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July 8th, 2018

mTORC1 Protein Complex Serves As Bridge Between Environmental Signals and Metabolic Programs to Influence Fate of Developing T Cells

Like a mentor helping medical students choose between specialties, a protein complex helps shape the destiny of developing T cells, St. Jude Children's Research Hospital scientists have reported. The research was published in the July 6, 2018 issue of Science Immunology and adds to growing evidence of the critical role cell metabolism plays in the immune system. The article is titled “Metabolic Signaling Directs the Reciprocal Lineage Decisions of αβ and γδ T Cells.” The protein complex is mTORC1, which regulates cell growth and metabolism. St. Jude immunologists found that mTORC1 acts in response to cues from in and around developing T cells, and intersects with metabolic activity, to influence whether the cells become conventional or unconventional T cells. To their surprise, researchers found that disrupting mTORC1 led to metabolic changes that favored development of unconventional T cells at the expense of conventional T cells. The research comes amid excitement about harnessing the immune system to fight cancer, tame autoimmune diseases, and combat infectious diseases. "We know that conventional and unconventional T cells are fundamentally different," said corresponding author Hongbo Chi (photo), PhD, a member of the St. Jude Department of Immunology faculty. "They express different cell surface receptors. The cells have different functions. But until now, the mechanism that helps decide their fates has remained largely unknown." T cells play a central role in the adaptive immune system, functioning like elite commando units trained to find and eliminate specific viruses and other threats. T cell development occurs in the thymus after immature (precursor) cells in the bone marrow travel there to mature and specialize.

Antifreeze Proteins in Polar Organisms Inspire Development of Revolutionary Bacteria Cryopreservation Technique

The new technique could radically improve the work to store and transport human tissue. Researchers from the Department of Chemistry and Warwick Medical School have established a way to cryopreserve (or “freeze”) a broad range of bacteria using synthetic reproductions of the natural antifreeze proteins found in polar organisms. The scientists found that adding the protein mimics slows ice crystal growth and stops them from destroying the bacteria cells. The revolutionary method has potential applications within the food industry, organ transportation, and medicine, as well as in laboratory research. Bacteria are used in a vast range of processes including food technology (e.g., in yoghurt and probiotics), pharmaceutical manufacturing (e.g., insulin), and enzyme production (e.g., for washing powders) and they are routinely used in research labs to study infection and the fundamentals of living processes. The traditional approach to preserve bacteria used in nearly every laboratory worldwide is to add glycerol to the bacteria to reduce cold-induced damage during freezing. However, not all the bacteria recover after thawing and the glycerol needs to be removed from the bacteria to enable their growth and usefulness. The Warwick team, led by Professor Matthew I. Gibson, has developed a new method for cryopreservation, inspired by the process by which organisms known as extremophiles, survive in some of the coldest regions on Earth. The group has a particular interest in polar fish species which produce antifreeze proteins. The research team has demonstrated that synthetic polymers which mimic the proteins from these fish are effective in doing the same job. By combining two polymers to slow ice growth during cryopreservation, the researchers were able to recover more bacteria after freezing than by using conventional methods.

July 7th

Preventative HIV Vaccine Candidate Triggers Desired Immune Responses in Humans and Monkeys, and Protects Monkeys from Infection

More than three decades after the identification of the human immunodeficiency virus (HIV), scientists are still working to develop a preventative vaccine that could finally put an end to the epidemic for which there are nearly two million new infections each year. In a new study, published online on July 6, 2016 in The Lancet, a team of researchers led by Beth Israel Deaconess Medical Center's (BIDMC’s) Dan H. Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research, in collaboration with Janssen Vaccines & Prevention and other partners, evaluated a series of preventative HIV vaccine regimens in uninfected human volunteers in five countries. In a similarly designed study, Dr. Barouch and colleagues tested the same vaccine for its ability to protect rhesus monkeys challenged with an HIV-like virus from infection. The findings showed the vaccines induced robust and comparable immune responses in humans and monkeys and protected monkeys against acquisition of infection. "This study demonstrates that the mosaic Ad26/Ad26 plus gp140 vaccine candidate induced robust and comparable immune responses in human and monkeys," said Dr. Barouch, who is also Professor of Medicine at Harvard Medical School. "Moreover, the vaccine provided 67 percent protection against viral challenge in monkeys." The Lancet article is titled “Evaluation of a Mosaic HIV-1 Vaccine in a Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 1/2a Clinical Trial (APPROACH) and in Rhesus Monkeys (NHP 13-19).”

Anti-TNF Drug Offers New Hope for Patients with Incurable and Disabling Hand Condition, Dupuytren's Disease

Researchers at the Kennedy Institute and Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, working with clinicians at NHS Lothian, have found that injection of the anti-TNF drug adalimumab (Humira) into Dupuytren's disease nodules results in the reduction of the cell characteristics responsible for progression of Dupuytren's disease. Based on their laboratory data that tumor necrosis factor (TNF) drives the development of myofibroblasts, the cell type that causes Dupuytren's disease, the research team explored the effect of an anti-TNF drug injected directly into the Dupuytren's nodule tissue. The results so far are very promising. "Our data have shown that a concentrated formulation of adalimumab injected directly into the diseased tissue may be effective in targeting the cells responsible for Dupuytren's disease," said Jagdeep Nanchahal, MD, PhD, University of Oxford Professor of Hand, Plastic, and Reconstructive Surgery, who led the study. "This brings new hope to people who suffer from this disabling condition, who currently have to wait for their situation to be deteriorate, watching their hand lose function until it is bad enough for surgery. And then there's the lengthy recovery ahead, a less than ideal situation to find yourself in." This randomized trial (phase 2a) recruited 28 patients with Dupuytren's disease who were scheduled to have surgery in Edinburgh to remove diseased tissue in their hand. Two weeks prior to surgery they received a single injection of varying doses of the anti-TNF drug, or placebo. The tissue removed during surgery, which is usually discarded, was then analyzed in the laboratory.

July 6th

Biomarkers Discovered for Rare Hypervirulent Klebsiella Bacterium That Can Rapidly Blind or Kill Healthy Young People

Imagine a pathogen that infects completely healthy people and can cause blindness in one day and flesh-eating infections, brain abscesses, and death in just a few days. Now imagine that this pathogen is also resistant to all antibiotics. This is the nightmare scenario that obsesses Thomas A. Russo, MD, Professor of Medicine in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo (UB). Since seeing his first case in Buffalo seven years ago, he has been investigating hypervirulent Klebsiella pneumoniae, a rare, but increasingly common, strain of K. pneumoniae. There is no accurate method for distinguishing between the hypervirulent strain from the classical strain of K. pneumoniae, which is most often seen in the Western hemisphere, is less virulent, and usually causes infections in hospital settings. Now Dr. Russo, who heads the Division of Infectious Diseases in the UB Department of Medicine, and his colleagues have discovered several biomarkers that can accurately identify hypervirulent K. pneumoniae. The research was published online on June 20, 2018 in the Journal of Clinical Microbiology. In a commentary paper the journal published on June 27, 2018, authors from the Fujita Health University School of Medicine in Japan and the University of Pittsburgh School of Medicine noted that the UB research is "a major step forward" in developing a consensus definition of the hypervirulent strain and in designing international studies to reveal more about its epidemiology and clinical presentation. "Presently, there is no commercially available test to accurately distinguish classical and hypervirulent strains," said Dr. Russo. "This research provides a clear roadmap as to how a company can develop such a test for use in clinical laboratories. It's sorely needed." Dr.

Scientists Identify Body’s Microreactors for Innate Immunity

A DNA-sensing enzyme forms droplets that act as tiny bioreactors creating molecules to stimulate innate immunity - the body's first response to infection, University of Texas (UT) Southwestern researchers report. The work, published online on July 5, 2018 in Science, could lead to novel treatments for infections, autoimmune disease, and cancer. A hallmark of all three of those illnesses is the presence of DNA - either foreign or self - in the cell's gel-like interior known as the cytoplasm, said Dr. Zhijian "James" Chen, Professor of Molecular Biology at UT Southwestern, a Howard Hughes Medical Institute Investigator, and senior author of the study. The study's lead author is graduate student Mingjian Du. In 2012, Dr. Chen's laboratory discovered the enzyme cyclic GMP-AMP synthase (cGAS), which acts as a sensor in a cellular alarm system for innate immunity. The body has two immune systems. The first is an inborn, or innate, immune system that guards the body against threats it first encounters. The second is the adaptive immune system that deploys specialized immune cells to eradicate pathogens. The innate immunity sensor cGAS sounds the alarm when it encounters DNA - either from pathogens or from the body's own cells in the case of autoimmune disease - in areas of the cell where that genetic material should not be. Dr. Chen also identified the small molecule cGAMP, which is produced by the enzyme cGAS and functions as a secondary messenger that triggers innate immune responses. The current Science article is titled “DNA-Induced Liquid Phase Condensation of cGAS Activates Innate Immune Signaling.” The current study finds that when cGAS encounters pathogenic DNA, it binds with the DNA to create droplet-size, microreactors that hold together despite the lack of a membrane.

New Model for Predicting Neuroblastoma Outcomes Incorporates Early Developmental Signals

Neuroblastoma, a rare childhood cancer of the sympathetic nervous system, is particularly deadly because it is difficult to detect and thus generally advanced before treatment begins. Scientists know that neuroblastoma develops from embryonic neural crest cells that fail to properly migrate or differentiate, but the details about exactly what causes these cells to go astray have been unclear. Motivated by a desire to better understand the molecular circuitry underlying neuroblastoma and limitations of current methods for predicting disease progression and outcome, researchers from the Kulesa Lab at the Stowers Institute for Medical Research (Kansas City, Missouri) and collaborators at the University of Michigan and Oxford University set out to construct a logic-based model incorporating information about developmental signaling pathways implicated in the disease. The scientists sought to test whether their model could predict disease outcomes more effectively than the current predictive methods, which are based on gene expression information from human patient samples but do not provide much insight about how these molecules interact to participate in disease progression. Using a six-gene input logic model, the team simulated a molecular network of developmental genes and downstream signals that predicted a favorable or unfavorable disease outcome based on the outcome of four cell states related to tumor development - cell differentiation, proliferation, apoptosis, and angiogenesis. The six genes of the model included three receptor tyrosine kinases involved in sympathetic nervous system development and implicated in neuroblastoma - trkA, trkB, and ALK - plus their three ligands.

In “Astonishing” Results, Ancient DNA Testing Solves 100-Year-Old Controversy in Southeast Asian Prehistory

Two competing theories about the human occupation of Southeast Asia have been debunked by ground-breaking analysis of ancient DNA extracted from 8,000 year-old skeletons. Southeast Asia is one of the most genetically diverse regions in the world, but for more than 100 years, scientists have disagreed about which theory of the origins of the population of the area was correct. One theory maintains that the indigenous Hòabìnhian hunter-gatherers who populated Southeast Asia from 44,000 years ago adopted agricultural practices independently, without the input from early farmers from East Asia. Another theory, referred to as the “two-layer model” favors the view that migrating rice farmers from what is now China replaced the indigenous Hòabìnhian hunter-gatherers. Academics from around the world collaborated on new research, just published in the July 6, 2018 issue of Science, which found that neither theory is completely accurate. Their study discovered that present-day Southeast Asian populations derive ancestry from at least four ancient populations. The article is titled “The prehistoric peopling of Southeast Asia.” DNA from human skeletal remains from Malaysia, Thailand, the Philippines, Vietnam, Indonesia, Laos, and Japan dating back as far as 8,000 years ago was extracted for the study (scientists had previously only been successful in sequencing 4,000-year-old samples from the region). The samples also included DNA from Hòabìnhian hunter-gatherers and a Jomon from Japan - a scientific first, revealing a long suspected genetic link between the two populations. In total, 26 ancient human genome sequences were studied by the group and they were compared with modern DNA samples from people living in Southeast Asia today.

Ancient Genome Analyses Reveal Mosaic Pattern of Goat Domestication Thousands of Years Ago

An international team of scientists, led by geneticists from Trinity College Dublin, have sequenced the genomes from ancient goat bones from areas in the Fertile Crescent where goats were first domesticated around 8,500 BC. The results reveal a 10,000-year history of local farmer practices featuring genetic exchange both with the wild and among domesticated herds, and selection by early farmers. This genetic data - including 83 mitochondrial sequences and whole genome data from 51 goats – was published in the July 6, 2018 issue of Science by PhD Researcher in Genetics, Kevin Daly, and colleagues. The article is titled “Ancient Goat Genomes Reveal Mosaic Domestication in the Fertile Crescent.” One of our first domesticates and a source of meat, milk and hides, goats now number almost a billion animals. They have been a partner animal since c. 8,500 BC. The earliest evidence for domestic goats occurs in the Fertile Crescent region of Southwest Asia, where crop farming and animal herding began. Before herding, local hunters targeted wild goats - also known as bezoar - and this local practice eventually became the basis of goat management and livestock keeping. However, reading the past from examining modern genetics is difficult due to thousands of years of migration and mixture. "Just like humans, modern goat ancestry is a tangled web of different ancestral strands. The only way to unravel these and reach reliably into the past is to sequence genomes from actual ancient animals; a kind of molecular time travel," said Professor of Population Genetics and ERC Advanced Investigator at Trinity College Dublin, Dr. Dan Bradley, who led the project.

July 5th

Spiders Use Their Silk to Go Ballooning for Thousands of Miles on Electric Fields

The aerodynamic capabilities of spiders have intrigued scientists for hundreds of years. Charles Darwin himself mused over how hundreds of the creatures managed to alight on the Beagle on a calm day out at sea and later take off from the ship with great speeds on windless day. Scientists have attributed the flying behavior of these wingless arthropods to “ballooning,” where spiders can be carried thousands of miles by releasing trails of silk that propel them up and out on the wind. However, the fact that ballooning has been observed when there is no wind to speak of, when skies are overcast, and even in rainy conditions, raises the question - how do spiders take off with low levels of aerodynamic drag? Biologists from the University of Bristol (UK) believe they have found the answer. "Many spiders balloon using multiple strands of silk that splay out in a fan-like shape, which suggests that there must be a repelling electrostatic force involved," explains lead researcher Dr. Erica Morley, an expert in sensory biophysics. "Current theories fail to predict patterns in spider ballooning using wind alone as the driver. Why is it that some days there are large numbers that take to the air, while other days no spiders will attempt to balloon at all? We wanted to find out whether there were other external forces as well as aerodynamic drag that could trigger ballooning and what sensory system they might use to detect this stimulus."