Like musicians in an orchestra who have the same musical score but start and finish playing at different intervals, cells with the same genes start and finish transcribing them at different points in the genome. For the first time, researchers at the European Molecular Biology Laboratory (EMBL) have described the striking diversity of messenger RNAs (mRNAs) that such start and end variation produces, even from the simple genome of yeast cells. Their findings, published online on April 24, 2013 in Nature, shed new light on the importance of mRNA boundaries in determining the functional potential of genes. Hundreds of thousands of unique mRNA transcripts are generated from a genome of only about 8,000 genes, even with the same genome sequence and environmental condition. “We knew that transcription could lead to a certain amount of diversity, but we were not expecting it to be so vast,” explains Dr. Lars Steinmetz, who led the project. “Based on this diversity, we would expect that no yeast cell has the same set of messenger RNA molecules as its neighbor.” The traditional understanding of transcription was that mRNA boundaries were relatively fixed. While it has long been known that certain parts of mRNAs can be selectively “spliced” out, this phenomenon is very rare in baker's yeast, meaning that the textbook one gene - one mRNA transcript relationship should hold. Recent studies have suggested that things aren't quite that simple, inspiring the EMBL scientists to create a new technique to capture both the start and end points of single mRNA molecules. They have now discovered that each gene can be transcribed into dozens or even hundreds of unique mRNA molecules, each with different boundaries. This suggests that not only transcript abundance, but also transcript boundaries, should be considered when assessing gene function.
Researchers report in Nature Genetics that they have increased the number of confirmed genes linked to juvenile idiopathic arthritis (JIA) from 3 to 17 – a finding that will clarify how JIA fits into the spectrum of autoimmune disorders and help identify potential treatment targets. Published online on April 21, 2013, the study involves an international research team that analyzed 2,816 JIA cases recruited from more than 40 pediatric rheumatology clinics. It was the largest collaborative patient population of JIA to date, including patient DNA samples from across the United States, Germany, and the United Kingdom, according to Susan Thompson, Ph.D., a researcher in the Division of Rheumatology at Cincinnati Children's Hospital Medical Center who was a leader for the study. "These findings will help us understand how the long suspected genetic contributions to JIA are driving the disease process, with the ultimate goal being earlier and improved diagnosis and treatment," Dr. Thompson said. JIA is the most common rheumatic disease of childhood that involves several different but related forms. Affecting some 50,000 children in the US, the actual cause of the disease remains unknown. JIA is considered an autoimmune disorder, in which the body's immune system mounts an attack against its own healthy tissues. JIA can be treated with medications and physical therapy, but the disease can persist for many patients into adulthood. Prior to the current study only three genes were associated with known JIA risk, although scientists have suspected the likelihood that more genes are involved. The research team used what is known as the Immunochip array to measure variation in the genes (DNA) coding for components of the immune system for 2,816 JIA patients in the study.
Dr. Gerald Zon’s second blog post in his column “Zone in with Zon—What’s Trending in Nucleic Acid Research,” (http://zon.trilinkbiotech.com/) was posted on April 15, 2013 and features an interview with Professor Shankar Balasubramanian (Cambridge University) on his quantitative visualization of cellular G-quadruplex DNA structures. This notable achievement, published in Nature Chemistry in January 2013, had over 82,000 page views within 3 weeks! Proposed G-quadruplex DNA and RNA cellular functions are exciting new topics to be aware of, according to Dr. Zon, who is an eminent nucleic acid chemist and Director of Business Development at TriLink BioTechnologies in San Diego, California. [Zon blog post] [Nature Chemistry abstract] [Nature Chemistry News & Views]
Researchers at Case Western Reserve School of Medicine have discovered a technique that directly converts skin cells to the type of brain cells destroyed in patients with multiple sclerosis (MS), cerebral palsy (CP), and other so-called myelin disorders. This discovery was published online on April 14, 2013 in Nature Biotechnology. This breakthrough now enables "on demand" production of myelinating cells, which provide a vital sheath of insulation that protects neurons and enables the delivery of brain impulses to the rest of the body. In patients with MS, CP, and rare genetic disorders called leukodystrophies, myelinating cells are destroyed and cannot be replaced. The new technique involves directly converting fibroblasts - an abundant structural cell present in the skin and most organs - into oligodendrocytes, the type of cell responsible for myelinating the neurons of the brain. "Its 'cellular alchemy,'" explained Paul Tesar, Ph.D., assistant professor of genetics and genome sciences at Case Western Reserve School of Medicine and senior author of the study. "We are taking a readily accessible and abundant cell and completely switching its identity to become a highly valuable cell for therapy." In a process termed "cellular reprogramming," researchers manipulated the levels of three naturally occurring transcription factors to induce fibroblast cells to become precursors to oligodendrocytes (called oligodendrocyte progenitor cells, or OPCs). Dr. Tesar's team, led by Case Western Reserve researchers and co-first authors Dr. Fadi Najm and Dr. Angela Lager, rapidly generated billions of these induced OPCs (called iOPCs). Even more important, they showed that iOPCs could regenerate new myelin coatings around nerves after being transplanted to mice—a result that offers hope the technique might be used to treat human myelin disorders.
As efforts to create a strong and effective vaccine for the dreaded dengue virus continue to hit snags, a new study from researchers at the La Jolla Institute for Allergy & Immunology offers surprising evidence that suggests the need for a revamped approach to dengue vaccine design. The finding runs counter to current scientific understanding of the key cells that need to be induced to develop a successful dengue vaccine. La Jolla Institute scientist Alessandro Sette, Dr. Biol.Sci., and his team found that T cells, which are key disease-fighting cells of the immune system, play an important protective role in controlling dengue virus infection, rather than creating an aberrant response that can ultimately worsen the disease as is the prevailing belief in the scientific community. "The current thinking in the field is that the goal of a dengue vaccine should be the induction of antibodies and not T cells," says Dr. Sette, an internationally recognized vaccine biologist and director of the Institute's Center for Infectious Disease. "But our results suggest that both cell types are needed to produce a strong immune response against dengue infection." Scott B. Halstead, M.D., a leading authority on dengue virus and senior scientific advisor to the international Dengue Vaccine Initiative, says the findings provide new insights that should be considered in future dengue vaccine efforts. "Their study of T cell responses in a large group of HLA-defined Sri Lankan adults naturally infected by dengue viruses found that T cell immunity contributed to host protection rather than to vascular permeability (which occurs in severe cases)," says Dr. Halstead.
Bioengineered rat kidneys developed by Massachusetts General Hospital (MGH) investigators successfully produced urine both in a laboratory apparatus and after being transplanted into living animals. In their report, receiving advance online publication on April 14, 2013 in Nature Medicine, the research team describes building functional replacement kidneys on the structure of donor organs from which living cells had been stripped, an approach previously used to create bioartificial hearts, lungs, and livers. "What is unique about this approach is that the native organ's architecture is preserved, so that the resulting graft can be transplanted just like a donor kidney and connected to the recipient's vascular and urinary systems," says Harald Ott, M.D., Ph.D., of the MGH Center for Regenerative Medicine, senior author of the Nature Medicine article. "If this technology can be scaled to human-sized grafts, patients suffering from renal failure who are currently waiting for donor kidneys or who are not transplant candidates could theoretically receive new organs derived from their own cells." Approximately18,000 kidney transplants are performed in the U.S. each year, but 100,000 Americans with end-stage kidney disease are still waiting for a donor organ. Even those fortunate enough to receive a transplant face a lifetime of immunosuppressive drugs, which pose many health risks and cannot totally eliminate the incidence of eventual organ rejection. The approach used in this study to engineer donor organs, based on a technology that Dr.
L-carnitine significantly improves cardiac health in patients after a heart attack, say a multicenter team of investigators in a study published on April 12, 2013 in Mayo Clinic Proceedings. The findings, based on analysis of key controlled trials, associate L-carnitine with significant reduction in death from all causes and a highly significant reduction in ventricular arrhythmias and anginal attacks following a heart attack, compared with placebo or control. Heart disease is the leading cause of death in the United States. Although many of the therapies developed in recent decades have markedly improved life expectancy, adverse cardiovascular events such as ventricular arrhythmias and angina attacks still occur frequently after an acute myocardial infarction (heart attack). It is known that during ischemic events L-carnitine levels are depleted. Investigators sought to determine the effects of targeting cardiac metabolic pathways using L-carnitine to improve free fatty acid levels and glucose oxidation in these patients. By performing a systematic review and meta-analysis of the available studies published over several decades, they looked at the role of L-carnitine compared with placebo or control in patients experiencing an acute myocardial infarction. L-carnitine is a trimethylamine which occurs in high amounts in red meat and is found in certain other foods, and is also widely available as an over-the-counter nutritional supplement which is claimed to improve energy, weight loss, and athletic performance. Its potential role in treating heart disease was first reported in the late 1970s. A comprehensive literature search yielded 153 studies; 13, published from 1989-2007 were deemed eligible.
Newcastle University scientists have revealed the mechanism that causes a slime to form, making bacteria hard to shift and resistant to antibiotics. When under threat, some bacteria can shield themselves in a slimy protective layer, known as a biofilm. It is made up of communities of bacteria held together to protect themselves from attack. Biofilms cause dental plaque and sinusitis; in healthcare, biofilms can lead to life threatening and difficult-to-treat infections, particularly on medical implants such as catheters, heart valves, artificial hips, and even breast implants. They also they coat the outside of ships and boats polluting the water. The article was published in the April 12, 2013 issue of the Journal of Biological Chemistry, and was cited as the “paper of the week.” In the article, the research team reveals how a molecular switch regulates biofilm formation. This new understanding could help identify a new target for antibiotics and prevent other biofilms from forming. In order to thwart them from causing disease and biopollution, a Newcastle University team has been studying at the molecular level how bacteria form biofilms in the first instance. They reveal how the master regulator of biofilm formation, a protein called SinR, acts in the model bacterium, Bacillus subtilis. Dr. Richard Lewis, Professor of Structural Biology in the Institute for Cell and Molecular Biosciences who led the research, said, “SinR is a bit like a rocker switch, a domestic light switch for instance. In the "down" position, when SinR is bound to DNA, the proteins required to make a biofilm are turned off and the bacteria are free to move.
Researchers at the Mayo Clinic in Florida participated in a nationwide study that found minor differences between genes that contribute to late-onset Alzheimer's disease in African-Americans and in Caucasians. The study, published in an open-access article in the April 10 issue The Journal of the American Medical Association (JAMA), was the first to look at the genetics of a large number of African-Americans diagnosed with this common form of Alzheimer's disease (1,968 patients) compared to 3,928 normal elderly African-American control participants. The Alzheimer's Disease Genetics Consortium conducted the study, which included Mayo Clinic in Florida investigators Neill R. Graff-Radford, M.D., and Nilufer Ertekin-Taner, M.D., Ph.D. They provided genetic samples and data from their Alzheimer's disease databank. The study found that the most common risk factor in these African-American patients was the APOE gene, which is also true for Caucasians with the disorder. In addition, another gene, ABCA7, which was discovered to be a risk locus for Caucasians, was also a significant risk factor in African-American patients. The study concluded that association with variants at the ABCA7 gene increased the risk for late-onset Alzheimer's disease approximately 1.8-fold in these African-American patients compared to 1.1-fold to 1.2-fold in individuals of European ancestry, although the biologic implications of this difference remains to be established. Still, these differences may not fully explain the genetic basis for development of Alzheimer's disease, the researchers say. The disorder is believed to arise from a number of different genes along with environmental influences.
A genetic analysis of the avian flu virus responsible for at least nine human deaths in China portrays a virus evolving to adapt to human cells, raising concern about its potential to spark a new global flu pandemic. The collaborative study, conducted by a group led by Dr. Masato Tashiro of the Influenza Virus Research Center, National Institute of Infectious Diseases, and Dr. Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo, appears in the April 11, 2013 issue of the journal Eurosurveillance. The group examined the genetic sequences of H7N9 isolates from four of the pathogen's human victims, as well as samples derived from birds and the environs of a Shanghai market. "The human isolates, but not the avian and environmental ones, have a protein mutation that allows for efficient growth in human cells and that also allows them to grow at a temperature that corresponds to the upper respiratory tract of humans, which is lower than you find in birds," says Dr. Kawaoka, a leading expert on avian influenza. The findings, drawn from genetic sequences deposited by Chinese researchers into an international database, provide some of the first molecular clues about a worrisome new strain of bird flu, the first human cases of which were reported on March 31, 2013, by the Chinese Center for Disease Control and Prevention. So far, the new virus has sickened at least 33 people, killing nine. Although it is too early to predict its potential to cause a pandemic, signs that the virus is adapting to mammalian and, in particular, human hosts are unmistakable, says Dr. Kawaoka. Access to the genetic information in the viruses, he adds, is necessary for understanding how the virus is evolving and for developing a candidate vaccine to prevent infection.