Macrophages play an important role in structural cardiac remodeling and the transition to heart failure following myocardial infarction (MI). Previous research has focused on the impact of ...blood-derived monocytes on cardiac repair. Here we examined the contribution of resident cavity macrophages located in the pericardial space adjacent to the site of injury. We found that disruption of the pericardial cavity accelerated maladaptive post-MI cardiac remodeling. Gata6+ macrophages in mouse pericardial fluid contributed to the reparative immune response. Following experimental MI, these macrophages invaded the epicardium and lost Gata6 expression but continued to perform anti-fibrotic functions. Loss of this specialized macrophage population enhanced interstitial fibrosis after ischemic injury. Gata6+ macrophages were present in human pericardial fluid, supporting the notion that this reparative function is relevant in human disease. Our findings uncover an immune cardioprotective role for the pericardial tissue compartment and argue for the reevaluation of surgical procedures that remove the pericardium.
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•Pericardial cavity in mouse and human serves as a reservoir for GPCMs•GPCMs are transcriptionally distinct from neighboring cardiac macrophages•GPCMs relocate rapidly to the ischemic heart and undergo phenotypic alterations•Absence of GPCMs in Lyz2cre;Gata6fl/fl mice promotes post-injury cardiac fibrosis
Deniset et al. describe the pericardial cavity as an important source of resident macrophages that migrate into the heart following ischemic injury and prevent detrimental repair caused by excessive fibrosis.
The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, ...functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
Hippocampal activity represents many behaviorally important variables, including context, an animal’s location within a given environmental context, time, and reward. Using longitudinal calcium ...imaging in mice, multiple large virtual environments, and differing reward contingencies, we derived a unified probabilistic model of CA1 representations centered on a single feature—the field propensity. Each cell’s propensity governs how many place fields it has per unit space, predicts its reward-related activity, and is preserved across distinct environments and over months. Propensity is broadly distributed—with many low, and some very high, propensity cells—and thus strongly shapes hippocampal representations. This results in a range of spatial codes, from sparse to dense. Propensity varied ∼10-fold between adjacent cells in salt-and-pepper fashion, indicating substantial functional differences within a presumed cell type. Intracellular recordings linked propensity to cell excitability. The stability of each cell’s propensity across conditions suggests this fundamental property has anatomical, transcriptional, and/or developmental origins.
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•Each CA1 pyramidal neuron has a propensity to have place fields that differs across cells•A cell’s propensity is fixed across contexts and time, scaled in rewarded and novel areas•The subpopulation of low propensity cells yields a sparse code for location•Intracellular data provide evidence that excitability underlies propensity differences
A unified response pattern of hippocampal place cells, driven by individual cell-intrinsic mechanisms, quantitatively predicts the structure of representation of space at the population level across varying conditions by the hippocampus in mice.
We examine trends in racial and ethnic discrimination in hiring in six European and North American countries: Canada, France, Germany, Great Britain, the Netherlands, and the United States. Our ...sample includes all available discrimination estimates from 90 field experimental studies of hiring discrimination, encompassing more than 170,000 applications for jobs. The years covered vary by country, ranging from 1969 to 2017 for Great Britain to 1994 to 2017 for Germany. We examine trends in discrimination against four racial-ethnic origin groups: African/Black, Asian, Latin American/Hispanic, and Middle Eastern or North African. The results indicate that levels of discrimination in callbacks have remained either unchanged or slightly increased overall for most countries and origin categories. There are three notable exceptions. First, hiring discrimination against ethnic groups with origins in the Middle East and North Africa increased during the 2000s relative to the 1990s. Second, we find that discrimination in France declined, although from very high to "merely" high levels. Third, we find evidence that discrimination in the Netherlands has increased over time. Controls for study characteristics do not change these trends. Contrary to the idea that discrimination will tend to decline in Western countries, we find that discrimination has not fallen over the last few decades in five of the six Western countries we examine.
Ganglion cells (GCs) are fundamental to retinal neural circuitry, processing photoreceptor signals for transmission to the brain via their axons. However, much remains unknown about their role in ...vision and their vulnerability to disease leading to blindness. A major bottleneck has been our inability to observe GCs and their degeneration in the living human eye. Despite two decades of development of optical technologies to image cells in the living human retina, GCs remain elusive due to their high optical translucency. Failure of conventional imaging—using predominately singly scattered light—to reveal GCs has led to a focus on multiply-scattered, fluorescence, two-photon, and phase imaging techniques to enhance GC contrast. Here, we show that singly scattered light actually carries substantial information that reveals GC somas, axons, and other retinal neurons and permits their quantitative analysis. We perform morphometry on GC layer somas, including projection of GCs onto photoreceptors and identification of the primary GC subtypes, even beneath nerve fibers. We obtained singly scattered images by: (i) marrying adaptive optics to optical coherence tomography to avoid optical blurring of the eye; (ii) performing 3D subcellular image registration to avoid motion blur; and (iii) using organelle motility inside somas as an intrinsic contrast agent. Moreover, through-focus imaging offers the potential to spatially map individual GCs to underlying amacrine, bipolar, horizontal, photoreceptor, and retinal pigment epithelium cells, thus exposing the anatomical substrate for neural processing of visual information. This imaging modality is also a tool for improving clinical diagnosis and assessing treatment of retinal disease.
Sodium-glucose cotransporter 2 inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, ...their effects on cardiac structure and function in HFrEF are uncertain.
We designed a multicenter, randomized, double-blind, placebo-controlled trial (the SUGAR-DM-HF trial Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus, or Prediabetes, and Heart Failure) to investigate the cardiac effects of empagliflozin in patients in New York Heart Association functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomly assigned 1:1 to empagliflozin 10 mg once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The coprimary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area and LV global longitudinal strain both measured using cardiovascular magnetic resonance. Secondary efficacy outcomes included other cardiovascular magnetic resonance measures (LV end-diastolic volume index, LV ejection fraction), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, B-lines on lung ultrasound, and biomarkers (including N-terminal pro-B-type natriuretic peptide).
From April 2018 to August 2019, 105 patients were randomly assigned: mean age 68.7 (SD, 11.1) years, 77 (73.3%) male, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LV ejection fraction 32.5% (9.8%), and 81 (77.1%) New York Heart Association II and 24 (22.9%) New York Heart Association III. Patients received standard treatment for HFrEF. In comparison with placebo, empagliflozin reduced LV end-systolic volume index by 6.0 (95% CI, -10.8 to -1.2) mL/m
(
=0.015). There was no difference in LV global longitudinal strain. Empagliflozin reduced LV end-diastolic volume index by 8.2 (95% CI, -13.7 to -2.6) mL/m
(
=0.0042) and reduced N-terminal pro-B-type natriuretic peptide by 28% (2%-47%),
=0.038. There were no between-group differences in other cardiovascular magnetic resonance measures, diuretic intensification, Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, or B-lines.
The sodium-glucose cotransporter 2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which sodium-glucose cotransporter 2 inhibitors reduce heart failure hospitalization and mortality in HFrEF. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03485092.
Abstract
Field experiments using fictitious applications have become an increasingly important method for assessing hiring discrimination. Most field experiments of hiring, however, only observe ...whether the applicant receives an invitation to interview, called the “callback.” How adequate is our understanding of discrimination in the hiring process based on an assessment of discrimination in callbacks, when the ultimate subject of interest is discrimination in job offers? To address this question, we examine evidence from all available field experimental studies of racial or ethnic discrimination in hiring that go to the job offer outcome. Our sample includes 12 studies encompassing more than 13,000 job applications. We find considerable additional discrimination in hiring after the callback: majority applicants in our sample receive 53% more callbacks than comparable minority applicants, but majority applicants receive 145% more job offers than comparable minority applicants. The additional discrimination from interview to job offer is weakly correlated (r = 0.21) with the level of discrimination earlier in the hiring process. We discuss the implications of our results for theories of discrimination, including statistical discrimination.
Background and purpose
Although COVID‐19 predominantly affects the respiratory system, recent studies have reported the occurrence of neurological disorders such as stroke in relation to COVID‐19 ...infection. Encephalitis is an inflammatory condition of the brain that has been described as a severe neurological complication of COVID‐19. Despite a growing number of reported cases, encephalitis related to COVID‐19 infection has not been adequately characterised. To address this gap, this systematic review and meta‐analysis aims to describe the incidence, clinical course, and outcomes of patients who suffer from encephalitis as a complication of COVID‐19.
Methods
All studies published between 1 November 2019 and 24 October 2020 that reported on patients who developed encephalitis as a complication of COVID‐19 were included. Only cases with radiological and/or biochemical evidence of encephalitis were included.
Results
In this study, 610 studies were screened and 23 studies reporting findings from 129,008 patients, including 138 with encephalitis, were included. The average time from diagnosis of COVID‐19 to onset of encephalitis was 14.5 days (range = 10.8–18.2 days). The average incidence of encephalitis as a complication of COVID‐19 was 0.215% (95% confidence interval CI = 0.056%–0.441%). The average mortality rate of encephalitis in COVID‐19 patients was 13.4% (95% CI = 3.8%–25.9%). These patients also had deranged clinical parameters, including raised serum inflammatory markers and cerebrospinal fluid pleocytosis.
Conclusions
Although encephalitis is an uncommon complication of COVID‐19, when present, it results in significant morbidity and mortality. Severely ill COVID‐19 patients are at higher risk of suffering from encephalitis as a complication of the infection.
Abstract
We present an overview of the Large Program, “Early Planet Formation in Embedded Disks (eDisk),” conducted with the Atacama Large Millimeter/submillimeter Array (ALMA). The ubiquitous ...detections of substructures, particularly rings and gaps, in protoplanetary disks around T Tauri stars raise the possibility that at least some planet formation may have already started during the embedded stages of star formation. In order to address exactly how and when planet formation is initiated, the program focuses on searching for substructures in disks around 12 Class 0 and 7 Class I protostars in nearby (<200 pc) star-forming regions through 1.3 mm continuum observations at a resolution of ∼7 au (0.″04). The initial results show that the continuum emission, mostly arising from dust disks around the sample protostars, has relatively few distinctive substructures, such as rings and spirals, in marked contrast to Class II disks. The dramatic difference may suggest that substructures quickly develop in disks when the systems evolve from protostars to Class II sources, or alternatively that high optical depth of the continuum emission could obscure internal structures. Kinematic information obtained through CO isotopologue lines and other lines reveals the presence of Keplerian disks around protostars, providing us with crucial physical parameters, in particular, the dynamical mass of the central protostars. We describe the background of the eDisk program, the sample selection and their ALMA observations, and the data reduction, and we also highlight representative first-look results.
Inhibitors of the JAK family of nonreceptor tyrosine kinases have demonstrated clinical efficacy in rheumatoid arthritis and other inflammatory disorders; however, the precise mechanisms by which JAK ...inhibition improves inflammatory immune responses remain unclear. In this study, we examined the mode of action of tofacitinib (CP-690,550) on JAK/STAT signaling pathways involved in adaptive and innate immune responses. To determine the extent of inhibition of specific JAK/STAT-dependent pathways, we analyzed cytokine stimulation of mouse and human T cells in vitro. We also investigated the consequences of CP-690,550 treatment on Th cell differentiation of naive murine CD4(+) T cells. CP-690,550 inhibited IL-4-dependent Th2 cell differentiation and interestingly also interfered with Th17 cell differentiation. Expression of IL-23 receptor and the Th17 cytokines IL-17A, IL-17F, and IL-22 were blocked when naive Th cells were stimulated with IL-6 and IL-23. In contrast, IL-17A production was enhanced when Th17 cells were differentiated in the presence of TGF-β. Moreover, CP-690,550 also prevented the activation of STAT1, induction of T-bet, and subsequent generation of Th1 cells. In a model of established arthritis, CP-690,550 rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. Furthermore, efficacy in this disease model correlated with the inhibition of both JAK1 and JAK3 signaling pathways. CP-690,550 also modulated innate responses to LPS in vivo through a mechanism likely involving the inhibition of STAT1 signaling. Thus, CP-690,550 may improve autoimmune diseases and prevent transplant rejection by suppressing the differentiation of pathogenic Th1 and Th17 cells as well as innate immune cell signaling.
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