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Microsoft Research Connections Blog

The Microsoft Research Connections blog shares stories of collaborations with computer scientists at academic and scientific institutions to advance technical innovations in computing, as well as related events, scholarships, and fellowships.

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    HLA-C: An Underappreciated Force in HIV Control

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    HLA-C: An Underappreciated Force in HIV ControlAlthough medical science has made great progress in managing HIV infection through modern drugs, 1.7 million people die of AIDS each year, with a disproportionate number of deaths in developing countries. Even access to life saving drugs cannot cure the disease: patients require lifelong drug maintenance and face the never-ending danger of developing resistance or adverse side effects to the medications.

    An HIV vaccine thus remains an utmost public health priority. To this end, studying the mechanisms by which some people are able to naturally control infection offers hope for researchers seeking insights into what constitutes an effective immune response—and how we might design a vaccine to illicit such a response. In the April 5 issue of Science, an investigative team, led by Richard Apps and Mary Carrington of the National Cancer Institute and aided by researchers in the eScience group at Microsoft Research, reported a new finding that sheds light on the protective potential of the human gene HLA-C, an often overlooked player in the adaptive immune response.

    Left untreated, the vast majority of HIV-infected individuals will progress to AIDS, marked by the loss of important cells of the immune system and the resulting onset of opportunistic infections. However, the rate of progression varies widely: the virus progresses within weeks in some individuals, while others control the virus and remain AIDS-free for decades.

    Epidemiologic studies of HIV control have repeatedly pointed to the importance of the MHC locus, a cluster of genes that encode proteins that the immune system uses to identify cells that have become virally infected. Of these genes, HLA-B has emerged as a dominant player. Its neighbor, HLA-C, has been largely ignored. The reasons for this are varied, including the relatively low cell-surface expression of HLA-C proteins compared to HLA-A and HLA-B, the observation that HIV actively down regulates surface expression of HLA-A and HLA-B but appears to ignore HLA-C, and the problem that HLA-B and HLA-C genes tend to be inherited together, so any positive effects that could be attributed to HLA-C are often assumed to be the result of neighboring HLA-B. The result is a relative dearth of scientific knowledge regarding the role HLA-C plays in controlling HIV.

    Recently, several genome wide association studies have been published that report common genetic variants that correlate with natural HIV control. One of the largest such studies, published in Science in 2010 and coauthored by many of the same investigators as the current study, found a number of important variations in MHC, but the most significant signal was immediately adjacent to the HLA-C gene. Several follow-up studies from Dr. Carrington’s group and others have provided circumstantial evidence that this genetic variant is an imperfect marker for variations in the level of HLA-C cell surface expression—that is, the number of HLA-C proteins present on the cell surface. Now, Dr. Carrington has provided epidemiological evidence that HLA-C expression directly correlates with control, while Microsoft Research Distinguished Scientist David Heckerman and I used models of sequence evolution combined with functional immune response data to provide a proposed mechanism and corroborating evidence that HLA-C expression modulates immune and viral responses. Thus, in contrast to HLA-A and HLA-B, it isn’t that individual variants of HLA-C proteins contribute to varying degrees of control (although that could also be the case), but that overall cell-surface quantities of the protein, regardless of variant, are directly correlated with control, rates of immune targeting, and magnitude of evolutionary pressure exerted upon the virus. These findings suggest a broader role for variations in HLA surface expression across a range of diseases. Indeed, in addition to the protective effect of HLA-C expression on HIV, we observed a correlation between HLA-C expression and increased susceptibility to Crohn’s disease, a complex inflammatory bowel disease that may be related to an overly active adaptive immune response.

    Although the finding that increased HLA-C expression levels can contribute to both pathogen control and disease susceptibility complicates our understanding of the immune system, it highlights the importance of this long-overlooked protein and may unlock new research into the mechanisms of natural control, providing potential new targets for vaccine design.

    Microsoft Research’s involvement in this study is the result of more than seven years of ongoing research in the HIV community. We have forged ongoing collaborations with more than a dozen labs and have developed statistical models of HIV evolution that have:

    Our ongoing research develops and uses tools derived from machine learning and applied statistics to move toward the development of an effective HIV vaccine.

    Jonathan Carlson, Researcher, eScience Research Group, Microsoft Research Connections

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    Bringing the heavens into the schoolhouse

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    In the five years since Microsoft Research initially launched the WorldWide Telescope (WWT), the product’s many features have been put to a variety of uses. Today in Chongqing, China, we saw yet another first for WorldWide Telescope: the unveiling of the first WWT-driven planetarium in China. The 8-meter dome installation is at the Shixinlu primary school and is powered by six high-resolution projectors. This installation enables students not only to see and study the stars and the universe in an immersive planetarium setting, but it also allows them to create their own tours of the heavens and have them displayed on the dome.

    The first WWT-driven planetarium in China was unveiled at the Shixinlu primary school in Chongqing.
    The first WWT-driven planetarium in China was unveiled at the Shixinlu primary school in Chongqing on October 23.

    I represented the WorldWide Telescope team at the grand unveiling of the dome, and as I did so, I was struck by the impact our small research project has had around the world. Even more so, I was in awe of the vision of Dr. Chenzhou Cui from the Chinese Academy of Sciences, who saw the potential of teaching and inspiring students via a planetarium placed directly in the school and who collaborated with Microsoft Research Asia to implement this vision via WorldWide Telescope. Dr. Cui and Mrs. Kailiang Song, the director of the school, worked tirelessly to get the installation built and running in six months and to provide a great environment for WWT. And above all, it is great to see the potential for many more students to gain a better understanding of astronomy by being immersed in the stars.

    Dan Fay represented the WorldWide Telescope team at the dome's unveiling.
    Representing the WorldWide Telescope team at the dome's unveiling, Fay was awed by the vision of Dr. Chenzhou Cui from the Chinese Academy of Sciences, who recognized the educational potential of WorldWide Telescope.

    The ability to use WorldWide Telescope in a multi-machine and multi-projector setup to display on planetarium domes is one of the features included in the Windows desktop client. The WWT client is freely available at www.worldwidetelescope.org.

    Dan Fay, Director of Earth, Energy, and Environment; Microsoft Research Connections

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    Workshop Explores Opportunities in Verified Software

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    Building verifiably reliable and trustworthy software is one of the ultimate objectives of software engineering. With this goal in mind, academics, scientists, and researchers gathered in Shanghai, China, for the second Verified Software Workshop and Summer School. The event, which took place from August 23 to 31, 2012, attracted approximately 250 faculty and student attendees from more than 70 universities and research institutes and nearly a dozen countries across the Asia Pacific region and beyond.

    World-class scientists and researchers—from Asia, Europe, and North America—provided the latest insights into verification theory, practice, and tools.
    World-class scientists and researchers—from Asia, Europe, and North America—provided the latest insights into verification theory, practice, and tools.

    Co-sponsored by Microsoft Research Asia and East China Normal University, the event explored new directions and emerging opportunities in verified software research, with 21 keynote presentations by world-class scientists and researchers—from Asia, Europe, and North America—providing the latest insights into verification theory, practice, and tools. Especially notable among the prominent presenters were the workshop co-chairs: Professor Tony Hoare, the 1980 Turing Award winner and a principal researcher at Microsoft Research Cambridge, who gave the opening speech, titled, “Algebra Unifies Theories of Programming”; and Professor Jifeng He of East China Normal University and a member of the of the Chinese Academy of Sciences, who delivered a keynote on “A Clock-Based Framework for Modeling Hybrid Systems.”

    The event began with a two-day workshop at East China Normal University that included inspiring lectures from technical and academic leaders. A broad and comprehensive workshop, it featured in-depth talks on such topics as detection of concurrency bugs, safe programming of asynchronous interaction, pervasive model checking, analysis and verification of multiple programs, automation of program verification, concurrent software verification, software analytics and its application, and modeling and verification of hybrid systems.

    A five-day summer school of intense training followed the workshop. Students were treated to lectures focusing on the theoretical nature of concurrency and separation logic. One particular highlight was the hybrid systems session, which taught the KeYmaera logical analysis approach in a single day’s time. In addition, a step-by-step tool session provided attendees with valuable hands-on practice and an in-depth learning experience.

    The event was popular with both students and presenters. Summing up the benefits of the event, one student said, “I acquired cutting-edge research and tools in [the] verification software field, and also had the opportunity to exchange my ideas with innovative peers and academic leads from across the world.”

    Capturing the perspective of the experienced researcher, co-chair Tony Hoare praised the event and laid out his goals for such venues, saying, “We hope to expand the opportunities for industrial application of mature academic research, and to encourage the next generation of advanced researchers to continue the pursuit of deep and interesting questions in areas of the software industry.”

    Professor Tony Hoare, the 1980 Turing Award winner and a principal researcher at Microsoft Research Cambridge, gave the opening speech, titled, “Algebra Unifies Theories of Programming."
    Professor Tony Hoare, the 1980 Turing Award winner and a principal researcher at Microsoft Research Cambridge, gave the opening speech, titled, “Algebra Unifies Theories of Programming."

    Co-chair Jifeng He added, “We have achieved a lot in [the] verified software field with everyone’s great effort, but there is always more work to do. With this event, we hoped to not only inspire our young talent but also provide researchers and faculties worldwide with the advantage of exchanging ideas.”

    Lolan Song, the senior director of Microsoft Research Asia, spoke of the company’s objectives in sponsoring such events, observing that “We hold this event in order to advance the state of the art in software and present a great opportunity for academics, researchers, and students in this area to share and exchange ideas. Also, we hope to identify and cultivate worldwide top talent in verified software areas and build up cadres of experienced users to support eventual use of the tools in the industry.” She also expressed the gratitude of Microsoft Research Asia for the assistance and participation of colleagues from Microsoft Research Cambridge, Microsoft Research Redmond, and Microsoft Research India.

    —Kangping Liu, University Relations Manager, Microsoft Research Connections Asia

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