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January 8th

Appetite Control Depends on Signaling at Primary Cilia in Brain Neurons, UCSF Mouse Study Shows

University of California-San Francisco (UCSF) researchers have discovered that the brain's ability to regulate body weight depends on a novel form of signaling in the brain's "hunger circuit" via antenna-like structures on neurons called primary cilia. Primary cilia are distinct from motile cilia, the finger-like projections that act as a sort of cellular conveyer belt, with functions such as removing debris from the lungs and windpipe. Immotile primary cilia were once thought to be vestigial, like a cellular appendix, but in the past decade, research at UCSF and elsewhere has revealed that these structures play a key role in many forms of hormonal signaling in the body. Now, the new UCSF study, published online on January 8, 2018 in Nature Genetics, shows that primary cilia also play a crucial role in signaling within the brain. The article is titled “Subcellular Localization of MC4R with ADCY3 at Neuronal Primary Cilia Underlies a Common Pathway for Genetic Predisposition to Obesity.” Neuroscientists are accustomed to thinking of brain signaling in terms of direct chemical or electrical communication among neurons at sites called synapses, but the new findings reveal that chemical signaling at primary cilia may also play an important, and previously overlooked role. In addition, the findings suggest potential new therapeutic approaches to the growing global obesity epidemic, the researchers say. "We're building a unified understanding of the human genetics of obesity," said senior author Christian Vaisse, MD, PhD, a professor in the Diabetes Center at UCSF and a member of the UCSF Institute for Human Genetics.

Study Reveals Reversibility of Friedreich’s Ataxia in Novel Mouse Model

Friedreich’s ataxia is an inherited disease that causes damage to the nervous system and a loss of coordination that typically progresses to muscle weakness. It can begin causing symptoms in childhood or early adulthood and, over time, it can also lead to vision loss and diabetes. Scientists seeking a better understanding of the disease have tried for years to replicate the disease’s symptoms and progression in laboratory mice, but until recently have been largely unsuccessful. Now, a team of UCLA researchers has recreated aspects of Friedreich’s ataxia in mice and shown that many early symptoms of the disease are completely reversible when the genetic defect linked to the ataxia is reversed. The findings were published online on December 19, 2017 in eLife. The open-access article is titled “Inducible and Reversible Phenotypes in a Novel Mouse Model of Friedreich’s Ataxia.” “Remarkably, most of the dysfunction we were seeing in the mice was reversible even after the mice showed substantial neurologic dysfunction,” said Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics, a UCLA Professor of Neurology and Psychiatry, and the study’s senior author. “We were very surprised by the extent to which the mice improved.” The results, however, need to be replicated in humans before researchers know whether they can lead to new therapeutics for people with Friedreich’s ataxia. Friedreich’s ataxia is known to be caused by a genetic mutation in a gene called FXN. The mutation leads to reduced levels of frataxin, the protein encoded by FXN. Although doctors can manage some of the symptoms, there are no treatments for the disease.

January 7th

Penn Study on Super-Silenced DNA Hints at New Ways to Reprogram Cells

Newly described stretches of super-silenced DNA reveal a fresh approach to reprogram cell identity to use in regenerative medicine studies and one day in the clinic, according to a study published in the December 21, 2017 issue of Molecular Cell by investigators from the Perelman School of Medicine at the University of Pennsylvania. The study is titled “Genomic and Proteomic Resolution of Heterochromatin and Its Restriction of Alternate Fate Genes.” "In the past, most labs, including my own, used gene activators to turn on a new program to change the identity in a given cell," said senior author Ken Zaret, PhD, Director of the Penn Institute for Regenerative Medicine and a Professor of Cell and Developmental Biology. "Our study shows that in some cases we will need to disassemble a cell's gene repression machinery to activate important genes to reprogram a cell's identity." The team attempted to reprogram skin cells to make new liver cells. Conversions of one cell type to another usually have low efficiencies, and this study identifies one reason why. The long-term goal of this preclinical research is to be able to replenish diseased liver tissue with healthy tissue derived from a different tissue, such as skin cells, from the same individual in a process called direct-cell reprogramming. The Zaret lab untangled an extreme form of gene silencing, opening up regions of tightly wound DNA that is difficult for activators to reach to turn on certain genes. The researchers found the regions by characterizing an increase in chemical cross-linking due to DNA being more compacted in the scaffolding of repressed regions of chromosomes. "Think of a piece of fishing line that has been used for a while, with several knots along its length," Dr. Zaret said.

Worm Species Lost 7,000 Genes After Evolving to Fertilize Itself; Genes for Sperm Competition Proteins Among Those Lost

Reproduction in most animal species requires breeding between two individuals. But some worms have evolved the ability to go it alone. In these species, a single individual can breed with itself to produce offspring. A new University of Maryland (UMD)-led study found that gaining this ability, known as "selfing," may have caused a worm species to lose a quarter of its genome, including genes that give male sperm a competitive edge during mating. "Our results suggest that genes that are essential for tens of millions of years can suddenly become useless or liabilities, even, when the sex system changes," said Eric Haag, PhD, a Professor of Biology at UMD and lead investigator of the study, which was published in the January 5, 2018 issue of Science. The article is titled “Rapid Genome Shrinkage in a Self-Fertile Nematode Reveals Sperm Competition Proteins.” A million years ago, a species of tiny worms called Caenorhabditis briggsae evolved the ability to breed via selfing. As a result, most C. briggsae are hermaphrodites with both male and female sex organs. Dr. Haag's group, which focuses on the evolution of sex, has long studied C. briggsae because of their unusual reproductive behavior. To study how selfing shaped the evolution of C. briggsae, Erich Schwarz, PhD, an Assistant Research Professor of Molecular Biology and Genetics at Cornell University and co-corresponding author of the study, sequenced the genome of Caenorhabditis nigoni, the closest relative of C. briggsae. C. nigoni always reproduce by mating with other individuals, or outcrossing. By comparing the genomes of the two species, the researchers found that the selfing C. briggsae worms had 7,000 fewer genes than C. nigoni. Over time, C. briggsae lost approximately a quarter of its genome.

Gene Therapy Restores Normal Blood Glucose Levels in Mice with Type 1 Diabetes

Type 1 diabetes is a chronic disease in which the immune system attacks and destroys insulin-producing beta cells in the pancreas, resulting in high blood levels of glucose. A study published in the January 4, 2018 of Cell Stem Cell demonstrates that a gene therapy approach can lead to the long-term survival of functional beta cells, as well as normal blood glucose levels for an extended period of time in mice with diabetes. The researchers used an adeno-associated viral (AAV) vector to deliver to the mouse pancreas two proteins, Pdx1 and MafA, which reprogrammed plentiful alpha cells into functional, insulin-producing beta cells. The article is titled "Endogenous Reprogramming of Alpha Cells into Beta Cells, Induced by Viral Gene Therapy, Reverses Autoimmune Diabetes." "This study is essentially the first description of a clinically translatable, simple single intervention in autoimmune diabetes that leads to normal blood sugars, and importantly with no immunosuppression," says senior study author George Gittes, MD, of the University of Pittsburgh School of Medicine. "A clinical trial in both type 1 and type 2 diabetics in the immediate foreseeable future is quite realistic, given the impressive nature of the reversal of the diabetes, along with the feasibility in patients to do AAV gene therapy." Approximately 9% of the world's adult population has diabetes, which can cause serious health problems such as heart disease, nerve damage, eye problems, and kidney disease. One fundamental goal of diabetes treatment is to preserve and restore functional beta cells, thereby replenishing levels of a hormone called insulin, which moves blood glucose into cells to fuel their energy needs.

January 5th

IV-Delivered Healing Exosomes Derived from Mesenchymal Stem Cells Specifically Target Healing M2-Type Macrophages in a Rat Model Spinal Cord Injury

Scientists at the Yale University School of Medicine have shown that, in a rat model of spinal cord injury (SCI), intravenously delivered exosomes from bone-marrow-derived mesenchymal stem cells (MSCs) rapidly associate specifically with M2-type healing macrophages at the site of the SCI, but not in the uninjured spinal cord. The researchers believe that their findings support the idea that such extracellular vesicles, released by MSCs, may mediate at least some of the therapeutic healing effects of IV MSC administration. The new work follows on a 2015 study (in Experimental Neurology), by members of the Yale group, that showed that IV infusion of bone marrow-derived MSCs improved functional and anatomical recovery after contusive SCI in the non-immunosuppressed rat, although the MSCs themselves were not detected at the spinal cord injury (SCI) site (http://www.sciencedirect.com/science/article/pii/S0014488615000679). The new work was published on January 2, 2018 in PLOS ONE. The open-access article is titled “Intravenously Delivered Mesenchymal Stem Cell-Derived Exosomes Target M2-Type Macrophages in the Injured Spinal Cord.” The authors also reported, in their new study, that the MSC exosomes were also detected in the spleen, which was notably reduced in weight in the rats with SCI. The researchers noted that further work is need to needed to determine whether IV exosomes fully replicate the therapeutic actions of MSCs on SCI recovery, as well as to elucidate the possible role of the spleen in SCI recovery. The authors of this work are Karen L. Lankford, Edgar J. Arroyo, Katarzyna Nazimek, Krysztof Bryniarski, Philip W. Askenase, and Jeffrey D. Kocsis, all affiliated with the Yale University School of Medicine.

Cicada Symbiotic Complexes of Bacteria Are Different from Any Known Organism

University of Montana (UM) researchers have made a discovery at the cellular level to help understand the basic processes of all life on our planet - this time within the unusual bacteria that has lived inside cicada insects since dinosaurs roamed Earth. During the past 70 million years, the bacteria underwent extreme adaptations to live within the insects' bodies, losing between an estimated 95 to 97 percent of their genes and resulting in some of the smallest genomes known to any organisms. In the process, they lost the ability to live anywhere outside of cicadas. "Cicada symbiotic complexes are very different from any other known organism," said Matt Campbell, a UM graduate student who studies cicadas in UM Biology Associate Professor John McCutcheon's lab, based in the Division of Biological Sciences. Many insects live in very close associations with symbiotic bacteria. These bacterial symbioses are critically important for insects that consume only one type of food that is missing some essential nutrients. Examples include blood-feeding lice, as well as insects that feed on plant sap - aphids, leafhoppers, and cicadas. The UM research has shown that cicadas' symbiotic bacteria produce amino acids and vitamins that their insect hosts require to grow and reproduce. During three field seasons studying a South American cicada, UM postdoctoral researcher Dr. Piotr Lukasik found that many of the species' single symbiotic bacterium evolved into complexes of several different types of bacterium in the same cicada. "Through that process, individual bacteria have lost many genes and now depend on each other because every type contains unique, essential genes," Dr. Lukasik said.

Treeshrews Defy Evolutionary Rules

A new study has exposed the common treeshrew, a small and skittish mammal that inhabits the tropical forests of Southeast Asia, as an ecogeographical rule breaker. According to the study, published online on January 4, 2017 in Ecology and Evolution, Tupaia glis, the common treeshrew, defies two widely tested rules that describe patterns of geographical variation within species: the “island rule” and “Bergmann's rule.” The open-access article is titled “Rule Reversal: Ecogeographical Patterns of Body Size Variation in the Common Treeshrew (Mammalia, Scandentia).” The island rule predicts that populations of small mammals evolve larger body size on islands than on the mainland, whereas island-bound large mammals evolve smaller body size than their mainland counterparts. Bergmann's rule holds that populations of a species in colder climates, generally located at higher latitudes, have larger body sizes than populations in warmer climates, which are usually at lower latitudes. In order to determine treeshrew body size from populations on the Malay Peninsula and 13 offshore islands, the researchers measured 260 specimens collected over the past 122 years and housed in 6 natural history museums in Europe and North America. The researchers tested multiple variables, analyzing how island size, distance from the mainland, maximum sea depth between the mainland and the islands, and latitude relate to body size in the treeshrew populations. They found that the island rule and Bergmann's rule, which are rarely tested together, do not apply to common treeshrews. The study revealed no size difference between mainland and island populations. It also revealed that treeshrews invert Bergmann's rule: individuals from lower latitudes tended to be larger than those located at higher latitudes.

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.

January 4th

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.