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News Article | November 22, 2016
Site: www.rdmag.com

Scientists from Rice University, Baylor College of Medicine and other institutions are using synthetic biology to capture elusive, short-lived snippets of DNA that healthy cells produce on their way to becoming cancerous. Researchers said the work could lead to the development of new drugs that could prevent cancer by neutralizing "DNA intermediates," key pieces of genetic code that are produced when healthy cells become cancerous. The research is described in a new paper in the open-access journal Science Advances. "In my lab we study how the genome -- the genes in an organism -- changes, in particular, how the genome of normal cells changes to transform the cells into cancerous cells," said project lead scientist Susan Rosenberg, Baylor's Ben F. Love Chair in Cancer Research and the leader of the Cancer Evolvability Program at Baylor's Dan L Duncan Comprehensive Cancer Center. When cells divide and make copies of the instructions encoded in their DNA, the DNA unwinds and becomes vulnerable to damage that must be repaired. Sometimes the process of repairing the DNA can also cause mutations and errors. When these errors accumulate, the cells may acquire characteristics of cancer. "The process of editing the DNA is carried out by specific enzymes -- proteins that work on DNA to fix the mistakes," said Rosenberg, who is also an adjunct professor in Rice's Department of BioSciences. She said DNA repair usually takes several steps to complete. Between the original DNA and the final product, cells produce DNA reaction intermediates, which are crucial to the reaction but are difficult to study because they are present for just a fraction of a second as an enzyme catalyzes the changing of one molecule into another. "The intermediate molecules are the most important parts of biochemical reactions," said Rosenberg, who holds appointments in Baylor's departments of Molecular and Human Genetics, Molecular Virology and Microbiology, and Biochemistry and Molecular Biology. "They define what the reaction is and how it will proceed. But because they are transient and elusive, it's really difficult to study them, especially in living cells. We wanted to do that. We decided to invent synthetic proteins that would trap DNA reaction intermediates in living cells." Qian Mei, a graduate student in Rice's Systems, Synthetic and Physical Biology program and a research assistant in the Rosenberg lab, took on the task of applying the synthetic protein that could capture the short-lived intermediates. Using the tools of synthetic biology, Rosenberg and colleagues created and added packages of genes to Escherichia coli, an organism that Rosenberg's group and others have shown to be a reliable model of the genetic changes that occur in animal cells. Rosenberg said other investigators also have attempted to trap intermediates, but they have only succeeded in a few biochemical reactions. "We want to use synthetic proteins to study mechanisms that change DNA sequence," she said. "We do that now with genetics and genomics in my lab. But genomics, which allows us to compare the genes of normal cells with those of cancerous cells, is like reading the fossil record of these processes. We want to see how the real-time processes that change DNA happen, including all the intermediate steps, which our synthetic proteins allow us to freeze in time and isolate." In their tests on , Mei, Rosenberg and colleagues from Baylor, the University of Texas at Austin and the University of Texas MD Anderson Cancer Center found they could discover molecular mechanisms underlying genome instability, a hallmark of cancer. In one instance, they discovered a new role for an protein that is related to five human cancer proteins. They then analyzed gene-expression data from human cancers and were able to implicate two of the five -related human cancer proteins in potentially promoting cancer by a similar mechanism -- one not previously implicated. "The most exciting part in this paper for me is that we can learn something new about the mechanisms of cancer from the model," said Mei, co-first author of the new paper. "Even though bacteria and human cells are very different, many DNA repair proteins are highly conserved through evolution; this makes a good model to study how cells repair DNA or accumulate mutations." Rosenberg and colleagues think that their approach offers significant advantages. For instance, with the synthetic proteins, they have been able to identify specific DNA-repair intermediate molecules, their numbers in cells, rates of formation and locations in the genome and the molecular reactions in which they participate. "It is most exciting that we are now able to trap, map and quantify transient DNA reaction intermediates in single living cells," said co-first author Jun Xia, graduate student in the Rosenberg lab and in the Integrative Molecular and Biomedical Sciences program at Baylor. "This new technology helps us reveal the origins of genome instability." "When you know these reactions and the role each intermediate plays in the mechanisms that change DNA, you can think about making drugs that will stop them," Rosenberg said. "In the future, we hope we will be able to design drugs that target specific types of cancers -- drugs that block the cells' ability to evolve into cancer cells, instead of, or in addition to, traditional chemotherapies that kill or stop cancer cells from growing."


News Article | November 18, 2016
Site: www.eurekalert.org

HOUSTON -- (Nov. 18, 2016) -- Scientists from Rice University, Baylor College of Medicine and other institutions are using synthetic biology to capture elusive, short-lived snippets of DNA that healthy cells produce on their way to becoming cancerous. Researchers said the work could lead to the development of new drugs that could prevent cancer by neutralizing "DNA intermediates," key pieces of genetic code that are produced when healthy cells become cancerous. The research is described in a new paper in the open-access journal Science Advances. "In my lab we study how the genome -- the genes in an organism -- changes, in particular, how the genome of normal cells changes to transform the cells into cancerous cells," said project lead scientist Susan Rosenberg, Baylor's Ben F. Love Chair in Cancer Research and the leader of the Cancer Evolvability Program at Baylor's Dan L Duncan Comprehensive Cancer Center. When cells divide and make copies of the instructions encoded in their DNA, the DNA unwinds and becomes vulnerable to damage that must be repaired. Sometimes the process of repairing the DNA can also cause mutations and errors. When these errors accumulate, the cells may acquire characteristics of cancer. "The process of editing the DNA is carried out by specific enzymes -- proteins that work on DNA to fix the mistakes," said Rosenberg, who is also an adjunct professor in Rice's Department of BioSciences. She said DNA repair usually takes several steps to complete. Between the original DNA and the final product, cells produce DNA reaction intermediates, which are crucial to the reaction but are difficult to study because they are present for just a fraction of a second as an enzyme catalyzes the changing of one molecule into another. "The intermediate molecules are the most important parts of biochemical reactions," said Rosenberg, who holds appointments in Baylor's departments of Molecular and Human Genetics, Molecular Virology and Microbiology, and Biochemistry and Molecular Biology. "They define what the reaction is and how it will proceed. But because they are transient and elusive, it's really difficult to study them, especially in living cells. We wanted to do that. We decided to invent synthetic proteins that would trap DNA reaction intermediates in living cells." Qian Mei, a graduate student in Rice's Systems, Synthetic and Physical Biology program and a research assistant in the Rosenberg lab, took on the task of applying the synthetic protein that could capture the short-lived intermediates. Using the tools of synthetic biology, Rosenberg and colleagues created and added packages of genes to Escherichia coli, an organism that Rosenberg's group and others have shown to be a reliable model of the genetic changes that occur in animal cells. Rosenberg said other investigators also have attempted to trap intermediates, but they have only succeeded in a few biochemical reactions. "We want to use synthetic proteins to study mechanisms that change DNA sequence," she said. "We do that now with genetics and genomics in my lab. But genomics, which allows us to compare the genes of normal cells with those of cancerous cells, is like reading the fossil record of these processes. We want to see how the real-time processes that change DNA happen, including all the intermediate steps, which our synthetic proteins allow us to freeze in time and isolate." In their tests on , Mei, Rosenberg and colleagues from Baylor, the University of Texas at Austin and the University of Texas MD Anderson Cancer Center found they could discover molecular mechanisms underlying genome instability, a hallmark of cancer. In one instance, they discovered a new role for an protein that is related to five human cancer proteins. They then analyzed gene-expression data from human cancers and were able to implicate two of the five -related human cancer proteins in potentially promoting cancer by a similar mechanism -- one not previously implicated. "The most exciting part in this paper for me is that we can learn something new about the mechanisms of cancer from the model," said Mei, co-first author of the new paper. "Even though bacteria and human cells are very different, many DNA repair proteins are highly conserved through evolution; this makes a good model to study how cells repair DNA or accumulate mutations." Rosenberg and colleagues think that their approach offers significant advantages. For instance, with the synthetic proteins, they have been able to identify specific DNA-repair intermediate molecules, their numbers in cells, rates of formation and locations in the genome and the molecular reactions in which they participate. "It is most exciting that we are now able to trap, map and quantify transient DNA reaction intermediates in single living cells," said co-first author Jun Xia, graduate student in the Rosenberg lab and in the Integrative Molecular and Biomedical Sciences program at Baylor. "This new technology helps us reveal the origins of genome instability." "When you know these reactions and the role each intermediate plays in the mechanisms that change DNA, you can think about making drugs that will stop them," Rosenberg said. "In the future, we hope we will be able to design drugs that target specific types of cancers -- drugs that block the cells' ability to evolve into cancer cells, instead of, or in addition to, traditional chemotherapies that kill or stop cancer cells from growing." Other contributors to the work include Li-Tzu Chen, Chien-Hui Ma, Jennifer Halliday, Hsin-Yu Lin, David Magnan, John Pribis, Devon Fitzgerald, Holly Hamilton, Megan Richters, Ralf Nehring, Xi Shen, Lei Li, David Bates, P.J. Hastings, Christophe Herman and Makkuni Jayaram. The research was supported by the WM Keck Foundation, the National Institutes of Health, NASA, the Cancer Prevention and Research Institute of Texas, the National Science Foundation, the Welch Foundation, Baylor College of Medicine, the Dan L Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. VIDEO is available at: High-resolution IMAGES are available for download at: CAPTION: (From left) Baylor College of Medicine's Susan Rosenberg discusses research aimed at capturing elusive, short-lived "DNA intermediates," key pieces of genetic code that are produced when healthy cells become cancerous, with Baylor graduate student Jun Xia and Rice University graduate student Qian Mei, who are co-first authors on a new paper about the work in Science Advances. (Photo courtesy of Baylor College of Medicine) CAPTION: The orange wheel shows the circular chromosome or genome of bacteria. The spikes indicate where a molecular intermediate in DNA repair -- four-way DNA junctions -- accumulate near a reparable double strand break in the genome. (Image courtesy of Jun Xia and Qian Mei) The DOI of the Science Advances paper is: 10.1126/sciadv.1601605 A copy of the paper is available at: http://advances. This release can be found online at news.rice.edu. Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation's top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,910 undergraduates and 2,809 graduate students, Rice's undergraduate student-to-faculty ratio is 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for happiest students and for lots of race/class interaction by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger's Personal Finance. To read "What they're saying about Rice," go to http://tinyurl. .


News Article | November 22, 2016
Site: www.rdmag.com

Scientists from Rice University, Baylor College of Medicine and other institutions are using synthetic biology to capture elusive, short-lived snippets of DNA that healthy cells produce on their way to becoming cancerous. Researchers said the work could lead to the development of new drugs that could prevent cancer by neutralizing "DNA intermediates," key pieces of genetic code that are produced when healthy cells become cancerous. The research is described in a new paper in the open-access journal Science Advances. "In my lab we study how the genome -- the genes in an organism -- changes, in particular, how the genome of normal cells changes to transform the cells into cancerous cells," said project lead scientist Susan Rosenberg, Baylor's Ben F. Love Chair in Cancer Research and the leader of the Cancer Evolvability Program at Baylor's Dan L Duncan Comprehensive Cancer Center. When cells divide and make copies of the instructions encoded in their DNA, the DNA unwinds and becomes vulnerable to damage that must be repaired. Sometimes the process of repairing the DNA can also cause mutations and errors. When these errors accumulate, the cells may acquire characteristics of cancer. "The process of editing the DNA is carried out by specific enzymes -- proteins that work on DNA to fix the mistakes," said Rosenberg, who is also an adjunct professor in Rice's Department of BioSciences. She said DNA repair usually takes several steps to complete. Between the original DNA and the final product, cells produce DNA reaction intermediates, which are crucial to the reaction but are difficult to study because they are present for just a fraction of a second as an enzyme catalyzes the changing of one molecule into another. "The intermediate molecules are the most important parts of biochemical reactions," said Rosenberg, who holds appointments in Baylor's departments of Molecular and Human Genetics, Molecular Virology and Microbiology, and Biochemistry and Molecular Biology. "They define what the reaction is and how it will proceed. But because they are transient and elusive, it's really difficult to study them, especially in living cells. We wanted to do that. We decided to invent synthetic proteins that would trap DNA reaction intermediates in living cells." Qian Mei, a graduate student in Rice's Systems, Synthetic and Physical Biology program and a research assistant in the Rosenberg lab, took on the task of applying the synthetic protein that could capture the short-lived intermediates. Using the tools of synthetic biology, Rosenberg and colleagues created and added packages of genes to Escherichia coli, an organism that Rosenberg's group and others have shown to be a reliable model of the genetic changes that occur in animal cells. Rosenberg said other investigators also have attempted to trap intermediates, but they have only succeeded in a few biochemical reactions. "We want to use synthetic proteins to study mechanisms that change DNA sequence," she said. "We do that now with genetics and genomics in my lab. But genomics, which allows us to compare the genes of normal cells with those of cancerous cells, is like reading the fossil record of these processes. We want to see how the real-time processes that change DNA happen, including all the intermediate steps, which our synthetic proteins allow us to freeze in time and isolate." In their tests on , Mei, Rosenberg and colleagues from Baylor, the University of Texas at Austin and the University of Texas MD Anderson Cancer Center found they could discover molecular mechanisms underlying genome instability, a hallmark of cancer. In one instance, they discovered a new role for an protein that is related to five human cancer proteins. They then analyzed gene-expression data from human cancers and were able to implicate two of the five -related human cancer proteins in potentially promoting cancer by a similar mechanism -- one not previously implicated. "The most exciting part in this paper for me is that we can learn something new about the mechanisms of cancer from the model," said Mei, co-first author of the new paper. "Even though bacteria and human cells are very different, many DNA repair proteins are highly conserved through evolution; this makes a good model to study how cells repair DNA or accumulate mutations." Rosenberg and colleagues think that their approach offers significant advantages. For instance, with the synthetic proteins, they have been able to identify specific DNA-repair intermediate molecules, their numbers in cells, rates of formation and locations in the genome and the molecular reactions in which they participate. "It is most exciting that we are now able to trap, map and quantify transient DNA reaction intermediates in single living cells," said co-first author Jun Xia, graduate student in the Rosenberg lab and in the Integrative Molecular and Biomedical Sciences program at Baylor. "This new technology helps us reveal the origins of genome instability." "When you know these reactions and the role each intermediate plays in the mechanisms that change DNA, you can think about making drugs that will stop them," Rosenberg said. "In the future, we hope we will be able to design drugs that target specific types of cancers -- drugs that block the cells' ability to evolve into cancer cells, instead of, or in addition to, traditional chemotherapies that kill or stop cancer cells from growing."


Researchers said the work could lead to the development of new drugs that could prevent cancer by neutralizing "DNA intermediates," key pieces of genetic code that are produced when healthy cells become cancerous. The research is described in a new paper in the open-access journal Science Advances. "In my lab we study how the genome—the genes in an organism—changes, in particular, how the genome of normal cells changes to transform the cells into cancerous cells," said project lead scientist Susan Rosenberg, Baylor's Ben F. Love Chair in Cancer Research and the leader of the Cancer Evolvability Program at Baylor's Dan L Duncan Comprehensive Cancer Center. When cells divide and make copies of the instructions encoded in their DNA, the DNA unwinds and becomes vulnerable to damage that must be repaired. Sometimes the process of repairing the DNA can also cause mutations and errors. When these errors accumulate, the cells may acquire characteristics of cancer. "The process of editing the DNA is carried out by specific enzymes—proteins that work on DNA to fix the mistakes," said Rosenberg, who is also an adjunct professor in Rice's Department of BioSciences. She said DNA repair usually takes several steps to complete. Between the original DNA and the final product, cells produce DNA reaction intermediates, which are crucial to the reaction but are difficult to study because they are present for just a fraction of a second as an enzyme catalyzes the changing of one molecule into another. "The intermediate molecules are the most important parts of biochemical reactions," said Rosenberg, who holds appointments in Baylor's departments of Molecular and Human Genetics, Molecular Virology and Microbiology, and Biochemistry and Molecular Biology. "They define what the reaction is and how it will proceed. But because they are transient and elusive, it's really difficult to study them, especially in living cells. We wanted to do that. We decided to invent synthetic proteins that would trap DNA reaction intermediates in living cells." Qian Mei, a graduate student in Rice's Systems, Synthetic and Physical Biology program and a research assistant in the Rosenberg lab, took on the task of applying the synthetic protein that could capture the short-lived intermediates. Using the tools of synthetic biology, Rosenberg and colleagues created and added packages of genes to Escherichia coli, an organism that Rosenberg's group and others have shown to be a reliable model of the genetic changes that occur in animal cells. Rosenberg said other investigators also have attempted to trap intermediates, but they have only succeeded in a few biochemical reactions. "We want to use synthetic proteins to study mechanisms that change DNA sequence," she said. "We do that now with genetics and genomics in my lab. But genomics, which allows us to compare the genes of normal cells with those of cancerous cells, is like reading the fossil record of these processes. We want to see how the real-time processes that change DNA happen, including all the intermediate steps, which our synthetic proteins allow us to freeze in time and isolate." In their tests on , Mei, Rosenberg and colleagues from Baylor, the University of Texas at Austin and the University of Texas MD Anderson Cancer Center found they could discover molecular mechanisms underlying genome instability, a hallmark of cancer. In one instance, they discovered a new role for an protein that is related to five human cancer proteins. They then analyzed gene-expression data from human cancers and were able to implicate two of the five -related human cancer proteins in potentially promoting cancer by a similar mechanism—one not previously implicated. "The most exciting part in this paper for me is that we can learn something new about the mechanisms of cancer from the model," said Mei, co-first author of the new paper. "Even though bacteria and human cells are very different, many DNA repair proteins are highly conserved through evolution; this makes a good model to study how cells repair DNA or accumulate mutations." Rosenberg and colleagues think that their approach offers significant advantages. For instance, with the synthetic proteins, they have been able to identify specific DNA-repair intermediate molecules, their numbers in cells, rates of formation and locations in the genome and the molecular reactions in which they participate. "It is most exciting that we are now able to trap, map and quantify transient DNA reaction intermediates in single living cells," said co-first author Jun Xia, graduate student in the Rosenberg lab and in the Integrative Molecular and Biomedical Sciences program at Baylor. "This new technology helps us reveal the origins of genome instability." "When you know these reactions and the role each intermediate plays in the mechanisms that change DNA, you can think about making drugs that will stop them," Rosenberg said. "In the future, we hope we will be able to design drugs that target specific types of cancers—drugs that block the cells' ability to evolve into cancer cells, instead of, or in addition to, traditional chemotherapies that kill or stop cancer cells from growing." Explore further: New subtypes of lung cancer can lead to personalized therapies with better outcome More information: "Holliday junction trap shows how cells use recombination and a junction-guardian role of RecQ helicase" Science Advances, DOI: 10.1126/sciadv.1601605


News Article | November 4, 2016
Site: www.rdmag.com

A pair of studies have suggested that the Ebola virus outbreak that began in 2013 may have gained a genetic mutation that appears to have helped it better target human cells. On Nov. 3, a study from the University of Nottingham and a second study conducted by the co-led by scientists at The Scripps Research Institute (TSRI), the University of Massachusetts Medical School, the Broad Institute of the Massachusetts Institute of Technology and Harvard University was published in Cell that conclude that the Ebola virus actually grew in strength as the outbreak started to spread. “There was this belief that Ebola virus essentially never changes,” said TSRI infectious disease researcher Kristian Andersen, who also serves as director of infectious disease genomics at the Scripps Translational Science Institute (STSI), in a statement. “But this study tells us that a natural mutation in Ebola virus—which occurred during an outbreak—changed infectivity of human cells.” In the Scripps study Andersen and his team used a sequence catalog of viral genomes previously generated from 1,438 of the mora than 28,000 Ebola cases during the recent outbreak, a much larger sample size than ever studied on Ebola before. During this research they discovered a mutation on a site on Ebola’s outer protein—called glycoprotein—that binds to its receptor on host cells, meaning that mutations in that site can affect a virus’s ability to infect. “This receptor binding domain of the virus has been the same since the first Ebola outbreak in 1976,” said Andersen. “This is the only time we’ve ever seen a mutation in this domain.” The researchers found that the version of Ebola carrying the mutation, being dubbed GP-A82V, caused about 90 percent of the infections in the recent outbreak The scientists then tested the mutation’s reaction to many types of animal cells, which proved the mutation specifically helps the virus infect primate cells. It is believed that Ebola normally lives in bats, but the virus had more opportunities to adapt to humans with more human hosts. However, questions still remain for researchers, including how the mutation actually boost the virus’s ability to enter human cells. One hypothesis is that the mutation shifts nearby amino acids in the Ebola receptor binding domain, helping the glycoprotein better fit with the human host receptor. Scientists in the Nottingham study infected human liver cells grown in a test tube with pseudoviruses containing different mutant surface proteins, which proved that the number of genetic changes that occurred during the outbreak increased infectivity. “I think our study reminds us that if you take a virus and allow it to infect a new host for a considerable amount of time, eventually it may acquire a set of mutations that will benefit it, for example increasing its ability to spread or changing the disease that it causes,” Jonathan Ball, Professor of Molecular Virology at the University of Nottingham, and one of the authors of the study said in a statement. “In order to be prepared we need to know whether similar things are occurring in other outbreaks such as the ongoing Zika and MERS-coronavirus epidemics.” Andersen also said there is a chance the GP-A82V form of Ebola is no longer a threat, but research is important because it answers questions as to whether the Ebola virus can gain mutations during outbreaks that can potentially change the function of viral proteins. “It’s important to understand that once the outbreak is over, this particular virus will likely disappear,” Andersen said. The scientists will now examine other mutations that recently showed up and to see if increased infectivity changes mortality rates and the likelihood of a person transmitting the disease.


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

A team of scientists from Baylor College of Medicine and Vanderbilt University Medical Center have determined a mechanism by which human antibodies target and block noroviruses. Their study, which appears in the Proceedings of the National Academy of Sciences, opens the possibility of developing therapeutic agents against this virus that causes the death of about 200,000 children every year. "Some people infected with norovirus do not get sick," said senior author Dr. B V Venkataram Prasad, professor of virology and the Alvin Romansky Chair in biochemistry at Baylor. "We wanted to understand how these protective human antibodies work." The researchers screened and isolated protective antibodies from human blood and discovered that the most protective were of the IgA type, an antibody mostly involved in gut immunity. According to the Centers for Disease Control and Prevention, norovirus is the leading cause of foodborne illness and of acute gastroenteritis in all age groups in the U.S. The virus enters the body hidden in contaminated food, travels through the digestive system and infects the top layer of cells, the epithelial cells, on the small intestine. To enter the epithelial cells the virus attaches to complex sugar molecules, or glycans, on the surface of the cells. "The initial attachment is very important for the virus to subsequently get in," said Prasad. "It is like knocking at the door, and then the door opens and the virus can get inside the cells." The epithelial cells have a thick cover of glycans of diverse types, but norovirus seems to selectively bind to a particular group of glycans, the histo-blood group antigens, or HBGA, which also determine our blood types. Different strains of norovirus interact with different types of HBGAs. "The site on the norovirus particles that binds to HBGA is located in a region of the virus called P domain," said Prasad. "We knew that human antibodies that bind to P domain of norovirus and block HBGA binding correlate with protection, but we didn't know where these antibodies bind on the P domain and how this interaction prevents norovirus from binding to HBGA. Do the antibodies change the structure of the P domain or disrupt the HBGA binding site so it can no longer bind to the glycans? Or do the antibodies physically block the glycan binding site on P domain preventing its binding to HBGAs? We answered these questions with X-ray crystallographic analysis." Scientists use X-ray crystallography to determine the three-dimensional structure of highly purified molecules in the form of crystals. Crystals are symmetrical structures that produce symmetrical diffraction patterns when irradiated with X rays. Scientists use the symmetrical X-ray diffraction patterns to determine how molecules would look in 3-D. "The hardest, most time-consuming part of this project was to obtain good quality diffracting crystals ready for X-ray crystallographic analysis," said first author Dr. Sreejesh Shanker, a senior scientist in the Prasad lab. To answer the question of how the antibodies prevent norovirus from binding to HBGA, Shanker purified the complex of the norovirus P domain with the part of the antibody that binds to the domain, called antigen binding fragment (Fab), of a human IgA antibody. He then successfully used X-ray crystallography to determine the structure of the complex. "We found that the Fab fragment binds close to the HBGA binding site. It does not change the structure of the HBGA binding site, but physically blocks access to the site," said Shanker. These results open the possibility of developing compounds that mimic the structure of the Fab fragment and using them as a therapeutic agent to block the virus binding to cells," said Prasad. Now that the scientific community has the ability to grow noroviruses in the lab (Science, 2016), it is possible to test whether blocking binding would inhibit infection and replication of the virus inside the cells. "We see the possibility of using these blocking therapeutic agents to treat norovirus infections in transplant recipients suffering from these infections, which can be fatal," said co-senior author Dr. Mary Estes, Cullen Endowed Professor of Human and Molecular Virology and Microbiology at Baylor and emeritus founding director of the Texas Medical Center Digestive Diseases Center.


News Article | November 4, 2016
Site: www.rdmag.com

A pair of studies have suggested that the Ebola virus outbreak that began in 2013 may have gained a genetic mutation that appears to have helped it better target human cells. On Nov. 3, a study from the University of Nottingham and a second study conducted by the co-led by scientists at The Scripps Research Institute (TSRI), the University of Massachusetts Medical School, the Broad Institute of the Massachusetts Institute of Technology and Harvard University was published in Cell that conclude that the Ebola virus actually grew in strength as the outbreak started to spread. “There was this belief that Ebola virus essentially never changes,” said TSRI infectious disease researcher Kristian Andersen, who also serves as director of infectious disease genomics at the Scripps Translational Science Institute (STSI), in a statement. “But this study tells us that a natural mutation in Ebola virus—which occurred during an outbreak—changed infectivity of human cells.” In the Scripps study Andersen and his team used a sequence catalog of viral genomes previously generated from 1,438 of the mora than 28,000 Ebola cases during the recent outbreak, a much larger sample size than ever studied on Ebola before. During this research they discovered a mutation on a site on Ebola’s outer protein—called glycoprotein—that binds to its receptor on host cells, meaning that mutations in that site can affect a virus’s ability to infect. “This receptor binding domain of the virus has been the same since the first Ebola outbreak in 1976,” said Andersen. “This is the only time we’ve ever seen a mutation in this domain.” The researchers found that the version of Ebola carrying the mutation, being dubbed GP-A82V, caused about 90 percent of the infections in the recent outbreak The scientists then tested the mutation’s reaction to many types of animal cells, which proved the mutation specifically helps the virus infect primate cells. It is believed that Ebola normally lives in bats, but the virus had more opportunities to adapt to humans with more human hosts. However, questions still remain for researchers, including how the mutation actually boost the virus’s ability to enter human cells. One hypothesis is that the mutation shifts nearby amino acids in the Ebola receptor binding domain, helping the glycoprotein better fit with the human host receptor. Scientists in the Nottingham study infected human liver cells grown in a test tube with pseudoviruses containing different mutant surface proteins, which proved that the number of genetic changes that occurred during the outbreak increased infectivity. “I think our study reminds us that if you take a virus and allow it to infect a new host for a considerable amount of time, eventually it may acquire a set of mutations that will benefit it, for example increasing its ability to spread or changing the disease that it causes,” Jonathan Ball, Professor of Molecular Virology at the University of Nottingham, and one of the authors of the study said in a statement. “In order to be prepared we need to know whether similar things are occurring in other outbreaks such as the ongoing Zika and MERS-coronavirus epidemics.” Andersen also said there is a chance the GP-A82V form of Ebola is no longer a threat, but research is important because it answers questions as to whether the Ebola virus can gain mutations during outbreaks that can potentially change the function of viral proteins. “It’s important to understand that once the outbreak is over, this particular virus will likely disappear,” Andersen said. The scientists will now examine other mutations that recently showed up and to see if increased infectivity changes mortality rates and the likelihood of a person transmitting the disease.


Lee H.W.,Korea University | Vaheri A.,University of Helsinki | Schmaljohn C.S.,Molecular Virology
Virus Research | Year: 2014

We three authors, the two past presidents (HWL and AV) and the current president (CSS) of the International Society for Hantaviruses (ISH) have attended most of the nine International Conferences on HFRS, HPS and Hantaviruses (Table 1). These conferences have provided a forum for a synergistic group of clinicians, basic researchers, mammalogists, epidemiologists and ecologists to share their expertise and interests in all aspects of hantavirus research. Much of what is now hantavirus dogma was only conjecture when HWL organized the first conference in Seoul, Korea in 1989. Herein, we provide our reflections on key events in hantavirus research. As we come from distinct areas of the world and have had individual historical experiences, we certainly have our own geocentric opinions about the key events. Nevertheless, we agree that the discovery of hantaviruses has taken an interesting and unpredictable track to where we are today. © 2014 .


Pawella L.M.,University of Heidelberg | Hashani M.,University of Heidelberg | Eiteneuer E.,University of Heidelberg | Renner M.,University of Heidelberg | And 3 more authors.
Journal of Hepatology | Year: 2014

Background & Aims Hepatocellular steatosis is the most frequent liver disease in the western world and may develop further to steatohepatitis, liver cirrhosis and hepatocellular carcinoma. We have previously shown that lipid droplet (LD)-associated proteins of the perilipin/PAT-family are differentially expressed in hepatocyte steatosis and that perilipin is expressed de novo. The aim of this study was to determine the conditions for the temporal regulation of de novo synthesis of perilipin in vitro and in vivo. Methods Immunohistochemical PAT-analysis was performed with over 120 liver biopsies of different etiology and duration of steatosis. Steatosis was induced in cultured hepatocytic cells with combinations of lipids, steatogenic substances and DMSO for up to 40 days under conditions of stable down-regulation of adipophilin and/or TIP47. Results Whereas perilipin and adipophilin were expressed in human chronic liver disease irrespective of the underlying etiology, in acute/microvesicular steatosis TIP47, and MLDP were recruited from the cytoplasm to LDs, adipophilin was strongly increased, but perilipin was virtually absent. In long-term steatosis models in vitro, TIP47, MLDP, adipophilin, and finally perilipin were gradually induced. Perilipin and associated formation of LDs were intricately regulated on the transcriptional (PPARs, C/EBPs, SREBP), post-transcriptional, and post-translational level (TAG-amount, LD-fusion, phosphorylation-dependent lipolysis). In long-term steatosis models under stable down-regulation of adipophilin and/or TIP47, MLDP substituted for TIP47, and perilipin for adipophilin. Conclusions LD-maturation in hepatocytes in vivo and in vitro involves sequential expression of TIP47, MLDP, adipophilin and finally perilipin. Thus, perilipin might be used for the differential diagnosis of chronic vs. acute steatosis. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


News Article | October 16, 2015
Site: news.yahoo.com

Four capules of Tamiflu are pictured on a Tamiflu box in Burbank, California, January 31, 2013. REUTERS/Fred Prouser More LONDON, Oct 8 (Reuters) - - Scientists still don't know if two commonly-used flu drugs -- Roche's Tamiflu and GlaxoSmithKline's Relenza -- really work in seasonal or pandemic flu outbreaks and say robust clinical trials are urgently needed to find out. While such medicines are stockpiled by governments around the world and were widely used in the 2009/2010 H1N1 "swine flu" pandemic, no randomised trials were conducted then, so evidence is scant on how effective that approach was. Publishing a report on the use of such antiviral drugs - known as neuraminidase inhibitors - against flu, experts co-led by Wellcome Trust director Jeremy Farrar said this had been a huge wasted opportunity and one that should not happen again. "In the H1N1 pandemic, a lot of Tamiflu was taken and distributed, but we have no idea whether that was right," said Chris Bulter, an expert on clinical trials at Britain's Oxford University who co-led the review. "Until we do the trials we don't really know what we should be doing - and we've wasted huge opportunities in the past by not randomising patients early on in pandemics." In their report on the evidence for using antivirals in seaonal flu, the experts found the medicines do significantly reduce deaths in hospitalised patients, particularly in those who start treatment within 48 hours of first becoming ill. This could be critical in a flu epidemic, Farrar and Butler told reporters at a briefing in London. Evidence also suggests anitivirals can reduce symptoms in seasonal flu by between 14 and 17 hours, they said, but it does not support routine use of the drugs for all patients since, unless the case is particularly serious, the benefits may not outweigh the side-effect risks. The report was produced in response to a government request for an evidence-based report to inform future policy decisions. Jonathan Ball, a professor of Molecular Virology at the University of Nottingham who was not involved in the report, said it raised some crucial issues: "We know the virus can become resistant to these antivirals so it is really important they are only used where there is clear evidence of their value," he said. "Also these drugs aren’t cheap, so government(s) could end up generating profit for drugs companies when there is no clear evidence that it is money well spent." "The evidence-base isn't as strong as it should be. We risk misusing these drugs until this...knowledge gap is filled."

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