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News Article | February 23, 2017
Site: phys.org

The discovery, published on February 23, 2017 in the journal Cell, reveals new details about the evolution of sex. The protein acts as a nearly universal, biochemical "key" that enables two cell membranes to become one, resulting in the combination of genetic material—a necessary step for sexual reproduction. New details about the protein's function could help fight parasitic diseases, such as malaria, and boost efforts to control insect pests. "Our findings show that nature has a limited number of ways it can cause cells to fuse together into a single cell," said William Snell, a senior author of the study and a research professor in the University of Maryland Department of Cell Biology and Molecular Genetics. Snell joined UMD in June 2016, but performed the majority of the work at his previous institution, the University of Texas Southwestern Medical Center. "A protein that first made sex possible—and is still used for sexual reproduction in many of Earth's organisms—is identical to the protein used by dengue and Zika viruses to enter human cells," Snell said. "This protein must have really put the spice in the primordial soup." Snell and his colleagues studied the protein, called HAP2, in the single-celled green alga Chlamydomonas reinhardtii. HAP2 is common among single-celled protozoans, plants and arthropods—although it is not found in fungi or vertebrates such as humans. Prior results from Snell and his collaborators, as well as other research groups, indicated that HAP2 is necessary for sex cell fusion in the organisms that possess the protein. But the precise mechanism remained unclear. For the current study, Snell and his colleagues at UT Southwestern used sophisticated computer analysis tools to compare the amino acid sequence of Chlamydomonas HAP2 with that of known viral fusion proteins. The results suggested a striking degree of similarity, especially in a region called the "fusion loop" that enables the viral proteins to successfully invade a cell. If HAP2 functioned like a viral fusion protein, Snell reasoned, then disrupting HAP2's fusion loop should block its ability to fuse sex cells. Sure enough, when Snell's team changed just a single amino acid in the fusion loop of Chlamydomonas HAP2, the protein entirely lost its function. The sex cells were able to stick together—a process that depends on other proteins—but they were not able to complete the final fusion of their cell membranes. Similarly, the cells could not fuse when the researchers introduced an antibody that covered up the HAP2 fusion loop. "We were thrilled with these results, because they supported our new model of HAP2 function," Snell said. "But we needed to visualize the three-dimensional structure of the HAP2 protein to be sure it was similar to viral fusion proteins." Snell reached out to Felix Rey, a structural biologist at the Pasteur Institute in Paris who specializes in viruses. Coincidentally, Rey and his colleagues had just determined the structure of Chlamydomonas HAP2 using X-ray crystallography. Rey's results demonstrated that, indeed, HAP2 was functionally identical to dengue and Zika viral fusion proteins. "The HAP2 protein from Chlamydomonas is folded in an identical fashion to the viral proteins," Rey said, referring to the molecular folding that creates the three-dimensional structure of all proteins from a simple chain of amino acids. "The resemblance is unmistakable." HAP2 appears to be necessary for cell fusion in a wide variety of organisms, including disease-causing protozoans, invasive plants and destructive insect pests. So far, every known version of HAP2 shares the one critical amino acid in the fusion loop region. As such, HAP2 could provide a promising target for vaccines, therapies and other control methods. Snell is particularly encouraged by the possibility of controlling malaria, which is caused by the single-celled protozoan Plasmodium falciparum. "Developing a vaccine that blocks the fusion of Plasmodium sex cells would be a huge step forward," Snell said, noting that Plasmodium has a complex life cycle that depends on both mosquito and human hosts. "Our findings strongly suggest new strategies to target Plasmodium HAP2 that could disrupt the mosquito-borne stage of the Plasmodium life cycle." Explore further: Sperm-egg fusion proteins have same structure as those used by Zika and other viruses More information: The research paper, "The ancient gamete fusogen HAP2 is a eukaryotic class II fusion protein," Juliette Fedry, Yanjie Liu, Gerard Péhau-Arnaudet, Jimin Pei, Wenhao Li, M. Alejandra Tortorici, Francois Traincard, Annalisa Meola, Gerard Bricogne, Nick Grishin, William J. Snell, Félix A. Rey and Thomas Krey, was published February 23, 2017 in the journal Cell.


News Article | February 23, 2017
Site: www.eurekalert.org

Researchers determine that a protein required for sperm-egg fusion is identical to a protein viruses use to invade host cells; discovery could help fight parasitic diseases like malaria Sexual reproduction and viral infections actually have a lot in common. According to new research, both processes rely on a single protein that enables the seamless fusion of two cells, such as a sperm cell and egg cell, or the fusion of a virus with a cell membrane. The protein is widespread among viruses, single-celled protozoans, and many plants and arthropods, suggesting that the protein evolved very early in the history of life on Earth. The discovery, published on February 23, 2017 in the journal Cell, reveals new details about the evolution of sex. The protein acts as a nearly universal, biochemical "key" that enables two cell membranes to become one, resulting in the combination of genetic material--a necessary step for sexual reproduction. New details about the protein's function could help fight parasitic diseases, such as malaria, and boost efforts to control insect pests. "Our findings show that nature has a limited number of ways it can cause cells to fuse together into a single cell," said William Snell, a senior author of the study and a research professor in the University of Maryland Department of Cell Biology and Molecular Genetics. Snell joined UMD in June 2016, but performed the majority of the work at his previous institution, the University of Texas Southwestern Medical Center. "A protein that first made sex possible -- and is still used for sexual reproduction in many of Earth's organisms -- is identical to the protein used by dengue and Zika viruses to enter human cells," Snell said. "This protein must have really put the spice in the primordial soup." Snell and his colleagues studied the protein, called HAP2, in the single-celled green alga Chlamydomonas reinhardtii. HAP2 is common among single-celled protozoans, plants and arthropods -- although it is not found in fungi or vertebrates such as humans. Prior results from Snell and his collaborators, as well as other research groups, indicated that HAP2 is necessary for sex cell fusion in the organisms that possess the protein. But the precise mechanism remained unclear. For the current study, Snell and his colleagues at UT Southwestern used sophisticated computer analysis tools to compare the amino acid sequence of Chlamydomonas HAP2 with that of known viral fusion proteins. The results suggested a striking degree of similarity, especially in a region called the "fusion loop" that enables the viral proteins to successfully invade a cell. If HAP2 functioned like a viral fusion protein, Snell reasoned, then disrupting HAP2's fusion loop should block its ability to fuse sex cells. Sure enough, when Snell's team changed just a single amino acid in the fusion loop of Chlamydomonas HAP2, the protein entirely lost its function. The sex cells were able to stick together -- a process that depends on other proteins--but they were not able to complete the final fusion of their cell membranes. Similarly, the cells could not fuse when the researchers introduced an antibody that covered up the HAP2 fusion loop. "We were thrilled with these results, because they supported our new model of HAP2 function," Snell said. "But we needed to visualize the three-dimensional structure of the HAP2 protein to be sure it was similar to viral fusion proteins." Snell reached out to Felix Rey, a structural biologist at the Pasteur Institute in Paris who specializes in viruses. Coincidentally, Rey and his colleagues had just determined the structure of Chlamydomonas HAP2 using X-ray crystallography. Rey's results demonstrated that, indeed, HAP2 was functionally identical to dengue and Zika viral fusion proteins. "The HAP2 protein from Chlamydomonas is folded in an identical fashion to the viral proteins," Rey said, referring to the molecular folding that creates the three-dimensional structure of all proteins from a simple chain of amino acids. "The resemblance is unmistakable." HAP2 appears to be necessary for cell fusion in a wide variety of organisms, including disease-causing protozoans, invasive plants and destructive insect pests. So far, every known version of HAP2 shares the one critical amino acid in the fusion loop region. As such, HAP2 could provide a promising target for vaccines, therapies and other control methods. Snell is particularly encouraged by the possibility of controlling malaria, which is caused by the single-celled protozoan Plasmodium falciparum. "Developing a vaccine that blocks the fusion of Plasmodium sex cells would be a huge step forward," Snell said, noting that Plasmodium has a complex life cycle that depends on both mosquito and human hosts. "Our findings strongly suggest new strategies to target Plasmodium HAP2 that could disrupt the mosquito-borne stage of the Plasmodium life cycle." In addition to Snell and Rey, co-authors of the study include: Juliette Fedry, Gerard Péhau-Arnaudet, M. Alejandra Tortorici, Francois Traincard and Annalisa Meola (Pasteur Institute); Yanjie Liu, Jimin Pei, Wenhao Li and Nick Grishin (UT Southwestern); Gerard Bricogne (Global Phasing, Ltd.); and Thomas Krey (Pasteur Institute, Hannover Medical School and German Center for Infection Research). The research paper, "The ancient gamete fusogen HAP2 is a eukaryotic class II fusion protein," Juliette Fedry, Yanjie Liu, Gerard Péhau-Arnaudet, Jimin Pei, Wenhao Li, M. Alejandra Tortorici, Francois Traincard, Annalisa Meola, Gerard Bricogne, Nick Grishin, William J. Snell, Félix A. Rey and Thomas Krey, was published February 23, 2017 in the journal Cell. This work was supported by the United States National Institutes of Health (Award Nos. GM56778 and GM094575), the Welch Foundation (Award No. I-1505), the European Research Council, the Pasteur Institute and the French National Center for Scientific Research. The content of this article does not necessarily reflect the views of these organizations. University of Maryland College of Computer, Mathematical, and Natural Sciences 2300 Symons Hall College Park, MD 20742 http://www. @UMDscience About the College of Computer, Mathematical, and Natural Sciences The College of Computer, Mathematical, and Natural Sciences at the University of Maryland educates more than 7,000 future scientific leaders in its undergraduate and graduate programs each year. The college's 10 departments and more than a dozen interdisciplinary research centers foster scientific discovery with annual sponsored research funding exceeding $150 million.


OXFORD, Inglaterra, December 8, 2016 /PRNewswire/ -- Oxford Gene Technology (OGT), The Molecular Genetics Company, ha ampliado su gama de panel personalizable SureSeq™ NGS con el lanzamiento del panel FH personalizado NGS SureSeq myPanel™ - que permite un estudio rápido y de coste...


OXFORD, England, Dec. 8, 2016 /PRNewswire/ -- Oxford Gene Technology (OGT), The Molecular Genetics Company, has expanded its customisable SureSeq™ NGS panel range with the launch of the SureSeq myPanel™ NGS Custom FH Panel - allowing fast and cost-effective study of variants in familial hypercholesterolemia (FH). The panel delivers single nucleotide variation (SNV) and copy number variation (CNV) detection on a single small panel and allows customisation by 'mix and match' of fully-optimised gene and hotspot content. This includes all exons for LDLR, PCSK9, APOB, LDLRAP1, APOE, LIPA and STAP1 and a further 14 SNPs. This enables researchers to selectively sequence relevant regions, increasing throughput and saving on reagents. FH is characterised by high LDL levels leading to early-onset coronary artery disease - treatable with statins. It is well characterised at the molecular level with various genes and multiple point mutations described. Analysis of mutations by multiple PCR or Sanger sequencing is often time-consuming. Around 5-10% of mutations are due to CNVs, requiring further detection by Multiplex Ligation-dependent Probe Amplification (MLPA). In order to streamline detection, OGT's FH panel enables sequencing of all relevant gene regions in one assay. In addition, hybridisation-based enrichment delivers unparalleled completeness and uniformity of coverage, removing the need for supplementary fill-in Sanger sequencing. Detection of CNVs has shown complete concordance with microarray results (the gold standard for CNV detection) in all samples tested by OGT. This means that researchers can analyse CNVs with confidence, removing the need for additional MLPA testing. OGT has customisable CytoSure™ microarrays for downstream CNV confirmation. OGT EVP Marketing, Emma Shipstone, added: "Being able to confidently detect SNVs and CNVs on one panel is a big step forward. Our hybridisation methodology and bait design expertise make this possible by ensuring our panels deliver outstanding completeness and uniformity of coverage. Areas of CNV can be easily identified within each sample - delivering an increased understanding of the sample more rapidly and cost-effectively for our customers." To find out more, please visit http://www.ogt.com/FH. SureSeq™: For Research Use Only; Not for Use in Diagnostic Procedures.


TORONTO, ON--(Marketwired - February 08, 2017) - Next generation sequencing (NGS) based clinical genomics assays are increasingly being offered by laboratories worldwide across a wide range of disease areas, including cancer, reproductive health, inherited disease and infectious disease. Developing, optimizing, and monitoring such assays however can be a time consuming and challenging task. Scientists and clinicians can build and implement robust and accurate clinical genomics assays with the help of highly multiplexed and patient-like reference materials. Join industry expert Sandi Deans, Consultant Clinical Scientist and Director of UK National External Quality Assessment Service (UK NEQAS) for Molecular Genetics as she discusses a case study of how a global external quality assessment (EQA) organization is using these reference materials to ensure the accuracy and consistency of one such clinical genomics application in non-invasive prenatal testing (NIPT). The live broadcast takes place on Wednesday, March 1, 2017 at 1pm EST. For more information or to register for this complimentary event, visit: Enabling Precision Medicine with Highly Multiplexed and Patient-like Reference Materials Xtalks, powered by Honeycomb Worldwide Inc., is a leading provider of educational webinars to the global Life Sciences community. Every year thousands of industry practitioners (from pharmaceutical & biotech companies, private & academic research institutions, healthcare centers, etc.) turn to Xtalks for access to quality content. Xtalks helps Life Science professionals stay current with industry developments, trends and regulations. Xtalks webinars also provide perspectives on key issues from top industry thought leaders and service providers. To learn more about Xtalks visit http://xtalks.com For information about hosting a webinar visit http://xtalks.com/sponsorship.ashx


News Article | November 22, 2016
Site: www.eurekalert.org

Researchers centered at Tokyo Medical and Dental University (TMDU) identify novel type of cell death in Huntington's disease that may uncover new treatments. Tokyo - In Huntington's disease (HD), the huntingtin gene is mutated, causing progressive neuronal death. This leads to defects in movement, behavior, and cognitive ability. Apoptosis, autophagy, and necrosis are the three main types of cell death, but researchers have not yet been able to determine what type of cell death causes neurodegeneration in the brain of HD patients. In a new study, Tokyo Medical and Dental University-led researchers examined the nature of cell death in HD using newly developed imaging techniques. The effects of mutant huntingtin in neuronal cells were visualized by live cell imaging. With this approach, the authors identified a novel type of cell death associated with mutant huntingtin, which they called ballooning cell death (BCD). These cells gradually expanded like a balloon, until they ruptured. To characterize the specific nature of BCD, the authors examined different cellular organelles by live cell imaging. "The endoplasmic reticulum was the main origin of ballooning," study first author Ying Mao explains. "Rupture of the endoplasmic reticulum into the cytosol was followed by gradual cell body ballooning, nuclear shrinkage, and cell rupture." The authors observed the same phenomena in vivo using two-photon endoplasmic reticulum imaging in a HD mouse model. Pharmacological inhibitors and genetic interventions showed that BCD was not like apoptosis or autophagy. "We noticed multiple similarities between BCD and a unique form of necrosis called TRIAD, which is caused by inhibition of RNA polymerase II in neurons," corresponding author Hitoshi Okazawa explains. "Based on our existing knowledge of how TRIAD is regulated, we were able to show that BCD is mediated by impaired TEAD/YAP transcription." These revelations provided the opportunity to test potential therapeutic targets for HD. The researchers introduced S1P and up-regulated TEAD/YAP transcription in HD mice. This stabilized endoplasmic reticulum and completely stopped the decline of motor function, suggesting that targeting TEAD/YAP-dependent necrosis may lead to development of effective therapies for HD. The article "Targeting TEAD/YAP-transcription-dependent necrosis, TRIAD, ameliorates Huntington's disease pathology" was published in Human Molecular Genetics at doi: 10.1093/hmg/ddw303


News Article | December 12, 2016
Site: www.eurekalert.org

PITTSBURGH, Dec. 12, 2016 - The chronic lung inflammation that is a hallmark of cystic fibrosis, has, for the first time, been linked to a new class of bacterial enzymes that hijack the patient's immune response and prevent the body from calling off runaway inflammation, according to a laboratory investigation led by the University of Pittsburgh School of Medicine. The discovery, published today by the Proceedings of the National Academy of Sciences, gives scientists two avenues to explore for the creation of therapies that could interrupt or correct this interference by the opportunistic bacterium Pseudomonas aeruginosa, which disproportionately infects people with cystic fibrosis. "There are about 30,000 patients in the U.S. with cystic fibrosis, and hundreds of thousands more with other chronic lung diseases. Once these diseases progress to the point that the patient is chronically infected with P. aeruginosa, current antimicrobial therapies are no longer effective and there are very few treatment options left," said Jennifer M. Bomberger, Ph.D., assistant professor in Pitt's Department of Microbiology & Molecular Genetics and senior author on the study. "Lung damage from these chronic P. aeruginosa infections, coupled with a robust but unproductive inflammatory response to the infection, will eventually lead to respiratory failure in the patient and the need for a lung transplant." Cystic fibrosis is caused by a genetic mutation that makes it difficult for patients to clear infections, allowing microorganisms to repeatedly infect the respiratory tract. By the time they reach adulthood, most cystic fibrosis patients are chronically infected with P. aeruginosa because this particular bacterium has an exceptional ability to outcompete other microorganisms and establish a stronghold in the lungs. Aiding its ability to outfight other infections, P. aeruginosa thrives when the body creates an inflammatory response aimed at isolating foreign invaders and attracting white blood cells to fight them. The body's own inflammatory response to fight infection is a major part of what actually damages a cystic fibrosis patient's lungs to the point that they no longer function. Bomberger's team, in collaboration with Dean Madden, Ph.D., at the Geisel School of Medicine at Dartmouth, discovered that P. aeruginosa perpetuates inflammation by secreting an enzyme called Cif that sabotages the body's ability to make a key molecule called a "pro-resolving lipid mediator" and put a stop to the inflammatory response it started. The scientists confirmed this mechanism by analyzing secretions drawn from the lungs of cystic fibrosis patients seen at Children's Hospital of Pittsburgh of UPMC and linking their findings to patient records. Patients with higher Cif levels in their lung secretions had reduced biological signaling to stop inflammation and increased levels of IL-8, a marker for inflammation. Increased Cif levels also correlated with reduced lung function, which leads to disease progression in patients. Previous studies in mice indicated that artificially boosting the levels of the pro-resolving lipid mediator reduces the inflammatory response and promotes clearance of P. aeruginosa in a pneumonia model. Bomberger and Madden, in collaboration with colleagues at the University of California, Davis, are exploring an alternative strategy to inhibit Cif activity, stopping the problem before it begins. "It will be key to devise a way to remove P. aeruginosa's ability to capitalize on the body's natural inflammatory response, without eliminating that response," said Bomberger. "Inflammation is happening for a reason--to clear infection. We just need it to temper the response when it is not effectively doing its job or is no longer needed." Becca A. Flitter, M.P.H., of Pitt, and Kelli L. Hvorecny, Ph.D., of Dartmouth are lead authors on this study. Additional authors are Christopher D. Bahl, Ph.D. and Thomas H. Hampton, M.S., both of Dartmouth; Emiko Ono, Ph.D., M.D., and Bruce D. Levy, M.D., both of Harvard University; Taylor Eddens, B.A., Jay K. Kolls, M.D., Daniel H. Kwak, Ph.D., Xinyu Liu, Ph.D., and Janet S. Lee, M.D., all of Pitt; and Jun Yang, Ph.D., Christophe Morisseu, Ph.D., Bruce D. Hammock, Ph.D., all of UC Davis. This research was funded by National Institutes of Health grants K99/R00HL098342, P30DK072506, T32AI060525, P01GM095467, U24AI118656, U24DK097154, R01AI091699, P20GM113132, P30GM106394, T32GM008704 and GM-0800, a Gilead Sciences Research Scholars in Cystic Fibrosis Award, Cystic Fibrosis Foundation grants MADDEN08G0 and STANTO19R0, and a Munck-Pfefferkorn Award. About the University of Pittsburgh Schools of the Health Sciences The University of Pittsburgh Schools of the Health Sciences include the schools of Medicine, Nursing, Dental Medicine, Pharmacy, Health and Rehabilitation Sciences and the Graduate School of Public Health. The schools serve as the academic partner to the UPMC (University of Pittsburgh Medical Center). Together, their combined mission is to train tomorrow's health care specialists and biomedical scientists, engage in groundbreaking research that will advance understanding of the causes and treatments of disease and participate in the delivery of outstanding patient care. Since 1998, Pitt and its affiliated university faculty have ranked among the top 10 educational institutions in grant support from the National Institutes of Health. For additional information about the Schools of the Health Sciences, please visit http://www. .


Researchers from University of Southern California, Interventional Pain Institute, and Proove Biosciences Publish Clinical Utility Study Supporting Precision Medicine in Pain Perception IRVINE, CA--(Marketwired - Feb 13, 2017) -  Proove Biosciences, Inc., the Healthcare Decision Company™, is pleased to announce the publication of a clinical study supporting the clinical utility of Proove Pain Perception® Profile in the latest edition of the peer-reviewed Journal of Psychiatric Research. In the study entitled, An observational study of the impact of genetic testing for pain perception in the clinical management of chronic non-cancer pain, researchers from the University of Southern California Keck School of Medicine in Los Angeles, Interventional Pain Institute in Baltimore, and Proove Biosciences published findings which demonstrate how clinicians use Proove Pain Perception to improve clinical outcomes for patients. Adding to the voluminous clinical validity evidence supporting Proove Pain Perception that is published in marquee peer-reviewed journals such as Human Molecular Genetics, Science, and Pain, this clinical utility study demonstrates the impact of physician decision-making and patient outcomes using this technology. "It is gratifying to see Proove's collaborative efforts gain acceptance among our vast community of discerning peers," says Dr. Maneesh Sharma, lead author of the study, Medical Director of the Interventional Pain Institute and member of Proove's Medical Advisory Board. "Proove is committed to uncovering the best treatment options for pain patients, and through this study, we hope to advance the adoption of precision medicine solutions in clinical settings to reduce the burden of chronic pain and prescription opioid abuse. We are grateful to our colleagues and to the Journal of Psychiatric Research for their recognition of our findings." Proove Pain Perception® Profile provides an objective measure of pain perception based, in part, on genetic markers in the catechol-O-methyltransferase (COMT) gene. The proprietary haplotype algorithm characterizing this gene was invented by NIH-funded scientists at the University of North Carolina at Chapel Hill, and the exclusive rights to this intellectual property was licensed to Proove Biosciences. In this study, authors found that using Proove Pain Perception substantially affected physician clinical decision-making and that the availability and utilization of this information was a contributing factor in clinical improvement. These findings demonstrate the clinical utility and actionability of the already clinically-validated algorithm behind the Proove Pain Perception Profile. "With opioid abuse and deaths from overdose at an all-time high as a result of mismanaged or misunderstood chronic pain, we have no doubt that these innovative treatment solutions may soon be the go-to option for thousands of doctors, surgeons and hospitals," adds Sharma. Since launching in 2009, Proove Biosciences has become the commercial and educational leader in the research, investigation and development of patent-protected tests that combine genetic and clinical data into reports to help physicians individualize -- and optimize -- medicine selection and dosing. Proove is backed by science, driven by data and supported by an advisory board of the world's leading medical experts. Its patented bioinformatics platform for collecting, storing, analyzing and integrating biological and genetic information, is changing the future of healthcare. "Over the past 5 years, Proove has been conducting a number of multi-center studies involving prospective outcomes of thousands of patients," explained Dr. Svetlana Kantorovich, Director of Research & Development at Proove. "Through these large studies, we look forward to many more publications in peer-reviewed journals providing continued evidence of the accuracy and positive impact of Proove's precision medicine technology." To learn more about Proove Biosciences, visit www.proove.com. With media inquiries, please contact Leslie Licano at leslie@beyondfifteen.com or (949)-733-8679. About Proove Biosciences: Proove Biosciences -- the Healthcare Decision Company™ -- is the commercial and educational leader in the research, investigation and development of patent-protected tests that combine genetic and clinical data into reports to help physicians to individualize -- and optimize -- medicine selection and dosing. Supported by leading medical experts and institutions across the globe, the reports facilitate objective decision-making to improve outcomes for patients, providers and insurers. Backed by science and driven by data, Proove is revolutionizing individualized medicine. With a patented bioinformatics platform that delivers therapy-defining information that allows prescribers to evaluate pain tolerance, assess patient drug metabolism, predict response and immunity to opioid and non-opioid pain medication, and identify risk for dependence and addiction, Proove provides the most technologically advanced solutions to enable accurate and evidence-based medical decision-making rather than "trial-and-error" approaches. Proove helps reduce the risk of treatment failure, decrease costs to insurers and relieve society of the emotional and financial burdens associated with addiction and other avoidable consequences. For more information, please visit www.proove.com or call toll free 855-PROOVE-BIO (855-776-6832).


News Article | November 4, 2016
Site: www.eurekalert.org

Two gene mutations that trigger a retinal disease that causes blindness in one in 5,000 males have been mapped, leading to the potential for new therapeutic treatments. Researchers from The University of Manchester undertook a structural analysis of X-linked Retinoschisis (XLRS), a genetic disease leading to a type of macular degeneration in which the inner layers of the retina split causing severe loss of vision and gradual blindness. Currently, there is no effective treatment for XLRS, with research focused on understanding how the disease occurs in the retina. XLRS is caused by mutations in the retinal protein retinoschisin. The protein plays a crucial role in the cellular organisation of the retina, assembling itself to form paired octameric (consisting of eight retinoschisin) rings. The rings each resemble an 8-bladed propeller. This new structural insight yielded important clues into how retinoschisin performs its crucial role in the retina and spurred efforts to investigate what happens to this structure when it is mutated in XLRS. Using a cryo-electron microscope, the team examined the paired rings as well as the effects on the rings of two XLRS-causing mutations. The effects of these mutations, despite being reported to cause the disease, were unknown and may offer explanations on how the normal protein functions in the retina. Clair Baldock, Professor of Biochemistry at The University of Manchester and lead author of the research team's resulting paper, said the cryo-electron microscopy allowed them to identify the location of the mutations on the rings. "We found that one disease-causing mutation sits in the interface between the octamer rings, causing retinoschisin to be less stable. The other mutation is on the propeller tip which we think is a novel interaction site for other binding proteins in the retina." As well as identifying the mutations and precisely mapping their locations, the research team held out the possibility that future work could lead to genetic interventions and treatments, which could limit or prevent the damage caused by XLRS. "XLRS is a promising candidate for gene therapy, so our findings on these two different classes of mutations will be informative for future therapeutic strategies," concluded Professor Baldock. The paper, entitled 'Structural analysis of X-linked retinoschisis mutations reveal distant classes which differently affect retinoschisin function', was published in the journal Human Molecular Genetics.


News Article | September 20, 2016
Site: www.treehugger.com

When writing about bathrooms in an earlier post, I suggested that Le Corbusier put a sink in the front hall of the Villa Savoye as an historical allusion. In fact, there is a much simpler and more straightforward reason: His client, like the clients for the Maison de Verre and the Lovell Health House, was a doctor and was obsessed about germs. People had known about germ theory since 1882, when Robert Koch identified that tuberculosis was caused by a bacillus, but they didn’t have antibiotics until after World War II. Architecture, planning and public policy were surprisingly effective at dealing with disease, once it was figured out what caused it; in her book The Drugs Don’t work, Professor Dame Sally Davies writes: Almost without exception, the decline in deaths from the biggest killers at the beginning of the twentieth century predates the introduction of antimicrobial drugs for civilian use at the end of the Second World War. Just over half the decline in infections diseases had occurred before 1931. The main influences on the decline of mortality were better nutrition, improved hygiene and sanitation, and less dense housing with all helped to prevent and to reduce transmission of infectious diseases. Then we got penicillin and other antibiotics and life became much easier and safer, until now, when the bugs are developing resistance to those drugs. Sally Davies notes: We are now at a crossroads in the journey towards the defeat of infection as a cause of disease, as our use of these valuable drugs is not only becoming threatened by the spectre of resistance among the bugs they are used to treat, but also as we recognize that their injudicious use can cause harm in its own right. In the New York Times recently, Ferris Jabr explains how this happened. In the Varsity, the University of Toronto newspaper, Ian T. D. Thompson describes the scope of the problem, and how it is bigger than just finding new drugs. “We must understand that microbes will always be able to evolve resistance to whatever we throw at them. Microbes have been found that can survive in extreme conditions like boiling acid,” explains Dr. William Navarre, Associate Professor in Molecular Genetics at the University of Toronto. “Any drugs we develop will only buy us a window of a few years before we start seeing resistance emerge.”… He paints a rather stark outlook for our society, if the problem of antibiotic resistance is not adequately addressed: “First of all — the future is already here. People are dying today of antibiotic-resistant microbes — not in small numbers either. More people die of antibiotic-resistant microbes each year in the US and Canada than… of AIDS. This is not just a medical issue, but is an economic and a planning and a design issue that will affect all of us. I live in Toronto, which was hit hard by Severe acute respiratory syndrome (SARS) in 2003, and which had a huge economic impact on the City. Conferences were cancelled, nobody would go out to restaurants, the tourist industry was traumatized, and knocked 1.5 percent off the entire economy’s growth for the year. We all learned to never shake hands, something I still feel strongly about. Imagine this on a much larger scale, in a world without antibiotics. 90 years ago, fear of infection was an important influence on design and planning. Beatriz Colimina writes in X-ray Architecture: Illness as Metaphor Modern architects offered health by providing exactly such a change of environment. Nineteenth-century architecture was demonized as unhealthy, and sun, light, ventilation, exercise, roof terraces, hygiene, and whiteness were offered as means to prevent, if not cure, tuberculosis. The publicity campaign of modern architecture was organized around contemporary beliefs about tuberculosis and fears of the disease. In his book The Radiant City of 1935, Le Corbusier dismisses the "natural ground" as "dispenser of rheumatism and tuberculosis" and declares it to be "the enemy of man." He insists on detaching buildings, with the help of pilotis, from the "wet, humid, ground where disease breeds" and using the roof as a garden for sunbathing and exercise. But now, as the risk of living without antibiotics returns, what are architects and planners going to do about it? In our recent post on healthy houses, the long list of things to worry about in living in a healthy home didn’t even touch on it. This is the first of a series where we are going to look at how infection affects architecture, how it was such a big part of the modern movement, and how we should be thinking about it and planning for it now. It will be critical in building and maintaining healthy homes and healthy cities.

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