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Archive - 2014

December 12th

Cause of Malaria Drug Resistance in SE Asia Identified

Growing resistance to malaria drugs in Southeast Asia is caused by a single mutated gene inside the disease-causing Plasmodium falciparum parasite, according to a study led by David Fidock, Ph.D., professor of microbiology & immunology and of medical sciences (in medicine) at Columbia University Medical Center. This finding provides public health officials around the world with a way to look for pockets of emerging resistance and potentially eliminate them before they spread. Though malaria deaths have dropped by 30 percent worldwide since the introduction of artemisinin-based combination therapies (ACTs) in the late 1990s, these gains are now threatened by the emergence of resistance to the core artemisinin component of ACTs in Southeast Asia. No alternative therapy is currently available to replace ACTs should resistance spread to other parts of the world. The current study, published online on December 11, 2014 in Science, builds on a recent report that mutations in the gene--K13--are frequently found in drug-resistant parasites in Southeast Asia. Dr. Fidock, working with scientists at the Pasteur Institutes in Paris and Cambodia, the University of Toulouse III, Sangamo Biosciences, Inc., and the National Institutes of Health (NIH), showed definitively that K13 mutations directly cause drug resistance. "The bad news about our finding is that it shows that resistance can arise through single mutations in one gene and pop up anywhere, at any time," Dr. Fidock says. "That's quite different from past instances with former first-line drugs, when complex sets of multiple mutations were required and resistance spread only as the mutated parasites spread."

Possible Way to Boost Healthy Cells During Chemotherapy

It’s well known that chemotherapy helps fight cancer. It’s also known that it wreaks havoc on normal, healthy cells. Michigan State University (MSU) scientists are closer to discovering a possible way to boost healthy cell production in cancer patients as they receive chemotherapy. By adding thymine – a natural building block found in DNA – into normal cells, they found it stimulated gene production and caused the cells to multiply. The study was published online on ecember 4, 2014 in Molecular Cell. In most cases, cancer patients who receive chemotherapy lose their fast-growing normal cells, including hair, nails, and lining of the gut,” said Dr. Sophia Lunt, a postdoctoral research associate who led the study along with Dr. Eran Andrechek, a physiology professor at MSU. “Therefore, it’s necessary to understand the differences between normal versus cancer cells if we want to improve cancer therapy, while minimizing the harsh side effects.” Thymine is made from sugar in the body and is necessary to make DNA. The research team wanted to understand how fast-growing normal cells metabolize sugar and other nutrients to stimulate growth compared to fast-growing cancer cells. They were surprised to discover that when a shared protein, found in both normal and cancer cells, was removed from the healthy ones, growth stopped. Previous studies have shown that deleting this protein, known as PKM2, from the cancer cells has no effect on cancer growth. “When we deleted the protein, we found it caused healthy cells to stop making DNA,” Dr. Andrechek said. “But when we added thymine, they began multiplying and producing DNA again.” Both researchers view this as a positive step in finding ways to boost healthy cell production, but indicate that more needs to be known on the effect thymine might have on cancer cells.

Collaboration Sheds New Light on Age-Related Macular Degeneration

Insilico Medicine along with scientists from Vision Genomics and Howard University shed light on AMD disease, introducing the opportunity for eventual diagnostic and treatment options. The scientific collaboration among Vision Genomics, Inc., Howard University, and Insilico Medicine, Inc., has revealed encouraging insight on the AMD disease using an interactome analysis approach. Resources such as publicly available gene expression data, Insilico Medicine's original algorithm OncoFinder™, and AMD Medicine™ from Vision Genomics allowed discovery of signaling pathways activated during AMD disease. "We are thrilled to collaborate with Drs. Alex Zhavoronkov and Evgeny Makarev, and their team at InSilico Medicine. Big Data analysis is part of the future of medicine, and with our technique of signaling pathway activation analysis, we will decipher the genetic network alterations that lead to age-related macular degeneration (AMD), and eventually human aging itself," said Antonei Benjamin Csoka, Ph.D., CEO of Vision Genomics, LLC, and Assistant Professor at Howard University. The research publication titled "Pathway activation profiling reveals new insights into Age-related Macular Degeneration and provides avenues for therapeutic interventions" was accepted by one of aging research's top-rated journals "Aging", detailing these findings and methodology. This study not only validates the efficacy of interactome analysis within aging, but also allows the investigation of cellular populations within AMD models. "We are happy to collaborate with Antonei Benjamin Csoka's teams at both Vision Genomics and Howard University on this exciting project.

Controversial Nitrite Hypothesis Confirmed

Understanding how nitrite can improve conditions such as hypertension, heart attack, and stroke has been the object of worldwide research studies. New research from Wake Forest University has potentially moved the science one step closer to this goal. In a paper published online on December 3, 2014 in the Journal of Biological Chemistry, senior co-author Dr. Daniel Kim-Shapiro, professor of physics at Wake Forest, and others, show that deoxygenated hemoglobin is indeed responsible for triggering the conversion of nitrite to nitric oxide, a process that affects blood flow and clotting. “We have shown that conversion of nitrite to nitric oxide by deoxygenated hemoglobin in red blood cells reduces platelet activation,” Dr. Kim-Shapiro said. “This action has implications in treatments to reduce clotting in pathological conditions including sickle cell disease and stroke.” In 2003, Dr. Kim-Shapiro collaborated with Dr. Mark Gladwin, now at the University of Pittsburgh, who led a study that showed that nitrite (which is also used to cure processed meats), is not biologically inert as had been previously thought, but can be converted to the important signaling molecule nitric oxide (NO), and thereby increase blood flow. At that time, the researchers hypothesized that the conversion of nitrite to NO was due to a reaction with deoxygenated hemoglobin in red blood cells. The main goal of the latest research, Dr. Kim-Shapiro said, was to determinehow red blood cells perform these important signaling functions that lead to increased blood flow. The researchers used several biophysical techniques to measure NO production from nitrite and red blood cells and examined the mechanism of NO production.

Biofilms Associated with Proximal Colon Cancer; Possible Diagnostic Tool

Since the first “catalog” of the normal bacterial makeup of the human body was published in 2012, numerous connections between illness and disturbances in the human microbiota have been found. This week, scientists report yet another: cancerous tumors in the ascending colon (the part nearest to the small intestine) are characterized by biofilms, which are dense clumps of bacterial cells encased in a self-produced matrix. “This is the first time that biofilms have been shown to be associated with colon cancer, to our knowledge,” says co-author Dr. Jessica Mark Welch, a scientist at the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts. The discovery, led by researchers at the Johns Hopkins Medical Institutions, draws on a novel way to “see” microbial community structure that was developed by Dr. Mark Welch and colleagues at the MBL. Called combinatorial imaging, it could potentially be used to clinically diagnose pre-cancerous and cancerous conditions in the ascending colon. In healthy people, the colon is covered in a mucus layer (mucosa) that helps keep bacteria away from the colon’s “skin,” or epithelia. Remarkably, the team found that colon cancer patients who have tumor-associated biofilms also have biofilms on tumor-free areas of the nearby mucosa. “This suggests that either the tumor allows the biofilm to form, or the biofilm is helping to cause the tumor,” says Dr. Welch. “The breaching of the mucus layer could allow bacteria to come into contact with the host epithelial cells, and that is one thing that could lead to cancer.” The team found that tumors in the descending colon (going to the rectum) do not have associated biofilms.

New Dopamine-Related Target Identified for Possible Treatment of Parkinson’s

Researchers in Montréal, Canada, led by Jacques Drouin (image), D.Sc., have uncovered a mechanism regulating dopamine levels in the brain by working on a mouse model of late-onset Parkinson’s disease. The study, conducted in collaboration with Dr. Rory A. Fisher from the Department of Pharmacology at the University of Iowa Carver College of Medicine, was published online on December 11, 2014 in the open-access journal PLOS Genetics. Using gene expression profiling, a method to measure the activity of thousands of genes, researchers investigated dopaminergic neurons in the midbrain, which are nerve cells that use dopamine to send signals to other nerve cells. These neurons are known to degenerate in Parkinson’s disease. “We identified the Rgs6 gene for its restricted expression in dopaminergic neurons,” explains Dr. Drouin, Director of the Molecular Genetics laboratory at the IRCM (Institut de Recherche Clinique de Montreal). “We had previously shown that this gene is itself controlled by a transcription factor called Pitx3, which plays an important role in the survival of these neurons. Through our study, we discovered that a defective Rgs6 gene causes the death of these neurons,” adds Dr. Drouin. “More specifically, we found that when we remove the Rgs6 gene, this relieves a brake against excessive dopaminergic signalling. As a result, excess free dopamine accumulation causes cellular stress, which, in turn, causes the neurons to die. Our work thus indicates that Rgs6 could be a new target for the development of drugs against Parkinson’s disease.”

December 11th

Ground-Breaking Studies of Bird Evolution Published in Science

A University of Nebraska-Lincoln (UNL) researcher has contributed to discoveries about bird evolution as part of a new study that sequenced the complete genomes of 45 avian species. Published as the cover story of the December 12, 2014 issue of Science, the study found that avian genomes -- the complete archive of genetic material present in cells -- have exhibited surprisingly slow rates of evolution when compared with their mammalian counterparts. Dr. Jay Storz, a Susan J. Rosowski Associate Professor of Biological Sciences, led a research group that assisted the study by examining the evolution of multi-gene families shared by birds and mammals. Each family comprises a collection of genes related to one another through a history of duplication, with all members of a given family descending from a single ancient gene. Dr. Storz and his colleagues used computational methods to measure "gene turnover," the rate at which genes are gained or lost over time. The researchers reported that the rate of turnover in avian gene families is roughly two times slower than in mammals. This finding reflects a larger-scale pattern of evolutionary stasis in avian genomes, according to Dr. Storz. "In mammals, there's this continual turnover -- it's like a genomic turnstile. With birds, it's far more conservative," Dr. Storz said. "There might be a gene family that consists of, say, 10 members in the common ancestor of birds and mammals. In mammals, that gene family has probably expanded and contracted in different lineages, and this results in dramatic differences in gene family size and membership composition among contemporary species. In birds, those 10 ancestral gene copies will remain intact and are inherited by all descendant lineages, so very little variation accumulates among species."

Scientist Use “Hi-C” Method to Map the Folded Human Genome; Shed Additional Light on Gene Regulation; Loops and CTCF Proteins Crucial

In a triumph for cell biology, researchers have assembled the first high-resolution, 3D maps of entire folded genomes and found a structural basis for gene regulation—a kind of "genomic origami" that allows the same genome to produce different types of cells. The research appears online on December 11, 2014 in Cell. A central goal of the five-year project, a collaboration among researchers at Harvard University, Baylor College of Medicine, Rice University, and the Broad Institute of Harvard and MIT, was to identify the loops in the human genome. Loops form when two bits of DNA that are far apart in the genome sequence end up in close contact in the folded version of the genome in a cell's nucleus. Researchers used a technology called "in situ Hi-C" to collect billions of snippets of DNA that were later analyzed for signs of loops. The team found that loops and other genome folding patterns are an essential part of genetic regulation. "More and more, we're realizing that folding is regulation," said study co-first author Suhas Rao, a researcher at Baylor's Center for Genome Architecture and a 2012 graduate of Harvard College. "When you see genes turn on or off, what lies behind that is a change in folding. It's a different way of thinking about how cells work." Co-first author Miriam Huntley, a doctoral student at the Harvard School of Engineering and Applied Sciences (SEAS), said, "Our maps of looping have revealed thousands of hidden switches that scientists didn't know about before. In the case of genes that can cause cancer or other diseases, knowing where these switches are is vital."

Study Finds Connection between Gut Microbiota and Parkinson's Disease

Parkinson's disease sufferers have a different microbiota in their intestines than their healthy counterparts, according to a study conducted at the University of Helsinki and the Helsinki University Central Hospital (HUCH). "Our most important observation was that patients with Parkinson's have much less bacteria from the Prevotellaceae family; unlike the control group, practically no one in the patient group had a large quantity of bacteria from this family," states Filip Scheperjans, M.D., Ph.D., neurologist at the HUCH Neurology Clinic. The researchers have not yet determined what the lack of Prevotellaceae bacteria in Parkinson's sufferers means - do these bacteria perhaps have a property which protects their host from the disease? Or does this discovery merely indicate that intestinal dysfunction is part of the pathology? "It's an interesting question which we are trying to answer," Dr. Sheperjans says. Another interesting discovery was that the amount of bacteria from the Enterobacteriaceae family in the intestine was connected to the degree of severity of balance and walking problems in the patients. The more Enterobacteriaceae patients had, the more severe the symptoms. The results were published online on December 5, 2014 in Moverment Disorders. "We are currently re-examining these same subjects to determine whether the differences are permanent and whether intestinal bacteria are associated with the progression of the disease and therefore its prognosis," explains Dr. Sheperjans. "In addition, we will have to see if these changes in the bacterial ecosystem are apparent before the onset of motor symptoms. We will of course also try to establish the basis of this connection between intestinal microbiota and Parkinson's disease - what kind of mechanism binds them."

Bird Study Indicates Mother Contributes Much to Telomere Length in Chicks; Differing from Humans, Where Father’s Role Is Key

In the hunt for better knowledge on the aging process, researchers from Lund University in Sweden have now enlisted the help of small birds. A new study investigates various factors which affect whether chicks are born with long or short chromosome ends, called telomeres. The genetic make-up of our cells consists of genes lined up on chromosomes. The ends of the chromosomes are called telomeres, and they protect the chromosomes from sticking to each other. The longer the telomeres, the longer time the chromosomes are able to function. And conversely, the shorter these ends, the less time left for the chromosomes, and therefore also less time for the cells to function properly. More knowledge of telomeres can therefore be valuable in understanding the aging process in humans and other animals. In the present study, published online on December 10, 2014 in an open-access article in the Proceedings of the Royal Society B, researchers from Lund University looked for explanations for the large variation in telomere length in newborn individuals. This is curious because it should be advantageous to start life with longer telomeres rather than shorter telomeres. "It is remarkable that already, so early on in life, there are already such major differences between individuals, both in humans and in animals," says Dr. Asghar Muhammad, one of the researchers behind the study. The researchers used data from a 30-year-long study of individually recognizable ringed great reed warblers at Lake Kvismaren, south Central Sweden. The aim of the study was to find out which inheritance factors affect the length of the chromosome ends in chicks. Thanks to the long series of measurements, it was possible to compare the length of telomeres in newborn individuals with that of their parents when these were newly hatched chicks.