Dermatologist and BioQuick News Science & Medicine Advisory Board Member (http://www.bioquicknews.com/node/34) Charles Halasz (photo), M.D., has had an article published online on March 9, 2017 in the Journal of the American Academy of Dermatology. The article is titled “Calciphylaxis: Comparison of Radiologic Imaging and Histopathology.” Dr. Halasz, Associate Professor of Dermatology at Columbia University, New York, and colleagues, sought to investigate whether radiologic imaging might offer any benefit over histopathology in the diagnosis of calciphylaxis. The current gold standard for diagnosis of calciphylaxis is a skin biopsy specimen demonstrating calcification of small-caliber arteries or arterioles. Calciphylaxis, or calcific uremic arteriolopathy (CUA), is a syndrome of calcification of small arteriolar blood vessels, with blood clots, and skin necrosis (https://en.wikipedia.org/wiki/Calciphylaxis). It is seen mostly in patients with stage 5 chronic kidney disease, but can occur in the absence of kidney failure. It results in chronic non-healing wounds and is often fatal. Here, the physicians sought to compare diameters of calcified vessels seen in skin biopsy specimens and radiology images of patients with calciphylaxis. They conducted a retrospective study of patients, with known calciphylaxis from 2009 to 2016 at a community hospital, who had both skin biopsy specimens and radiology images taken as part of their routine care. Vascular calcification was compared in skin biopsy specimens and radiology images. Seven patients were identified. Small-vessel calcification as fine as 0.1 to 0.3 mm was identified on plain films in 3 patients; 0.1 to 0.2 mm by mammography in 3 patients, and 0.1 to 0.2 mm by computed tomography imaging in 1 patient, nearly as fine a resolution as on histopathology.
Tuberculosis (TB), once better known as consumption for the way its victims wasted away, has a long and deadly history, with estimates indicating it may have killed more people than any other bacterial pathogen. Studies have discovered evidence of TB’s human impact going back to as early as 8,000 BCE, and estimates suggest that it has killed a billion people over the past two centuries. Now, a group of scientists from Arizona, Texas, and Washington, D.C. has teamed up to develop the first rapid blood test to diagnose and quantitate the severity of active TB cases. Led by Tony Hu (photo), Ph.D., a researcher at Arizona State University's Biodesign Institute, eight research groups, including the Houston Methodist Research Institute and scientists at the NIH, are harnessing the new field of nanomedicine to improve worldwide TB control. "In the current frontlines of TB testing, coughed-up sputum, blood culture tests, invasive lung and lymph biopsies, or spinal taps are the only way to diagnose TB," said Dr. Hu, a scientist in the Biodesign Institute's Virginia G. Piper Center for Personalized Diagnostics. "The results can give false negatives, and these tests are further constrained because they can take days to weeks to get the results." Despite $6.6 billion spent for international TB care and prevention efforts, TB remains a major risk to human health, particularly for the developing world and people with HIV infections. Making matters worse, TB bacteria can lurk dormant in a person's lung tissue, often for decades, before spontaneously producing full-blown TB disease that can then spread to others. Currently, the World Health Organization (WHO) estimates that up to one-third of the world's population may have such dormant TB infections.
Scientists at The Rockefeller University have mapped the three-dimensional structure for one of the more notorious disease-causing molecules in the human body: the protein responsible for the genetic disorder cystic fibrosis. In research described in the March 23, 2017 issue of Cell, the researchers report that the human structure is almost identical to one they have determined previously for the zebrafish version of the protein. The Cell article is titled “Molecular Structure of the Human CFTR Ion Channel.” “With these detailed new reconstructions, we can begin to understand how this protein functions normally, and how errors within it cause cystic fibrosis,” says Jue Chen, Ph.D., William E. Ford Professor at Rockefeller. “We now know that the conclusions we drew from our previous work in zebrafish also apply to us.” Cystic fibrosis arises from mutations in a single gene, which encodes a protein that forms a channel through which chloride ions pass in and out of cells. Errors in this protein, called the cystic fibrosis transmembrane conductance regulator (CFTR), can lead to the accumulation of thick, sticky mucus. The buildup of mucus has the deadliest effects in the lungs, where it can cause potentially fatal breathing problems or respiratory infections. Although cystic fibrosis is a human disorder, many animals also express CFTR. When the human protein proved difficult to work with in the lab, Dr. Chen and her colleagues instead turned to the more-cooperative zebrafish version. Among other things, they used it to map the location of disease-causing mutations—findings that can now be applied to studying how the faulty human protein can spark disease.
Researchers have identified more than 100 genes important for memory in people. The study is the first to identify correlations between gene data and brain activity during memory processing, providing a new window into human memory. "This is very exciting because the identification of these gene-to-behavior relationships opens up new research avenues for testing the role of these genes in specific aspects of memory function and dysfunction," says Genevieve Konopka, Ph.D., of the University of Texas (UT) Southwestern, who is presented this new work in San Francisco on March 26, 2017 at the Cognitive Neuroscience Society (CNS) annual conference. "It means we are closer to understanding the molecular mechanisms supporting human memory and thus will be able to use this information someday to assist with all kinds of memory issues." The study is part of the nascent but growing field of "imaging genetics," which aims to relate genetic variation to variation in brain anatomy and function. "Genes shape the anatomy and functional organization of the brain, and these structural and functional characteristics of the brain give rise to the observable behaviors," says Evelina Fedorenko, Ph.D., of Harvard Medical School and Massachusetts General Hospital, who is chairing the symposium on imaging genetics at the CNS conference. While past work has aimed to connect behavior to genes, researchers have lacked neural markers, which can provide a powerful bridge between the two. "Probing the genes-brain relationship is likely to yield a rich understanding of the human cognitive and neural architecture, including insights into human uniqueness in the animal kingdom," says Dr. Fedorenko. Dr. Konopka and Dr.
The annual meeting of the International Society for Extracellular Vesicles (ISEV 2017) (https://isev.site-ym.com/), will take place from May 17-21 in Toronto, Canada, and will offer an unparalleled opportunity to network with, and learn from, the preeminent leaders in extracellular vesicle (EV) research. To register for this meeting, please click here (https://isev.site-ym.com/page/ISEV2017Registration). The scope and quality of the anticipated scientific exchange make ISEV 2017 the largest and the premier meeting in EV research in the world. This event features five days of the best in vesicle science covering all aspects of basic, clinical, and translational research. The research theme includes diverse areas of science encompassing rare and neglected diseases, infectious disease, coagulation, cancer, neuroscience, cardiovascular studies, immunology, regenerative medicine, virology, parasitology, and more. The overall theme of ISEV 2017 is “Diversity of EV Composition and Function in Disease Diagnosis and Therapeutics.” Amidst growing interest in the promise of EVs in disease detection and treatment, ISEV 2017 will bring scientists and clinicians in medical and biotechnology communities together to translate their research. No other meeting in the world offers the scope, participation level, and thematic focus of ISEV 2017 concentrating and cross-pollinating scientific investigations in the field of disease biomarkers and therapeutic tools by disseminating cutting-edge developments in EV research. Among the plenary speakers scheduled to address the meeting are Clotilde Thery, Ph.D. (Research Director, Institut Curie), Philip Stahl, Ph.D. (Professor Emeritus of Cell Biology and Physiology, Washington University School of Medicine), Thomas Thum M.D., Ph.D. (Professor of Cardiology, Imperial College-London), Jeff Wrana, Ph.D.
A team spanning Baylor College of Medicine, Rice University, Texas Children's Hospital, and the Broad Institute of MIT and Harvard has developed a new way to sequence genomes, which can assemble the genome of an organism, entirely from scratch, dramatically cheaper and faster. While there is much excitement about the so-called "$1000 genome" in medicine, when a doctor orders the DNA sequence of a patient, the test merely compares fragments of DNA from the patient to a reference genome. The task of generating a reference genome from scratch is an entirely different matter; for instance, the original human genome project took 10 years and cost $4 billion. The ability to quickly and easily generate a reference genome from scratch would open the door to creating reference genomes for everything from patients to tumors to all species on earth. In an article published online on March 23, 2017 in Science, the multi-institutional team reports a method -- called 3D genome assembly -- that can create a human reference genome, entirely from scratch, for less than $10,000. The article is titled “De novo Assembly of the Aedes aegypti Genome Using Hi-C Yields Chromosome-Length Scaffolds.” To illustrate the power of 3D genome assembly, the researchers have assembled the 1.2 billion letter genome of the Aedes aegypti mosquito, which carries the Zika virus, producing the first end-to-end assembly of each of its three chromosomes. The new genome will enable scientists to better combat the Zika outbreak by identifying vulnerabilities in the mosquito that the virus uses to spread. The human genome is a sequence of 6 billion chemical letters, called base-pairs, divided up among 23 pairs of chromosomes.
Science commentary]Scientists have long believed that the central amygdala, a structure located deep within the brain, is linked with fear and responses to unpleasant events. However, a team of MIT neuroscientists has now discovered a circuit in this structure that responds to rewarding events. In a study of mice, activating this circuit with certain stimuli made the animals seek those stimuli further. The researchers also found a circuit that controls responses to fearful events, but most of the neurons in the central amygdala are involved in the reward circuit, they report. “It’s surprising that positive-behavior-promoting subsets are so abundant, which is contrary to what many people in the field have been thinking,” says Susumu Tonegawa, Ph.D., the Picower Professor of Biology and Neuroscience and director of the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory. Dr. Tonegawa, who won the Nobel Prize for Physiology or Medicine in 1987 for his discovery of the genetic mechanism that produces antibody diversity is the senior author of the study, which appears in the March 22, 2017 issue of Neuron. The paper’s lead authors are graduate students Joshua Kim and Xiangyu Zhang. The article is titled “Basolateral to Central Amygdala Neural Circuits for Appetitive Behaviors.” The paper builds on a study published last year in which Tonegawa’s lab identified two distinct populations of neurons in a different part of the amygdala, known as the basolateral amygdala (BLA). These two populations are genetically programmed to encode either fearful or happy memories.
How do mammals keep two biologically crucial metabolites in balance during times when they are feeding, sleeping, and fasting? The answer may require rewriting some textbooks. In a study published online on March 17, 2017 in Science, University of Texas (UT) Southwestern Medical Center researchers report that fat cells “have the liver’s back,” so to speak, to maintain tight regulation of glucose (blood sugar) and uridine, a metabolite the body uses in a range of fundamental processes such as building RNA molecules, properly making proteins, and storing glucose as energy reserves. The article is titled “An Adipo-Biliary-Uridine Axis That Regulates Energy Homeostasis.” The scientists’ study may have implications for several diseases, including diabetes, cancer, and neurological disorders. Metabolites are substances produced by a metabolic process, such as glucose generated in the metabolism of complex sugars and starches, or amino acids used in the biosynthesis of proteins. “Like glucose, every cell in the body needs uridine to stay alive. Glucose is needed for energy, particularly in the brain’s neurons. Uridine is a basic building block for a lot of things inside the cell,” said Dr. Philipp Scherer, senior author of the study and Director of UT Southwestern’s Touchstone Center for Diabetes Research. “Biology textbooks indicate that the liver produces uridine for the circulatory system,” said Dr. Scherer, also Professor of Internal Medicine and Cell Biology. “But what we found is that the liver serves as the primary producer of this metabolite only in the fed state. In the fasted state, the body’s fat cells take over the production of uridine.” Basically, this method of uridine production can be viewed as a division of labor.
The parasite that causes deadly sleeping sickness has its own biological clock that makes it more vulnerable to medications during the afternoon, according to international research that may help improve treatments for one of Africa’s most lethal diseases. The finding, from the Peter O’Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (UTSWMC), could be especially beneficial for patients whose bodies can’t handle side effects of toxic treatments used to eradicate the parasite. By knowing the optimal time to administer these medications – which can be fatal – doctors hope to reduce the duration and dosage of the treatment and save more lives. “This research has opened a door,” said Dr. Filipa Rijo-Ferreira, first author of the study from the O’Donnell Brain Institute. “If the same therapeutic effect can be obtained with a lower dose, then it may be possible to reduce the mortality associated with the treatment.” Establishing that parasites have their own internal clock is a key step in finding new ways to treat a variety of parasitic conditions, from sleeping sickness to malaria. While many of these diseases are often not deadly, sleeping sickness has been among the most lethal. The condition – known formally as African trypanosomiasis – is transmitted through the bite of the tsetse fly and threatens tens of millions of people in sub-Saharan African countries. After entering the body, the parasite causes such symptoms as inverted sleeping cycles, fever, muscle weakness, and itching. It eventually invades the central nervous system and, depending on its type, can kill its host in anywhere from a few months to several years. Control efforts have significantly reduced the number of cases over the last decade.
In the era of genome sequencing, it's time to update the old "bench-to-bedside" shorthand for how basic research discoveries inform clinical practice, researchers from The Jackson Laboratory (JAX), the National Human Genome Research Institute (NHGRI), and institutions across the U.S. declare in a Leading Edge commentary published in the March 23, 2017 issue of Cell. The article is titled “Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research.” "Interactions between basic and clinical researchers should be more like a 'virtuous cycle' of bench to bedside and back again," says JAX Professor Carol Bult, Ph.D., senior author of the commentary. "New technologies to determine the function of genetic variants, together with new ways to share data, mean it's now possible for basic and clinical scientists to build upon each other's work. The goal is to accelerate insights into the genetic causes of disease and the development of new treatments." Genome sequencing technologies are generating massive quantities of patient data, revealing many new genetic variants. The challenge, says commentary first author Teri Manolio, M.D., Ph.D., Director of the NHGRI Division of Genomic Medicine, "is in mining all these data for genes and variants of high clinical relevance." In April 2016, NHGRI convened a meeting of leading researchers from 26 institutions to explore ways to build better collaborations between basic scientists and clinical genomicists, in order to link genetic variants with disease causation. The Cell commentary outlines the group's recommendations, which include promoting data sharing and prioritizing clinically relevant genes for functional studies.