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July 5th, 2018

Natural Killer (NK) Cell Recruitment and Activation in Viral Infection Requires Interaction of Three Cell Types in Lymph Node

One of the most important cell types for controlling certain viral infections are natural killer (NK) cells. As part of the innate and rapid immune response, NK-cell recruitment and activation was thought to be a straightforward process. New research, however, shows that NK-cell recruitment and activation requires a rather carefully choreographed interaction of three cell types in the headquarters of the slower adaptive immune-activation: the lymph node. In a new paper published in the July 3, 2018 issue of Cell Reports, Luis J. Sigal, PhD, Professor Microbiology and Immunology at Jefferson (Philadelphia University + Thomas Jefferson University) and colleagues show that after a mousepox infection in the skin of mice, sentinel immune cells called dendritic cells become infected and rapidly migrate to the draining lymph node carrying the virus along. Within the first 24 hours after the initial infection, these dendritic cells perform at least two tasks in the draining lymph node. First, they produce chemokines that specifically attract inflammatory monocytes to the draining lymph node. Second, the dendritic cells stimulate the few NK cells already in the draining lymph node to produce a cytokine known as interferon gamma that stimulates the recently arrived monocytes to produce other chemokines that attract reinforcements in the form of larger numbers protective NK cells to the draining lymph node. The work unveils a cascade of events whereby three types of innate immune cell collaborate to recruit protective NK cells, which are essential for resistance to mousepox. "Although we knew that that cytokines and chemokines are important for NK-cell recruitment to infected tissues," said Dr.

Precision Genomics Approach May Point Way to Mutations Associated with Accelerated Aging; Mayo Researchers Analyze DNA of Individuals with Short Telomere Syndromes

Mayo Clinic researchers are using precision genomics to search for undiscovered, inheritable genetic mutations that cause accelerated aging. In an article published in the July 2018 issue of Mayo Clinic Proceedings, researchers describe their study assessing 17 patients with short telomere syndromes -- rare conditions that result in premature DNA and cellular deterioration. The ability to pinpoint the genetic abnormalities associated with short telomere syndromes is key to finding better ways to screen, diagnose, and treat patients. The article is titled “Short Telomere Syndromes in Clinical Practice: Bridging Bench and Bedside.” "We're using precision genomics like a heat-seeking missile," says Mrinal Patnaik, MBBS, a Mayo Clinic hematologist and clinical researcher. "Not to destroy, but to zero in on genetic mutations that may be linked with short telomere and other inherited bone marrow failure syndromes, providing unique insights into their disease biology." Mayo Clinic is one of the few medical institutions in the world committed to building the necessary expertise in telomere biology, combined with access to a dedicated clinic for such unique patients. This effort has enabled the researchers to undertake the study. Telomeres are DNA-protein structures that protect the ends of chromosomes, similar to plastic tips at the ends of shoelaces. As people age, telomeres naturally break down and become shorter during the process of DNA replication. This process happens faster in parts of the body with higher cell turnover, such as the skin, hair, bone marrow, liver, lungs, and immune system. Scientists hypothesize that this is why certain parts of the body tend to show visible signs of aging, such as hair turning gray and skin becoming wrinkled.

Compound in Plastics May Exacerbate Inflammatory Bowel Disease (IBD), Animal Study Suggests

A recent study in a preclinical model of inflammatory bowel disease (IBD) shows that dietary exposure to bisphenol-A, or BPA, found in polycarbonate plastics and epoxy resins, can increase mortality and worsen its symptoms. Dr. Clint Allred, a Texas A&M AgriLife researcher in the Nutrition and Food Science Department at Texas A&M University in College Station, led a study published online on June 6, 2018 in the Experimental Biology and Medicine journal. The article is titled “Bisphenol-A Alters Microbiota Metabolites Derived From Aromatic Amino Acids And Worsens Disease Activity During Colitis.” The full text can be viewed online at https://tinyurl.com/IBDresearchBPA. "This is the first study to show that BPA can negatively impact gut microbial amino acid metabolism in a way that has been associated with irritable bowel disease," said Jennifer DeLuca, a graduate student in the Nutrition and Food Science Department and first author for the study. Also participating on the study were Dr. Kimberly Allred, also with the Nutrition and Food Science Department, and Rami Menon, a chemical engineer in the Department of Chemical Engineering at Texas A&M. IBD is a complex collection of diseases that include ulcerative colitis and Crohn's disease. There is chronic inflammation of the digestive tract, and symptoms related to IBD can include severe diarrhea, abdominal pain, fatigue, and weight loss. More serious instances can require lifelong treatment or possibly surgery. "While the causes of IBD have not yet been determined, environmental exposures such as diet, smoking, infections, altered gut microbiome, and toxins or pollutants are risk-factors for development and relapse," Dr. Clint Allred said. "In this study, we wanted to focus on what effect BPA may have on IBD."

July 4th

New Tools Used to Identify Childhood Cancer Genes

Using a new computational strategy, researchers at the University of Texas (UT) Southwestern Medical Center have identified 29 genetic changes that can contribute to rhabdomyosarcoma, an aggressive childhood cancer. The group used Bayesian analysis, a method for statistical inference, in conjunction with screening using CRISPR/Cas9, the much-heralded gene-editing tool, to confirm the statistical predictions. The work helps to explain "the engine" driving formation of rhabdomyosarcoma and suggests potential treatments. Furthermore, their research method can be used to identify genetic drivers of other cancers. Nearly all genes occur in cells as pairs. This research focused on genes for which there was only one copy or for which there were three or more copies. "We came up with the idea that the altered expression of key cancer genes may be driven by genomic copy-number amplifications or losses. We then developed a new computational algorithm called iExCN to predict cancer genes based on genome-wide copy-number and gene expression data," said Dr. Stephen Skapek, Chief of the Division of Pediatric Hematology-Oncology and with the Harold C. Simmons Comprehensive Cancer Center. The work also used several new experimental tools, including CRISPR/Cas9 screening technology, to verify the function of these predicted cancer genes in rhabdomyosarcoma. "The iExCN algorithm was developed based on Bayesian statistics, which is fundamentally different from commonly used statistics methodologies, and usually provides more accurate estimation of statistical associations, though it involves more complicated computation and longer processing time," said Dr. Lin Xu, Instructor in the Departments of Clinical Sciences and Pediatrics and with the Quantitative Biomedical Research Center.

Large Spiriform Nucleus (SpM) May Be Secret to Intelligence in Parrots; Key Brain Structure Is Much Larger in Parrots Than in Other Birds

University of Alberta neuroscientists have identified the neural circuit that may underlie intelligence in birds, according to a new study. The discovery is an example of convergent evolution between the brains of birds and primates, with the potential to provide insight into the neural basis of human intelligence. "An area of the brain that plays a major role in primate intelligence is called the pontine nuclei," explained Dr. Cristian Gutierrez-Ibanez, postdoctoral fellow in the Department of Psychology. "This structure transfers information between the two largest areas of the brain, the cortex and cerebellum, which allows for higher-order processing and more sophisticated behavior. In humans and primates, the pontine nuclei are large compared to other mammals. This makes sense given our cognitive abilities." Birds have very small pontine nuclei. Instead, they have a similar structure called the medial spiriform nucleus (SpM) that has similar connectivity. Located in a different part of the brain, the SpM does the same thing as the pontine nuclei, circulating information between the cortex and the cerebellum. "This loop between the cortex and the cerebellum is important for the planning and execution of sophisticated behaviors," said Dr. Doug Wylie, Professor of Psychology and co-author on the new study. Using samples from 98 birds from the largest collection of bird brains in the world, including everything from chickens and waterfowl to parrots and owls, the scientists studied the brains of birds, comparing the relative size of the SpM to the rest of the brain. They determined that parrots have a SpM that is much larger than that of other birds. "The SpM is very large in parrots. It's actually two to five times larger in parrots than in other birds, like chickens," said Dr. Gutierrez.

July 3rd

Bio-Techne to Acquire Exosome Diagnostics

On June 25, 2018, Bio-Techne Corporation (NASDAQ: TECH) announced that it had reached agreement to acquire Exosome Diagnostics, Inc. for $250 million in cash, plus contingent consideration of up to $325 million due upon the achievement of certain future milestones. The transaction is expected to close in July or early August 2018. The transaction will be financed through a combination of cash on hand and a revolving line of credit facility that Bio-Techne expects to obtain prior to the closing of the acquisition. Bio-Techne's management team held a conference call on June 26, 2018 at 8:00 am CDT to discuss the Exosome Diagnostics acquisition. Charles R. Kummeth, President and CEO of Bio-Techne commented, "We are excited to acquire the Exosome Diagnostic technology platform and integrate it into the Bio-Techne portfolio. ExosomeDx's technology is a game-changer, and positions Bio-Techne to be a leader in the rapidly-growing non-invasive liquid biopsy market. There are multipl e synergies with our core company, including our 40-year track record of developing and commercializing the highest-quality biologicals, especially in the field of cytokines. We will leverage our strong brand and market leadership position to extend these core competencies to the science of exosomes and cell free-DNA (cfDNA) biology and their utility as novel diagnostic tools. The non-invasive nature of this technology creates a new process for liquid biopsies and is likely to transform medical practice. Exosome Diagnostics complements our molecular pathology business, Advanced Cellular Diagnostics (ACD), which remains a robust growth segment for the Company." Currently Exosome Diagnostics markets a urine-based test, ExoDx® Prostate(IntelliScore) (EPI), to assist physicians in determining the need for a prostate biopsy in patients with an ambiguous PSA test result.

Sound Waves for Liquid Biopsies—Acoustic Microfluidic Platform Separates Circulating Tumor Cells (CTCs) from Blood Samples

Using sound waves, an international team of researchers has developed a gentle, contact-free method for separating circulating tumor cells from blood samples that is fast and efficient enough for clinical use. Circulating tumor cells (CTCs) are small pieces of a tumor that break away and flow through the bloodstream. They contain a wealth of information about the tumor, such as its type, physical characteristics, and genetic mutations. The ability to quickly and efficiently harvest and grow these cells from a blood sample would enable "liquid biopsies" capable of providing robust diagnosis, prognosis, and suggestions for treatment strategies based on individual CTC profiling. CTCs are, however, extremely rare and difficult to catch. There are typically only a handful for every few billion blood cells running through a patient's veins. And while there are many technologies designed to separate tumor cells from normal blood cells, none of them is perfect. They tend to damage or kill the cells in the process, lack efficiency, only work on specific types of cancer, or take far too long to be used in many situations. In a new study, researchers from Duke University, MIT, and Nanyang Technological University (Singapore) demonstrate a platform based on sound waves that is capable of separating CTCs from a 7.5-mL vial of blood with at least 86 percent efficiency in less than an hour. With additional improvements, the researchers hope the technology will form the basis of a new test through an inexpensive, disposable chip. The results were published online on July 3, 2018 in the journal Small. The article is titled “Circulating Tumor Cell Phenotyping via High‐Throughput Acoustic Separation.”

New Insight Into Maturation of miRNAs

An international research team led by researchers at Helmholtz Zentrum München, Technical University of Munich, and the University of Edinburgh has used an integrated structural biological approach to elucidate the maturation of a cancer-causing microRNA in gene regulation. In the future, the authors hope to develop new therapies based on the findings published online on June 26, 2018 in Nature Communications. The open-access article is titled “Structural Basis for Terminal Loop Recognition and Stimulation of pri-miRNA-18a Processing by hnRNP A1.” MicroRNAs (miRNAs) are a class of molecules consisting of short RNA sequences that inhibit the formation of certain proteins by destroying the corresponding RNA blueprint. Cancer-causing miRNAs, so-called oncomiRs, also function according to this principle and inhibit the production of proteins that protect the cell against uncontrolled growth. "Thus, an increased presence of these molecules in cells leads to the development of cancer in the long term," said Professor Michael Sattler, Director of the Institute of Structural Biology at Helmholtz Zentrum München and Professor of Biomolecular NMR Spectroscopy at the Technical University of Munich. "However, some molecular mechanisms of miRNA maturation in the cell remain elusive." Usually, before a miRNA can act in the cell, it undergoes several maturation steps and develops from a so-called primary pri-miRNA via a precursor stage (pre-miRNA) to a mature miRNA. In the current study, Professor Sattler, together with researchers led by Professor Javier Caceres and Dr. Gracjan Michlewski from the University of Edinburgh and his former doctoral student Hamed Kooshapur (now at the National Institutes of Health, USA), investigated the maturation of a specific pri-miRNA.

Drugs That Block Structural Changes to Collagen Could Prevent Lung Fibrosis

Scientists have found that it is the structure of collagen, rather than the amount, that leads to the devastating condition of lung fibrosis, according to a report published online on July 3, 2018 in the journal eLife. The open-access article is titled “Nanoscale Dysregulation of Collagen Structure-Function Disrupts Mechano-Homeostasis and Mediates Pulmonary Fibrosis.” The study provides the first evidence in humans that altered collagen structure affects tissue stiffness during progression of lung fibrosis and identifies a potential new target for drugs to prevent the condition. It is widely thought that fibrosis occurs when components that hold together a tissue's architecture [called the extracellular matrix (ECM)] build up in the tissue and lead to tissue stiffness. But recently evidence has suggested that this increased stiffness causes the build-up of yet more ECM components, resulting in a cycle that causes more scar tissue. "We knew that stiffness is an important factor in the build-up of scar tissue in the lung," explains lead author Dr. Mark Jones, National Institute for Health Research (NICR) Clinical Lecturer in Respiratory Medicine at the NIHR Southampton Biomedical Research Centre and the University of Southampton, UK. "But we didn't understand what specifically causes increased stiffness in diseased human tissue. Given that excessive build-up of collagen is considered a hallmark of fibrosis, we wanted to see whether this molecule has a role in tissue stiffness." The researches started by looking at the biological and mechanical features of lung tissue from people with lung fibrosis and compared this to healthy lung tissue. They found that the lung fibrosis samples were much stiffer than those from healthy people but, surprisingly, had similar levels of collagen.

CRISPR-Cas9 Genome Editing Technology Can Correct Alpha-1 Antitrypsin Deficiency (AATD) in Mouse Models

Recent groundbreaking research has demonstrated proof-of-concept for using CRISPR-Cas9 genome editing technology to correct the gene mutation responsible for alpha-1 antitrypsin (AAT) deficiency, successfully making a targeted gene correction in the livers of affected mice that restored at least low levels of normal AAT. In two studies, both published in Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., Publishers, two groups of researchers used somewhat different approaches to achieve these historic results in mouse models of AAT deficiency (AATD) and discuss why their findings are so important for the future treatment of patients with ATTD, The articles are available free for download on the Human Gene Therapy website until August 2, 2018. The article entitled "In vivo Genome Editing Partially Restores Alpha1-Antitrypsin in a Murine Model of AAT Deficiency " was coauthored by Dr. Terence Flotte, Editor-in-Chief of Human Gene Therapy, and Wen Xue, both from the University of Massachusetts Medical School (Worcester), together with a team of researchers from UMass Medical School, Tongji University (Shanghai, China), and Wuhan University (China). The researchers co-injected two adeno-associated viral (AAV) vectors: one to deliver the Cas9 component of the CRISPR-Cas9 system; and the second encoding an AAT gene-targeted guide RNA and carrying a homology-dependent repair template. This article was published online on May 14, 2018. Dr. Shen Shen, Editas Medicine, together with researchers from Editas and St.