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Mismatch Repair Preferentially Targets Genes Rather Than Non-Genic Regions in Arabidopsis

Researchers at the University of Oxford have discovered that a cellular mechanism preferentially protects plant genes from the damaging effects of mutation. Whilst DNA sequence mutation is the fundamental fuel of species evolution, mutations in genes are often harmful. As a form of defense, organisms have evolved repair mechanisms to correct the DNA sequence following mutation. One of these mechanisms, is termed DNA mismatch repair (MMR). It corrects mutations that arise during the replication of the genome during cell division. A new study, published in the January 2018 issue of Genome Research, has shown for the first time that MMR is targeted to particular regions of the genome, and preferentially repairs genes. The article is titled “DNA Mismatch Repair Preferentially Protects Genes from Mutation.” The research was carried out in the Department of Plant Sciences, together with colleagues from Zhejiang University (China) and Lahore University of Management Studies (Pakistan). Led by Oxford's Professor Nicholas Harberd, the team looked at 9,000 mutations accumulated in five generations of an MMR-deficient strain of the model plant species Arabidopsis thaliana, and compared them with mutations arising in an MMR-proficient strain. The study has important implications for human health, and is particularly useful for understanding the changes that occur in cells during the development of the tumors that underlie cancers. MMR-deficiency predisposes cells to become tumorous, presumably because MMR-deficient cells lack the gene protection that reduces the risk of mutation in the genes that normally suppress tumor formation. The team has no plans to expand on these implications, but would welcome interest from anyone keen to follow up the study from a medical science perspective.

Combination of Oncolytic Virus and Checkpoint Inhibitor Shows Treatment Effectiveness in Mouse Models of Triple-Negative Breast Cancer

The Alliance for Cancer Gene Therapy (ACGT), a non-profit based in Stamford, Connecticut, dedicated to funding breakthrough cancer gene therapy treatments, has had its funding pay off with a promising study on breast cancer coming out of The Ottawa Hospital and the University of Ottawa in Ottawa, Canada. The study suggests that a combination of two immunotherapies -- oncolytic viruses and checkpoint inhibitors -- could be much more successful than traditional treatments in fighting breast cancer and possibly other cancers. The study, which used mouse models, was published in the January 3, 2018 issue of Science Translational Medicine and was conducted by ACGT grantee, Dr. John Bell, and his research lab, in conjunction with Dr. Marie-Claude Bourgeois-Daigneault, lead author of the study and postdoctoral fellow in Dr. Bell's research group. The article is titled “Neoadjuvant Oncolytic Virotherapy Before Surgery Sensitizes Triple-Negative Breast Cancer to Immune Checkpoint Therapy.” Cancer immunotherapy has proven to be a powerful tool in fighting cancer and has revolutionized treatment for cancers such as melanoma and leukemia. Unfortunately though, other forms of cancer, and especially solid tumor cancers, have remained resistant. ACGT has a track record of funding innovative, breakthrough cancer treatments and was one of the initial funders for laboratory research and clinical trials of immunotherapy in support of Dr. Carl June's work at the University of Pennsylvania, where Dr. June’s team has been successfully treating relapsed pediatric leukemia with gene therapy. ACGT started funding cancer cell and gene therapies in the early 2000's when it was still deemed “risky” science.

Adaptive Phage Therapeutics & Progress in Treating Deadly Multidrug-Resistant Bacterial Infections

On April 26, 2017, Adaptive Phage Therapeutics, Inc. (APT), a clinical-stage company founded to provide an effective therapeutic response to the global rise of multi-drug resistant (MDR) pathogenic bacteria, announced that a therapeutic approach leveraging bacteriophage (phage), as outlined in 2003 by NIH Emeritus Scientist, Carl R Merril, MD, (Merril, et al, Nature Reviews; Drug Discovery, 2003) had been used by the University of California-San Diego Medical Center to successfully rescue a terminally ill patient (Tom Patterson) infected with multidrug resistant Acinetobacter baumannii (MDRAB). A detailed story on the use of phage therapy to treat MDR pathogenic bacterial infections was published in the December 25, 2017 issue of Time Magazine (http://time.com/5068513/superbugs-are-nearly-impossible-to-fight/). Titled “Superbugs Are Nearly Impossible to Fight. This Last-Resort Medical Treatment Offers Hope” and authored by Alexandra Sifferlin, the Time story outlines the history of phage-based therapies, which actually dates back almost to the time phage were first discovered (just over 100 years ago). That history is fraught with controversy and mixed results, but great progress in molecular biology and, particularly, the very recent success in the treatment of Tom Patterson, have rekindled interest and hope in this approach to therapy to fight deadly MDR bacterial infections. The Time story also describes the very recent phage-based effort to save the life of 25-year-old Mallory Smith, a cystic fibrosis patient who was in critical condition with a drug-resistant Burkholderia cepacia infection. According to Time, after being notified of Mallory’s plight, APT identified a phage that might be able to kill the bacteria and shipped the virus to the University of Pittsburgh hospital where Mallory was being treated.

Differences in “Silent Code” of Nucleotides (Synonymous Codons), Not Amino Acids, Determine Functions of Actin Isoforms, According to Provocative New Study; Results May Point to Global Form of Functional Regulation

Humans possess six forms of the protein actin that perform essential functions in the body. Two in particular, β-actin and γ-actin, are nearly identical, differing only by four amino acids. Yet these near-twin proteins carry out distinct roles. A long-standing question for biologists has been, how is this possible? "It's a mystery that's been debated in the field for the past 40 years," said Anna Kashina (photo), PhD, a Professor of Biochemistry in the University of Pennsylvania School of Veterinary Medicine (Penn Vet). New findings by Dr. Kashina and colleagues have pointed to a surprising answer. The differing functions of these proteins are determined not by their amino acid sequences but by their genetic code. "We like to call it the 'silent code,'" Dr. Kashina said. "Our findings show that the parts of genes that we think of as being silent actually encode very key functional information." The researchers found that these "silent" differences in the nucleotide sequence seem to influence the density of ribosomes, the molecular machines that translate RNA into proteins. Such differences may enable each individual actin form to take on a different role in the cell. Dr. Kashina coauthored the work, published in the journal eLife, with Penn Vet's Pavan Vedula, Satoshi Kurosaka, Nicolae Adrian Leu, Junling Wang, Stephanie Sterling, and Dawei Dong and the National Institutes of Health's Yuri I. Wolf and Svetlana A. Shabalina. The article is titled “Diverse Functions of Homologous Actin Isoforms Are Defined by Their Nucleotide, Rather Than Their Amino Acid Sequence.” Actin is so ubiquitious and essential that it's known as a "housekeeping protein." It's the most abundant protein in most cells, and its different forms play roles during cell migration, muscle contraction, and development.

ArunA Biomedical Launches New Class of Exosome Biologics to Treat Central Nervous System and Neurodegenerative Disorders; Company Rapidly Moving Toward Clinical Development of Cell-Free Biologic Therapy, Plans to Initiate First-in-Human Studies in 2019

On January 3, 2018, ArunA Biomedical announced the official launch of a new class of cell-free exosome biologics to treat central nervous system and neurodegenerative disorders. With an initial focus on an exosome therapeutic for stroke, the company published, on January 3, 2018, results of a study in Translational Stroke Research that found that extracellular vesicles (EVs) derived from human neural stem cells improved tissue and functional recovery in murine thromboembolic stroke models. The open-access article is titled “Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model.” The study was led by Dr. Steven Stice, a Georgia Research Alliance Eminent Scholar endowed chair, Professor and Director of the Regenerative Bioscience Center at The University of Georgia, and who serves as Co-Founder, Chief Executive, and Chief Scientific Officer for ArunA Biomedical. The study was conducted in collaboration with Dr. Nasrul Hoda at Augusta University in Augusta, Georgia. Neural stem cells (NSCs) and mesenchymal stem cells (MSCs) were evaluated for changes in infarct volume as well as sensorimotor function. Results showed that the NSC EVs improved cellular, tissue, and functional outcomes in middle-aged rodents, whereas MSC EVs were less effective. Acute differences in lesion volume following NSC EV treatment were corroborated by MRI in aged rodents. NSC EVs mechanistically increased circulating regulatory T cell numbers, which are known to enhance remyelination in the injured brain. Specifically, neural stem cell EV treatment has a positive effect on motor function as indicated by beam walk, instances of foot faults, and strength evaluated by a hanging wire test.

Cancer Researchers Investigate How Cells Communicate Using Exosomes, with Special Focus on Increased Exosome Production by Glioblastoma Cells After Chemical Stimulation

by Zehui (Lesley) Li. (The following article was authored by Zehui (Lesley) Li (photo), a PhD student in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. Lesley is studying chemical messengers between cells and how they can potentially be used to treat cancer. Lesley is doing her research in the laboratory of William Maltese, PhD, in the Department of Cancer Biology. Lesley's article first appeared in Toledo’s "The Blade" newspaper on December 31, 2017, and is reprinted here with permission. Lesley’s article from The Blade follows here): Cells are the basic structural units that are used to build all of the organs in your body. A surface membrane surrounds each cell, just as your skin surrounds you. The cell membrane controls the entry and exit of different things, including food and specific molecules that can change the rate of cell growth and division. One way that the cell membrane can bring in other molecules is within small bubble-like structures that pinch off and move inside the cell. Such bubbles are called endosomes (inside cell). Once [formed] inside the cell, each endosome can make even smaller bubbles within it. These smaller bubbles are called intraluminal vesicles (ILVs). These ILVs are so small that they can only be seen using a very high-powered microscope. Scientists have now discovered that endosomes can return to the cell surface, where they fuse back with the cell membrane and release small ILV bubbles outside the cell. Once they leave the cell, the tiny bubbles are called exosomes (outside cell). These exosomes float in your body fluid and eventually attach to other cell membranes and enter the new cell. After they move in, molecules inside of the bubbles will be released into the new cell to affect cell growth and other cell activities.

New Work Demonstrates Breakdown of Simplest, But Most Widely Used Version of “Kill the Winner” Model to Explain High Levels of Biodiversity, Presents Way to Restore Model’s Explanatory Power

There is remarkable biodiversity in all but the most extreme ecosystems on Earth. When many species are competing for the same finite resource, a theory called “competitive exclusion” suggests one species will outperform the others and drive them to extinction, limiting biodiversity. But this isn't what is actually observed in nature. Theoretical models of population dynamics have not presented a fully satisfactory explanation for what has come to be known as the “diversity paradox.” Now, researchers at the Carl R. Woese Institute for Genomic Biology at the University of Illinois at Urbana-Champaign have shed new light on this fundamental question in ecology, by improving a popular proposed scenario for diversity known as "Kill the Winner." Dr. Chi Xue and Dr. Nigel Goldenfeld (pictured together here), supported by the NASA Astrobiology Institute for Universal Biology, which Dr. Goldenfeld directs, approached the diversity paradox from the perspective of non-equilibrium statistical mechanics. Dr. Goldenfeld and Dr. Xue developed a stochastic model that accounts for multiple factors observed in ecosystems, including competition among species and simultaneous predation on the competing species. Using bacteria and their host-specific viruses as an example, the researchers showed that as the bacteria evolve defenses against the virus, the virus population also evolves to combat the bacteria. This "arms race" leads to diverse populations of both and to boom-bust cycles when a particular species dominates the ecosystem then collapses--the so-called "Kill the Winner" phenomenon. This coevolutionary arms race is sufficient to yield a possible solution to the diversity paradox.

Epigenetic Changes to CRH Gene Linked to Severity of Suicide Attempts

Researchers have linked genetic changes in the corticotropin-releasing hormone (CRH) gene, which affects the regulation of the body's stress system, to suicide risk and psychiatric illness. The study of epigenetic changes in the body's hormone-based stress system has shown that stress-related changes in the CRH gene are linked to both serious suicide attempts in adults and psychiatric illness in adolescents. The research study, which is a collaboration among researchers at Umeå University, Karolinska Institutet, and Uppsala University in Sweden, was published online on December 18, 2017 in EBioMedicine. The open-access article is titled “Epigenetic Changes in the CRH Gene Are Related to Severity of Suicide Attempt and a General Psychiatric Risk Score in Adolescents.” Previous studies have indicated an overactive stress system in individuals with increased suicide risk. In the current study, researchers report that epigenetic changes in the CRH gene, which are linked to serious suicide attempts in adults, could also be found in adolescents with high risk of psychiatric illness. Recently published research output shows that serious suicide attempts lead to a heavily reduced lifespan with an increased suicide risk and risk of mortality from natural causes, particularly in adolescents. In the last ten years, it has become twice as common for Swedish adolescents between the ages of 10 and 17 to suffer from psychiatric illness. An alarming increase also in young adults can be seen. This is according to a recently published report from the Swedish National Board of Health and Welfare. In the current study described in EBioMedicine, researchers examined 88 individuals who had attempted suicide. The participants were divided into high- and low-risk groups based upon the severity of their suicidal behavior.

Nature’s Smallest Rainbows Created by Specialized Abdominal Scales of Peacock Spider; Finding May Have Application to Wide Array of Fields, from Life Sciences & Biotechnologies to Material Sciences & Engineering

Brightly colored Australian peacock spiders (Maratus spp.) captivate even the most arachnophobic viewers with their flamboyant courtship displays featuring diverse and intricate body colorations, patterns, and movements - all packed into miniature bodies measuring less than 5 mm (~0.2 inches) in size for many species. However, these displays aren't just pretty to look at, they also inspire new ways for humans to produce color in technology. One species of peacock spider - the rainbow peacock spider (Maratus robinsoni) - is particularly impressive, because it showcases an intense rainbow iridescent signal in males' courtship displays to the females. This is the first known instance in nature of males using an entire rainbow of colors to entice females to mate. But how do males make their rainbows? Figuring out the answer was inherently interdisciplinary so Dr. Bor-Kai Hsiung - now a postdoctoral scholar at Scripps Institution of Oceanography at the University of California San Diego - assembled a team that included biologists, physicists, and engineers while he was a PhD student at The University of Akron's (UA) Integrated Bioscience PhD program under the mentorship of Dr. Todd Blackledge and Dr. Matthew Shawkey (now at University of Ghent), and supported by UA's Biomimicry Research and Innovation Center. The team included researchers from the United States - UA, Scripps Institution of Oceanography, California Institute of Technology (Caltech), and University of Nebraska-Lincoln (UNL) - Belgium (University of Gent), Netherlands (University of Groningen), and Australia to discover how rainbow peacock spiders produce this unique iridescent signal.

Lethal Fungus That Causes White-Nose Syndrome in Bats May Have Achilles' Heel; Fungus Lacks DNA Repair Enzyme and Is Vulnerable to UV Light

The fungus that causes white-nose syndrome (WNS), a disease that has ravaged bat populations in North America, may have an Achilles' heel: UV light. WNS has spread steadily for the past decade and is caused by the fungus Pseudogymnoascus destructans, known as P. destructans or Pd. In the course of genomic analyses of P. destructans, a team of scientists from the U.S. Forest Service, U.S. Department of Agriculture, and the University of New Hampshire found that the fungus is highly sensitive to UV light. P. destructans can only infect bats during hibernation because it has a strict temperature growth range of about 39-68 degrees Fahrenheit. However, treating bats for the disease during hibernation is challenging, so any weakness of the fungus may be good news to managers trying to develop treatment strategies. In an open-access article published online on January 2, 2018 in Nature Communications titled "Extreme Sensitivity to Ultra-Violet Light in the Fungal Pathogen Causing White-Nose Syndrome of Bats," the research team suggests that P. destructans is likely a true fungal pathogen of bats that evolved alongside bat species in Europe and Asia for millions of years, allowing Eurasian bats to develop defenses against it. In the course of comparing P. destructans to six closely related non-pathogenic fungi, researchers discovered that P. destructans is unable to repair DNA damage caused by UV light, which could lead to novel treatments for the disease. The study, which was funded by the U.S. Fish and Wildlife Service, is available at: https://www.nature.com/articles/s41467-017-02441-z "This research has tremendous implications for bats and people," said Dr. Tony Ferguson, Director of the Forest Service's Northern Research Station and the Forest Products Laboratory.

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