and treating cystic fibrosis, blood disorders and HIV by harnessing the CRISPR system to replace one version of a gene with another or to add a working copy for a mutated gene.

    Scientists studied one particular CRISPR-associated complex called Cascade using bright X-rays at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL)., a DOE Office of Science User Facility. In the bacteria Escherichia coli, 11 proteins assemble together with an RNA guide that helps Cascade target invading DNA sequences. Once Cascade confirms that the target DNA is from an invader, a molecular signal recruits a nuclease called Cas3 to finish off the invader by chewing it up.

    1`
    An overview of the crystal structure of Cascade, showing each gene in a different color. The red ribbon represents the RNA guide. (Ryan N. Jackson et al.)

    SLAC SSRL TunnelSLAC SSRL

    Previous work by Blake Wiedenheft, the Montana State University assistant professor of microbiology and immunology who led one of the studies, and his colleagues revealed Cascade’s seahorse-shaped architecture, but studies undertaken at SSRL now reveal how all the parts of this machine assemble into a functional surveillance machine that patrols the intracellular environment for invading DNA.

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    A simplified representation of the Cascade RNA guide (green) forming an under-wound ribbon-like structure with invading viral DNA (orange). (Scott Bailey et al.)

    “Determining high-resolution structures of large macromolecules remains challenging,” Wiedenheft said. “Several technical aspects of SSRL, including intensity of light, ability to focus the beam, and shutterless X-ray detector made these results possible.”

    The studies also revealed that Cascade’s RNA guide does not twist together with the viral DNA to form a helix, as was expected. Instead, they form an under-wound ribbon-like structure.

    “A high-resolution structure is essentially a molecular blueprint of a biological machine,” said Wiedenheft. Determining the structure of this complex “is a technical accomplishment that provides the first molecular explanation of how all the parts assemble into a functional surveillance machine.”

    See the full article here.

    Please help promote STEM in your local schools.

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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.
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