It is unclear why some SARS-CoV-2 patients readily resolve infection while others develop severe disease. By interrogating metabolic programs of immune cells in severe and recovered coronavirus ...disease 2019 (COVID-19) patients compared with other viral infections, we identify a unique population of T cells. These T cells express increased Voltage-Dependent Anion Channel 1 (VDAC1), accompanied by gene programs and functional characteristics linked to mitochondrial dysfunction and apoptosis. The percentage of these cells increases in elderly patients and correlates with lymphopenia. Importantly, T cell apoptosis is inhibited in vitro by targeting the oligomerization of VDAC1 or blocking caspase activity. We also observe an expansion of myeloid-derived suppressor cells with unique metabolic phenotypes specific to COVID-19, and their presence distinguishes severe from mild disease. Overall, the identification of these metabolic phenotypes provides insight into the dysfunctional immune response in acutely ill COVID-19 patients and provides a means to predict and track disease severity and/or design metabolic therapeutic regimens.
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•T cells with a unique metabolic profile are expanded in acute COVID-19•These T cells are prone to mitochondrial apoptosis, correlating with lymphopenia•Metabolically distinct myeloid-derived suppressor cells increase in acute COVID-19•The presence of these M-MDSCs in acute COVID-19 correlates with disease severity
The precise immunological defects that correlate with disease severity in COVID-19 have yet to be determined. Based on immune-metabolic profiling, Thompson et al. identify unique populations of T cells and myeloid cells that correlate with disease severity. These findings highlight metabolic pathways as possible therapeutic targets for COVID-19.
Objectives The aim of this study was to test the hypothesis that rare variants are associated with drug-induced long QT interval syndrome (diLQTS) and torsades de pointes. Background diLQTS is ...associated with the potentially fatal arrhythmia torsades de pointes. The contribution of rare genetic variants to the underlying genetic framework predisposing to diLQTS has not been systematically examined. Methods We performed whole-exome sequencing on 65 diLQTS patients and 148 drug-exposed control subjects of European descent. We used rare variant analyses (variable threshold and sequence kernel association test) and gene-set analyses to identify genes enriched with rare amino acid coding (AAC) variants associated with diLQTS. Significant associations were reanalyzed by comparing diLQTS patients with 515 ethnically matched control subjects from the National Heart, Lung, and Blood Grand Opportunity Exome Sequencing Project. Results Rare variants in 7 genes were enriched in the diLQTS patients according to the sequence kernel association test or variable threshold compared with drug-exposed controls (p < 0.001). Of these, we replicated the diLQTS associations for KCNE1 and ACN9 using 515 Exome Sequencing Project control subjects (p < 0.05). A total of 37% of the diLQTS patients also had 1 or more rare AAC variants compared with 21% of control subjects (p = 0.009), in a pre-defined set of 7 congenital long QT interval syndrome (cLQTS) genes encoding potassium channels or channel modulators ( KCNE1 , KCNE2 , KCNH2 , KCNJ2 , KCNJ5 , KCNQ1 , AKAP9 ). Conclusions By combining whole-exome sequencing with aggregated rare variant analyses, we implicate rare variants in KCNE1 and ACN9 as risk factors for diLQTS. Moreover, diLQTS patients were more burdened by rare AAC variants in cLQTS genes encoding potassium channel modulators, supporting the idea that multiple rare variants, notably across cLQTS genes, predispose to diLQTS.
Early growth response 1 (EGR1) is an immediate early gene and transcription factor previously found to be significantly upregulated in human astrocytoma cells infected with Venezuelan equine ...encephalitis virus (VEEV). The loss of EGR1 resulted in decreased cell death but had no significant impact on viral replication. Here, we extend these studies to determine the impacts of EGR1 on gene expression following viral infection. Inflammatory genes CXCL3, CXCL8, CXCL10, TNF, and PTGS2 were upregulated in VEEV-infected cells, which was partially dependent on EGR1. Additionally, transcription factors, including EGR1 itself, as well as ATF3, FOS, JUN, KLF4, EGR2, and EGR4 were found to be partially transcriptionally dependent on EGR1. We also examined the role of EGR1 and the changes in gene expression in response to infection with other alphaviruses, including eastern equine encephalitis virus (EEEV), Sindbis virus (SINV), and chikungunya virus (CHIKV), as well as Zika virus (ZIKV) and Rift Valley fever virus (RVFV), members of the Flaviviridae and Phenuiviridae families, respectively. EGR1 was significantly upregulated to varying degrees in EEEV-, CHIKV-, RVFV-, SINV-, and ZIKV-infected astrocytoma cells. Genes that were identified as being partially transcriptionally dependent on EGR1 in infected cells included ATF3 (EEEV, CHIKV, ZIKV), JUN (EEEV), KLF4 (SINV, ZIKV, RVFV), CXCL3 (EEEV, CHIKV, ZIKV), CXCL8 (EEEV, CHIKV, ZIKV, RVFV), CXCL10 (EEEV, RVFV), TNF-α (EEEV, ZIKV, RVFV), and PTGS2 (EEEV, CHIKV, ZIKV). Additionally, inhibition of the inflammatory gene PTGS2 with Celecoxib, a small molecule inhibitor, rescued astrocytoma cells from VEEV-induced cell death but had no impact on viral titers. Collectively, these results suggest that EGR1 induction following viral infection stimulates multiple inflammatory mediators. Managing inflammation and cell death in response to viral infection is of utmost importance, especially during VEEV infection where survivors are at-risk for neurological sequalae.
The purification and cloning of the acyl-coenzyme A: cholesterol acyltransferase (ACAT) enzymes and the sterol O-acyltransferase (
) genes has opened new areas of interest in cholesterol metabolism ...given their profound effects on foam cell biology and intestinal lipid absorption. The generation of mouse models deficient in
or
confirmed the importance of their gene products on cholesterol esterification and lipoprotein physiology. Although these studies supported clinical trials which used non-selective ACAT inhibitors, these trials did not report benefits, and one showed an increased risk. Early genetic studies have implicated common variants in both genes with human traits, including lipoprotein levels, coronary artery disease, and Alzheimer's disease; however, modern genome-wide association studies have not replicated these associations. In contrast, the common
variants are most reproducibly associated with testosterone levels.
Here, we show that apolipoprotein A1 (apoA1), the major protein component of high density lipoprotein (HDL), through both innate and adaptive immune processes, potently suppresses tumor growth and ...metastasis in multiple animal tumor models, including the aggressive B16F10L murine malignant melanoma model. Mice expressing the human apoA1 transgene (A1Tg) exhibited increased infiltration of CD11b+ F4/80+ macrophages with M1, anti-tumor phenotype, reduced tumor burden and metastasis, and enhanced survival. In contrast, apoA1-deficient (A1KO) mice showed markedly heightened tumor growth and reduced survival. Injection of human apoA1 into A1KO mice inoculated with tumor cells remarkably reduced both tumor growth and metastasis, enhanced survival, and promoted regression of both tumor and metastasis burden when administered following palpable tumor formation and metastasis development. Studies with apolipoprotein A2 revealed the anti-cancer therapeutic effect was specific to apoA1. In vitro studies ruled out substantial direct suppressive effects by apoA1 or HDL on tumor cells. Animal models defective in different aspects of immunity revealed both innate and adaptive arms of immunity contribute to complete apoA1 anti-tumor activity. This study reveals a potent immunomodulatory role for apoA1 in the tumor microenvironment, altering tumor-associated macrophages from a pro-tumor M2 to an anti-tumor M1 phenotype. Use of apoA1 to redirect in vivo elicited tumor-infiltrating macrophages toward tumor rejection may hold benefit as a potential cancer therapeutic.
Background: ApoA1, a component of HDL, promotes anti-inflammatory, immunomodulatory, and cardioprotective functions.
Results: ApoA1 suppresses tumor growth and metastasis, primarily via modulation of innate and adaptive immune responses.
Conclusion: ApoA1 impacts tumor biology at multiple levels, which appear to be linked to immunomodulatory function.
Significance: ApoA1 redirects elicited immune cells toward tumor suppression and rejection and may hold benefit as a cancer therapeutic.
SUMMARY
The Groningen gas reservoir, situated in the northeast of the Netherlands, is western Europe’s largest producing gas field and has been in production since 1963. The gas production has ...induced both subsidence and seismicity. Seismicity is detected and located using the Koninklijk Nederlands Meteorologisch Instituut shallow-borehole array for the period 2015–2017, incorporating the back projection techniques of QuakeMigrate and the nonlinear location procedure to constrain earthquake locations and depths. The uncertainties on the estimated depths are estimated taking into account velocity model, changes in station array geometry and uncertainties in the measurement of arrival times of the P and S waves. We show that the depth distribution of seismicity is consistent with nucleation within the reservoir (28 per cent) or in the overburden (60 per cent) within ∼500 m from the top of the reservoir. Earthquakes with hypocentres in the overburden likely originate from overlying Zechstein anhydrite caprock. Based on their depth distribution, it seems like the earthquakes are primarily driven by the elastic strain in the reservoir and overburden, induced by the reservoir compaction. We estimate the probability of earthquakes nucleating beneath the reservoir in the underlying Carboniferous limestone and basement, to be no more than 12 per cent.
How ecosystem productivity and species richness are interrelated is one of the most debated subjects in the history of ecology. Decades of intensive study have yet to discern the actual mechanisms ...behind observed global patterns. Here, by integrating the predictions from multiple theories into a single model and using data from 1,126 grassland plots spanning five continents, we detect the clear signals of numerous underlying mechanisms linking productivity and richness. We find that an integrative model has substantially higher explanatory power than traditional bivariate analyses. In addition, the specific results unveil several surprising findings that conflict with classical models. These include the isolation of a strong and consistent enhancement of productivity by richness, an effect in striking contrast with superficial data patterns. Also revealed is a consistent importance of competition across the full range of productivity values, in direct conflict with some (but not all) proposed models. The promotion of local richness by macroecological gradients in climatic favourability, generally seen as a competing hypothesis, is also found to be important in our analysis. The results demonstrate that an integrative modelling approach leads to a major advance in our ability to discern the underlying processes operating in ecological systems.
The redistribution of species has emerged as one of the most pervasive impacts of anthropogenic climate warming, and presents many societal challenges. Understanding how temperature regulates species ...distributions is particularly important for mobile marine fauna such as sharks given their seemingly rapid responses to warming, and the socio‐political implications of human encounters with some dangerous species. The predictability of species distributions can potentially be improved by accounting for temperature's influence on performance, an elusive relationship for most large animals. We combined multi‐decadal catch data and bio‐logging to show that coastal abundance and swimming performance of tiger sharks Galeocerdo cuvier are both highest at ~22°C, suggesting thermal constraints on performance may regulate this species' distribution. Tiger sharks are responsible for a large proportion of shark bites on humans, and a focus of controversial control measures in several countries. The combination of distribution and performance data moves towards a mechanistic understanding of tiger shark's thermal niche, and delivers a simple yet powerful indicator for predicting the location and timing of their occurrences throughout coastlines. For example, tiger sharks are mostly caught at Australia's popular New South Wales beaches (i.e. near Sydney) in the warmest months, but our data suggest similar abundances will occur in winter and summer if annual sea surface temperatures increase by a further 1–2°C.
Being able to predict how temperature regulates species distributions is particularly important for mobile marine animals such as sharks given their seemingly rapid responses to warming, and implications of human encounters with some dangerous species. We combined catch data and accelerometry tagging to show that coastal abundance and swimming activity of tiger sharks Galeocerdo cuvier are both highest at ~22°C. Our combination of distribution and performance data takes a step towards a mechanistic understanding of tiger shark's thermal niche, and delivers a simple indicator that may be useful for predicting coastal occurrences of this potentially dangerous species.
Deterministic earthquake prediction remains elusive, but time‐dependent probabilistic seismicity forecasting seems within reach thanks to the development of physics‐based models relating seismicity ...to stress changes. Difficulties include constraining the earthquake nucleation model and fault initial stress state. Here, we analyze induced earthquakes from the Groningen gas field, where production is strongly seasonal, and seismicity began 3 decades after production started. We use the seismicity response to stress variations to constrain the earthquake nucleation process and calibrate models for time‐dependent forecasting of induced earthquakes. Remarkable agreements of modeled and observed seismicity are obtained when we consider (a) the initial strength excess, (b) the finite duration of earthquake nucleation, and (c) the seasonal variations of gas production. We propose a novel metric to quantify the nucleation model's ability to capture the damped amplitude and the phase of the seismicity response to short‐timescale (seasonal) stress variations which allows further tightening the model's parameters.
Plain Language Summary
Earthquakes are difficult to predict with certainty, but progress in forecasting their likelihood using probabilistic models based on stress changes has been made. However, challenges remain in understanding how earthquakes start and the initial conditions of faults. Here, we analyzed induced earthquakes in the Groningen gas field, where production is seasonal and seismic activity began 34 years after gas production started. By studying how the earthquakes respond to rapid changes in stress, we could better understand how they start and develop models to forecast their temporal occurrence. By considering factors like the initial strength of the faults, the duration of earthquake initiation, and seasonal variations in gas production we could accurately match the observed seismic activity. We introduced a new measure to evaluate how well the models captured the dampened strength and timing of seismic activity in response to short‐term stress changes (such as seasonal variations), which helped refine the model's parameters.
Key Points
An improved reservoir, geomechanical, and seismicity modeling workflow is proposed for forecasting induced seismicity at various timescales
Short‐timescale stress variations allow constraining the characteristics of the earthquake nucleation process using Groningen as case study
Initial strength excess and finite duration of the nucleation process allow reproducing long‐and‐short timescale characteristics of seismicity
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