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  • richardmitnick 8:43 pm on April 24, 2018 Permalink | Reply
    Tags: , Dengue fever, , , , Wolbachia,   

    From Vanderbilt: “Unraveling genetic mystery next step in Zika and dengue fight” 

    Vanderbilt U Bloc

    Vanderbilt University

    Apr. 23, 2018
    Heidi Hall
    (615) 322-NEWS
    heidi.hall@vanderbilt.edu

    A Vanderbilt team took the next leap forward in using a little-known bacteria to stop the spread of deadly mosquito-borne viruses such as Zika and dengue.

    Wolbachia are bacteria that occur widely in insects and, once they do, inhibit certain pathogenic viruses the insects carry. The problem with using Wolbachia broadly to protect humans is that the bacteria do not normally occur in mosquitoes that transmit Zika and dengue. So success in modifying mosquitoes relies on the bacteria’s cunning ability to spread like wildfire into mosquito populations.

    Wolbachia do so by hijacking the insect reproductive system in a process called cytoplasmic incompatibility, or CI. This makes the sperm of infected fathers lethal to eggs of uninfected mothers. However, if infected fathers mate with infected mothers, the eggs live, and the infected mothers carrying Wolbachia will also infect all her offspring with it. Then those offspring pass on Wolbachia to the next generation, and so on, until they eventually replace all of the resident mosquitoes. As Wolbachia spreads in the population, the risk of dengue and Zika virus transmission drops.

    How that sperm and egg hijacking worked in infected fathers and mothers remained a mystery for decades, until Associate Professor of Biological Sciences Seth Bordenstein and his team helped solve it. They set out to dissect the number and types of genes that Wolbachia use to spread with the long-term goal of harnessing that genetic ability for protecting humans against diseases transmission.

    “In this new study, we’ve dissected a simple set of Wolbachia genes that replicate how Wolbachia change sperm and egg” Bordenstein said. “There are two genes that cause the incompatibility, and one of those same genes rescues the incompatibility. Engineering mosquitoes or Wolbachia for expression of these two genes could enhance or cause the spread of Wolbachia through target mosquito populations.”

    Their achievement is based on inserting genes into the genome of fruit flies. It is described in a paper appearing today in the Proceedings of the National Academy of Sciences.

    1
    Wolbachia spreads itself by hijacking the insect reproductive system in a process called cytoplasmic incompatibility, or CI. (J. Dylan Shropshire/Vanderbilt University)

    In a previous study last year Nature, the team identified the two genes in Wolbachia — named cytoplasmic incompatibility factors cifA and cifB — and learned that they modify the sperm to kill eggs. Now they solved the other half of the genetic mystery: cifA single-handedly can protect embryos from death.

    “It’s a microbial encryption and de-encryptyion system that ensures Wolbachia spread through insect populations so they can adequately block the transmission of viruses and ultimately save lives” Bordenstein said.

    Coauthors of the paper include Ph.D. student and National Science Foundation Graduate Research Fellow J. Dylan Shropshire and Vanderbilt undergraduates Emily Layton and Helen Zhou.

    Vanderbilt University has filed patent applications on this new finding and seeks industry partners for further development through its Center for Technology Transfer and Commercialization.

    This work was supported by National Institutes of Health (NIH) awards R01 AI132581 and R21 HD086833, National Science Foundation award IOS 1456778, a National Science Foundation Graduate Research Fellowship, and Vanderbilt University Medical Center Cell Imaging Shared Resources (supported by NIH grants CA68485, DK20593, DK58404, DK59637 and EY08126).

    See the full article here .

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    Commodore Cornelius Vanderbilt was in his 79th year when he decided to make the gift that founded Vanderbilt University in the spring of 1873.

    The $1 million that he gave to endow and build the university was the commodore’s only major philanthropy. Methodist Bishop Holland N. McTyeire of Nashville, husband of Amelia Townsend who was a cousin of the commodore’s young second wife Frank Crawford, went to New York for medical treatment early in 1873 and spent time recovering in the Vanderbilt mansion. He won the commodore’s admiration and support for the project of building a university in the South that would “contribute to strengthening the ties which should exist between all sections of our common country.”

    McTyeire chose the site for the campus, supervised the construction of buildings and personally planted many of the trees that today make Vanderbilt a national arboretum. At the outset, the university consisted of one Main Building (now Kirkland Hall), an astronomical observatory and houses for professors. Landon C. Garland was Vanderbilt’s first chancellor, serving from 1875 to 1893. He advised McTyeire in selecting the faculty, arranged the curriculum and set the policies of the university.

    For the first 40 years of its existence, Vanderbilt was under the auspices of the Methodist Episcopal Church, South. The Vanderbilt Board of Trust severed its ties with the church in June 1914 as a result of a dispute with the bishops over who would appoint university trustees.

    kirkland hallFrom the outset, Vanderbilt met two definitions of a university: It offered work in the liberal arts and sciences beyond the baccalaureate degree and it embraced several professional schools in addition to its college. James H. Kirkland, the longest serving chancellor in university history (1893-1937), followed Chancellor Garland. He guided Vanderbilt to rebuild after a fire in 1905 that consumed the main building, which was renamed in Kirkland’s honor, and all its contents. He also navigated the university through the separation from the Methodist Church. Notable advances in graduate studies were made under the third chancellor, Oliver Cromwell Carmichael (1937-46). He also created the Joint University Library, brought about by a coalition of Vanderbilt, Peabody College and Scarritt College.

    Remarkable continuity has characterized the government of Vanderbilt. The original charter, issued in 1872, was amended in 1873 to make the legal name of the corporation “The Vanderbilt University.” The charter has not been altered since.

    The university is self-governing under a Board of Trust that, since the beginning, has elected its own members and officers. The university’s general government is vested in the Board of Trust. The immediate government of the university is committed to the chancellor, who is elected by the Board of Trust.

    The original Vanderbilt campus consisted of 75 acres. By 1960, the campus had spread to about 260 acres of land. When George Peabody College for Teachers merged with Vanderbilt in 1979, about 53 acres were added.

    wyatt centerVanderbilt’s student enrollment tended to double itself each 25 years during the first century of the university’s history: 307 in the fall of 1875; 754 in 1900; 1,377 in 1925; 3,529 in 1950; 7,034 in 1975. In the fall of 1999 the enrollment was 10,127.

    In the planning of Vanderbilt, the assumption seemed to be that it would be an all-male institution. Yet the board never enacted rules prohibiting women. At least one woman attended Vanderbilt classes every year from 1875 on. Most came to classes by courtesy of professors or as special or irregular (non-degree) students. From 1892 to 1901 women at Vanderbilt gained full legal equality except in one respect — access to dorms. In 1894 the faculty and board allowed women to compete for academic prizes. By 1897, four or five women entered with each freshman class. By 1913 the student body contained 78 women, or just more than 20 percent of the academic enrollment.

    National recognition of the university’s status came in 1949 with election of Vanderbilt to membership in the select Association of American Universities. In the 1950s Vanderbilt began to outgrow its provincial roots and to measure its achievements by national standards under the leadership of Chancellor Harvie Branscomb. By its 90th anniversary in 1963, Vanderbilt for the first time ranked in the top 20 private universities in the United States.

    Vanderbilt continued to excel in research, and the number of university buildings more than doubled under the leadership of Chancellors Alexander Heard (1963-1982) and Joe B. Wyatt (1982-2000), only the fifth and sixth chancellors in Vanderbilt’s long and distinguished history. Heard added three schools (Blair, the Owen Graduate School of Management and Peabody College) to the seven already existing and constructed three dozen buildings. During Wyatt’s tenure, Vanderbilt acquired or built one-third of the campus buildings and made great strides in diversity, volunteerism and technology.

    The university grew and changed significantly under its seventh chancellor, Gordon Gee, who served from 2000 to 2007. Vanderbilt led the country in the rate of growth for academic research funding, which increased to more than $450 million and became one of the most selective undergraduate institutions in the country.

    On March 1, 2008, Nicholas S. Zeppos was named Vanderbilt’s eighth chancellor after serving as interim chancellor beginning Aug. 1, 2007. Prior to that, he spent 2002-2008 as Vanderbilt’s provost, overseeing undergraduate, graduate and professional education programs as well as development, alumni relations and research efforts in liberal arts and sciences, engineering, music, education, business, law and divinity. He first came to Vanderbilt in 1987 as an assistant professor in the law school. In his first five years, Zeppos led the university through the most challenging economic times since the Great Depression, while continuing to attract the best students and faculty from across the country and around the world. Vanderbilt got through the economic crisis notably less scathed than many of its peers and began and remained committed to its much-praised enhanced financial aid policy for all undergraduates during the same timespan. The Martha Rivers Ingram Commons for first-year students opened in 2008 and College Halls, the next phase in the residential education system at Vanderbilt, is on track to open in the fall of 2014. During Zeppos’ first five years, Vanderbilt has drawn robust support from federal funding agencies, and the Medical Center entered into agreements with regional hospitals and health care systems in middle and east Tennessee that will bring Vanderbilt care to patients across the state.

    studentsToday, Vanderbilt University is a private research university of about 6,500 undergraduates and 5,300 graduate and professional students. The university comprises 10 schools, a public policy center and The Freedom Forum First Amendment Center. Vanderbilt offers undergraduate programs in the liberal arts and sciences, engineering, music, education and human development as well as a full range of graduate and professional degrees. The university is consistently ranked as one of the nation’s top 20 universities by publications such as U.S. News & World Report, with several programs and disciplines ranking in the top 10.

    Cutting-edge research and liberal arts, combined with strong ties to a distinguished medical center, creates an invigorating atmosphere where students tailor their education to meet their goals and researchers collaborate to solve complex questions affecting our health, culture and society.

    Vanderbilt, an independent, privately supported university, and the separate, non-profit Vanderbilt University Medical Center share a respected name and enjoy close collaboration through education and research. Together, the number of people employed by these two organizations exceeds that of the largest private employer in the Middle Tennessee region.
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  • richardmitnick 7:40 am on October 12, 2016 Permalink | Reply
    Tags: , Dengue fever, , ,   

    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.

    SLAC/LCLS
    SLAC/LCLS

    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.
    i1

     
  • richardmitnick 9:59 am on September 5, 2016 Permalink | Reply
    Tags: , Dengue fever, ,   

    From ICL: “Dengue vaccine may increase risk of severe disease in low infection rate areas” 

    Imperial College London
    Imperial College London

    01 September 2016
    Kate Wighton

    1
    Dengue fever is transmitted by mosquitoes. No image credit.

    The world’s only licensed vaccine for dengue may worsen subsequent dengue infections if used in areas with low rates of dengue infection.

    These infections are also more likely to need hospitalisation, suggests the study, by scientists from Imperial College London, John Hopkins Bloomberg School of Public Health and the University of Florida.

    The research, published in the journal Science, analysed all publicly available clinical trial data for the vaccine. The results suggest that in people who have never been exposed to dengue before, the vaccine primes the immune system so that if they are subsequently infected, the infection is more severe.

    However in people who are have been exposed to the virus before vaccination, the vaccine reduces the severity of future infections.

    The researchers recommend testing people before they receive the vaccine, to establish if they have previously been exposed to the dengue virus. This would help avoid triggering an increase in serious cases of the disease.

    Dengue is a viral infection that causes just under 400 million cases per year. According to the latest estimates, around half of the world’s population are thought to be at risk. The virus is spread by mosquitoes, and causes fever, headache, muscle and joint pain. In some cases, it can lead to a life-threatening condition called haemorrhagic fever which is a leading cause of death and serious illness among children in some Asian and Latin American countries.

    Unlike most infectious diseases, the second time a person is infected with dengue is usually far more serious than the first. This may be why the vaccine appears to amplify the illness in some individuals, particularly young children.

    Normally, when a person is infected with a virus their immune system builds defences against it. This means when they are infected a second time, the virus is destroyed before triggering symptoms. However, with dengue, the virus primes the immune system to work against the body. So when a person is infected a second time, a component of the immune system – called antibodies – help the virus infect the cells, leading to a more severe infection.

    This has serious implications for the vaccine, explains Professor Neil Ferguson, co-lead author, who is the Director of the MRC Centre for Outbreak Analysis and Modelling at Imperial College London: “If someone has never been exposed to dengue, the vaccine seems to act like a silent infection. The initial exposure to the virus from the vaccine primes the immune system, so when they are infected again, the symptoms are more likely to be severe.”

    The vaccine, produced by the company Sanofi-Pasteur, is available in six countries and has been trialled on around 30,000 people from ten countries.

    After analysing the data, the research team formulated a computer model to predict the effectiveness of the vaccine if used more widely.

    Professor Neil Ferguson said: “Having a licensed dengue vaccine available is a significant step forward for dengue control. However, we should be careful in considering where and how to use this vaccine as there is still uncertainty about the impact.”

    The team stress the vaccine stills holds benefits – but only if used in areas heavily affected by dengue, where individuals being vaccinated are likely to have encountered the virus before.

    Derek Cummings, Professor of Biology at the University of Florida and co-author of the study added: “In places with high transmission intensity, most people have been already exposed to dengue at the time of vaccination, and the vaccine has higher efficacy on average. However, in places with lower transmission intensity, were individuals haven’t been previously exposed, the vaccine can place people at risk of severe disease and overall, increase the number of hospitalized cases.”

    Dr Isabel Rodriguez-Barraquer, joint first author of the research from Johns Hopkins Bloomberg School of Public Health, explained: “Our results indicate that screening potential vaccine recipients could maximize the benefits and minimise the risk of negative outcomes.”

    The World Health Organization recommends that countries consider introduction of the dengue vaccine only in geographic settings (national or subnational) where data suggests a high burden of disease.

    Professor Ferguson added: “Our model refines estimates of which places would see a decline in dengue incidence with large scale vaccination programmes, and which places should not implement programmes at this point in time. These results present the first published, independent predictions of the potential impact of vaccination that take account of recent data showing that the vaccine can increase the risk of severe dengue disease in young children.”

    The authors hope their analysis can help inform policy-makers in evaluating this and other candidate dengue vaccines.

    The work was funded by the UK Medical Research Council, the NIHR UK National Institute of Health Research Health Protection Research Unit (HPRU) in Healthcare Associated Infections and Antimicrobial Resistance under the Health Protection Research Unit initiative, National Institute of Allergy and Infectious Diseases and National Institute of General Medical Sciences (NIH) under the MIDAS initiative, and the Bill and Melinda Gates Foundation.

    See the full article here .

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    Imperial College London

    Imperial College London is a science-based university with an international reputation for excellence in teaching and research. Consistently rated amongst the world’s best universities, Imperial is committed to developing the next generation of researchers, scientists and academics through collaboration across disciplines. Located in the heart of London, Imperial is a multidisciplinary space for education, research, translation and commercialisation, harnessing science and innovation to tackle global challenges.

     
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