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Archive - Apr 2015

April 9th

Wasabi Receptor Structure, Finally Revealed by Cryo-Electron Microscopy at 4 Angstrom Resolution, May Offer Clues to Relieving Pain with Targeted Drugs

In a feat that would have been unachievable only a few years ago, researchers at the Univeristy of California at San Francisco (UCSF) have pulled aside the curtain on a protein informally known as the "wasabi receptor," revealing at near-atomic resolution structures that could be targeted with anti-inflammatory pain drugs. Officially named TRPA1 (pronounced "trip A1"), the newly visualized protein resides in the cellular membrane of sensory nerve cells. It detects certain chemical agents originating outside our bodies--pungent irritants found in substances ranging from wasabi to tear gas--but is also triggered by pain-inducing signals originating within the body, especially those that arise in response to tissue damage and inflammation. "The pain system is there to warn us when we need to avoid things that can cause injury, but also to enhance protective mechanisms," said David Julius, Ph.D., Professor and Chair of UCSF's Department of Physiology, and co-senior author of the new study, which was published online on April 8, 2015 in Nature. "We've known that TRPA1 is very important in sensing environmental irritants, inflammatory pain, and itch, and so knowing more about how TRPA1 works is important for understanding basic pain mechanisms. Of course, this information may also help guide the design of new analgesic drugs." TRPA1 receptor proteins form pores called ion channels in sensory nerve cell membranes. These channels, normally closed, open in response to certain chemical signals, which allows ions to pass into the cell's interior, triggering a warning impulse. But without knowing enough about the receptor's overall structure to see where a given compound might connect, designing a drug to alleviate pain by controlling the action of the ion channel is something of a shot in the dark. Dr.

First Whole-Genome Sequencing of Mountain Gorillas Reveals Impact of Long-Term Population Decline & Inbreeding; Some Surprisingly Positive Results Found

The first project to sequence whole genomes from mountain gorillas has given scientists and conservationists new insight into the impact of population decline on these critically endangered apes. While mountain gorillas are extensively inbred and at risk of extinction, research published in the April 10, 2015 issue of Science finds more to be optimistic about in their genomes than expected. "Mountain gorillas are among the most intensively studied primates in the wild, but this is the first in-depth, whole-genome analysis," says Dr. Chris Tyler-Smith, corresponding author from the Wellcome Trust Sanger Institute. "Three years on from sequencing the gorilla reference genome, we can now compare the genomes of all gorilla populations, including the critically endangered mountain gorilla, and begin to understand their similarities and differences, and the genetic impact of inbreeding." The number of mountain gorillas living in the Virunga volcanic mountain range on the borders of Rwanda, Uganda, and the Democratic Republic of Congo plummeted to approximately 253 in 1981 as a result of habitat destruction and hunting. Since then, conservation efforts led by the Rwanda Development Board and conservation organizations like the Gorilla Doctors (a partnership between the non-profit Mountain Gorilla Veterinary Project and the University of California at Davis Wildlife Health Center), and supported by tourists keen to see the gorillas made famous by late primatologist Dian Fossey, have bolstered numbers to approximately 480 among the Virunga population.

Shorter Height Genetically Linked to Increased Risk of Coronary Heart Disease; New Study in NEJM Discounts Confounding Factors; 2.5 Inches Shorter, CHD Risk Increases 13.5%

The shorter you are- the more your risk of coronary heart disease. That's the key finding of a new study led by the University of Leicester which discovered that every 2.5 inches change in your height affected your risk of coronary heart disease by 13.5%. For example, compared to a 5’6” tall person, a 5’ tall person on average has a 32% higher risk of coronary heart disease because of their relatively shorter stature. The research, led by Professor Sir Nilesh Samani, British Heart Foundation Professor of Cardiology at the University of Leicester, was published online on April 8, 2015 in the New England Journal of Medicine. The research was supported by the British Heart Foundation, The National Institute for Health Research (NIHR) and others. Professor Samani said: "For more than 60 years it has been known that there is an inverse relationship between height and risk of coronary heart disease. "It is not clear whether this relationship is due to confounding factors such as poor socioeconomic environment, or nutrition, during childhood that on the one hand determine achieved height and on the other the risk of coronary heart disease, or whether it represents a primary relationship between shorter height and more coronary heart disease. "Now, using a genetic approach, researchers at the University of Leicester undertaking the study on behalf of an international consortium of scientists (the CADIoGRAM+C4D consortium) have shown that the association between shorter height and higher risk of coronary heart disease is a primary relationship and is not due to confounding factors." Coronary heart disease is the most common cause of premature death worldwide. It is the condition where the arteries that supply blood to the heart muscle (coronary arteries) become narrowed due to a deposition of fatty material (plaque) in the walls of the arteries.

April 9th

Indigenous Bacteria Regulate Serotonin Synthesis in Gut

Although serotonin (image)is well known as a brain neurotransmitter, it is estimated that 90 percent of the body's serotonin is made in the digestive tract. In fact, altered levels of this peripheral serotonin have been linked to diseases such as irritable bowel syndrome, cardiovascular disease, and osteoporosis. New research at Caltech, published in the April 9 issue of the journal Cell, shows that certain bacteria in the gut are important for the production of peripheral serotonin. The title of the article is “Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis.” The Cell article is accompanied by a Cell Preview entitled “Gut Microbiota: The Link to Your Second Brain.” "More and more studies are showing that mice or other model organisms with changes in their gut microbes exhibit altered behaviors," explains Dr. Elaine Hsiao, Research Assistant Professor of Biology and Biological Engineering and senior author of the study. "We are interested in how microbes communicate with the nervous system. To start, we explored the idea that normal gut microbes could influence levels of neurotransmitters in their hosts." Peripheral serotonin is produced in the digestive tract by enterochromaffin (EC) cells and also by particular types of immune cells and neurons. Dr. Hsiao and her colleagues first wanted to know if gut microbes have any effect on serotonin production in the gut and, if so, in which types of cells. They began by measuring peripheral serotonin levels in mice with normal populations of gut bacteria and also in germ-free mice that lack these resident microbes. The researchers found that the EC cells from germ-free mice produced approximately 60 percent less serotonin than did their peers with conventional bacterial colonies.

Horizontal Transmission of Clonal Cancer Found in Soft-Shelled Clams; Only Third Such Example in Nature; Cover Article in Cell

Outbreaks of leukemia that have devastated some populations of soft-shell clams along the east coast of North America for decades can be explained by the spread of cancerous tumor cells from one clam to another. Researchers call the discovery, which was featured as the cover story in the April 9, 2015 issue of Cell, "beyond surprising." The article is titled “Horizontal Transmission of Clonal Cancer Cells Causes Leukemia in Soft-Shell Clam.” "The evidence indicates that the tumor cells themselves are contagious--that the cells can spread from one animal to another in the ocean," said Dr. Stephen Goff of the Howard Hughes Medical Institute and Columbia University. "We know this must be true because the genotypes of the tumor cells do not match those of the host animals that acquire the disease, but instead all derive from a single lineage of tumor cells." In other words, the cancer that has killed so many clams all trace to one incidence of disease. The cancer originated in some unfortunate clam somewhere and has persisted ever since as those cancerous cells divide, break free, and make their way to other clams. Only two other examples of transmissible cancer are known in the wild. These cancers include the canine transmissible venereal tumor, transmitted by sexual contact, and the Tasmanian devil facial tumor disease, transmitted through biting. In early studies of the cancer in clams, Dr. Goff and his colleagues found that a particular sequence of DNA (which they named Steamer) was found at incredibly high levels in leukemic versus normal clam cells. While normal cells contain only two to five copies of Steamer, cancerous clam cells can have 150 copies. The researchers at first thought that this difference was the result of a genetic amplification process occurring within each individual clam.

Next-Generation Optogenetics Program Launched in Germany

Optogenetics is a new field of research that introduces light-sensitive proteins into cells in a genetically targeted manner, for example, to obtain information on signalling pathways and the function of neurons in a living organism. A new priority program supported by the German Research Foundation (DFG) under the auspices of Goethe University has now set itself the goal of developing the next generation of optogenetic tools and expanding their application both in basic research and also for medical purposes. DFG will provide six million Euros in funding for the program over the next three years. "We see our role as a pathfinder, to build a scientific network for optogenetics in Germany," says Professor Alexander Gottschalk, spokesperson for the priority program, which is titled "Next Generation Optogenetics: Tool Development and Applications." After an application phase in the autumn of 2015, between 30 and 40 scientists from different universities will become involved; primarily biophysicists, cell biologists, chemists, medical scientists, and "photo-biologists." These are the types of specialists who will search for new, light-sensitive proteins, which will be introduced into cells and act like light switches to turn cellular processes on and off. "Optogenetics already has many applications in basic research, but as a technology it is still in its infancy," explains Professor Gottschalk. In order to achieve more widespread use of optogenetics in cell biology and neurobiology, the researchers want to develop new optogenetic tools. These will have higher light sensitivity, clarify the processes within individual cells and between different cells, and ultimately also be tested in animal models.

Low-Temperature Plasmas Show Promise As Novel Treatment for Early-Stage Prostate Cancer; Clinical Application Not Likely for 10 or More Years, However

Scientists at the University of York in the UK have discovered a potential new treatment for prostate cancer using low-temperature plasmas (LTPs). Published online on April 2, 2015 in an open-access article in the British Journal of Cancer (BJC), the study represents the first time LTPs have been applied on cells grown directly from patient tissue samples. The article title is “Low-Temperature Plasma Treatment Induces DNA Damage Leading to Necrotic Cell Death in Primary Prostate Epithelial Cells.” The study is the result of a unique collaboration between the York Plasma Institute in the Department of Physics and the Cancer Research Unit (CRU) in York's Department of Biology. Taking both healthy prostate cells and prostate cancer tissue cells from a single patient, the study allowed for direct comparison of the effectiveness of the treatment. Scientists discovered that LTPs may be a potential option for treatment of patients with organ-confined prostate cancer, and a viable, more cost-effective alternative to current radiotherapy and photodynamic therapy (PDT) treatments. Low-temperature plasmas are formed by applying a high electric field across a gas using an electrode, which breaks down the gas to form plasma. This creates a complex, unique reactive environment containing high concentrations of reactive oxygen and nitrogen species (RONS). Operated at atmospheric pressure and around room temperature, the delivery of RONS, when transferred through plasma to a target source, is a key mediator of oxidative damage and cell death in biological systems. The way cell death occurs when using LTP treatment is different from other therapies. The active agents in the LTP break up DNA and destroy cells by necrosis, where cell membranes are ruptured, resulting in cell death.

Delicate Magnolia Scent Activates Putative Human Pheromone Receptor

The question as to whether or not humans can communicate via pheromones in the same way as animals is under debate. Cell physiologists at the Ruhr-Universität Bochum, however, have recently demonstrated that the odorous substance Hedione activates the putative pheromone receptor VN1R1, which occurs in the human olfactory epithelium. Together with colleagues from Dresden, the Bochum-based researchers showed that the scent of Hedione generates sex-specific activation patters in the brain, which do not occur with traditional fragrances. "These results constitute compelling evidence that a pheromone effect different from normal olfactory perception indeed exists in humans," says scent researcher Professor Dr. Hanns Hatt. The team published the results online on March 19, 2015 in the Journal NeuroImage. Using genetic-analysis approaches, the researchers from Bochum confirmed the pheromone receptor's existence in human olfactory mucosa. Subsequently, they transferred the genetic code for the receptor into cell cultures and, using these cells, demonstrated that Hedione activates the receptor. Hedione - derived from the Greek word "hedone," for fun, pleasure, lust; has a pleasant fresh jasmine-magnolia scent and is utilized in many perfumes. It is also called the scent of success. Together with the team headed by Professor Dr. Thomas Hummel from the University Hospital Dresden, the group from Bochum analyzed what happens in the brain when a person smells Hedione. They compared the results with the effects triggered by phenylethyl alcohol, a traditional floral fragrance. Hedione activated brain areas in the limbic system significantly more strongly than did phenylethyl alcohol. The limbic system is associated with emotions, memory, and motivation.

April 8th

MIT & Whitehead Researchers ID Metabolic Weakness in Subset of Glioblastoma Cells; May Be New Therapeutic Target

Biologists at MIT and the Whitehead Institute for Biomedical Research have discovered a vulnerability of brain cancer cells that could be exploited to develop more-effective drugs against brain tumors. The study, led by researchers from the Whitehead Institute and MIT’s Koch Institute for Integrative Cancer Research, found that a subset of glioblastoma tumor cells is dependent on a particular enzyme (glycine decarboxylase, GLDC) that breaks down the amino acid glycine. Without this enzyme, toxic metabolic byproducts build up inside the tumor cells, and they die. Blocking this enzyme in glioblastoma cells could offer a new way to combat such tumors, says Dr. Dohoon Kim, a postdoc at the Whitehead Institute and lead author of the study, which was published online on April 8, 2015 in Nature. Dr. David Sabatini, a Professor of Biology at MIT and member of the Whitehead Institute, is the paper’s senior author. Dr. Matthew Vander Heiden, the Eisen and Chang Career Development Associate Professor of Biology and a member of the Koch Institute, also contributed to the research, along with members of his lab. GLDC caught the researchers’ attention as they investigated diseases known as “inborn errors of metabolism,” which occur when cells are missing certain metabolic enzymes. Many of these disorders specifically affect brain development; the most common of these is phenylketonuria, marked by an inability to break down the amino acid phenylalanine. Such patients must avoid eating phenylalanine to prevent problems such as intellectual disability and seizures. Loss of GLDC produces a disorder called nonketotic hyperglycinemia, which causes glycine to build up in the brain and can lead to severe mental retardation. GLDC is also often overactive in certain cells of glioblastoma, the most common and most aggressive type of brain tumor found in humans.

Clearer Understanding of DNA Replication Origin Recognition Complex (ORC), As Well As Related Meier-Gorlin Genetic Dwarfism Syndrome Offered by Atomic-Level Resolution Analysis of ORC Crystal Structure

A clearer understanding of the origin recognition complex (ORC) - a protein complex that directs DNA replication - through its crystal structure offers new insight into fundamental mechanisms of DNA replication initiation. This will also provide insight into how ORC may be compromised in a subset of patients with Meier-Gorlin syndrome, a form of dwarfism in humans. ORC is a six-subunit protein complex that directly binds DNA to recruit other protein factors involved in DNA replication. Researchers collected data at the Advanced Photon Source (APS), a U.S. Department of Energy User Facility based at Argonne National Laboratory in Illinois, to obtain the first atomic-level resolution picture of this complex. The structure shows that ORC's main body has five subunits that contain a common fold that is found in proteins binding ATP, a small molecule that cells use as fuel. One of the largest subunits, ORC3, has a structural element that protrudes from the ORC core to contact ORC6, according to the paper, "Crystal Structure of the Eukaryotic Origin Recognition Complex," which was published in the March 19, 2015 issue of in Nature. "The crystal structure explains why a mutation in ORC6 that is linked to Meier-Gorlin syndrome in a subset of patients results in defective binding of this subunit to ORC3," said Dr. Franziska Bleichert, the paper's lead author. "The structure also makes specific predictions on how the different ORC protein subunits might interact with DNA in the central channel of ORC and with other replication initiation factors."