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Archive - Feb 2015

February 18th

DNA Damage Causes Immune Reaction and Inflammation, and Is Linked to Cancer Development; Crucial Clues to New Understanding Come from Rare Genetic Disease Ataxia Telangiectasia (AT)

For the first time, scientists from Umeå University have shown the importance of DNA damage in fine-tuning our innate immune system and hence the ability to mount the optimal inflammatory response to infections and other biological dangers. The study was published in the February 17, 2015 issue of Immunity. The title of the article is “DNA Damage Primes the Type I Interferon System via the Cytosolic DNA Sensor STING to Promote Anti-Microbial Innate Immunity.” The research group of Dr. Nelson Gekara, within the Laboratory for Molecular Infection Medicine Sweden (MIMS) at Umeå University, is interested in understanding how the innate immune system, our first line of defense, is regulated and how defects in the innate immune system contribute to infectious and inflammatory diseases. Our immune system does not lie idle waiting to be attacked before it responds. Even in the absence of infections, our immune system is in a constant state of alert. Among the immune mediators that are constantly produced at low levels, and that keep our immune system awake, are a group of factors called type I interferons. A very delicate balance in the production of type I interferons is essential for health: insufficient production results in susceptibility to viral infections, while excessive production normally leads to autoimmune/inflammatory diseases. One of the questions Dr. Gekara´s lab has been investigating is aimed at understanding the signaling processes that control type I interferon production and, in particular, to identify the endogenous "danger signals" that constantly trigger basal production of interferons and therefore keep our immune system in a "ready-to-attack" state. The clue to answering this question came from a rare, but complex disease called ataxia telangiectasia (AT).

Mutated Genes Causing Autism in Children Are Linked to RhoA Biochemical Pathway That Regulates Neuronal Migration and Brain Morphogenesis during Early Stages of Brain Development; Plans to Test RhoA Pathway Inhibitors Using a Stem Cell Model of Autism

Scientists at the University of California, San Diego (UCSD) School of Medicine have found that mutations that cause autism in children are connected to a pathway that regulates brain development. The research, led by Lilia Iakoucheva, Ph.D, Assistant Professor in the Department of Psychiatry, was published in the February 18, 2015 issue of Neuron. The article was entitled “Spatiotemporal 16p11.2 Protein Network Implicates Cortical Late Mid-Fetal Brain Development and KCTD13-Cul3-RhoA Pathway in Psychiatric Diseases.” The researchers studied a set of well-known autism mutations called copy number variants or CNVs. They investigated when and where these mutated genes were expressed during brain development. “One surprising thing that we immediately observed was that different CNVs seemed to be turned on in different developmental periods,” said Dr. Iakoucheva. Specifically, the scientists noted that one CNV located in a region of the genome known as 16p11.2 (on chromosome 16), contained genes active during the late mid-fetal period. Ultimately, the researchers identified a network of genes that showed a similar pattern of activation including KCTD13 within 16p11.2 and CUL3, a gene from a different chromosome that is also mutated in children with autism. “The most exciting moment for us was when we realized that the proteins encoded by these genes form a complex that regulates the levels of a third protein, RhoA,” said Dr. Iakoucheva. Rho proteins play critical roles in neuronal migration and brain morphogenesis at early stages of brain development. “Suddenly, everything came together and made sense.”

World’s Most Comprehensive Map of Human Genomics Unveiled Simultaneously in 24 Journals

Two dozen scientific papers published online simultaneously on Feb. 18, 2015 present the first comprehensive maps and analyses of the epigenomes of a wide array of human cell and tissue types. Epigenomes are patterns of chemical annotations to the genome that determine whether, how, and when genes are activated. Because epigenomes orchestrate normal development of the body, and disruptions in epigenetic control are known to be involved in a wide range of disorders, from cancer to autism to heart disease, the massive trove of data is expected to yield many new insights into human biology in both health and disease. The 24 papers describing human epigenomes will appear in print on Feb. 19, 2015 in the journal Nature and in six other journals under the aegis of Nature Publishing Group. Collectively, the papers are a culmination of years of research by hundreds of participants in the Roadmap Epigenomics Program (REP), first proposed in 2006 by academic scientists and key members of the National Institutes of Health. All will be freely available at Nature's Epigenome Roadmap website. "The DNA sequence of the human genome is identical in all cells of the body, but cell types--such as heart, brain, or skin cells--have unique characteristics and are uniquely susceptible to various diseases," said University of California, San Francisco's (UCSF’s) Joseph F. Costello, Ph.D., director of one of the four NIH Roadmap Epigenome Mapping Centers (REMC) that contributed data to the REP. "By guiding how genes are expressed, epigenomes allow cells carrying the same DNA to differentiate into the more than 200 types found in the human body." In cancer research, said Dr. Costello, the new data will hasten a merging of genomic and epigenomic perspectives that was already underway.

Microbial Metabolite of Linoleic Acid Meliorates Intestinal Inflammation; Potentially Helpful in Crohn Disease & Ulcerative Colitis

A Japanese research group has demonstrated that 10-hydroxy-cis-12-octadecenoic acid (HYA), a gut microbial metabolite of linoleic acid, has a suppressive effect on intestinal inflammation. HYA is expected to be practically applied as a functional food. Inflammatory bowel diseases (IBDs), including Crohn disease and ulcerative colitis, are hard to completely cure. Globally, IBDs affect more than 4 million people, today. However, Professor Soichi Tanabe (Graduate School of Biosphere Science, Hiroshima University) and his collaborators have demonstrated that 10-hydroxy-cis-12-octadecenoic acid (HYA), a gut microbial metabolite of linoleic acid, has a suppressive effect on intestinal inflammation. HYA is expected to be practically applied as a functional food. The results of this group’s research were published in the January 30, 2015 issue of The Journal of Biological Chemistry in an article entitled "A Gut Microbial Metabolite of Linoleic Acid, 10-Hydroxy-Cis-12-Octadecenoic Acid, Ameliorates Intestinal Epithelial Barrier Impairment Partially via GPR40–MEK–ERK Pathway." IBD patients characteristically demonstrate increased expression of tumor necrosis factor receptor-2 (TNFR-2) and an upregulated inflammatory NF-κB pathway. Professor Tanabe and his colleagues have demonstrated that HYA binds to a G protein-coupled receptor (GPR40) and meliorates intestinal epithelial barrier impairment in an intestinal epithelial cell line, Caco-2 cells; oral administration of HYA also alleviates colitis in mice. The physiological activity of gut microbial metabolites has recently attracted considerable attention. HYA may be useful in the treatment of tight junction-related disorders, such as IBD.

February 17th

Major Advance May Enable Safe Islet Transplants to Cure Type 1 Diabetes; CXCL12-Encapsulated Islets Protect Insulin-Producing Cells from Recipient's Immune Response

An approach developed by Massachusetts General Hospital (MGH) investigators may provide a solution to the limitations that have kept pancreatic islet transplantation from meeting its promise as a cure for type 1 diabetes. In the March 2015 issue of the American Journal of Transplantation, the research team reports that encapsulating insulin-producing islets in gel capsules, infused with a protein that repels key immune cells, protected islets from attack by the recipient's immune system, without the need for immunosuppressive drugs, restoring long-term blood sugar control in mouse models. The technique was effective both for islets from unrelated mice and for islets harvested from pigs. "Protecting donor islets from the recipient's immune system is the next big hurdle toward making islet transplantation a true cure for type 1 diabetes," says Mark Poznansky, M.D., Ph.D., Director of the MGH Vaccine and Immunotherapy Center, who led the study. "The first was generating enough insulin-producing islets, which has been addressed by several groups using pig islets, or, as announced last fall by Doug Melton's team at the Harvard Stem Cell Institute, with islet cells derived from human stem cells. Now our technology provides a way to protect islets or other stem-cell-derived insulin-producing cells from being destroyed as soon as they are implanted into a diabetic individual, without the need for high-intensity immunosuppression, which has its own serious side effects." While transplantation of pancreatic islets has been investigated for several decades, as a treatment and potential cure for type 1 diabetes, its success has been limited.

Secondary Metabolites in Floral Nectar May Play Vital Role in Reducing Bee-Parasite Interactions

Nicotine isn't healthy for people, but such naturally occurring chemicals found in flowers of tobacco and other plants could be just the right prescription for ailing bees, according to a Dartmouth College-led study. The researchers found that chemicals in floral nectar, including the alkaloids anabasine and nicotine, the iridoid glycoside catalpol, and the terpenoid thymol, significantly reduce parasite infection in bees. The results suggest that growing plants high in these compounds around farm fields could create a natural "medicine cabinet" that improves survival of diseased bees and pollination of crops. The researchers studied parasite infections in bumble bees, which like honey bees are important pollinators that are in decline around the world, a trend that threatens fruits, vegetables, and other crops that make up much of the food supply for people. The findings appear in the journal Proceedings of the Royal Society B. The study included researchers from Dartmouth and the University of Massachusetts-Amherst. Plants produce chemicals called secondary metabolites to defend leaves against herbivores. These chemicals are also found in nectar for pollinators, but little is known about the impacts of nectar chemistry on pollinators, including bees. The researchers hypothesized that some nectar compounds could reduce parasite infections in bees, so they inoculated individual bumble bees with an intestinal parasite and tested the effects of eight naturally occurring nectar chemicals on parasite population growth. The results showed that consumption of these chemicals lessened the intensity of infection by up to 81 percent, which could significantly reduce the spread of parasites within and between bee colonies.

Genetic Editing for Immediate Adaptation: The “Astonishing” Squid Edits Up to 60% of Its Nervous System RNA Transcripts On-the-Fly; Drosophila Just 3%

The principle of adaptation--the gradual modification of a species' structures and features--is one of the pillars of evolution. While there exists ample evidence to support the slow, ongoing process that alters the genetic makeup of a species, scientists could only suspect that there were also organisms capable of transforming themselves ad hoc to adjust to changing conditions. Now, a new study published online on January 8, 2015 in eLife by Dr. Eli Eisenberg of Tel Aviv University's (TAU’s) Department of Physics and Sagol School of Neuroscience, in collaboration with Dr. Joshua J. Rosenthal of the University of Puerto Rico, showcases the first example of an animal editing its own genetic makeup on-the-fly to modify most of its proteins, enabling adjustments to its immediate surroundings. The article is titled “The Majority of Transcripts in the Squid Nervous System Are Extensively Recoded by A-to-I RNA Editing.” The research, conducted in part by TAU graduate student Shahar Alon, explored RNA editing in the Doryteuthis pealieii squid. "We have demonstrated that RNA editing is a major player in genetic information processing, rather than an exception to the rule," said Dr. Eisenberg. "By showing that the squid's RNA editing dramatically reshaped its entire proteome — the entire set of proteins expressed by a genome, cell, tissue, or organism at a certain time — we proved that an organism’s self-editing of mRNA is a critical evolutionary and adaptive force." This demonstration, he said, may have implications for human diseases as well. RNA is a copy of the genetic code that is translated into protein. But the RNA "transcript" can be edited before being translated into protein, paving the way for different versions of proteins. Abnormal RNA editing in humans has been observed in patients with neurological diseases.

New Results Suggest That Altered Electrical Activity of Selective Dopamine Midbrain Neurons Is Crucial for Schizophrenia

Schizophrenia is not only associated with positive symptoms such as hallucinations and delusions, but also with negative symptoms e.g., cognitive deficits and impairments of the emotional drive. Until now, the underlying mechanisms for these negative symptoms have not been well characterized. In an article published online on February 9, 2015 in PNAS, a German-American team of researchers, with the cooperation of the Goethe University, reports that a selective dopamine midbrain neuron population that is crucial for emotional and cognitive processing shows reduced electrical in vivo activity in a disease mouse model. The title of the PNAS article is “Increased Dopamine D2 Receptor Activity in the Striatum Alters the Firing Pattern of Dopamine Neurons in the Ventral Tegmental Area.” ”Schizophrenia is a severe and incurable psychiatric illness, which affects approximately one percent of the world population. While acute psychotic states of the disease have been successfully treated with psycho-pharmaceutical drugs (anti-psychotic agents) for many decades, cognitive deficits and impairments of motivation do not respond well to standard drug therapy. This is a crucial problem, as the long-term prognosis of a patient is determined above all by the severity of these negative symptoms. Therefore, the shortened average life-span of about 25 years for schizophrenia patients remained largely unaltered in recent decades. "In order to develop new therapy strategies, we need an improved neurobiological understanding of the negative symptoms of schizophrenia" explains Professor Jochen Roeper of the Institute for Neurophysiology of the Goethe University.

Can Dingoes Help Halt Australia’s Biodiversity Collapse? Will They Suppress Red Foxes, Feral Cats, and Introduced Species; Will They Assist Re-Introduction of Greater Bilby and Burrowing Bettong?

Allowing dingoes to return to Sturt National Park in New South Wales, Australia and researching the results may be the key to managing the future of dingoes and many threatened native mammals, University of Sydney researchers believe. "Our approach is purposefully bold because only an experiment on this scale can resolve the long-running debate over whether the dingo can help halt Australia's biodiversity collapse and restore degraded rangeland environments," said Dr. Thomas Newsome from the School of Biological Sciences at the University of Sydney and lead author of an article published February 16, 2015 in Restoration Ecology. Written with Dr. Newsome's colleagues from the University of Sydney and other universities in Australia, and in America, where Dr. Newsome completed a Fulbright Scholarship, the article outlines how the experiment could be undertaken. "Half the world's mammal extinctions over the last two hundred years have occurred in Australia and we are on track for an acceleration of that loss. This experiment would provide robust data to address an issue of national and international significance," said Dr. Newsome. "Our approach is based on dingoes' ability to suppress populations of invasive predators such as red foxes and feral cats that prey on threatened native species. Dingoes can also control numbers of introduced species such as European wild rabbits, feral pigs, and goats or native herbivores such as kangaroos, that in high numbers can contribute to rangeland degradation. "There are major challenges, including convincing livestock producers and local communities to support the experiment, but we currently have almost no understanding of the impact of increased dingo populations over large areas.

Single Nucleotide Mutation Found to Alter Staph aureus ST21 Tropism from Humans to Rabbits; Surprising Result Dictates Paradigm Shift in Thinking about Transmission of Bacterial Diseases between Humans and Animals

A new study suggests that bacteria may be able to jump between host species far more easily than was previously thought. Researchers have discovered that a single genetic mutation in a strain of bacteria infectious to humans enables it to jump species to also become infectious to rabbits. The discovery has major implications for how we assess the risk of bacterial diseases that can pass between humans and animals. It is well known that relatively few mutations are required to support the transmission of viruses, such as influenza, from one species to another. Until now, it was thought that the process was likely to be far more complicated for bacteria. The new study was published online on February 16, 2015 in Nature Genetics. The title of the article was “A Single Natural Nucleotide Mutation Alters Bacterial Pathogen Host Tropism.” Scientists at the Universities of CEU Cardenal Herrera (Spain), and of Glasgow (UK), and of Edinburgh (UK) studied a strain of bacteria called Staphylococcus aureus ST121, which is responsible for widespread epidemics of disease in the global rabbit farming industry. The team looked at the genetic make-up of S. aureus ST121 to work out where the strain originated and the changes that occurred that enabled it to infect rabbits. The scientists found that S. aureus ST121 most likely evolved through a host jump from humans to rabbits approximately 40 years ago, with a genetic mutation at a single site in the bacterial DNA code being the cause for this.