Showing papers by "University of Texas Medical Branch published in 2016"
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.
For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
5,187 citations
TL;DR: A miniaturized spinning bioreactor (SpinΩ) is developed to generate forebrain-specific organoids from human iPSCs that recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and, notably, a distinct human-specific outer radial glia cell layer.
1,526 citations
Evandro Chagas Institute1, University of Oxford2, University of São Paulo3, Wellcome Trust Centre for Human Genetics4, Oswaldo Cruz Foundation5, State University of Feira de Santana6, Institute for Health Metrics and Evaluation7, St. Michael's Hospital8, University of Toronto9, University of Texas Medical Branch10
TL;DR: Results of phylogenetic and molecular clock analyses show a single introduction of ZikV into the Americas, which is estimated to have occurred between May and December 2013, more than 12 months before the detection of ZIKV in Brazil.
Abstract: Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015, and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. We performed next-generation sequencing to generate seven Brazilian ZIKV genomes sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Results of phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, which we estimated to have occurred between May and December 2013, more than 12 months before the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV-endemic areas, as well as with reported outbreaks in the Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however, no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this correlation does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology of this emerging virus in the Americas.
921 citations
TL;DR: Zika virus (ZIKV), a previously obscure flavivirus closely related to dengue, West Nile, Japanese encephalitis and yellow fever viruses, has emerged explosively since 2007 to cause a series of epidemics in Micronesia, the South Pacific, and most recently the Americas as discussed by the authors.
560 citations
TL;DR: There are no viable predictive molecular biomarkers for predicting the severity of ARDS, or molecular-based ARDS therapies, and the proinflammatory cytokines TNF-α (tumor necrosis factor α), interleukin (IL-1β), IL-6, IL-8, and IL-18 are among the most promising as biomarker for predicting morbidity and mortality.
Abstract: Context.—Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are a continuum of lung changes arising from a wide variety of lung injuries, frequently resulting in significant morbidity and frequently in death. Research regarding the molecular pathophysiology of ALI/ARDS is ongoing, with the aim toward developing prognostic molecular biomarkers and molecular-based therapy. Objective.—To review the clinical, radiologic, and pathologic features of ALI/ARDS; and the molecular pathophysiology of ALI/ARDS, with consideration of possible predictive/prognostic molecular biomarkers and possible molecular-based therapies. Data Sources.—Examination of the English-language medical literature regarding ALI and ARDS. Conclusions.—ARDS is primarily a clinicoradiologic diagnosis; however, lung biopsy plays an important diagnostic role in certain cases. A significant amount of progress has been made in the elucidation of ARDS pathophysiology and in predicting patient response, however, currently there i...
527 citations
Columbia University1, George Washington University2, University of Texas Health Science Center at Houston3, University of Alabama at Birmingham4, National Institutes of Health5, University of Texas Medical Branch6, Brown University7, Ohio State University8, University of Utah9, University of North Carolina at Chapel Hill10, Case Western Reserve University11, Northwestern University12, University of Colorado Boulder13, Duke University14, Stanford University15, University of Texas Southwestern Medical Center16, University of Pittsburgh17, Oregon Health & Science University18, Wayne State University19, Medical University of South Carolina20, Emory University21
TL;DR: Administration of betamethasone to women at risk for late preterm delivery significantly reduced the rate of neonatal respiratory complications and caused no significant between-group differences in the incidence of chorioamnionitis or neonatal sepsis.
Abstract: BackgroundInfants who are born at 34 to 36 weeks of gestation (late preterm) are at greater risk for adverse respiratory and other outcomes than those born at 37 weeks of gestation or later. It is not known whether betamethasone administered to women at risk for late preterm delivery decreases the risks of neonatal morbidities. MethodsWe conducted a multicenter, randomized trial involving women with a singleton pregnancy at 34 weeks 0 days to 36 weeks 5 days of gestation who were at high risk for delivery during the late preterm period (up to 36 weeks 6 days). The participants were assigned to receive two injections of betamethasone or matching placebo 24 hours apart. The primary outcome was a neonatal composite of treatment in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or still...
524 citations
TL;DR: Aβ oligomers and their toxicity in relation to size and conformation as well as their influence on inflammation and the potential of Aβ oligomer immunotherapy are discussed.
505 citations
TL;DR: The role of each gasotransmitter in cancer and the effects of pharmacological agents — some of which are in early-stage clinical studies — that modulate the levels of eachGasotransmitters are discussed.
Abstract: The three endogenous gaseous transmitters - nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) - regulate a number of key biological functions. Emerging data have revealed several new mechanisms for each of these three gasotransmitters in tumour biology. It is now appreciated that they show bimodal pharmacological character in cancer, in that not only the inhibition of their biosynthesis but also elevation of their concentration beyond a certain threshold can exert anticancer effects. This Review discusses the role of each gasotransmitter in cancer and the effects of pharmacological agents - some of which are in early-stage clinical studies - that modulate the levels of each gasotransmitter. A clearer understanding of the pharmacological character of these three gases and the mechanisms underlying their biological effects is expected to guide further clinical translation.
448 citations
TL;DR: Characterization of an Asian lineage ZIKV strain in a murine model, and one of the few studies reporting a model of Zika disease and demonstrating age-dependent morbidity and mortality, could provide a platform for testing the efficacy of antivirals and vaccines.
Abstract: The mosquito-borne Zika virus (ZIKV) is responsible for an explosive ongoing outbreak of febrile illness across the Americas. ZIKV was previously thought to cause only a mild, flu-like illness, but during the current outbreak, an association with Guillain-Barre syndrome and microcephaly in neonates has been detected. A previous study showed that ZIKV requires murine adaptation to generate reproducible murine disease. In our study, a low-passage Cambodian isolate caused disease and mortality in mice lacking the interferon (IFN) alpha receptor (A129 mice) in an age-dependent manner, but not in similarly aged immunocompetent mice. In A129 mice, viremia peaked at ∼10(7) plaque-forming units/mL by day 2 postinfection (PI) and reached high titers in the spleen by day 1. ZIKV was detected in the brain on day 3 PI and caused signs of neurologic disease, including tremors, by day 6. Robust replication was also noted in the testis. In this model, all mice infected at the youngest age (3 weeks) succumbed to illness by day 7 PI. Older mice (11 weeks) showed signs of illness, viremia, and weight loss but recovered starting on day 8. In addition, AG129 mice, which lack both type I and II IFN responses, supported similar infection kinetics to A129 mice, but with exaggerated disease signs. This characterization of an Asian lineage ZIKV strain in a murine model, and one of the few studies reporting a model of Zika disease and demonstrating age-dependent morbidity and mortality, could provide a platform for testing the efficacy of antivirals and vaccines.
417 citations
TL;DR: A library of FDA-approved drugs was interrogated for their ability to block infection of human HuH-7 cells by a newly isolated ZIKV strain (ZIKV MEX_I_7) and established anti-flaviviral drugs and others that had no previously known antiviral activity were identified as inhibitors of ZikV infection.
405 citations
United States Department of Agriculture1, Washington University in St. Louis2, Hungarian Academy of Sciences3, National Institutes of Health4, Georgia State University5, United States Army Medical Research Institute of Infectious Diseases6, Commonwealth Scientific and Industrial Research Organisation7, Columbia University8, University of Texas Medical Branch9, Colorado State University10, Yeshiva University11, Huazhong Agricultural University12, University of Queensland13, University of Marburg14, University of Illinois at Urbana–Champaign15, University of Warwick16, Empresa Brasileira de Pesquisa Agropecuária17, World Health Organization18, Erasmus University Rotterdam19, New York University20, University of Kentucky21, Public Health England22, Kagoshima University23, Murdoch University24, University of São Paulo25, Public Health Agency of Canada26, Okayama University27, United States Geological Survey28, Northwestern University29, Centers for Disease Control and Prevention30, University of Cambridge31, Boston University32, Novosibirsk State University33, University of Veterinary Medicine Vienna34, University of Medicine and Health Sciences35, Texas Biomedical Research Institute36, Texas A&M University37, University of St Andrews38, Queen's University Belfast39, University of Freiburg40, Chinese Center for Disease Control and Prevention41, Defence Science and Technology Laboratory42, Hokkaido University43, Kyoto University44, Pasteur Institute45, Wageningen University and Research Centre46, University of Lyon47, National University of Singapore48, Kansas State University49, University of Hong Kong50
TL;DR: The updated taxonomy of the order Mononegavirales is presented as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
Abstract: In 2016, the order Mononegavirales was emended through the addition of two new families (Mymonaviridae and Sunviridae), the elevation of the paramyxoviral subfamily Pneumovirinae to family status (Pneumoviridae), the addition of five free-floating genera (Anphevirus, Arlivirus, Chengtivirus, Crustavirus, and Wastrivirus), and several other changes at the genus and species levels. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
University of Pittsburgh1, University of Edinburgh2, University of Birmingham3, Baylor University Medical Center4, University of California, San Francisco5, Queen Elizabeth Hospital Birmingham6, Harvard University7, Royal Prince Alfred Hospital8, Cleveland Clinic9, Oslo University Hospital10, Kyoto University11, University Health Network12, Mayo Clinic13, Mount Sinai Hospital14, Icahn School of Medicine at Mount Sinai15, University of São Paulo16, University of Cambridge17, Columbia University18, Cincinnati Children's Hospital Medical Center19, Universidade Federal do Rio Grande do Sul20, Loma Linda University21, Ain Shams University22, Hospital of the University of Pennsylvania23, University Medical Center Groningen24, Toronto General Hospital25, University of Chicago26, Beni-Suef University27, Kobe University28, Temple University29, Lahey Hospital & Medical Center30, Duke University31, University of North Carolina at Chapel Hill32, University of California, Los Angeles33, Cliniques Universitaires Saint-Luc34, Northwestern University35, St. Joseph's Hospital and Medical Center36, Sahlgrenska University Hospital37, Beth Israel Deaconess Medical Center38, University of Kansas39, Hadassah Medical Center40, University of Southern California41, University of Miami42, Dokuz Eylül University43, University of Pennsylvania44, University of Alberta Hospital45, University of Texas Medical Branch46, University of Rome Tor Vergata47, University of Patras48, Karolinska University Hospital49, Tulane University50
TL;DR: New recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization are included.
TL;DR: The need for novel treatments is paramount, and future efforts to improve outcomes and quality of life should include optimisation of wound healing to attenuate or prevent hypertrophic scarring, well-designed trials to confirm treatment efficacy, and further elucidation of molecular mechanisms to allow development of new preventive and therapeutic strategies.
TL;DR: H-bonds enhance receptor-ligand interactions when both the donor and acceptor have either significantly stronger or significantly weaker H-bonding capabilities than the hydrogen and oxygen atoms in water, demonstrating a new conceptual framework to evaluate the H- bonding process in biological systems.
Abstract: Hydrogen (H)-bonds potentiate diverse cellular functions by facilitating molecular interactions. The mechanism and the extent to which H-bonds regulate molecular interactions are a largely unresolved problem in biology because the H-bonding process continuously competes with bulk water. This interference may significantly alter our understanding of molecular function, for example, in the elucidation of the origin of enzymatic catalytic power. We advance this concept by showing that H-bonds regulate molecular interactions via a hitherto unappreciated donor-acceptor pairing mechanism that minimizes competition with water. On the basis of theoretical and experimental correlations between H-bond pairings and their effects on ligand binding affinity, we demonstrate that H-bonds enhance receptor-ligand interactions when both the donor and acceptor have either significantly stronger or significantly weaker H-bonding capabilities than the hydrogen and oxygen atoms in water. By contrast, mixed strong-weak H-bond pairings decrease ligand binding affinity due to interference with bulk water, offering mechanistic insight into why indiscriminate strengthening of receptor-ligand H-bonds correlates poorly with experimental binding affinity. Further support for the H-bond pairing principle is provided by the discovery and optimization of lead compounds targeting dietary melamine and Clostridium difficile toxins, which are not realized by traditional drug design methods. Synergistic H-bond pairings have therefore evolved in the natural design of high-affinity binding and provide a new conceptual framework to evaluate the H-bonding process in biological systems. Our findings may also guide wider applications of competing H-bond pairings in lead compound design and in determining the origin of enzymatic catalytic power.
TL;DR: It is demonstrated that m6A modulates infection by hepatitis C virus (HCV) and is identified as a conserved regulatory mark across Flaviviridae genomes.
University of Utah1, George Washington University2, Case Western Reserve University3, Northwestern University4, National Institutes of Health5, Columbia University6, University of North Carolina at Chapel Hill7, University of Pittsburgh8, Ohio State University9, University of Alabama at Birmingham10, University of Texas Medical Branch11, Wayne State University12, Brown University13, University of Texas Health Science Center at Houston14, Oregon Health & Science University15
TL;DR: The data show that there is a continuum of outcomes, with each additional week of gestation conferring survival benefit while reducing the length of initial hospitalization, and these contemporary data can be useful for patient counseling regarding preterm outcomes.
TL;DR: This review highlights recent advances in the development of biologically active spirooxindoles for their antiviral potential, primarily focusing on the structure-activity relationships (SARs) and modes of action, as well as future directions to achieve more potent analogues toward a viable antiviral therapy.
Abstract: Antiviral therapeutics with profiles of high potency, low resistance, panserotype, and low toxicity remain challenging, and obtaining such agents continues to be an active area of therapeutic development. Due to their unique three-dimensional structural features, spirooxindoles have been identified as privileged chemotypes for antiviral drug development. Among them, spiro-pyrazolopyridone oxindoles have been recently reported as potent inhibitors of dengue virus NS4B, leading to the discovery of an orally bioavailable preclinical candidate (R)-44 with excellent in vivo efficacy in a dengue viremia mouse model. This review highlights recent advances in the development of biologically active spirooxindoles for their antiviral potential, primarily focusing on the structure–activity relationships (SARs) and modes of action, as well as future directions to achieve more potent analogues toward a viable antiviral therapy.
TL;DR: This case report provides evidence that in addition to microcephaly, there may be a link between Zika virus infection and hydrops fetalis and fetal demise and systematic investigation of spontaneous abortions and stillbirths is warranted.
Abstract: The rapid spread of Zika virus in the Americas and outbreak of microcephaly in Brazil has
raised attention to the possible deleterious effects that the virus may have on fetuses. We
report a case of a 20-year-old pregnant woman from Salvador, Brazil whose fetus had
developed hydrops fetalis, a condition where there is abnormal accumulation of fluid in
the fetus, as well as severe central nervous system defects such as microcephaly and hydranencephaly.
After fetal demise, ZIKV RNA was detected in central nervous system tissues
and amniotic fluid. The case report provides evidence that in addition to microcephaly,
there may be a link between Zika virus infection and hydrops fetalis and fetal demise.
Given the recent spread of the virus, systematic investigation of spontaneous abortions
and stillbirths may be warranted to evaluate the risk that ZIKV infection imparts on these
outcomes.
TL;DR: A method is described that leverages the advantages of bottom-up and top-down strategies to incorporate proteins derived from the leukocyte plasma membrane into lipid nanoparticles that retained the versatility and physicochemical properties typical of liposomal formulations and enabled the selective and effective delivery of dexamethasone to inflamed tissues.
Abstract: A multitude of micro- and nanoparticles have been developed to improve the delivery of systemically administered pharmaceuticals, which are subject to a number of biological barriers that limit their optimal biodistribution. Bioinspired drug-delivery carriers formulated by bottom-up or top-down strategies have emerged as an alternative approach to evade the mononuclear phagocytic system and facilitate transport across the endothelial vessel wall. Here, we describe a method that leverages the advantages of bottom-up and top-down strategies to incorporate proteins derived from the leukocyte plasma membrane into lipid nanoparticles. The resulting proteolipid vesicles-which we refer to as leukosomes-retained the versatility and physicochemical properties typical of liposomal formulations, preferentially targeted inflamed vasculature, enabled the selective and effective delivery of dexamethasone to inflamed tissues, and reduced phlogosis in a localized model of inflammation.
TL;DR: The aim of this systematic review was to provide a concise review and identify studies reporting on identification, prevention, or intervention for surgeons suffering from burnout.
Abstract: Burnout is a syndrome characterized by emotional exhaustion, depersonalization, and a decreased sense of personal accomplishment caused by work-related stress.1,2 Physicians are at increased risk for burnout as a result of long work hours, delayed gratification, challenges with work and home balance, and challenges associated with patient care, especially in the changing healthcare environment.1,3-5
In a recent study, more than half of physicians met criteria for burnout. In addition, the prevalence of burnout increased 10% in U.S. physicians between 2011 and 2014.6 The prevalence of burnout was lower in a probability-based sample of the general U.S. working population, with no increase over the same time period. This increase was observed across specialties, with many specialties reporting well over 50% of physicians being burned out.6 This disturbing trend is likely multifactorial, with increasing demands in clinical productivity, difficulty in funding research endeavors, more patients to care for with fewer resources, changes in reimbursement, rising student debt, and difficulty balancing personal and work life.7-10
Burnout is especially prevalent in surgical specialties. In the 2015 Medscape Physician Lifestyle Report, burnout rates ranged from 37-53% across specialties, with general surgeons nearly topping the list at 50%.11 Burnout has severe adverse consequences, including substance abuse, disruptive behavior, absenteeism, attrition, strained personal relationships, divorce, depression, suicidal ideation, and suicide.12-14 Over the past decade, awareness has been raised and the ability to accurately assess and identify physicians suffering from burnout has improved. The aim of this systematic review was to provide a concise review and identify studies reporting on identification, prevention, or intervention for surgeons suffering from burnout.
TL;DR: The accelerated mobilization and oxidation of lipids upon BAT activation supports a putative role for BAT in the regulation of lipid metabolism in humans.
TL;DR: An infectious cDNA clone of ZIKV that was generated using a clinical isolate of the Asian lineage is reported, which may help identify viral determinants of human virulence and mosquito transmission as well as inform vaccine and therapeutic strategies.
TL;DR: Inactivated Mers-CoV vaccine appears to carry a hypersensitive-type lung pathology risk from MERS- coV infection that is similar to that found with inactivated SARS-Cov vaccines from SARS -CoV infection.
Abstract: To determine if a hypersensitive-type lung pathology might occur when mice were given an inactivated MERS-CoV vaccine and challenged with infectious virus as was seen with SARS-CoV vaccines, we prepared and vaccinated mice with an inactivated MERS-CoV vaccine. Neutralizing antibody was induced by vaccine with and without adjuvant and lung virus was reduced in vaccinated mice after challenge. Lung mononuclear infiltrates occurred in all groups after virus challenge but with increased infiltrates that contained eosinophils and increases in the eosinophil promoting IL-5 and IL-13 cytokines only in the vaccine groups. Inactivated MERS-CoV vaccine appears to carry a hypersensitive-type lung pathology risk from MERS-CoV infection that is similar to that found with inactivated SARS-CoV vaccines from SARS-CoV infection.
University of Minnesota1, Association of American Medical Colleges2, University of Florida3, Virginia Commonwealth University4, State University of New York Upstate Medical University5, University of California, San Francisco6, University of Colorado Denver7, University of Texas Medical Branch8, Johns Hopkins University9, University of Michigan10, University of Texas Southwestern Medical Center11, University of Toronto12, Mayo Clinic13, University of Iowa14
TL;DR: Adoption of these core EPAs could significantly narrow the gap between program directors’ expectations and new residents’ performance, enhancing patient safety and increasing residents', educators’, and patients’ confidence in the care these learners provide in the first months of their residency training.
Abstract: Currently, no standard defines the clinical skills that medical students must demonstrate upon graduation. The Liaison Committee on Medical Education bases its standards on required subject matter and student experiences rather than on observable educational outcomes. The absence of such established outcomes for MD graduates contributes to the gap between program directors' expectations and new residents' performance.In response, in 2013, the Association of American Medical Colleges convened a panel of experts from undergraduate and graduate medical education to define the professional activities that every resident should be able to do without direct supervision on day one of residency, regardless of specialty. Using a conceptual framework of entrustable professional activities (EPAs), this Drafting Panel reviewed the literature and sought input from the health professions education community. The result of this process was the publication of 13 core EPAs for entering residency in 2014. Each EPA includes a description, a list of key functions, links to critical competencies and milestones, and narrative descriptions of expected behaviors and clinical vignettes for both novice learners and learners ready for entrustment.The medical education community has already begun to develop the curricula, assessment tools, faculty development resources, and pathways to entrustment for each of the 13 EPAs. Adoption of these core EPAs could significantly narrow the gap between program directors' expectations and new residents' performance, enhancing patient safety and increasing residents', educators', and patients' confidence in the care these learners provide in the first months of their residency training.
TL;DR: The traditional view on the evolutionary history, host range, and genomic structures of a major group of RNA viruses is revised, suggesting that arthropods may be the ultimate reservoir of the Flaviviridae and related viruses, harboring considerable genetic and phenotypic diversity.
Abstract: Viruses of the family Flaviviridae are important pathogens of humans and other animals, and currently classified into four genera. To better understand their diversity, evolutionary history and genomic flexibility, we used RNA-seq to search for the viruses related to the Flaviviridae in a range of potential invertebrate and vertebrate hosts. Accordingly, we recovered the full genomes of 5 segmented Jingmenviruses and 12 distant relatives of the known Flaviviridae (‘flavi-like9 viruses) from a range of arthropod species. Although these viruses are highly divergent, they share a similar genomic plan and common ancestry with the Flaviviridae in the NS3 and NS5 regions. Remarkably, while these viruses fill in major gaps in the phylogenetic diversity of the Flaviviridae , genomic comparisons reveal important changes in genome structure, genome size, and replication/gene regulation strategy during evolutionary history. In addition, the wide diversity of flavi-like viruses found in invertebrates, as well as their deep phylogenetic positions, suggests that they may represent the ancestral forms from which the vertebrate-infecting viruses evolved. For the vertebrate viruses, we expanded the previously mammal-only pegivirus-hepacivirus group to include a virus from the graceful catshark ( Proscyllium habereri ), which in turn implies that these viruses possess a larger host range than is currently known. In sum, our data show that the Flaviviridae infect a far wider range of hosts and exhibit greater diversity in genome structure than previously anticipated. IMPORTANCE The family Flaviviridae of RNA viruses contains several notorious human pathogens, including dengue virus, West Nile virus, and hepatitis C virus. To date, however, our understanding of the biodiversity and evolution of the Flaviviridae has largely been directed toward vertebrate hosts and their blood-feeding arthropod vectors. Therefore, we investigated an expanded group of potential arthropod and vertebrate host species that have generally been ignored by surveillance programs. Remarkably, these species contained diverse flaviviruses and related viruses that are characterized by major changes in genome size and genome structure, such that these traits are more flexible than previously thought. More generally, these data suggest that arthropods may be the ultimate reservoir of the Flaviviridae and related viruses, harbouring considerable genetic and phenotypic diversity. In sum, this study revises the traditional view on the evolutionary history, host range, and genomic structures of a major group of RNA viruses.
TL;DR: It is concluded that GAG interactions and receptor activity of CXCL1 monomers and dimers are fine-tuned to regulate neutrophil trafficking for successful resolution of tissue injury.
Abstract: The chemokine CXCL1/MGSA plays a pivotal role in the host immune response by recruiting and activating neutrophils for microbial killing at the tissue site. CXCL1 exists reversibly as monomers and dimers, and mediates its function by binding glycosaminoglycans (GAG) and CXCR2 receptor. We recently showed that both monomers and dimers are potent CXCR2 agonists, the dimer is the high-affinity GAG ligand, lysine and arginine residues located in two non-overlapping domains mediate GAG interactions, and there is extensive overlap between GAG and receptor-binding domains. To understand how these structural properties influence in vivo function, we characterized peritoneal neutrophil recruitment of a trapped monomer and trapped dimer and a panel of WT lysine/arginine to alanine mutants. Monomers and dimers were active, but WT was more active indicating synergistic interactions promote recruitment. Mutants from both domains showed reduced GAG heparin binding affinities and reduced neutrophil recruitment, providing compelling evidence that both GAG-binding domains mediate in vivo trafficking. Further, mutant of a residue that is involved in both GAG binding and receptor signaling showed the highest reduction in recruitment. We conclude that GAG interactions and receptor activity of CXCL1 monomers and dimers are fine-tuned to regulate neutrophil trafficking for successful resolution of tissue injury.
TL;DR: The authors solved the structure of one of ZIKV's sfRNAs by x-ray crystallography and found that the multi-pseudoknot structure that it adopts underlies its exonuclease resistance, clarifying the mechanism of exonuclelease resistance and identifies features that may modulate function in diverse flaviviruses.
Abstract: The outbreak of Zika virus (ZIKV) and associated fetal microcephaly mandates efforts to understand the molecular processes of infection. Related flaviviruses produce noncoding subgenomic flaviviral RNAs (sfRNAs) that are linked to pathogenicity in fetal mice. These viruses make sfRNAs by co-opting a cellular exonuclease via structured RNAs called xrRNAs. We found that ZIKV-infected monkey and human epithelial cells, mouse neurons, and mosquito cells produce sfRNAs. The RNA structure that is responsible for ZIKV sfRNA production forms a complex fold that is likely found in many pathogenic flaviviruses. Mutations that disrupt the structure affect exonuclease resistance in vitro and sfRNA formation during infection. The complete ZIKV xrRNA structure clarifies the mechanism of exonuclease resistance and identifies features that may modulate function in diverse flaviviruses.
National Institutes of Health1, University of California, San Francisco2, Yale University3, University of Kansas4, University of Calgary5, Rutgers University6, University of Texas Health Science Center at San Antonio7, University of Texas Medical Branch8, Indiana University – Purdue University Indianapolis9, University of Pittsburgh10, University of Mississippi11
TL;DR: A major theme that developed from the workshop was that the scientific community must change their thinking of the pregnant woman and her fetus as a vulnerable patient population for which drug development should be avoided, but rather be thought of as a deprived population in need of more effective therapeutic interventions.
TL;DR: This article aims to distill the current knowledge pertaining to the stress response to burn trauma, highlighting recent developments and important knowledge gaps that need to be pursued in order to develop novel therapeutic strategies which improve outcomes in burn survivors.
TL;DR: An imaging technique was developed that allowed for simultaneously monitor the activities of >1,600 neurons/DRG in live mice and discovered a striking neuronal coupling phenomenon that adjacent neurons tend to activate together following tissue injury, which contributes to pain hypersensitivity by "hijacking" neighboring neurons through gap junctions.