Showing papers by "University of Texas Medical Branch published in 2019"
University of New South Wales1, Oregon State University2, Braunschweig University of Technology3, University of California, San Diego4, Norwegian University of Life Sciences5, University of Liverpool6, Max Planck Society7, University of Tasmania8, University of Vermont9, ETH Zurich10, Stazione Zoologica Anton Dohrn11, Montana State University12, University of Amsterdam13, University of Southern California14, Pacific Northwest National Laboratory15, University of Hawaii at Manoa16, University of California, Berkeley17, Marine Biological Laboratory18, University of California, Irvine19, University of Georgia20, California Institute of Technology21, University of Edinburgh22, Ohio State University23, University of Sydney24, University of Alberta25, Georgia Institute of Technology26, Australian Institute of Marine Science27, University of Melbourne28, University of Texas Medical Branch29, University of Queensland30
TL;DR: This Consensus Statement documents the central role and global importance of microorganisms in climate change biology and puts humanity on notice that the impact of climate change will depend heavily on responses of micro organisms, which are essential for achieving an environmentally sustainable future.
Abstract: In the Anthropocene, in which we now live, climate change is impacting most life on Earth. Microorganisms support the existence of all higher trophic life forms. To understand how humans and other life forms on Earth (including those we are yet to discover) can withstand anthropogenic climate change, it is vital to incorporate knowledge of the microbial 'unseen majority'. We must learn not just how microorganisms affect climate change (including production and consumption of greenhouse gases) but also how they will be affected by climate change and other human activities. This Consensus Statement documents the central role and global importance of microorganisms in climate change biology. It also puts humanity on notice that the impact of climate change will depend heavily on responses of microorganisms, which are essential for achieving an environmentally sustainable future.
963 citations
TL;DR: An important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies is identified and the amyloid-cascade hypothesis in Alzheimer’s disease is supported, demonstrating that neurofibrillary tangles develop downstream of amyloids-beta-induced microglial activation.
Abstract: Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline1. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release2. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice3, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer's disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation.
659 citations
Cornell University1, University of Virginia2, University of Texas Health Science Center at San Antonio3, University of Illinois at Chicago4, University of Pennsylvania5, Stanford University6, Colorado State University7, Providence Portland Medical Center8, Johns Hopkins University9, University of California, San Diego10, Brown University11, Northwestern University12, University of California, Davis13, Harvard University14, International University, Cambodia15, University of Bonn16, University of Washington17, Mayo Clinic18, Rush University Medical Center19, Keio University20, University of Texas Medical Branch21, Baylor College of Medicine22
TL;DR: Given that the majority of the biological and human health variables remained stable, or returned to baseline, after a 340-day space mission, these data suggest that human health can be mostly sustained over this duration of spaceflight.
Abstract: INTRODUCTION To date, 559 humans have been flown into space, but long-duration (>300 days) missions are rare (n = 8 total). Long-duration missions that will take humans to Mars and beyond are planned by public and private entities for the 2020s and 2030s; therefore, comprehensive studies are needed now to assess the impact of long-duration spaceflight on the human body, brain, and overall physiology. The space environment is made harsh and challenging by multiple factors, including confinement, isolation, and exposure to environmental stressors such as microgravity, radiation, and noise. The selection of one of a pair of monozygotic (identical) twin astronauts for NASA’s first 1-year mission enabled us to compare the impact of the spaceflight environment on one twin to the simultaneous impact of the Earth environment on a genetically matched subject. RATIONALE The known impacts of the spaceflight environment on human health and performance, physiology, and cellular and molecular processes are numerous and include bone density loss, effects on cognitive performance, microbial shifts, and alterations in gene regulation. However, previous studies collected very limited data, did not integrate simultaneous effects on multiple systems and data types in the same subject, or were restricted to 6-month missions. Measurement of the same variables in an astronaut on a year-long mission and in his Earth-bound twin indicated the biological measures that might be used to determine the effects of spaceflight. Presented here is an integrated longitudinal, multidimensional description of the effects of a 340-day mission onboard the International Space Station. RESULTS Physiological, telomeric, transcriptomic, epigenetic, proteomic, metabolomic, immune, microbiomic, cardiovascular, vision-related, and cognitive data were collected over 25 months. Some biological functions were not significantly affected by spaceflight, including the immune response (T cell receptor repertoire) to the first test of a vaccination in flight. However, significant changes in multiple data types were observed in association with the spaceflight period; the majority of these eventually returned to a preflight state within the time period of the study. These included changes in telomere length, gene regulation measured in both epigenetic and transcriptional data, gut microbiome composition, body weight, carotid artery dimensions, subfoveal choroidal thickness and peripapillary total retinal thickness, and serum metabolites. In addition, some factors were significantly affected by the stress of returning to Earth, including inflammation cytokines and immune response gene networks, as well as cognitive performance. For a few measures, persistent changes were observed even after 6 months on Earth, including some genes’ expression levels, increased DNA damage from chromosomal inversions, increased numbers of short telomeres, and attenuated cognitive function. CONCLUSION Given that the majority of the biological and human health variables remained stable, or returned to baseline, after a 340-day space mission, these data suggest that human health can be mostly sustained over this duration of spaceflight. The persistence of the molecular changes (e.g., gene expression) and the extrapolation of the identified risk factors for longer missions (>1 year) remain estimates and should be demonstrated with these measures in future astronauts. Finally, changes described in this study highlight pathways and mechanisms that may be vulnerable to spaceflight and may require safeguards for longer space missions; thus, they serve as a guide for targeted countermeasures or monitoring during future missions.
538 citations
TL;DR: Crystal structures indicated that EK1 can form a stable six-helix bundle structure with both short α-HCoV and long β-H CoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site.
Abstract: Continuously emerging highly pathogenic human coronaviruses (HCoVs) remain a major threat to human health, as illustrated in past SARS-CoV and MERS-CoV outbreaks. The development of a drug with broad-spectrum HCoV inhibitory activity would address this urgent unmet medical need. Although previous studies have suggested that the HR1 of HCoV spike (S) protein is an important target site for inhibition against specific HCoVs, whether this conserved region could serve as a target for the development of broad-spectrum pan-CoV inhibitor remains controversial. Here, we found that peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, exhibited broad fusion inhibitory activity against multiple HCoVs. EK1, the optimized form of OC43-HR2P, showed substantially improved pan-CoV fusion inhibitory activity and pharmaceutical properties. Crystal structures indicated that EK1 can form a stable six-helix bundle structure with both short α-HCoV and long β-HCoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site.
375 citations
Washington University in St. Louis1, Technical University of Madrid2, Beijing Institute of Genomics3, Georgia State University4, United States Army Medical Research Institute of Infectious Diseases5, Commonwealth Scientific and Industrial Research Organisation6, Columbia University7, University of Texas Medical Branch8, Friedrich Loeffler Institute9, National Institutes of Health10, Instituto Biológico11, Albert Einstein College of Medicine12, Erasmus University Rotterdam13, University of Queensland14, University of Marburg15, Humboldt University of Berlin16, Robert Koch Institute17, International Atomic Energy Agency18, University of Pittsburgh19, University of Warwick20, World Health Organization21, Empresa Brasileira de Pesquisa Agropecuária22, Boston University23, Public Health England24, Kyoto University25, Murdoch University26, Huazhong Agricultural University27, University of São Paulo28, Laval University29, Okayama University30, United States Geological Survey31, United States Department of Agriculture32, Northwestern University33, Icahn School of Medicine at Mount Sinai34, Institut de recherche pour le développement35, Ohio State University36, Katholieke Universiteit Leuven37, South Dakota State University38, Novosibirsk State University39, University of Veterinary Medicine Vienna40, University of Medicine and Health Sciences41, University of Bergen42, Texas A&M University43, Queen's University Belfast44, Centers for Disease Control and Prevention45, University of Sydney46, University of Oxford47, Defence Science and Technology Laboratory48, Queensland University of Technology49, Colorado State University50, Hokkaido University51, Pasteur Institute52, National University of Singapore53, North Carolina State University54, Universidade Federal de Viçosa55, Chinese Center for Disease Control and Prevention56, Fudan University57
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 February 2019, following the annual taxon ratification vote, the order Mononegavirales was amended by the addition of four new subfamilies and 12 new genera and the creation of 28 novel species. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
238 citations
Centers for Disease Control and Prevention1, United States Department of Agriculture2, University of Naples Federico II3, University of Ljubljana4, Mississippi State University5, University of Texas Medical Branch6, Friedrich Loeffler Institute7, Colorado State University8, Columbia University9, University of California, Irvine10, University of the Free State11, Xinjiang University12, Aix-Marseille University13, International Rice Research Institute14, Scripps Research Institute15, Public Health Agency of Canada16, Mayo Clinic17, Hacettepe University18, United States Army Medical Research Institute of Infectious Diseases19, Chinese Center for Disease Control and Prevention20, Kansas State University21, Bernhard Nocht Institute for Tropical Medicine22, Paris Diderot University23, University of Queensland24, University of Helsinki25, University of Zurich26, Public Health England27, Seoul National University28, Charité29, Slovak Academy of Sciences30, Karolinska Institutet31, Katholieke Universiteit Leuven32, University of Washington33, Wuhan University of Science and Technology34, University of Louisville35, University of São Paulo36, University of Bari37, Hokkaido University38, University of Hamburg39, Public Health Agency of Sweden40, Washington State University41, Aristotle University of Thessaloniki42, Oswaldo Cruz Foundation43, University of Brasília44, National University of La Plata45, Pasteur Institute46, University of Maryland, Baltimore47, National Agriculture and Food Research Organization48, University of Glasgow49, University of Tokyo50, University of Oxford51, Korea University52, National Research Council53, Fujian Agriculture and Forestry University54, North Carolina State University55, Universidade Federal de Viçosa56, Fudan University57, National Institutes of Health58
TL;DR: The updated taxonomy of the order Bunyavirales now accepted by the International Committee on Taxonomy of Viruses (ICTV) is presented.
Abstract: In February 2019, following the annual taxon ratification vote, the order Bunyavirales was amended by creation of two new families, four new subfamilies, 11 new genera and 77 new species, merging of two species, and deletion of one species. This article presents the updated taxonomy of the order Bunyavirales now accepted by the International Committee on Taxonomy of Viruses (ICTV).
237 citations
Bundelkhand University1, Indian Agricultural Research Institute2, National Cheng Kung University3, Sejong University4, Universiti Teknologi Malaysia5, Czech University of Life Sciences Prague6, Virginia Tech College of Natural Resources and Environment7, University of Texas Medical Branch8, University of Delhi9
TL;DR: Different methods to remove fluoride from water such as reverse osmosis, electrocoagulation, nanofiltration, adsorption, ion-exchange and precipitation/coagulating were introduced in this study.
210 citations
University of California, San Francisco1, Oswaldo Cruz Foundation2, Yale University3, Federal University of Bahia4, University of Pittsburgh5, Universidade de Pernambuco6, Federal University of Pernambuco7, University of Texas Medical Branch8, University of California, Berkeley9, Faculdade de Medicina de São José do Rio Preto10, University of Florida11
TL;DR: Zika transmission within a Brazilian slum community indicates that prior dengue immunity and local variations influence transmission, and the landscape of ZIKV immunity that now exists may affect the risk for future transmission.
Abstract: The clinical outcomes associated with Zika virus (ZIKV) in the Americas have been well documented, but other aspects of the pandemic, such as attack rates and risk factors, are poorly understood. We prospectively followed a cohort of 1453 urban residents in Salvador, Brazil, and, using an assay that measured immunoglobulin G3 (IgG3) responses against ZIKV NS1 antigen, we estimated that 73% of individuals were infected during the 2015 outbreak. Attack rates were spatially heterogeneous, varying by a factor of 3 within a community spanning 0.17 square kilometers. Preexisting high antibody titers to dengue virus were associated with reduced risk of ZIKV infection and symptoms. The landscape of ZIKV immunity that now exists may affect the risk for future transmission.
190 citations
TL;DR: It is reported that TDP-43 participates in the DNA damage response and its nuclear clearance in motor neurons causes DNA double-strand break repair defects in ALS, and is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA doubleStrand break (DSB) repair pathway.
Abstract: Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in Caenorhabditis elegans mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.
184 citations
TL;DR: A regular meal pattern including breakfast consumption, consuming a higher proportion of energy early in the day, reduced meal frequency, and regular fasting periods may provide physiological benefits such as reduced inflammation, improved circadian rhythmicity, increased autophagy and stress resistance, and modulation of the gut microbiota.
Abstract: The influence of meal frequency and timing on health and disease has been a topic of interest for many years. While epidemiological evidence indicates an association between higher meal frequencies and lower disease risk, experimental trials have shown conflicting results. Furthermore, recent prospective research has demonstrated a significant increase in disease risk with a high meal frequency (≥6 meals/day) as compared to a low meal frequency (1–2 meals/day). Apart from meal frequency and timing we also have to consider breakfast consumption and the distribution of daily energy intake, caloric restriction, and night-time eating. A central role in this complex scenario is played by the fasting period length between two meals. The physiological underpinning of these interconnected variables may be through internal circadian clocks, and food consumption that is asynchronous with natural circadian rhythms may exert adverse health effects and increase disease risk. Additionally, alterations in meal frequency and meal timing have the potential to influence energy and macronutrient intake.A regular meal pattern including breakfast consumption, consuming a higher proportion of energy early in the day, reduced meal frequency (i.e., 2–3 meals/day), and regular fasting periods may provide physiological benefits such as reduced inflammation, improved circadian rhythmicity, increased autophagy and stress resistance, and modulation of the gut microbiota
167 citations
TL;DR: This review summarizes the current understanding of the essential role of the Wnt pathway in bone regeneration and repair and suggests that Wnt factors could be used to promote bone healing after trauma.
Abstract: Wnt signaling plays a central regulatory role across a remarkably diverse range of functions during embryonic development, including those involved in the formation of bone and cartilage. Wnt signaling continues to play a critical role in adult osteogenic differentiation of mesenchymal stem cells. Disruptions in this highly-conserved and complex system leads to various pathological conditions, including impaired bone healing, autoimmune diseases and malignant degeneration. For reconstructive surgeons, critically sized skeletal defects represent a major challenge. These are frequently associated with significant morbidity in both the recipient and donor sites. The Wnt pathway is an attractive therapeutic target with the potential to directly modulate stem cells responsible for skeletal tissue regeneration and promote bone growth, suggesting that Wnt factors could be used to promote bone healing after trauma. This review summarizes our current understanding of the essential role of the Wnt pathway in bone regeneration and repair.
TL;DR: In this paper, the authors examined the temporal trends and outcomes of mechanical complications after myocardial infarction in the contemporary era, including Papillary muscle rupture, ventricular septal defect, and free wall rupture.
Abstract: Objectives The aim of this study was to examine the temporal trends and outcomes of mechanical complications after myocardial infarction in the contemporary era. Background Data regarding temporal trends and outcomes of mechanical complications after ST-segment elevation myocardial infarction (STEMI) and non–ST-segment elevation myocardial infarction (NSTEMI) are limited in the contemporary era. Methods The National Inpatient Sample database (2003 to September 2015) was queried to identify all STEMI and NSTEMI hospitalizations. Temporal trends and outcomes of mechanical complications after STEMI and NSTEMI, including papillary muscle rupture, ventricular septal defect, and free wall rupture, were described. Results The analysis included 3,951,861 STEMI and 5,114,270 NSTEMI hospitalizations. Mechanical complications occurred in 10,726 of STEMI hospitalizations (0.27%) and 3,041 of NSTEMI hospitalizations (0.06%), with no changes in trends (p = 0.13 and p = 0.83, respectively). The rates of in-hospital mortality in patients with mechanical complications were 42.4% after STEMI and 18.0% after NSTEMI, with no significant trend changes (p = 0.62 and p = 0.12, respectively). After multivariate adjustment, patients who had mechanical complications after myocardial infarction had higher in-hospital mortality, cardiogenic shock, acute kidney injury, hemodialysis, and respiratory complications compared with those without mechanical complications. Predictors of lower mortality in patients with mechanical complications who developed cardiogenic shock included surgical repair in the STEMI and NSTEMI cohorts and percutaneous coronary intervention in the STEMI cohort. Conclusions Contemporary data from a large national database show that the rates of mechanical complications are low in patients presenting with STEMI and NSTEMI. Post–myocardial infarction mechanical complications continue to be associated with high mortality rates, which did not improve during the study period.
TL;DR: Data revealed that exercise and probiotic treatment can decrease the progress of Alzheimer's Disease and the beneficial effects could be partly mediated by alteration of the microbiome.
TL;DR: AgNP-mediated reduction in RSV replication is demonstrated, both in epithelial cell lines and in experimentally infected BALB/c mice, the first in vivo report demonstrating antiviral activity of AgNPs during RSV infection.
Abstract: Respiratory syncytial virus (RSV) is an important etiological agent of respiratory infection in children for which no specific treatment option is available. The RSV virion contains two surface glycoproteins (F and G) that are vital for the initial phases of infection, making them critical targets for RSV therapeutics. Recent studies have identified the broad-spectrum antiviral properties of silver nanoparticles (AgNPs) against respiratory pathogens, such as adenovirus, parainfluenza, and influenza. AgNPs achieve this by attaching to viral glycoproteins, blocking entry into the host cell. The objective of this study was to evaluate the antiviral and immunomodulatory effects of AgNPs in RSV infection. Herein we demonstrate AgNP-mediated reduction in RSV replication, both in epithelial cell lines and in experimentally infected BALB/c mice. Marked reduction in pro-inflammatory cytokines (i.e., IL-1α, IL-6, TNF-α) and pro-inflammatory chemokines (i.e., CCL2, CCL3, CCL5) was also observed. Conversely, CXCL1, G-CSF, and GM-CSF were increased in RSV-infected mice treated with AgNPs, consistent with an increase of neutrophil recruitment and activation in the lung tissue. Following experimental antibody-dependent depletion of neutrophils, the antiviral effect of AgNPs in mice treated was ablated. To our knowledge, this is the first in vivo report demonstrating antiviral activity of AgNPs during RSV infection.
TL;DR: A pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias is identified, providing functional evidence that mutations in splicing factors drive myeloid malignancy development, and identifying spliceosomal changes as a mediator of IDH2-mutantLeukaemogenesis.
Abstract: Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis. Analyses of transcriptomes from patients with acute myeloid leukaemia identified frequently co-occurring mutations of IDH2 and SRSF2, which functional analyses showed to have distinct and coordinated leukaemogenic effects on the epigenome and RNA splicing.
TL;DR: The pathology and pathogenesis of the most common adverse sequela of T. cruzi infection-Chagas heart disease-is highlighted and a discussion of key unanswered questions and a view to the future is discussed.
Abstract: Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of people infected with the protozoan parasite Trypanosoma cruzi. One way T. cruzi is transmitted to people is through contact with infected kissing bugs, which are found in much of the Western Hemisphere, including in vast areas of the United States. The epidemiology of T. cruzi and Chagas heart disease and the varied mechanisms leading to myocyte destruction, mononuclear cell infiltration, fibrosis, and edema in the heart have been extensively studied by hundreds of scientists for more than 100 years. Despite this wealth of knowledge, it is still impossible to predict what will happen in an individual infected with T. cruzi because of the tremendous variability in clonal parasite virulence and human susceptibility to infection and the lack of definitive molecular predictors of outcome from either side of the host-parasite equation. Further, while several distinct mechanisms of pathogenesis have been studied in isolation, it is certain that multiple coincident mechanisms combine to determine the ultimate outcome. For these reasons, Chagas disease is best considered a collection of related but distinct illnesses. This review highlights the pathology and pathogenesis of the most common adverse sequela of T. cruzi infection-Chagas heart disease-and concludes with a discussion of key unanswered questions and a view to the future.
TL;DR: These findings uncover a previously unappreciated mechanism of metazoan gene repression, akin to bacterial transcription attenuation, wherein promoter-proximal Pol II is prevented from entering productive elongation through factor-regulated termination.
TL;DR: ERAS pathways significantly reduce opioid use and length of hospital stay following autologous breast reconstruction without increasing complication rates, which is salient given the current US healthcare climate of rising expenditures and an opioid crisis.
Abstract: Enhanced recovery after surgery (ERAS) pathways are increasingly promoted in post-mastectomy reconstruction, with several articles reporting their benefits and safety. This meta-analysis appraises the evidence for ERAS pathways in breast reconstruction. A systematic search of Medline, EMBASE, and Cochrane databases was performed to identify reports of ERAS protocols in post-mastectomy breast reconstruction. Two reviewers screened studies using predetermined inclusion criteria. Studies evaluated at least one of the following end-points of interest: length of stay (LOS), opioid use, or major complications. Risk of bias was assessed for each study. Meta-analysis was performed via a mixed-effects model to compare outcomes for ERAS versus traditional standard of care. Surgical techniques were assessed through subgroup analysis. A total of 260 articles were identified; 9 (3.46%) met inclusion criteria with a total of 1191 patients. Most studies had “fair” methodological quality and incomplete implementation of ERAS society recommendations was noted. Autologous flaps comprised the majority of cases. In autologous breast reconstruction, ERAS significantly reduces opioid use [Mean difference (MD) = − 183.96, 95% CI − 340.27 to 27.64, p = 0.02) and LOS (MD) = − 1.58, 95% CI − 1.99 to 1.18, p < 0.00001] versus traditional care. There is no significant difference in the incidence of complications (major complications, readmission, hematoma, and infection). ERAS pathways significantly reduce opioid use and length of hospital stay following autologous breast reconstruction without increasing complication rates. This is salient given the current US healthcare climate of rising expenditures and an opioid crisis.
TL;DR: It is proposed that two forms of the ligand binding two receptors and activating two signaling pathways enables fine-tuned neutrophil function compared to a single form, a single receptor, or a single pathway.
TL;DR: Together, the biocompatible hollow nanoparticle described herein provides an excellent strategy for delivering both subunit vaccine candidates and novel adjuvants, enabling accelerated development of effective and safe vaccines against emerging viral pathogens.
Abstract: The continued threat of emerging, highly lethal infectious pathogens such as Middle East respiratory syndrome coronavirus (MERS-CoV) calls for the development of novel vaccine technology that offers safe and effective prophylactic measures. Here, a novel nanoparticle vaccine is developed to deliver subunit viral antigens and STING agonists in a virus-like fashion. STING agonists are first encapsulated into capsid-like hollow polymeric nanoparticles, which show multiple favorable attributes, including a pH-responsive release profile, prominent local immune activation, and reduced systemic reactogenicity. Upon subsequent antigen conjugation, the nanoparticles carry morphological semblance to native virions and facilitate codelivery of antigens and STING agonists to draining lymph nodes and immune cells for immune potentiation. Nanoparticle vaccine effectiveness is supported by the elicitation of potent neutralization antibody and antigen-specific T cell responses in mice immunized with a MERS-CoV nanoparticle vaccine candidate. Using a MERS-CoV-permissive transgenic mouse model, it is shown that mice immunized with this nanoparticle-based MERS-CoV vaccine are protected against a lethal challenge of MERS-CoV without triggering undesirable eosinophilic immunopathology. Together, the biocompatible hollow nanoparticle described herein provides an excellent strategy for delivering both subunit vaccine candidates and novel adjuvants, enabling accelerated development of effective and safe vaccines against emerging viral pathogens.
TL;DR: U uptake of the HPV vaccine remains modest, despite evidence that vaccine-type HPV prevalence is decreasing as a result of HPV vaccination, and geographic disparities in vaccination uptake across different US regions and by race/ethnicity may contribute to continuing disparities in HPV-related cancers.
Abstract: Human papillomavirus (HPV) is a common sexually transmitted infection which is the cause of several cancers, including cervical cancer, and genital warts. Although cervical cancer can be prevented through screening, this cancer persists in the US. More recently, HPV vaccination has the potential to decrease the burden of HPV-related disease among young HPV-unexposed adolescents. Several initiatives aimed to encourage HPV vaccination have been adopted. Unfortunately, uptake of the HPV vaccine remains modest, despite evidence that vaccine-type HPV prevalence is decreasing as a result of HPV vaccination. Further, geographic disparities in vaccination uptake across different US regions and by race/ethnicity may contribute to continuing disparities in HPV-related cancers. More data are needed to evaluate impact of HPV vaccination on HPV prevalence in smaller geographic areas. Further, more information is needed on the impact of individual vaccination programs and policy on population level vaccination and HPV prevalence.
Johns Hopkins University1, Memorial Sloan Kettering Cancer Center2, University of Washington3, University of Texas Southwestern Medical Center4, University of Pennsylvania5, Mayo Clinic6, Alfaisal University7, University of Texas MD Anderson Cancer Center8, Vanderbilt University9, Sheba Medical Center10, Harvard University11, National Marrow Donor Program12, University of Minnesota13, Children's National Medical Center14, Washington University in St. Louis15, Medical College of Wisconsin16, Baylor College of Medicine17, Fred Hutchinson Cancer Research Center18, University of Miami19, Case Western Reserve University20, University of Texas Medical Branch21, University of Paris22, Stanford University23, Vanderbilt University Medical Center24, National Institutes of Health25, Cornell University26
TL;DR: Advice is provided from experts in the fields of hematopoietic cell transplantation, cellular immunotherapy, and lymphoma regarding key clinical questions pertinent to the utilization of CD19 CAR T for the treatment of NHL.
TL;DR: Findings on aging and the immigrant health effect in the 3 most common immigrant destinations the United States, Canada, Australia, as well as in Europe are summarized.
Abstract: The rising number of immigrants to the United States and other western countries has been accompanied by rising interest in the characteristics of immigrants including their mortality risk and health status. In general, immigrants to the United States, Canada, and Australia enjoy a health advantage over the native populations, which has been coined the healthy immigrant effect. The purpose of this review is to summarize findings on aging and the immigrant health effect in the 3 most common immigrant destinations the United States, Canada, Australia, as well as in Europe. Much of the research in the United States has focused on the so-called Hispanic Paradox or the favorable health of Hispanics relative to non-Hispanic whites despite lower average socioeconomic status as well as other risk factors, with recent research beginning to pay attention to dietary and genetic factors. In all 3 countries, there is evidence of a health convergence of immigrants relative to the native-born population over approximately 10-20 years. By the time they reach old age, immigrants experience high rates of comorbidity and disability. Immigrant health selection appears to be the key reason explaining the immigrant health advantage. Immigrants to Europe also appear to be health selected but not as consistently as in the United States, Canada, and Australia. Immigrant enclaves appear to confer health advantages in the United States among older Hispanics but appear to have negative consequences in Europe. More attention needs to be given to the health and health care needs of the rising numbers of refugees to Europe as well as refugees in the Middle East, Africa, and elsewhere.
Imperial College London1, Monash University2, Johns Hopkins University3, University of Texas Medical Branch4, University of the West Indies5, University of London6, University of São Paulo7, Environment Agency8, Thailand Ministry of Public Health9, International Vaccine Institute10, National Autonomous University of Mexico11, Wellcome Trust12, University of Melbourne13
TL;DR: Important research and implementation questions remain for CYD-TDV, including the development of a highly sensitive and specific rapid diagnostic test to determine serostatus, simplified immunisation schedules, and assessment of the need for booster doses.
Abstract: The Strategic Advisory Group of Experts (SAGE) on Immunization advises WHO on global policies for vaccines. In April, 2016, SAGE issued recommendations on the use of the first licenced dengue vaccine, CYD-TDV. In November, 2017, a retrospective analysis of clinical trial data, stratifying participants according to their dengue serostatus before the first vaccine dose, showed that although in high seroprevalence settings the vaccine provides overall population benefit, there was an excess risk of severe dengue in seronegative vaccinees. SAGE's working group on dengue vaccines met to discuss the new data and mainly considered two vaccination strategies: vaccination of populations with dengue seroprevalence rates above 80% or screening of individuals before vaccination, and vaccinating only seropositive individuals. We report on the deliberations that informed the recommendation of the pre-vaccination screening strategy, in April, 2018. Important research and implementation questions remain for CYD-TDV, including the development of a highly sensitive and specific rapid diagnostic test to determine serostatus, simplified immunisation schedules, and assessment of the need for booster doses.
University of Minnesota1, China Agricultural University2, Tongji University3, Capital Medical University4, Imperial College London5, Xiamen University6, Chinese PLA General Hospital7, Tongji Medical College8, Fourth Military Medical University9, Peking University10, University of California, Irvine11, University of Texas Medical Branch12, University of Pennsylvania13
TL;DR: MIR31, increased in colon tissues from patients with CD or UC, reduces the inflammatory response in colon epithelium of mice by preventing expression of inflammatory cytokine receptors (Il7R and Il17RA) and signaling proteins (GP130), and regulates the WNT and Hippo signaling pathways to promote epithelial regeneration following injury.
Katholieke Universiteit Leuven1, United States Department of Agriculture2, University of Ljubljana3, Mississippi State University4, University of Texas Medical Branch5, Friedrich Loeffler Institute6, Centers for Disease Control and Prevention7, Colorado State University8, Columbia University9, University of California, Irvine10, University of the Free State11, National Health Laboratory Service12, Aix-Marseille University13, International Rice Research Institute14, Scripps Research Institute15, University of California, San Francisco16, Public Health Agency of Canada17, Mayo Clinic18, Hacettepe University19, United States Army Medical Research Institute of Infectious Diseases20, Chinese Center for Disease Control and Prevention21, Kansas State University22, Fudan University23, Bernhard Nocht Institute for Tropical Medicine24, Paris Diderot University25, University of Queensland26, Public Health England27, Indian Agricultural Research Institute28, Seoul National University29, Slovak Academy of Sciences30, Karolinska Institutet31, Wageningen University and Research Centre32, University of Washington33, University of Louisville34, University of Bari35, University of Hamburg36, Washington State University37, Aristotle University of Thessaloniki38, University of Helsinki39, University of Brasília40, National University of La Plata41, Pasteur Institute42, University of Maryland, Baltimore43, National Agriculture and Food Research Organization44, University of Glasgow45, University of Tokyo46, University of Oxford47, Korea University48, Fujian Agriculture and Forestry University49, North Carolina State University50, National Chung Hsing University51, Universidade Federal de Viçosa52, National Institutes of Health53
TL;DR: The updated taxonomy of the order Bunyavirales is presented as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
Abstract: In October 2018, the order Bunyavirales was amended by inclusion of the family Arenaviridae, abolishment of three families, creation of three new families, 19 new genera, and 14 new species, and renaming of three genera and 22 species. This article presents the updated taxonomy of the order Bunyavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
TL;DR: Oral dietary glutamine supplements dramatically and safely reduced all major IBS-related endpoints and ‘Intestinal hyperpermeability’ (elevated urinary lactulose/mannitol ratios) was normalised in the glutamine but not the control group.
Abstract: Background More effective treatments are needed for patients with postinfectious, diarrhoea-predominant, irritable bowel syndrome (IBS-D). Accordingly, we conducted a randomised, double-blind, placebo-controlled, 8-week-long trial to assess the efficacy and safety of oral glutamine therapy in patients who developed IBS-D with increased intestinal permeability following an enteric infection. Methods Eligible adults were randomised to glutamine (5 g/t.i.d.) or placebo for 8 weeks. The primary end point was a reduction of ≥50 points on the Irritable Bowel Syndrome Severity Scoring System (IBS-SS). Secondary endpoints included: raw IBS-SS scores, changes in daily bowel movement frequency, stool form (Bristol Stool Scale) and intestinal permeability. Results Fifty-four glutamine and 52 placebo subjects completed the 8-week study. The primary endpoint occurred in 43 (79.6%) in the glutamine group and 3 (5.8%) in the placebo group (a 14-fold difference). Glutamine also reduced all secondary endpoint means: IBS-SS score at 8 weeks (301 vs 181, p Conclusions In patients with IBS-D with intestinal hyperpermeability following an enteric infection, oral dietary glutamine supplements dramatically and safely reduced all major IBS-related endpoints. Large randomised clinical trials (RCTs) should now be done to validate these findings, assess quality of life benefits and explore pharmacological mechanisms. Trial registration number NCT 1414244; Results.
TL;DR: Applying CapQuant to RNA from purified dengue virus, Escherichia coli, yeast, mouse tissues, and human cells, it is reported that CapQuant accurately captured the preference for purine nucleotides at eukaryotic transcription start sites and the correlation between metabolite levels and metabolite caps.
Abstract: Chemical modification of transcripts with 5' caps occurs in all organisms. Here, we report a systems-level mass spectrometry-based technique, CapQuant, for quantitative analysis of an organism's cap epitranscriptome. The method was piloted with 21 canonical caps-m7GpppN, m7GpppNm, GpppN, GpppNm, and m2,2,7GpppG-and 5 'metabolite' caps-NAD, FAD, UDP-Glc, UDP-GlcNAc, and dpCoA. Applying CapQuant to RNA from purified dengue virus, Escherichia coli, yeast, mouse tissues, and human cells, we discovered new cap structures in humans and mice (FAD, UDP-Glc, UDP-GlcNAc, and m7Gpppm6A), cell- and tissue-specific variations in cap methylation, and high proportions of caps lacking 2'-O-methylation (m7Gpppm6A in mammals, m7GpppA in dengue virus). While substantial Dimroth-induced loss of m1A and m1Am arose with specific RNA processing conditions, human lymphoblast cells showed no detectable m1A or m1Am in caps. CapQuant accurately captured the preference for purine nucleotides at eukaryotic transcription start sites and the correlation between metabolite levels and metabolite caps.
TL;DR: The results suggest that attenuation via Integrator cleavage limits production of many full-length mRNAs, allowing precise control of transcription outputs.
Abstract: Cellular homeostasis requires transcriptional outputs to be coordinated, and many events post-transcription initiation can dictate the levels and functions of mature transcripts. To systematically identify regulators of inducible gene expression, we performed high-throughput RNAi screening of the Drosophila Metallothionein A (MtnA) promoter. This revealed that the Integrator complex, which has a well-established role in 3' end processing of small nuclear RNAs (snRNAs), attenuates MtnA transcription during copper stress. Integrator complex subunit 11 (IntS11) endonucleolytically cleaves MtnA transcripts, resulting in premature transcription termination and degradation of the nascent RNAs by the RNA exosome, a complex also identified in the screen. Using RNA-seq, we then identified >400 additional Drosophila protein-coding genes whose expression increases upon Integrator depletion. We focused on a subset of these genes and confirmed that Integrator is bound to their 5' ends and negatively regulates their transcription via IntS11 endonuclease activity. Many noncatalytic Integrator subunits, which are largely dispensable for snRNA processing, also have regulatory roles at these protein-coding genes, possibly by controlling Integrator recruitment or RNA polymerase II dynamics. Altogether, our results suggest that attenuation via Integrator cleavage limits production of many full-length mRNAs, allowing precise control of transcription outputs.
TL;DR: The ROS-mediated activation of the ASK1-signalosome p38 MAPK pathway suggests it is a major center of dissemination of the ROS signals that promote senescence, aging and cardiovascular diseases, and pharmacological intervention is feasible through the continued identification of potent, non-toxic small molecule inhibitors of either ASK 1 or p38MAPK activity.
Abstract: The ASK1-signalosome→p38 MAPK and SAPK/JNK signaling networks promote senescence (in vitro) and aging (in vivo, animal models and human cohorts) in response to oxidative stress and inflammation. These networks contribute to the promotion of age-associated cardiovascular diseases of oxidative stress and inflammation. Furthermore, their inhibition delays the onset of these cardiovascular diseases as well as senescence and aging. In this review we focus on whether the (a) ASK1-signalosome, a major center of distribution of reactive oxygen species (ROS)-mediated stress signals, plays a role in the promotion of cardiovascular diseases of oxidative stress and inflammation; (b) The ASK1-signalosome links ROS signals generated by dysfunctional mitochondrial electron transport chain complexes to the p38 MAPK stress response pathway; (c) the pathway contributes to the sensitivity and vulnerability of aged tissues to diseases of oxidative stress; and (d) the importance of inhibitors of these pathways to the development of cardioprotection and pharmaceutical interventions. We propose that the ASK1-signalosome regulates the progression of cardiovascular diseases. The resultant attenuation of the physiological characteristics of cardiomyopathies and aging by inhibition of the ASK1-signalosome network lends support to this conclusion. Importantly the ROS-mediated activation of the ASK1-signalosome p38 MAPK pathway suggests it is a major center of dissemination of the ROS signals that promote senescence, aging and cardiovascular diseases. Pharmacological intervention is, therefore, feasible through the continued identification of potent, non-toxic small molecule inhibitors of either ASK1 or p38 MAPK activity. This is a fruitful future approach to the attenuation of physiological aspects of mammalian cardiomyopathies and aging.