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Today's genomics workflows typically require alignment to a reference sequence, which limits discovery. We introduce a unifying paradigm, SPLASH (Statistically Primary aLignment Agnostic Sequence Homing), which directly analyzes raw sequencing data, using a statistical test to detect a signature of regulation: sample-specific sequence variation. SPLASH detects many types of variation and can be efficiently run at scale. We show that SPLASH identifies complex mutation patterns in SARS-CoV-2, discovers regulated RNA isoforms at the single-cell level, detects the vast sequence diversity of adaptive immune receptors, and uncovers biology in non-model organisms undocumented in their reference genomes: geographic and seasonal variation and diatom association in eelgrass, an oceanic plant impacted by climate change, and tissue-specific transcripts in octopus. SPLASH is a unifying approach to genomic analysis that enables expansive discovery without metadata or references.
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Algoritmos , Genómica , Genoma , Análisis de Secuencia de ARN , Humanos , Antígenos HLA/genética , Análisis de la Célula IndividualRESUMEN
Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
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Prurito/inmunología , Células Receptoras Sensoriales/inmunología , Células Receptoras Sensoriales/metabolismo , Transducción de Señal , Enfermedades de la Piel/inmunología , Animales , Ganglios Espinales , Humanos , Interleucina-13/inmunología , Interleucina-4/inmunología , Janus Quinasa 1/metabolismo , Ratones , Ratones Endogámicos C57BL , Prurito/metabolismo , Enfermedades de la Piel/patologíaRESUMEN
Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNFΔARE mice, a model of ileitis, revealed TLO formation at valves of CLVs. TLOs obstructed cellular and molecular outflow from the gut and were sites of lymph leakage and backflow. Tumor necrosis factor (TNF) neutralization begun at early stages of TLO formation restored lymph transport. However, robustly developed, chronic TLOs resisted regression and restoration of flow after TNF neutralization. TNF stimulation of cultured lymphatic endothelial cells reprogrammed responses to oscillatory shear stress, preventing the induction of valve-associated genes. Disrupted transport of immune cells, driven by loss of valve integrity and TLO formation, may contribute to the pathology of Crohn's disease.
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Enfermedad de Crohn/inmunología , Células Endoteliales/inmunología , Íleon/inmunología , Linfa/metabolismo , Vasos Linfáticos/inmunología , Mesenterio/inmunología , Estructuras Linfoides Terciarias/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Movimiento Celular , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Ileítis , Linfangitis , Ratones , Ratones Noqueados , Estrés MecánicoRESUMEN
The nervous system plays important roles in homeostasis and inflammatory responses in tissues. However, the regulation of lymph nodes (LN) by nerves remains largely unknown. Huang et al. demonstrate that LNs are innervated by unique peptidergic nociceptors that signal to various endothelial, stromal, and immune cell types in LNs.
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Inmunidad , Ganglios Linfáticos , Homeostasis , Células Receptoras Sensoriales , Células del EstromaRESUMEN
RATIONALE & OBJECTIVE: The decision to initiate kidney replacement therapy (KRT) for acute kidney injury (AKI) in cirrhosis remains controversial because it is unclear which patients will benefit. We sought to characterize factors associated with recovery from KRT-treated AKI in patients with cirrhosis to inform shared clinical decision-making. STUDY DESIGN: Population-based retrospective cohort study. SETTING & PARTICIPANTS: Adult patients from Ontario, Canada, identified using administrative data to have cirrhosis at the time of hospital admission with AKI (based on serum creatinine level) who were treated with KRT (January 1, 2009, to December 31, 2016) and followed up until the end of 2017. EXPOSURES: Demographic characteristics and comorbidities before admission. OUTCOMES: Kidney recovery defined as the absence of KRT for at least 30 days. ANALYTICAL APPROACH: The cumulative incidences of kidney recovery, death, and liver transplant were calculated at 1, 3, 6, and 12 months, and independent predictors of kidney recovery were evaluated using Fine and Gray competing risk regression models that generated subdistribution hazards ratios (sHRs). RESULTS: Overall, 722 patients were included (median age, 61 [interquartile range, 54-68] years; Model for End-Stage Liver Disease (MELD)-Na score, 26 [interquartile range, 22-34]; 66% were male; 52% had viral hepatitis, 25% nonalcoholic fatty liver disease, 18% alcohol-associated liver disease). The cumulative incidences of kidney recovery at 1, 3, 6, and 12 months were 3%, 22%, 25%, and 26%, respectively. Higher MELD-Na score (sHR per 5 units greater, 0.72 [95% CI, 0.65-0.80]), acute-on-chronic liver failure (sHR, 0.61 [95% CI, 0.43-0.86]), and sepsis (sHR, 0.57 [95% CI, 0.41-0.81]) were associated with a lower hazard of kidney recovery, whereas those on a liver transplant waitlist (sHR, 3.10 [95% CI, 1.96-4.88]) and who were admitted to a teaching hospital (sHR, 1.48 [95% CI, 1.05-2.08]) were more likely to experience kidney recovery. LIMITATIONS: Observational design, AKI etiology not identified. CONCLUSIONS: Kidney recovery from KRT occurred in only one quarter of patients and was very unlikely after 3 months. These findings provide information regarding prognosis that may guide decisions regarding KRT initiation and continuation.
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Lesión Renal Aguda , Enfermedad Hepática en Estado Terminal , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/etiología , Lesión Renal Aguda/terapia , Adulto , Enfermedad Hepática en Estado Terminal/complicaciones , Femenino , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/epidemiología , Cirrosis Hepática/terapia , Masculino , Persona de Mediana Edad , Ontario/epidemiología , Diálisis Renal , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Abstract: The COVID-19 pandemic triggered a surge in demand for N95 or equivalent respirators that the global supply chain was unable to satisfy. This shortage in critical equipment has inspired research that addresses the immediate problems and has accelerated the development of the next-generation filtration media and respirators. This article provides a brief review of the most recent work with regard to face respirators and filtration media. We discuss filtration efficiency of the widely utilized cloth masks. Next, the sterilization of and reuse of existing N95 respirators to extend the existing stockpile is discussed. To expand near-term supplies, optimization of current manufacturing methods, such as melt-blown processes and electrospinning, has been explored. Future manufacturing methods have been investigated to address long-term supply shortages. Novel materials with antiviral and sterilizable properties with the ability for multiple reuses have been developed and will contribute to the development of the next generation of longer lasting multi-use N95 respirators. Finally, additively manufactured respirators are reviewed, which enable a rapidly deployable source of reusable respirators that can use any filtration fabric.
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Calculated profile mode mass spectrometry (MS) data are fitted to lineshape-calibrated liquid chromatography LC/MS data using a Multiple Linear Regression (MLR) model to quantitate the relative concentrations of stable or radiolabeled compound mixtures. This alternative approach significantly improves the precision and accuracy over existing MS methods while providing the much-needed statistical diagnostics on the goodness-of-fit model and thus reliability of the quantitative results obtained. Test compound data containing S/Cl atoms have been measured with either stable deuterium labeling or radioisotope uniform 14 C labeling onto an aromatic ring. Since the entire relative distribution of variously labeled compounds is automatically obtained through this approach, it is feasible to directly calculate the Specific Activity (SA) from such mass spectral analysis without radioactivity detection and the usual standard curve quantitation. The applicability of this approach to systematically and accurately accommodate and account for incomplete labeling chemistry or other impurities is also discussed, with wide-ranging implications including metabolic flux, HDX (Hydrogen/Deuterium Exchange), and quantitative proteomics.
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CCCTC-binding factor (CTCF) is an 11 zinc finger DNA-binding domain protein that regulates gene expression by modifying 3D chromatin structure. Human mutations in CTCF cause intellectual disability and autistic features. Knocking out Ctcf in mouse embryonic neurons is lethal by neonatal age, but the effects of CTCF deficiency in postnatal neurons are less well studied. We knocked out Ctcf postnatally in glutamatergic forebrain neurons under the control of Camk2a-Cre. CtcfloxP/loxP;Camk2a-Cre+ (Ctcf CKO) mice of both sexes were viable and exhibited profound deficits in spatial learning/memory, impaired motor coordination, and decreased sociability by 4 months of age. Ctcf CKO mice also had reduced dendritic spine density in the hippocampus and cerebral cortex. Microarray analysis of mRNA from Ctcf CKO mouse hippocampus identified increased transcription of inflammation-related genes linked to microglia. Separate microarray analysis of mRNA isolated specifically from Ctcf CKO mouse hippocampal neurons by ribosomal affinity purification identified upregulation of chemokine signaling genes, suggesting crosstalk between neurons and microglia in Ctcf CKO hippocampus. Finally, we found that microglia in Ctcf CKO mouse hippocampus had abnormal morphology by Sholl analysis and increased immunostaining for CD68, a marker of microglial activation. Our findings confirm that Ctcf KO in postnatal neurons causes a neurobehavioral phenotype in mice and provide novel evidence that CTCF depletion leads to overexpression of inflammation-related genes and microglial dysfunction.SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a DNA-binding protein that organizes nuclear chromatin topology. Mutations in CTCF cause intellectual disability and autistic features in humans. CTCF deficiency in embryonic neurons is lethal in mice, but mice with postnatal CTCF depletion are less well studied. We find that mice lacking Ctcf in Camk2a-expressing neurons (Ctcf CKO mice) have spatial learning/memory deficits, impaired fine motor skills, subtly altered social interactions, and decreased dendritic spine density. We demonstrate that Ctcf CKO mice overexpress inflammation-related genes in the brain and have microglia with abnormal morphology that label positive for CD68, a marker of microglial activation. Our findings suggest that inflammation and dysfunctional neuron-microglia interactions are factors in the pathology of CTCF deficiency.
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Factor de Unión a CCCTC/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Inflamación/genética , Inflamación/patología , Microglía/patología , Neuronas/patología , Transcripción Genética/genética , Animales , Electroencefalografía , Femenino , Expresión Génica/genética , Integrasas , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/genética , Trastornos de la Memoria/psicología , Ratones , Ratones Noqueados , Análisis por Micromatrices , Neuronas/metabolismo , Desempeño Psicomotor , Conducta SocialRESUMEN
BACKGROUND: Mechanical chest compression devices have been proposed to improve the effectiveness of cardiopulmonary resuscitation (CPR). OBJECTIVES: To assess the effectiveness of resuscitation strategies using mechanical chest compressions versus resuscitation strategies using standard manual chest compressions with respect to neurologically intact survival in patients who suffer cardiac arrest. SEARCH METHODS: On 19 August 2017 we searched the Cochrane Central Register of Controlled Studies (CENTRAL), MEDLINE, Embase, Science Citation Index-Expanded (SCI-EXPANDED) and Conference Proceedings Citation Index-Science databases. Biotechnology and Bioengineering Abstracts and Science Citation abstracts had been searched up to November 2009 for prior versions of this review. We also searched two clinical trials registries for any ongoing trials not captured by our search of databases containing published works: Clinicaltrials.gov (August 2017) and the World Health Organization International Clinical Trials Registry Platform portal (January 2018). We applied no language restrictions. We contacted experts in the field of mechanical chest compression devices and manufacturers. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-RCTs and quasi-randomised studies comparing mechanical chest compressions versus manual chest compressions during CPR for patients with cardiac arrest. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included five new studies in this update. In total, we included 11 trials in the review, including data from 12,944 adult participants, who suffered either out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (IHCA). We excluded studies explicitly including patients with cardiac arrest caused by trauma, drowning, hypothermia and toxic substances. These conditions are routinely excluded from cardiac arrest intervention studies because they have a different underlying pathophysiology, require a variety of interventions specific to the underlying condition and are known to have a prognosis different from that of cardiac arrest with no obvious cause. The exclusions were meant to reduce heterogeneity in the population while maintaining generalisability to most patients with sudden cardiac death.The overall quality of evidence for the outcomes of included studies was moderate to low due to considerable risk of bias. Three studies (N = 7587) reported on the designated primary outcome of survival to hospital discharge with good neurologic function (defined as a Cerebral Performance Category (CPC) score of one or two), which had moderate quality evidence. One study showed no difference with mechanical chest compressions (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.82 to 1.39), one study demonstrated equivalence (RR 0.79, 95% CI 0.60 to 1.04), and one study demonstrated reduced survival (RR 0.41, CI 0.21 to 0.79). Two other secondary outcomes, survival to hospital admission (N = 7224) and survival to hospital discharge (N = 8067), also had moderate quality level of evidence. No studies reported a difference in survival to hospital admission. For survival to hospital discharge, two studies showed benefit, four studies showed no difference, and one study showed harm associated with mechanical compressions. No studies demonstrated a difference in adverse events or injury patterns between comparison groups but the quality of data was low. Marked clinical and statistical heterogeneity between studies precluded any pooled estimates of effect. AUTHORS' CONCLUSIONS: The evidence does not suggest that CPR protocols involving mechanical chest compression devices are superior to conventional therapy involving manual chest compressions only. We conclude on the balance of evidence that mechanical chest compression devices used by trained individuals are a reasonable alternative to manual chest compressions in settings where consistent, high-quality manual chest compressions are not possible or dangerous for the provider (eg, limited rescuers available, prolonged CPR, during hypothermic cardiac arrest, in a moving ambulance, in the angiography suite, during preparation for extracorporeal CPR [ECPR], etc.). Systems choosing to incorporate mechanical chest compression devices should be closely monitored because some data identified in this review suggested harm. Special attention should be paid to minimising time without compressions and delays to defibrillation during device deployment.
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Reanimación Cardiopulmonar/métodos , Paro Cardíaco/terapia , Masaje Cardíaco/métodos , Circulación Sanguínea , Reanimación Cardiopulmonar/instrumentación , Reanimación Cardiopulmonar/mortalidad , Paro Cardíaco/mortalidad , Masaje Cardíaco/instrumentación , Masaje Cardíaco/mortalidad , Hospitalización , Humanos , Alta del Paciente , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Early pathological descriptions of Crohn disease (CD) argued for a potential defect in lymph transport; however, this concept has not been thoroughly investigated. In mice, poor healing in response to infection-induced tissue damage can cause hyperpermeable lymphatic collecting vessels in mesenteric adipose tissue that impair antigen and immune cell access to mesenteric lymph nodes (LNs), which normally sustain appropriate immunity. To investigate whether analogous changes might occur in human intestinal disease, we established a three-dimensional imaging approach to characterize the lymphatic vasculature in mesenteric tissue from controls or patients with CD. In CD specimens, B-cell-rich aggregates resembling tertiary lymphoid organs (TLOs) impinged on lymphatic collecting vessels that enter and exit LNs. In areas of creeping fat, which characterizes inflammation-affected areas of the bowel in CD, we observed B cells and apparent innate lymphoid cells that had invaded the lymphatic vessel wall, suggesting these cells may be mediators of lymphatic remodeling. Although TLOs have been described in many chronic inflammatory states, their anatomical relationship to preestablished LNs has never been revealed. Our data indicate that, at least in the CD-affected mesentery, TLOs are positioned along collecting lymphatic vessels in a manner expected to affect delivery of lymph to LNs.
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Enfermedad de Crohn/diagnóstico por imagen , Ganglios Linfáticos/diagnóstico por imagen , Vasos Linfáticos/diagnóstico por imagen , Adulto , Animales , Linfocitos B/patología , Enfermedad de Crohn/patología , Enfermedad de Crohn/cirugía , Femenino , Humanos , Íleon/diagnóstico por imagen , Íleon/patología , Imagenología Tridimensional , Inflamación , Intestinos/patología , Intestinos/cirugía , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Vasos Linfáticos/patología , Vasos Linfáticos/cirugía , Masculino , Mesenterio/diagnóstico por imagen , Mesenterio/patología , Mesenterio/cirugía , Ratones , Persona de Mediana Edad , Estructuras Linfoides Terciarias/diagnóstico por imagen , Estructuras Linfoides Terciarias/patologíaRESUMEN
Thousands of loci in the human and mouse genomes give rise to circular RNA transcripts; at many of these loci, the predominant RNA isoform is a circle. Using an improved computational approach for circular RNA identification, we found widespread circular RNA expression in Drosophila melanogaster and estimate that in humans, circular RNA may account for 1% as many molecules as poly(A) RNA. Analysis of data from the ENCODE consortium revealed that the repertoire of genes expressing circular RNA, the ratio of circular to linear transcripts for each gene, and even the pattern of splice isoforms of circular RNAs from each gene were cell-type specific. These results suggest that biogenesis of circular RNA is an integral, conserved, and regulated feature of the gene expression program.
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Regulación de la Expresión Génica , ARN Mensajero/genética , ARN/genética , Transcripción Genética , Animales , Linaje de la Célula , Drosophila melanogaster/genética , Exones/genética , Humanos , Ratones , Poli A/genética , Isoformas de Proteínas/genética , ARN/biosíntesis , Empalme del ARN/genética , ARN Circular , Análisis de Secuencia de ARNRESUMEN
OBJECTIVES: If being weighed impacts perceptions of eating behavior, it is important that the order of questionnaires and weighing be considered in research and practice. A quasi-experimental study was performed to examine whether being weighed immediately prior to completing a questionnaire affects responses to eating behavior questions. It was hypothesized that being weighed would serve as a priming stimulus and increase measures of dietary restraint, disinhibition, and hunger. METHODS: Trained researchers collected a sample of volunteers (n = 355) in 8 locations in the United States on two Saturdays in the summer of 2011. Half of the participants were weighed immediately prior to completing the Three Factor Eating Questionnaire (TFEQ), with the remaining half weighed immediately after TFEQ completion. RESULTS: A priori hypotheses were not supported despite replicating known relationships between weight, dietary restraint and disinhibition. Results indicated that being weighed first produced a difference in differences on disinhibition scores between low restraint score (95% CI = 4.65-6.02) and high restraint score (95% CI = 6.11-7.57) compared to being weighed after questionnaire completion (p = 0.003). However, this relationship was not significant when modeling restraint as a continuous variable, questioning the use of dichotomization. CONCLUSIONS: Being weighed is unlikely to be a strong enough prime to significantly change scores on eating behavior questionnaires for everyone, but may allow differences in restraint status to become more evident. Researchers assessing dietary restraint should be wary of the possibility of producing different results when treating restraint as continuous or dichotomous, which could lead to different interpretations.
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Peso Corporal , Conducta Alimentaria/psicología , Encuestas y Cuestionarios , Adulto , Femenino , Humanos , Hambre , Inhibición Psicológica , Masculino , Percepción , Autoinforme , Factores de Tiempo , Estados UnidosRESUMEN
Every year, ovarian cancer kills approximately 14,000 women in the United States and more than 140,000 women worldwide. Most of these deaths are caused by tumors of the serous histological type, which is rarely diagnosed before it has disseminated. By deep paired-end sequencing of mRNA from serous ovarian cancers, followed by deep sequencing of the corresponding genomic region, we identified a recurrent fusion transcript. The fusion transcript joins the 5' exons of ESRRA, encoding a ligand-independent member of the nuclear-hormone receptor superfamily, to the 3' exons of C11orf20, a conserved but uncharacterized gene located immediately upstream of ESRRA in the reference genome. To estimate the prevalence of the fusion, we tested 67 cases of serous ovarian cancer by RT-PCR and sequencing and confirmed its presence in 10 of these. Targeted resequencing of the corresponding genomic region from two fusion-positive tumor samples identified a nearly clonal chromosomal rearrangement positioning ESRRA upstream of C11orf20 in one tumor, and evidence of local copy number variation in the ESRRA locus in the second tumor. We hypothesize that the recurrent novel fusion transcript may play a role in pathogenesis of a substantial fraction of serous ovarian cancers and could provide a molecular marker for detection of the cancer. Gene fusions involving adjacent or nearby genes can readily escape detection but may play important roles in the development and progression of cancer.
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Biomarcadores de Tumor/genética , Cromosomas Humanos Par 11/genética , Cistadenocarcinoma Seroso/genética , Neoplasias Glandulares y Epiteliales/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias Ováricas/genética , Receptores de Estrógenos/genética , Empalme Alternativo , Secuencia de Aminoácidos , Canadá , Carcinoma Epitelial de Ovario , Estudios de Casos y Controles , Aberraciones Cromosómicas , Cromosomas Humanos Par 11/química , Cistadenocarcinoma Seroso/epidemiología , Cistadenocarcinoma Seroso/patología , Variaciones en el Número de Copia de ADN , Exones , Femenino , Humanos , Datos de Secuencia Molecular , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/epidemiología , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/patología , Prevalencia , ARN Mensajero , Análisis de Secuencia de ADN , Análisis de Secuencia de ARN , Estados Unidos , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
In combination with cell-intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with neoadjuvant chemotherapy and radiotherapy. We developed spatially constrained optimal transport interaction analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid coculture system. We identified enrichment in interleukin-6 family signaling that functionally confers resistance to chemotherapy. Overall, this study demonstrates that characterization of the tumor microenvironment using single-cell spatial transcriptomics allows for the identification of molecular interactions that may play a role in the emergence of therapeutic resistance and offers a spatially based analysis framework that can be broadly applied to other contexts.
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BACKGROUND: Although patients with cirrhosis are at increased risk of death, the exact causes of death have not been reported in the contemporary era. This study aimed to describe cause-specific mortality in patients with cirrhosis in the general population. METHODS: Retrospective cohort study using administrative health care data from Ontario, Canada. Adult patients with cirrhosis from 2000-2017 were identified. Cirrhosis etiologies were defined as HCV, HBV, alcohol-associated liver disease (ALD), NAFLD, or autoimmune liver disease/other with validated algorithms. Patients were followed until death, liver transplant, or end of study. Primary outcome was the cause of death as liver-related, cardiovascular disease, non-hepatic malignancy, and external causes (accident/self-harm/suicide/homicide). Nonparametric analyses were used to describe the cumulative incidence of cause-specific death by cirrhosis etiology, sex, and compensation status. RESULTS: Overall, 202,022 patients with cirrhosis were identified (60% male, median age 56 y (IQR 46-67), 52% NAFLD, 26% alcohol-associated liver disease, 11% HCV). After a median follow-up of 5 years (IQR 2-12), 81,428 patients died, and 3024 (2%) received liver transplant . Patients with compensated cirrhosis mostly died from non-hepatic malignancies and cardiovascular disease (30% and 27%, respectively, in NAFLD). The 10-year cumulative incidence of liver-related deaths was the highest among those with viral hepatitis (11%-18%) and alcohol-associated liver disease (25%), those with decompensation (37%) and/or HCC (50%-53%). Liver transplant occurred at low rates (< 5%), and in men more than women. CONCLUSIONS: Cardiovascular disease and cancer-related mortality exceed liver-related mortality in patients with compensated cirrhosis.
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Carcinoma Hepatocelular , Enfermedades Cardiovasculares , Hepatitis C , Hepatopatías Alcohólicas , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Adulto , Humanos , Masculino , Femenino , Persona de Mediana Edad , Causas de Muerte , Carcinoma Hepatocelular/epidemiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Neoplasias Hepáticas/patología , Estudios de Cohortes , Enfermedades Cardiovasculares/complicaciones , Estudios Retrospectivos , Ontario/epidemiología , Cirrosis Hepática/complicaciones , Hepatitis C/complicacionesRESUMEN
Diversity-generating and mobile genetic elements are key to microbial and viral evolution and can result in evolutionary leaps. State-of-the-art algorithms to detect these elements have limitations. Here, we introduce DIVE, a new reference-free approach to overcome these limitations using information contained in sequencing reads alone. We show that DIVE has improved detection power compared to existing reference-based methods using simulations and real data. We use DIVE to rediscover and characterize the activity of known and novel elements and generate new biological hypotheses about the mobilome. Building on DIVE, we develop a reference-free framework capable of de novo discovery of mobile genetic elements.
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Transferencia de Gen Horizontal , Secuencias Repetitivas Esparcidas , Elementos Transponibles de ADNRESUMEN
Today's genomics workflows typically require alignment to a reference sequence, which limits discovery. We introduce a new unifying paradigm, SPLASH (Statistically Primary aLignment Agnostic Sequence Homing), an approach that directly analyzes raw sequencing data to detect a signature of regulation: sample-specific sequence variation. The approach, which includes a new statistical test, is computationally efficient and can be run at scale. SPLASH unifies detection of myriad forms of sequence variation. We demonstrate that SPLASH identifies complex mutation patterns in SARS-CoV-2 strains, discovers regulated RNA isoforms at the single cell level, documents the vast sequence diversity of adaptive immune receptors, and uncovers biology in non-model organisms undocumented in their reference genomes: geographic and seasonal variation and diatom association in eelgrass, an oceanic plant impacted by climate change, and tissue-specific transcripts in octopus. SPLASH is a new unifying approach to genomic analysis that enables an expansive scope of discovery without metadata or references.
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The authors have withdrawn this manuscript due to a duplicate posting of manuscript number BIORXIV/2022/497555. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. The correct preprint can be found at doi: https://doi.org/10.1101/2022.06.24.497555.
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Microglia, resident macrophages of the CNS, are essential to brain development, homeostasis, and disease. Microglial activation and proliferation are hallmarks of many CNS diseases, including neuropathic pain. However, molecular mechanisms that govern the spinal neuroimmune axis in the setting of neuropathic pain remain incompletely understood. Here, we show that genetic ablation or pharmacological blockade of transient receptor potential vanilloid type 4 (TRPV4) markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury. Mechanistically, microglia-expressed TRPV4 mediated microglial activation and proliferation and promoted functional and structural plasticity of excitatory spinal neurons through release of lipocalin-2. Our results suggest that microglial TRPV4 channels reside at the center of the neuroimmune axis in the spinal cord, which transforms peripheral nerve injury into central sensitization and neuropathic pain, thereby identifying TRPV4 as a potential new target for the treatment of chronic pain.
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Neuralgia , Neuroinmunomodulación , Ratones , Animales , Canales Catiónicos TRPV/genética , Médula Espinal , Neuralgia/genética , MicroglíaRESUMEN
In combination with cell intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged high-plex single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with specific malignant subtypes and neoadjuvant chemotherapy/radiotherapy. We developed Spatially Constrained Optimal Transport Interaction Analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid co-culture system. Overall, this study demonstrates that characterization of the tumor microenvironment using high-plex single-cell spatial transcriptomics allows for identification of molecular interactions that may play a role in the emergence of chemoresistance and establishes a translational spatial biology paradigm that can be broadly applied to other malignancies, diseases, and treatments.