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August 10th, 2014

Target Identified for Rare Inherited Neurological Disease in Men

Researchers at the University of California, San Diego School of Medicine have identified the mechanism by which a rare, inherited neurodegenerative disease causes often crippling muscle weakness in men, in addition to reduced fertility. The study, published August 10, 2014 in the journal Nature Neuroscience, shows that a gene mutation long recognized as a key to the development of Kennedy's disease impairs the body's ability to degrade, remove, and recycle clumps of "trash" proteins that may otherwise build up on neurons, progressively impairing their ability to control muscle contraction. This mechanism, called autophagy, is akin to a garbage disposal system and is the only way for the body to purge itself of non-working, misshapen trash proteins. "We've known since the mid-1990s that Alzheimer's disease, Parkinson's disease, and Huntington's disease are caused by the accumulation of misfolded proteins that should have been degraded, but cannot be turned over," said senior author Albert La Spada, M.D., Ph.D., and professor of pediatrics, cellular and molecular medicine, and neurosciences. "The value of this study is that it identifies a target for halting the progression of protein build-up, not just in this rare disease, but in many other diseases that are associated with impaired autophagy pathway function." Of the 400 to 500 men in the U.S. with Kennedy's disease (see image), the slow but progressive loss of motor function results in about 15 to 20 percent of those with the disease becoming wheel-chair bound during later stages of the disease. Kennedy's disease, also known as spinal and bulbar muscular atrophy, is a recessive X-linked disease men inherit from their mothers. Women don't get the disease because they have two copies of the X chromosome.

Scientists ID a Key to Blood Vessel Formation

Researchers from the University of Leeds in the UK have discovered a gene that plays a vital role in blood vessel formation, research which adds to our knowledge of how early life develops. The discovery could also lead to greater understanding of how to treat cardiovascular diseases and cancer. Professor David Beech, of the School of Medicine at the University of Leeds, who led the research, said: "Blood vessel networks are not already pre-constructed but emerge rather like a river system. Vessels do not develop until the blood is already flowing and they are created in response to the amount of flow. This gene, Piezo1, provides the instructions for sensors that tell the body that blood is flowing correctly and gives the signal to form new vessel structures. The gene gives instructions to a protein which forms channels that open in response to mechanical strain from blood flow, allowing tiny electrical charges to enter cells and trigger the changes needed for new vessels to be built." The research team is planning to study the effects of manipulating the gene on cancers, which require a blood supply to grow, as well as in heart diseases such as atherosclerosis, where plaques form in parts of blood vessels with disturbed blood flow. Professor Beech added: "This work provides fundamental understanding of how complex life begins and opens new possibilities for treatment of health problems such as cardiovascular disease and cancer, where changes in blood flow are common and often unwanted. "We need to do further research into how this gene can be manipulated to treat these diseases.

August 9th

Scientists in Singapore Make Breakthroughs in Ovarian Cancer Research

Scientists at A*STAR’s Institute of Medical Biology (IMB) and the Bioinformatics Institute (BII) in Singapore have found new clues to early detection and personalized treatment of ovarian cancer, currently one of the most difficult cancers to diagnose early due to the lack of symptoms that are unique to the illness. There are three predominant cancers that affect women – breast, ovarian, and womb cancer. Of the three, ovarian cancer is of the greatest concern as it is usually diagnosed only at an advanced stage due to the absence of clear early warning symptoms. Successful treatment is difficult at this late stage, resulting in high mortality rates. Ovarian cancer has increased in prevalence in Singapore as well as other developed countries recently. It is now the fifth most common cancer in Singapore amongst women, with about 280 cases diagnosed annually and 90 deaths per year. IMB scientists have successfully identified a biomarker of ovarian stem cells, which may allow for earlier detection of ovarian cancer and thus allow treatment at an early stage of the illness. The team has identified a molecule, known as Lgr5, on a subset of cells in the ovarian surface epithelium. Lgr5 has been previously used to identify stem cells in other tissues, including the intestine and stomach, but this is the first time that scientists have successfully located this important biomarker in the ovary. In doing so, they have unearthed a new population of epithelial stem cells in the ovary which produce Lgr5 and control the development of the ovary. Using Lgr5 as a biomarker of ovarian stem cells, ovarian cancer can potentially be detected earlier, allowing for more effective treatment at an early stage of the illness. These findings were published online in Nature Cell Biology on July 6, 2014.

"Game-Changer" in Nerve Repair

A multicenter study including University of Kentucky researchers has found that a new nerve repair technique yields better results and fewer side effects than other existing techniques. Traumatic nerve injuries are common, and when nerves are severed, they do not heal on their own and must be repaired surgically. Injuries that are not clean-cut – such as saw injuries, farm equipment injuries, and gunshot wounds – may result in a gap in the nerve. To fill these gaps, surgeons have traditionally used two methods: a nerve autograft (bridging the gap with a patient's own nerve taken from elsewhere in the body), which leads to a nerve deficit at the donor site; or nerve conduits (synthetic tubes), which can cause foreign body reactions or infections. The prospective, randomized study, conducted by UK Medical Director of Hand Surgery Service Dr. Brian Rinker and others, compared the nerve conduit to a newer technique called a nerve allograft. The nerve allograft uses human nerves harvested from cadavers. The nerves are processed to remove all cellular material, preserving their architecture while preventing disease transmission or allergic reactions. Participants with nerve injuries were randomized into either conduit or allograft repair groups. Following the surgeries, independent blind observers performed standardized assessments at set time points to determine the degree of sensory or motor recovery. The results of the study suggested that nerve allografts had more consistent results and produced better outcomes than nerve conduits, while avoiding the donor site morbidity of a nerve autograft. Dr. Rinker, a principal investigator of the study, describes it as a "game-changer.

Scientists Use CRISPR Tool to Silence HPV Genes in Cervical Carcinoma Cells

Researchers have hijacked a defense system normally used by bacteria to fend off viral infections and redirected it against the human papillomavirus (HPV), the virus that causes cervical, head and neck, and other cancers. Using the genome editing tool known as CRISPR (see image), the Duke University researchers were able to selectively destroy two viral genes responsible for the growth and survival of cervical carcinoma cells, causing the cancer cells to self-destruct. The findings, appearing online August 6, 2014 in the Journal of Virology, give credence to an approach only recently attempted in mammalian cells, and could pave the way toward antiviral strategies targeted against other DNA-based viruses like hepatitis B and herpes simplex. "Because this approach is only going after viral genes, there should be no off-target effects on normal cells," said Bryan R. Cullen, Ph.D., senior study author and professor of molecular genetics and microbiology at Duke University School of Medicine. "You can think of this as targeting a missile that will destroy a certain target. You put in a code that tells the missile exactly what to hit, and it will only hit that, and it won't hit anything else because it doesn't have the code for another target." The CRISPR targeted system was only discovered a decade ago. Looking at the genomes of different types of bacteria, researchers had noticed long stretches where the same genetic sequence was repeated. In between these repeats lay DNA sequences that differed from bacteria to bacteria. Scientists figured out that these unique sequences -- known as clustered regularly interspaced short palindromic repeats or CRISPR -- were derived from viruses that had previously infected the bacteria.

August 8th

Uric Acid May Be New Culprit in Metabolic Syndrome

A new study suggests uric acid may play a role in causing metabolic syndrome, a cluster of risk factors that increases the risk of heart disease and type 2 diabetes. Uric acid is a normal waste product removed from the body by the kidneys and intestines and released in urine and stool. Elevated levels of uric acid are known to cause gout, an accumulation of the acid in the joints. High levels also are associated with the markers of metabolic syndrome, which is characterized by obesity, high blood pressure, elevated blood sugar, and high cholesterol. But it has been unclear whether uric acid itself is causing damage or is simply a byproduct of other processes that lead to dysfunctional metabolism. Published online on August 7, 2014 in Nature Communications, the new research at Washington University School of Medicine in St. Louis suggests excess uric acid in the blood is no innocent bystander. Rather, it apipears to be a culprit in disrupting normal metabolism. “Uric acid may play a direct, causative role in the development of metabolic syndrome,” said first author Brian J. DeBosch, M.D., Ph.D., an instructor in pediatrics. “Our work showed that the gut is an important clearance mechanism for uric acid, opening the door to new potential therapies for preventing or treating type 2 diabetes and metabolic syndrome.” Recent research by the paper’s senior author, Kelle H. Moley, M.D., the James P. Crane Professor of Obstetrics and Gynecology, and her collaborators has shown that a protein called GLUT9 is an important transporter of uric acid. Dr. DeBosch, a pediatric gastroenterologist who treats patients at St. Louis Children’s Hospital, studied mice to learn what happens when GLUT9 stops working in the gut, essentially blocking the body’s ability to remove uric acid from the intestine.

Leukemia Is Prominent in Down Syndrome

Children affected by trisomy 21 (or Down syndrome) are 50 to 500 times more likely to develop leukemia than other children. A group of geneticists working in the Faculty of Medicine at the University of Geneva (UNIGE) focused for many years on the genetic characteristics of Down syndrome. They have sequenced the exome, a specific part of our genome, in a cohort of patients affected both by Down Syndrome and Acute Lymphoblastic Leukemia (DS-ALL), a type of cancer relative to the cells of the immune system in the bone marrow. They were able to sketch an outline of the "genetic identity card" of this disease. They found that RAS, an important oncogene in many cancers, is involved in the tumorigenesis of one third of DS-ALL cases. This work was published online on August 8, 2014 in Nature Communications. The senior author was Dr. Stylianos Antonarakis. [Press release] [Nature Communications abstract]

Living Organisms Found in Oil

Miniscule water droplets in oil provide a habitat for a number of microorganisms. Scientists from the Helmholtz Zentrum München in Germany have discovered that these communities of microorganisms play a part in breaking down the oil and have published their findings online on August 8, 2014 in the renowned journal Science. Oil might not, at first sight, seem like an inhabited terrain. Within the oil, however, are tiny, suspended water droplets. “Inside them we found complex microbial communities, which play an active part in oil degradation in situ,” says first author Professor Rainer Meckenstock (image, credit: HMGU)) from the Helmholtz Zentrum München (HMGU). Previously, it was assumed that microbial oil degradation only occurred at the oil-water interface. The team headed by Professor Meckenstock from the Institute of Groundwater Ecology and the Department of Biogeochemistry at HMGU, along with international colleagues from the Technical University of Berlin, Washington State University (USA) and the University of West Indies (Trinidad and Tobago) have now been able to demonstrate that degradation processes also occur within the oil phase. “Degradation changes the chemical composition of the oil and ultimately leads to the formation of viscous bitumen, as in oil sands, “ Professor Meckenstock explains. “Our data thus supplies important information about oil quality and is therefore essential for the industry that surrounds what is still the most important energy source worldwide.” Although the breakdown of chemical compounds (hydrocarbons) damages the oil, this can be highly desirable in contaminated groundwater. The microorganisms, which have adapted to an extremely toxic habitat, could pave the way for new concepts for cleaning up pollution in groundwater.

Scientists Unravel Mystery of Brain Cell Growth

In the developing brain, special proteins that act like molecular tugboats push or pull on growing nerve cells, or neurons, helping them navigate to their assigned places amidst the brain’s wiring. How a single protein can exert both a push and a pull force to nudge a neuron in the desired direction is a longstanding mystery that has now been solved by scientists from Dana-Farber Cancer Institute and collaborators in Europe and China. Jia-huai Wang, PhD, who led the work at Dana-Farber and Peking University in Beijing, is a corresponding author of a report published in the August 7, 2014 online edition of Neuron that explains how one guidance protein, netrin-1 (see image), can either attract or repel a brain cell to steer it along its course. Dr. Wang and co-authors at the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, used X-ray crystallography to reveal the three-dimensional atomic structure of netrin-1 as it bound to a docking molecule, called DCC, on the axon of a neuron. The axon is the long, thin extension of a neuron that connects to other neurons or to muscle cells. As connections between neurons are established – in the developing brain and throughout life – axons grow out from a neuron and extend through the brain until they reach the neuron they are connecting to. To choose its path, a growing axon senses and reacts to different molecules it encounters along the way. One of these molecules, netrin-1, posed an interesting puzzle: an axon can be both attracted to and repelled from this cue. The axon’s behavior is determined by two types of receptors on its tip: DCC drives attraction, while UNC5 in combination with DCC drives repulsion. “How netrin works at the molecular level has long been a puzzle in neuroscience field,” said Dr.

Non-Standard MicroRNA Silencing Interactions Appear More Prevalent in Human Bology Than Previously Believed, Suggesting More Complex Roles for MicroRNAs

MicroRNAs (miRNAs) regulate protein-coding gene abundance levels by interacting with the 3´ end of various messenger RNAs. Each target site matches the first few nucleotides of the targeting miRNA, the so called "seed" region, and this interaction leads to the degradation of the target or prevents its translation into amino acids. This dogma has led researchers to largely look for perfect base-pair matching of the "seed" region among candidate targets. New research published today (August 8, 2014) in Nature's open-access journal Scientific Reports suggests that non-canonical binding may be much more prevalent than previously expected, revealing a much broader array of targets for miRNAs that includes both regions that code for proteins and others that do not. "The findings may help explain why the microRNA field has run into difficulty when translating these powerful molecules into therapies for diseases ranging from cancer to diabetes," says senior author Isidore Rigoutsos, Ph.D., Director of the Computational Medicine Center in the Sidney Kimmel Medical College at Thomas Jefferson University. "There is still so much we don't know about how miRNAs work in the body." The research add to previous reports by the Jefferson group and by others demonstrating that the miRNA "targetome" – the spectrum of RNAs that miRNAs attack – is much more complex than previously anticipated. "Our study shows that even conserved miRNAs that we share with animals and insects can have very different behavior across organisms and even across different tissues in our bodies," says Dr. Rigoutsos.