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Blood Factor (GDF11) Stimulates Secretion of Adiponectin and Induces Calorie-Restriction-Like Phenotype in Aged Mice; Injection of GDF11 Stimulates Neurogenesis and Blood Vessel Remodeling

Aging is a process that affects all functions of the human body, particularly brain function. However, aging can be delayed through lifestyle changes (physical exercise, restricting calorie intake, etc.). Researchers at the Institut Pasteur and CNRS (Centre National de la Recherche Scientifique) have elucidated the properties of a molecule in the blood - GDF11 (image) - whose mechanisms were previously unknown. In a mouse model, they showed that this molecule could mimic the benefits of certain calorie restrictions - dietary regimens that have proven their efficacy in reducing cardiovascular disease, preventing cancer, and increasing neurogenesis in the brain. The results of this research were published in the journal Aging Cell on October 22, 2019. The open-access article is titled “Systemic GDF11 Stimulates the Secretion of Adiponectin and Induces a Calorie Restriction-Like Phenotype in Aged Mice.” Today it is possible to maintain a healthy brain in the long term. For the past 30 years, it has been generally acknowledged that certain diet restrictions such as intermittent fasting can improve cognitive performance and extend life expectancy in several species. It has also been proven that calorie restriction (a reduction in calorie intake of 20% to 30% while preserving nutritional quality) reduces the risk of cardiovascular disease and cancer, while increasing production of new neurons in the brain. In a previous study using mouse models, scientists observed that injecting aged mice with blood from young mice rejuvenated blood vessels in the brain, and consequently improved cerebral blood flow, while increasing neurogenesis and cognition .

White Bellbirds in Amazon Shatter Record for Loudest Bird Call Ever Measured

Researchers reporting in the journal Current Biology, on October 21, 2019, have captured the loudest bird calls yet documented. The calls are the mating songs of male white bellbirds, which live atop mountains in the Amazon region of northern Brazil. The open-access Current Biology article is titled “"Extremely Loud Mating Songs At Close Range In White Bellbirds.” The calls have a sound pressure about three times that of screaming pihas, now the second loudest bird singer that's been documented. In fact, the calls are so loud that the researchers are left to wonder how white bellbird females listen to them at close range without doing permanent damage to their hearing. "While watching white bellbirds, we were lucky enough to see females join males on their display perches," said Jeff Podos, PhD, of the University of Massachusetts, Amherst. "In these cases, we saw that the males sing only their loudest songs. Not only that, they swivel dramatically during these songs, so as to blast the song's final note directly at the females." "We would love to know why females willingly stay so close to males as they sing so loudly," he says. "Maybe they are trying to assess males up close, though at the risk of some damage to their hearing systems." The researchers say it's hard to describe just how loud the call really is because it's tough to make comparisons between sounds heard at different distances. Dr. Podos says that the howls of howler monkeys and bellows of bison are well studied and are both pretty loud. But they are not nearly as loud as the songs of bellbirds. That's especially impressive because of the bellbird's tiny size in comparison to those mammals. Bellbirds weigh only about a quarter of a kilogram.

Promising Treatment for Incurable, Deadly Kidney Disease—Autosomal Dominant Polycystic Kidney Disease (AD-PKD); New Drug Blocks Cyst-Promoting MicroRNA

A potential drug treatment for autosomal dominant polycystic kidney disease (AD-PKD)– a genetic disorder that causes the kidneys to swell with multiple cysts and can eventually lead to organ failure – has shown promising results in animal testing. A study describing the drug’s development and testing was published on September 12, 2019 in Nature Communications (https://www.nature.com/articles/s41467-019-11918-y). (Note: Image shows polycystic kidney at left and normal kidney at right). The study shows an approximately 50 percent reduction in kidney size in afflicted mice following treatment. The drug is now in early clinical trials in human subjects, said Dr. Vishal Patel, Associate Professor of Internal Medicine at the University of Texas (UT) Southwestern Medical Center and senior author of the study. The open-access article is titled “Discovery and Preclinical Evaluation of Anti-miR-17 Oligonucleotide RGLS4326 for the Treatment of Polycystic Kidney Disease.” Autosomal dominant polycystic kidney disease (AD-PKD) affects approximately 12 million people worldwide, with half developing end-stage kidney disease by age 60, according to the study. “Once the kidneys have failed, the only options for survival are dialysis or a kidney transplant,” Dr. Patel said.

Takeda Acquires License for First-in-Class Celiac Disease Therapy from COUR Pharmaceuticals Following Positive Phase 2a Proof-of-Concept Study

On October 22, 2019, Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) and COUR Pharmaceutical Development Company, Inc. (“COUR”) announced that Takeda has acquired an exclusive global license to develop and commercialize the investigational medicine CNP-101/TAK-101, an immune-modifying nanoparticle containing gliadin proteins. Based on COUR’s antigen-specific immune tolerance platform, TAK-101 is a potential first-in-class treatment targeting the aberrant immune response in celiac disease, a serious autoimmune disease where the ingestion of gluten leads to inflammation and damage in the small intestine. Results of a randomized, double-blind, placebo-controlled clinical trial to assess the markers of potential efficacy and safety of the investigational medicine in 34 adults with proven celiac disease was presented on October 22, 2019 as a late-breaking abstract at UEG Week 2019, Barcelona, Spain (https://live.ueg.eu/week/). At inclusion, patients had well-controlled, biopsy-proven celiac disease. After inclusion, they underwent an oral gluten challenge. Based on the study, Takeda exercised its option to acquire the exclusive global license to TAK-101. “While many people living with celiac disease can manage their symptoms by following a gluten-free diet, there are currently no treatment options for those who continue to have symptoms,” said Asit Parikh MD, PhD, Head, Gastroenterology Therapeutic Area Unit at Takeda. “Our collaboration with COUR has shown, for the first time, that it is possible to induce specific immune tolerance to a foreign antigen in autoimmune diseases such as celiac disease.

New Treatment May Reverse Celiac Disease; Novel Nanotechnology Approach May Be Applicable to Other Autoimmune Diseases and Allergies, Including Multiple Sclerosis, Type 1 Diabetes, & Asthma; Takeda Acquires License for First-in-Kind Celiac Disease Therapy

Results of a new phase 2 clinical trial using technology developed at Northwestern Medicine show it is possible to induce immune tolerance to gluten in individuals with celiac disease. The findings may pave the way for treated celiac patients to eventually tolerate gluten in their diet. After treatment with the technology, the patients were able to eat gluten with a substantial reduction in inflammation. The results also show a trend toward protecting patients' small intestine from gluten exposure. The findings were presented as a late-breaking presentation on October 22 at the European Gastroenterology Week 2019 conference in Barcelona, Spain (October 19-23) (https://live.ueg.eu/week/). The technology is a biodegradable nanoparticle containing gluten that “teaches” the immune system that the antigen (allergen) is safe. The nanoparticle acts like a Trojan horse, hiding the allergen in a friendly shell, to convince the immune system not to attack it. Beyond celiac disease, the finding sets the stage for the technology -- a nanoparticle containing the antigen triggering the allergy or autoimmune disease -- to treat a host of other diseases and allergies including multiple sclerosis, type 1 diabetes, peanut allergy, asthma, and more. The technology was developed in the lab of Stephen Miller, PhD, Professor of Microbiology and Immunology at Northwestern University Feinberg School of Medicine, who has spent decades refining the technology. "This is the first demonstration the technology works in patients," said Dr. Miller, the Judy Gugenheim Research Professor of Microbiology and Immunology.

Autism Spectrum Disorder Risk Linked to Insufficient Placental Steroid (ALLO); Single ALLO Injection During Pregnancy Enough to Avert Cerebellar Abnormalities and Aberrant Social Behaviors In Experimental Models

A study in experimental models suggests that allopregnanolone (ALLO), one of many hormones produced by the placenta during pregnancy, is so essential to normal fetal brain development that when provision of that hormone decreases or stops abruptly - as occurs with premature birth - offspring are more likely to develop autism-like behaviors. A Children's National Hospital research team reports the findings Oct. 20, 2019, at the Neuroscience 2019 annual meeting in Chicago (October 19-23) (https://www.sfn.org/meetings/neuroscience-2019). The presentation was titled “"Preterm ASD Risk Linked to Cerebellar White Matter Changes.” "To our knowledge, no other research team has studied how placental allopregnanolone (ALLO) contributes to brain development and long-term behaviors," says Claire-Marie Vacher, PhD, lead author. "Our study finds that targeted loss of ALLO in the womb leads to long-term structural alterations of the cerebellum - a brain region that is essential for motor coordination, balance, and social cognition - and increases the risk of developing autism," Dr. Vacher says. According to the Centers for Disease Control and Prevention, about 1 in 10 infants is born preterm, before 37 weeks gestation; and 1 in 59 children has autism spectrum disorder. In addition to presenting the abstract on Sunday, Anna Penn, MD, PhD, the abstract's senior author, discussed the research with reporters on Monday, October 21, during a Neuroscience 2019 news conference. This Children's National abstract is among 14,000 abstracts submitted for the meeting, the world's largest source of emerging news about brain science and health. ALLO production by the placenta rises in the second trimester of pregnancy, and levels of the neurosteroid peak as fetuses approach full term.

5-Year Funding of $71 Million to Spur Efforts of Trans-Atlantic Collaboration (ACED) of Five Institutions in UK and US to Pursue Earliest Possible Detection of Cancers

Developing radical new strategies and technologies to detect cancer at its earliest stage is the bold ambition of a new trans-atlantic research alliance—the International Alliance for Cancer Early Detection (ACED) -- announced on October 21, 2019 by Cancer Research UK and partners, and to be funded by over £55 million (~$71 million) over the next five years. Early detection is essential to help more people beat cancer – a patient’s chance of surviving his or her disease improves dramatically when cancer is found and treated earlier. Understanding the biology of early cancers and pre-cancerous states will allow doctors to find accurate ways to spot the disease earlier and, where necessary, treat it effectively. It could even enable “precision prevention” – where the disease could be stopped from ever occurring in the first place. UK statistics highlight the major improvements in survival that could be achieved. 5-year survival for six different types of cancer is more than three times higher if the disease is diagnosed at stage one, when the tumor tends to be small and remains localized, compared with survival when diagnosed at stage four, when the cancer tends to be larger and has started to invade surrounding tissue and other organs. Advances in early-detection technologies will help decrease late-stage diagnosis and increase the proportion of people diagnosed at an early and treatable stage, so a future for more patients can be secured. Cancer Research UK is setting out a bold ambition to jump-start this under-explored field of research in a collaboration with teams of scientists from across the UK and the US.

Researchers Quantify Cas9-Caused Off-Target Mutagenesis in Mice; Thoughtful Design of Guide RNAs Can Significantly Limit Off-Target Mutagenesis; Inbred Lines Show Surprising Number of Natural Mutations

Scientists are finding new ways to improve the use of the CRISPR enzyme Cas9 and reduce the chances of off-target mutations in laboratory mice, according to new results from a research collaboration including Lauryl Nutter (photo), PhD, Senior Director, Science and Technology Development at The Centre for Phenogenomics at The Hospital for Sick Children (SickKids) in Toronto, Canada The findings, which help scientists contextualize a common concern related to gene editing and identify new strategies to improve its precision, were presented on October 18, 2019 as a featured plenary abstract at the American Society of Human Genetics (ASHG) 2019 Annual Meeting in Houston (October 15-19). The presentation abstract (https://eventpilotadmin.com/web/page.php?page=IntHtml&project=ASHG19&id=...) is titled “Whole Genome Sequencing Puts Cas9 Off-Target Mutagenesis into the Context Of Genetic Drift.” Dr. Nutter and her collaborators from the multi-institution Knockout Mouse Phenotyping Project (KOMP2) regularly use Cas9 and gene editing to produce lines of laboratory mice with specific mutations. In this work, they often encounter questions about the likelihood of off-target mutagenesis – unintended genetic mutations introduced by the gene-editing process – in their mouse lines. “We wanted to know: to what extent do we need to worry about off-target mutagenesis?” Dr. Nutter explained. By demonstrating the degree of the problem in mice, the researchers hoped to be better able to evaluate it in human cell lines being studied in the laboratory, as well as generate new ways to improve the precision of Cas9-based gene editing.

Cystic Fibrosis Carriers at Increased Risk of Digestive Symptoms

Researchers have found that carriers of the most common genetic variant that causes cystic fibrosis experience some symptoms similar to those of people with cystic fibrosis. These findings were enabled by large-scale genomic data made available just a few years ago. Yu-Chung (Jerry) Lin, BA, MSc, a graduate student at the University of Toronto, presented the research on October 17, 2019 at the American Society of Human Genetics (ASHG) 2019 Annual Meeting in Houston, Texas (October 15-19). The presentation abstract is titled “Defining the Phenotypic Signature of CFTR Mutation Carriers in the UK Biobank.” Cystic fibrosis is a recessive disease caused by variants of the CFTR gene, which means that affected individuals have two such variants. It affects many organs, and symptoms vary from patient to patient. They can include lung function decline, intestinal obstruction, diabetes, and pancreatic dysfunction. The extent of a person’s symptoms can be affected by modifier genes, which do not directly cause cystic fibrosis, but can affect how an individual’s experience of the disease. Researchers have long assumed that carriers, who have one copy of a disease-causing CFTR variant, do not experience any symptoms. However, given the disease’s wide breadth of symptoms, Mr. Lin explained, researchers needed a very large sample size to definitively answer this question. Senior author Lisa Strug, PhD, Associate Director of The Centre for Applied Genomics at The Hospital for Sick Children, explained, “Although many individuals are learning of their CFTR carrier status through family planning or the use of personal genomics companies, researchers have not yet thoroughly investigated whether a phenotype for cystic fibrosis carriers exists.”

Metabolic Dysfunction in Mitochondria & Not Protein Accumulation Is Key Cause of Alzheimer’s Disease, New Study Shows; Common Anti-Diabetes Drug (Metformin) Identified As Potential Treatment

A team of researchers led by Yale-National University of Singapore (NUS) College scientists has found evidence that metabolic dysfunction is a primary cause of Alzheimer’s disease. Alzheimer’s disease is the most common neurodegenerative disease affecting the elderly worldwide, as well as one of the most common causes of dementia. In Singapore, 1 in 10 people aged 60 or above is believed to suffer from dementia. After more than twenty years of research effort worldwide, scientists are still unable to identify the exact causes of Alzheimer’s and no proven treatment is available. Two competing theories are currently proposed to explain the cause of Alzheimer’s: the first is focused on the accumulation of a specific protein, called amyloid-beta protein, in the brain as the primary cause; whilst a second and more recent theory proposes that metabolic dysfunction, specifically a dysfunction of the cell’s energy-producing machinery called mitochondria is responsible. In a new study published online on October 18, 2019 in eLife (https://elifesciences.org/articles/50069), a team led by Assistant Professor of Science (Biochemistry) Jan Gruber, PhD, from Yale-NUS College discovered that metabolic defects occur well before any significant increase in the amount of amyloid-beta protein could be detected. The open-access article is titled "Metabolic Stress Is a Primary Pathogenic Event In Transgenic Caenorhabditis Elegans Expressing Pan-Neuronal Human Amyloid Beta." The research used a tiny worm called Caenorhabditis elegans to identify these changes because this worm shares many similarities at the molecular level with human cells.

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