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Genetic Differences in Trees’ Susceptibility to Mountain Pine Beetle

A University of Montana (UM) researcher has discovered that mountain pine beetles may avoid certain trees within a population they normally would kill due to genetics in the trees. UM Professor Dr. Diana Six made the discovery after studying mature whitebark and lodgepole trees that were the age and size that mountain pine beetle prefer, but had somehow escaped attack during a recent outbreak. After DNA screening, survivor trees were all found to contain a similar genetic makeup that was distinctly different from that of the general population that were mostly susceptible to the beetle. "Our findings suggest that survivorship is genetically based and, thus, heritable," Dr. Six said, "which is what gives us hope." In western North America, whitebark pine, a high elevation keystone species recommended for listing as an endangered species, and lodgepole pine, a widespread ecologically and economically important tree, have experienced extensive mortality in recent climate-driven outbreaks of the mountain pine beetle. "Our results suggest that surviving trees possess a wealth of information that can be used to inform our understanding of the genetic and phenotypic bases for resistance and to develop management approaches that support forest adaptation," Dr. Six said. The study was published July 23, 2018 in Frontiers in Plant Science. The open-access article is titled “Are Survivors Different? Genetic-Based Selection of Trees by Mountain Pine Beetle During a Climate Change-Driven Outbreak in a High-Elevation Pine Forest.”

[Press release] [Frontiers in Plant Science article]

CRISPR Tool Reactivates Silenced FMR1 Gene of Fragile X Syndrome in Human Stem Cells

Using a gene editing tool, researchers successfully reactivated the FMR1 gene — which is silenced in fragile X syndrome patients — in human stem cells. This news was reported on August 16, 2018 in an article in Fragile X News Today written by Diogo Pinto. The open-access scientific article, “Targeted Reactivation of FMR1 Transcription In Fragile X Syndrome Embryonic Stem Cells,” was published online on August 15, 2018 in Frontiers in Molecular Neuroscience. Fragile X syndrome (FXS) is caused by a mutation in the FMR1 gene that results from the addition of three extra nucleotides — the building blocks of DNA — to its sequence. This is called a CGG repeat, which varies in number from 5 to 55 in healthy individuals. The more repeats, the higher the risk of developing the disease. This mutation results in the loss of the fragile X mental retardation protein (FMRP), the protein that is produced by the FMR1 gene. Treatments tested so far attempt to compensate for the loss of the FMRP protein and usually target only one of the protein’s functions. However, they have proven insufficient to treat the disease. Researchers believe one potential explanation for the lack of success in human clinical trials to date is that the different functions played by FMRP in nerve cells and other cell types may be difficult to correct with any treatment targeting only one dysregulated molecular pathway. In the newly reported therapeutic approach, researchers from the University of Michigan and the VA Ann Arbor Healthcare System used the CRISPR/Cas9 gene editing technology to target the CGG repeat that causes the mutation, and reactivates transcription of the silenced FMR1 gene. The CRISPR/Cas9 system is a genome editing tool that can edit parts of the genome by removing, adding, or altering sections of the DNA sequence.

Scientists ID Nearly 200 Interactions Between Tuberculosis Proteins and Human Proteins; These Human Proteins Represent Potential New Targets for TB Treatment and Prevention

Tuberculosis is one of the top ten causes of death worldwide. Nearly 2 million people die every year from this infectious disease, and an estimated 2 billion people are chronically infected. The only vaccine, developed almost 100 years ago, offers limited protection and patients are becoming increasingly resistant to available drugs. Despite this significant impact on humankind, very little is known about how tuberculosis develops and spreads in the body. A group of researchers from the Gladstone Institutes, UC San Francisco (UCSF), and UC Berkeley used a systematic approach to get an entirely new look at the way tuberculosis infects people. Their study, published in the august 16, 2018 issue of Molecular Cell, uncovered interactions between tuberculosis and human proteins that could provide new approaches to combat infection. The article is titled “An Mtb-Human Protein-Protein Interaction Map Identifies a Switch Between Host Anti-Viral and Anti-Bacterial Responses.” "With a better understanding of the mechanisms used by tuberculosis to disrupt our immune response, we could eventually optimize vaccine strategies, as well as explore therapies to supplement antibiotics," said Nevan J. Krogan, PhD, Senior Investigator at the Gladstone Institutes and Director of the Quantitative Biosciences Institute at UCSF. Tuberculosis is a complex disease, given that it's caused by a mycobacterium made up of 4,000 genes, as compared to viruses that generally have 10 or 15 genes. During infection, these genes produce approximately 100 proteins inside human cells. But, until now, scientists knew virtually nothing about what these proteins do in the body. Dr. Krogan, along with his colleague Jeffery S.

Complex Wheat Genome (5X Size of Human Genome) Sequenced in Culmination of 13-Year Effort; DNA Sequence of World’s Most Cultivated Crop Should Contribute to Global Food Security

In the August 17, 2018 issue of Science, the International Wheat Genome Sequencing Consortium (IWGSC) published a detailed description of the genome of bread wheat, the world’s most widely cultivated crop. This work will pave the way for the production of wheat varieties better adapted to climate challenges, with higher yields, enhanced nutritional quality and improved sustainability. The research article – authored by more than 200 scientists from 73 research institutions in 20 countries – presents the reference genome of the bread wheat variety Chinese Spring. The article is titled “Shifting the Limits In Wheat Research and Breeding Using a Fully Annotated Reference Genome.” The DNA sequence ordered along the 21 wheat chromosomes is the highest-quality genome sequence produced to date for wheat. It is the result of 13 years of collaborative international research. A key crop for food security, wheat is the staple food of more than a third of the global human population and accounts for almost 20% of the total calories and protein consumed by humans worldwide, more than any other single food source. It also serves as an important source of vitamins and minerals. To meet future demands of a projected world population of 9.6 billion by 2050, wheat productivity needs to increase by 1.6 per cent each year. In order to preserve biodiversity, water, and nutrient resources, the majority of this increase has to be achieved via crop and trait improvement on land currently cultivated rather than committing new land to cultivation. With the reference genome sequence now completed, breeders have at their disposal new tools to address these challenges.

Congenital Blindness Reversed in Mice by Müller Glia-Driven Regenerative Therapy

Researchers funded by the National Eye Institute (NEI) of the NIH have reversed congenital blindness in mice by changing supportive cells in the retina called Müller glia into rod photoreceptors. The findings advance efforts toward regenerative therapies for blinding diseases such as age-related macular degeneration and retinitis pigmentosa. A report of the findings was published online on August 15, 2018 in Nature. The article is titled “Restoration of Vision After De Novo Genesis of Rod Photoreceptors in Mammalian Retinas.” "This is the first report of scientists reprogramming Müller glia to become functional rod photoreceptors in the mammalian retina," said Thomas N. Greenwell, PhD, NEI Program Director for Retinal Neuroscience. "Rods allow us to see in low light, but they may also help preserve cone photoreceptors, which are important for color vision and high visual acuity. Cones tend to die in later-stage eye diseases. If rods can be regenerated from inside the eye, this might be a strategy for treating diseases of the eye that affect photoreceptors." Photoreceptors are light-sensitive cells in the retina in the back of the eye that signal the brain when activated. In mammals, including mice and humans, photoreceptors fail to regenerate on their own. Like most neurons, once mature, they don't divide. Scientists have long studied the regenerative potential of Müller glia because in other species, such as zebrafish, these cells divide in response to injury and can turn into photoreceptors and other retinal neurons. The zebrafish can thus regain vision after severe retinal injury. In the lab, scientists can coax mammalian Müller glia cells to behave more as they do in the fish. But it requires injuring the tissue.

New Form of Genome Analysis (Polygenic Risk Scoring) May Enable Risk Prediction for Five Common Deadly Diseases, Including Breast Cancer, Type 2 Diabetes, and Coronary Artery Disease

A research team at the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and Harvard Medical School reports a new kind of genome analysis that could identify large fractions of the population who have a much higher risk of developing serious common diseases, including coronary artery disease, breast cancer, atrial fibrillation, inflammatory bowel disease, or type 2 diabetes. These tests, which use information from millions of places in the genome to ascertain risk for five diseases, can flag greater likelihood of developing the potentially fatal conditions well before any symptoms appear. While the study was conducted with data from the UK, it suggests that up to 25 million people in the US may be at more than triple the normal risk for coronary artery disease, and millions more may be at similar elevated risk for the other conditions, based on genetic variation alone. The genomic information could allow physicians to focus particular attention on these individuals, perhaps enabling early interventions to prevent disease. The research raises important questions about how this method, called polygenic risk scoring, should be further developed and used in the medical system. In addition, the authors note that the genetic tests are largely based on information from individuals of European descent, and the results underscore the need for larger studies of other ethnic groups to ensure equity. The study was published online on August 13, 2018 in Nature Genetics and has already received significant attention from the popular press (see links below).

First Study on Physical Properties of Giant Cancer Cells May Inform New Treatments

Polyploidal cancer cells--cells that have more than two copies of each chromosome--are much larger than most other cancer cells, are resistant to chemotherapy and radiation treatments, and are associated with disease relapse. A new study by Brown University researchers is the first to reveal key physical properties of these "giant" cancer cells. The research, published online on August 9, 2018 in Scientific Reports, shows that the giant cells are stiffer and have the ability to move further than other cancer cells, which could help explain why they're associated with more serious disease. The open-access article is titled “Dysregulation in Actin Cytoskeletal Organization Drives Increased Stiffness and Migratory Persistence in Polyploidal Giant Cancer Cells.” "I think these polyploidal giant cancer cells (PGCCs) are the missing link for why tumors become so complex and heterogeneous so quickly," said Dr. Michelle Dawson, an Assistant Professor of Molecular Pharmacology, Physiology and Biotechnology at Brown and the study's corresponding author. "By understanding the physical properties of this weird population of cells we might identify a new way to eliminate them. Patients will benefit from that." Dr. Dawson, who is also an Assistant Professor of Engineering with an appointment in Brown's Center for Biomedical Engineering, worked with graduate student Botai Xuan and two undergraduate students on the study, which focused on a common strain of triple-negative breast cancer, an extremely aggressive and hard-to-eradicate kind of breast cancer. The researchers found that 2-5 percent of cells from this breast cancer strain were PGCCs with four, eight, or sixteen copies of each chromosome, instead of the normal two copies.

$2 Million for Study of Targeted Exosomes to Aid Bone & Tisssue Regeneration

According to an August 13, 2018 UIC press release, University of Illinois at Chicago (UIC) researchers have received approximately $2 million in funding from the National Institutes of Health to develop a better way to regenerate bone or tissues that have been lost to disease or injury. The UIC work will pursue the use of engineered exosomes to aid regeneration. Currently, most treatments rely on the use of growth factors or other chemical agents to stimulate stem cells, which have the ability to grow into any type of cell in the body, to regenerate what has been lost. But this approach has many limitations, including side effects and uncontrolled abnormal growths due to dosing and toxicity, which have caused complications and prevented regulatory organizations from approving the treatments for use in humans. "We need a replacement for growth factor-based interventions so that we can reduce side effects and advance these therapies to the bedside," said Dr. Sriram Ravindran, co-principal investigator of the project. "We need therapies that better mimic the body's natural processes, so the body is better able to tolerate treatment." Bone is the second most transplanted organ in the human body, after blood. Grafting and regeneration procedures are performed by health care providers to treat anything from complex bullet wounds and spinal injuries to gum disease. Dr. Ravindran, research assistant professor of oral biology, and his colleague, Dr. Praveen Gajendrareddy, jointly run a lab at the UIC College of Dentistry that develops biomimetic tools -- those that mimic natural biology -- for tissue regeneration.

Disrupted Nitrogen Metabolism Might Signal Cancer

Nitrogen is a basic building block of all the body's proteins, RNA, and DNA, so cancerous tumors are greedy for this element. Researchers at the Weizmann Institute of Science in Israel, in collaboration with colleagues from the National Cancer Institute (NCI) and elsewhere, have now shown that, in many cancers, the patient's nitrogen metabolism is altered, producing detectable changes in the body fluids and contributing to the emergence of new mutations in cancerous tissue. The study's findings, published online on August 9, 2018 in Cell, may in the future facilitate early detection of cancer and help predict the success of immunotherapy. The article is titled “Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures.” When the body makes use of nitrogen, it generates from the leftovers a nitrogenous waste substance called urea in a chain of biochemical reactions that take place in the liver, which are known as the “urea cycle.” As a result of this cycle, urea is expelled into the bloodstream, and is later excreted from the body in the urine. In previous research, Dr. Ayelet Erez of Weizmann's Biological Regulation Department showed that one of the enzymes in the urea cycle has been inactivated within many cancerous tumors, increasing the availability of nitrogen for the synthesis of an organic substance called pyrimidine, which, in turn, supports RNA and DNA synthesis and cancerous growth. In the new study, conducted with Professor Eytan Ruppin of the NCI and other researchers, Dr. Erez's team identified a number of precisely defined alterations in additional enzymes of the urea cycle, which together increase the availability of nitrogenous compounds for pyrimidine synthesis. These alterations lead to increased pyrimidine levels in the tumor and predispose the cancer to mutations.

Report Highlights Feasibility of Generating DNA Sequence Data in the Developing World

Globally, biodiversity is concentrated around the equator, but the scientific institutions generating DNA sequence data to study that biodiversity tend to be clustered in developed countries toward the poles. However, the rapidly decreasing cost of DNA sequencing has the potential to change this dynamic and create a more equitable global distribution of genetic research. In a review article published online on July 13, 2018 in Applications in Plant Sciences, Dr. Gillian Dean (photo), from the Department of Botany at the University of British Columbia, and colleagues show the feasibility of producing high-quality sequence data at a laboratory in Indonesia. The open-access article is titled “Generating DNA Sequence Data with Limited Resources for Molecular Biology: Lessons from a Barcoding Project in Indonesia.” For many laboratories in the developing world, a lack of funding and practical experience are major hurdles to generating their own DNA sequence data. However, the financial, technical, and logistical burden of producing DNA sequence data has dropped precipitously in recent years. DNA sequencing is increasingly done at centralized "core" facilities dedicated to producing high-quality sequence data from prepared samples at high volume and low cost. This means that laboratories need only do initial processing of tissue to prepare DNA samples to be sent to a sequencing core facility. Molecular techniques like DNA extraction, purification, and PCR, which are necessary to prepare samples for sequencing, are now quite well established, with protocols that are relatively simple using fairly inexpensive reagents (ingredients).

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