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Arterioles and sinusoids of the bone marrow (BM) are accompanied by stromal cells that express nerve/glial antigen 2 (NG2) and leptin receptor (LepR), and constitute specialized niches that regulate quiescence and proliferation of haematopoietic stem cells (HSCs). However, how niche cells differentially regulate HSC functions remains unknown. Here, we show that the effects of cytokines regulating HSC functions are dependent on the producing cell sources. Deletion of chemokine C-X-C motif ligand 12 (Cxcl12) or stem cell factor (Scf) from all perivascular cells marked by nestin-GFP dramatically depleted BM HSCs. Selective Cxcl12 deletion from arteriolar NG2 + cells, but not from sinusoidal LepR + cells, caused HSC reductions and altered HSC localization in BM. By contrast, deletion of Scf in LepR + cells, but not NG2 + cells, led to reductions in BM HSC numbers. These results uncover distinct contributions of cytokines derived from perivascular cells in separate vascular niches to HSC maintenance. Asada  et al.  examine differential effects of CXCL12 and SCF expression by perivascular bone marrow niche cells, such as arteriolar NG2 + vascular smooth muscle cells and sinusoidal LepR + cells, on haematopoietic stem cell maintenance and mobilization.

Most tools developed to visualize hierarchically clustered heatmaps generate static images. Clustergrammer is a web-based visualization tool with interactive features such as: zooming, panning, filtering, reordering, sharing, performing enrichment analysis, and providing dynamic gene annotations. Clustergrammer can be used to generate shareable interactive visualizations by uploading a data table to a web-site, or by embedding Clustergrammer in Jupyter Notebooks. The Clustergrammer core libraries can also be used as a toolkit by developers to generate visualizations within their own applications. Clustergrammer is demonstrated using gene expression data from the cancer cell line encyclopedia (CCLE), original post-translational modification data collected from lung cancer cells lines by a mass spectrometry approach, and original cytometry by time of flight (CyTOF) single-cell proteomics data from blood. Clustergrammer enables producing interactive web based visualizations for the analysis of diverse biological data.

Increased levels of peripheral cytokines have been previously associated with depression in preclinical and clinical research. Although the precise nature of peripheral immune dysfunction in depression remains unclear, evidence from animal studies points towards a dysregulated response of peripheral leukocytes as a risk factor for stress susceptibility. This study examined dynamic release of inflammatory blood factors from peripheral blood mononuclear cells (PBMC) in depressed patients and associations with neural and behavioral measures of reward processing. Thirty unmedicated patients meeting criteria for unipolar depressive disorder and 21 healthy control volunteers were enrolled. PBMCs were isolated from whole blood and stimulated ex vivo with lipopolysaccharide (LPS). Olink multiplex assay was used to analyze a large panel of inflammatory proteins. Participants completed functional magnetic resonance imaging with an incentive flanker task to probe neural responses to reward anticipation, as well as clinical measures of anhedonia and pleasure including the Temporal Experience of Pleasure Scale (TEPS) and the Snaith-Hamilton Pleasure Scale (SHAPS). LPS stimulation revealed larger increases in immune factors in depressed compared to healthy subjects using an aggregate immune score (t49 = 2.83, p = 0.007). Higher peripheral immune score was associated with reduced neural responses to reward anticipation within the ventral striatum (VS) (r = −0.39, p = 0.01), and with reduced anticipation of pleasure as measured with the TEPS anticipatory sub-score (r = −0.318, p = 0.023). Our study provides new evidence suggesting that dynamic hyper-reactivity of peripheral leukocytes in depressed patients is associated with blunted activation of the brain reward system and lower subjective anticipation of pleasure.

Atherosclerosis is driven by multifaceted contributions of the immune system within the circulation and at vascular focal sites. However, specific characteristics of dysregulated immune cells within atherosclerotic lesions that lead to clinical events such as ischemic stroke or myocardial infarction are poorly understood. Here, using single-cell proteomic and transcriptomic analyses, we uncovered distinct features of both T cells and macrophages in carotid artery plaques of patients with clinically symptomatic disease (recent stroke or transient ischemic attack) compared to asymptomatic disease (no recent stroke). Plaques from symptomatic patients were characterized by a distinct subset of CD4 + T cells and by T cells that were activated and differentiated. Moreover, some T cell subsets in these plaques presented markers of T cell exhaustion. Additionally, macrophages from these plaques contained alternatively activated phenotypes, including subsets associated with plaque vulnerability. In plaques from asymptomatic patients, T cells and macrophages were activated and displayed evidence of interleukin-1β signaling. The identification of specific features of innate and adaptive immune cells in plaques that are associated with cerebrovascular events may enable the design of more precisely tailored cardiovascular immunotherapies. Single-cell proteomic and transcriptional profiling of atherosclerotic lesions from human carotid arteries reveals specific features of lesional T cells and macrophages associated with symptomatic disease.

Infants born prematurely or with low birth weights are more susceptible to kidney dysfunction throughout their lives. Multiple proteins measured in urine are noninvasive biomarkers of subclinical kidney damage, but few studies have examined the joint effects of multiple biomarkers. We conducted an exploratory study of 103 children in the Programing Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) longitudinal birth cohort, and measured nine proteins selected a priori in banked spot urine samples collected at ages 4-6. The goal of our study was to explore the combined effects of kidney damage biomarkers previously associated with birth outcomes. To do this, we generated kidney biomarker indices using weighted quantile sum regression and assessed associations with length of gestation or birth weight. A decile increase in each kidney biomarker index was associated with 2-day shorter gestations (β = -2.0, 95% CI: -3.2, -0.9) and 59-gram lower birth weights (β = -58.5, 95% CI: -98.3, -18.7), respectively. Weights highlighting the contributions showed neutrophil gelatinase-associated lipocalin (NGAL) (60%) and osteopontin (19%) contributed most to the index derived for gestational age. NGAL (66%) and beta-2-microglobulin (10%) contributed most to the index derived for birth weight. Joint analyses of multiple kidney biomarkers can provide integrated measures of kidney dysfunction and improved statistical assessments compared to biomarkers assessed individually. Additionally, shorter gestations and lower birth weights may contribute to subclinical kidney damage measurable in childhood.

The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially localized multicellular ‘immunity hubs’ defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens and found an association with beneficial response to PD-1 blockade. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcome. This hub is distinct from mature tertiary lymphoid structures and is enriched for stem-like TCF7 + PD-1 + CD8 + T cells, activated CCR7 + LAMP3 + dendritic cells and CCL19 + fibroblasts as well as chemokines that organize these cells. Within the stem-immunity hub, we find preferential interactions between CXCL10 + macrophages and TCF7 − CD8 + T cells as well as between mature regulatory dendritic cells and TCF7 + CD4 + and regulatory T cells. These results provide a picture of the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes. The spatial organization of cells in solid tumors is considered to be important for immune response and response to therapy. Here the authors use multiomics including spatial transcriptomics of human lung tumors prior to patients being treated and show among other things an association of stem-immunity hubs rich in stem-like CD8 + T cells with positive response to anti-PD-1 therapy.

The library of integrated network-based cellular signatures (LINCS) L1000 data set currently comprises of over a million gene expression profiles of chemically perturbed human cell lines. Through unique several intrinsic and extrinsic benchmarking schemes, we demonstrate that processing the L1000 data with the characteristic direction (CD) method significantly improves signal to noise compared with the MODZ method currently used to compute L1000 signatures. The CD processed L1000 signatures are served through a state-of-the-art web-based search engine application called L1000CDS 2 . The L1000CDS 2 search engine provides prioritization of thousands of small-molecule signatures, and their pairwise combinations, predicted to either mimic or reverse an input gene expression signature using two methods. The L1000CDS 2 search engine also predicts drug targets for all the small molecules profiled by the L1000 assay that we processed. Targets are predicted by computing the cosine similarity between the L1000 small-molecule signatures and a large collection of signatures extracted from the gene expression omnibus (GEO) for single-gene perturbations in mammalian cells. We applied L1000CDS 2 to prioritize small molecules that are predicted to reverse expression in 670 disease signatures also extracted from GEO, and prioritized small molecules that can mimic expression of 22 endogenous ligand signatures profiled by the L1000 assay. As a case study, to further demonstrate the utility of L1000CDS 2 , we collected expression signatures from human cells infected with Ebola virus at 30, 60 and 120 min. Querying these signatures with L1000CDS 2 we identified kenpaullone, a GSK3B/CDK2 inhibitor that we show, in subsequent experiments, has a dose-dependent efficacy in inhibiting Ebola infection in vitro without causing cellular toxicity in human cell lines. In summary, the L1000CDS 2 tool can be applied in many biological and biomedical settings, while improving the extraction of knowledge from the LINCS L1000 resource. Gene expression: Search engine helps find drug leads A new search engine can help scientists identify small molecules that will alter gene expression patterns in human cells. The resource, known as L1000CDS2, can also predict drug targets for some 20,000 compounds. A US team led by Avi Ma’ayan from the Icahn School of Medicine at Mount Sinai developed the search engine, which improves previous methods for interrogating chemicals in the LINCS L1000 database, a large library of compound-induced gene expression signatures. As a proof-of-principle, the researchers used L1000CDS2 to identify a chemical called kenpaullone as a potential inhibitor of Ebola virus in human cells—a finding they confirmed in lab experiments. The authors suggest the search engine can aid in discovering new uses for old drugs, plus help predict candidate agents for many complex diseases.

Gene expression data are accumulating exponentially in public repositories. Reanalysis and integration of themed collections from these studies may provide new insights, but requires further human curation. Here we report a crowdsourcing project to annotate and reanalyse a large number of gene expression profiles from Gene Expression Omnibus (GEO). Through a massive open online course on Coursera, over 70 participants from over 25 countries identify and annotate 2,460 single-gene perturbation signatures, 839 disease versus normal signatures, and 906 drug perturbation signatures. All these signatures are unique and are manually validated for quality. Global analysis of these signatures confirms known associations and identifies novel associations between genes, diseases and drugs. The manually curated signatures are used as a training set to develop classifiers for extracting similar signatures from the entire GEO repository. We develop a web portal to serve these signatures for query, download and visualization. A wealth of gene expression data is publicly available, yet is little use without additional human curation. Ma’ayan and colleagues report a crowdsourcing project involving over 70 participants to annotate and analyse thousands of human disease-related gene expression datasets.

Background To analyse differences in confirmed cases, hospitalisations and deaths due to COVID-19 related to census section socioeconomic variables.  Methods Ecological study in the 12 largest municipalities in Andalusia (Spain) during the first three epidemic waves of the COVID-19 (02/26/20—03/31/21), covering 2,246 census sections (unit of analysis) and 3,027,000 inhabitants. Incidence was calculated, standardised by age and sex, for infection, hospitalisation and deaths based on average gross income per household (AGI) for the census tracts in each urban area. Association studied using a Poisson Bayesian regression model with random effects for spatial smoothing. Results There were 140,743 cases of COVID-19, of which 12,585 were hospitalised and 2,255 died. 95.2% of cases were attributed to the second and third waves, which were jointly analysed. We observed a protective effect of income for infection in 3/12 cities. Almeria had the largest protective effect (smoothed relative risk (SRR) = 0.84 (0.75–0.94 CI 95%). This relationship reappeared with greater magnitude in 10/12 cities for hospitalisation, lowest risk in Algeciras SRR = 0.41 (0.29–0.56). The pattern was repeated for deaths in all urban areas and reached statistical significance in 8 cities. Lowest risk in Dos Hermanas SRR = 0.35 (0.15–0.81). Conclusions Income inequalities by geographical area were found in the incidence of COVID-19. The strengths of the association increased when analysing the severe outcomes of hospitalisations and, above all, deaths.

The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular 'immunity hubs' defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens, and found that they were associated with beneficial responses to PD-1-blockade. Immunity hubs were enriched for many interferon-stimulated genes, T cells in multiple differentiation states, and CXCL9/10/11 + macrophages that preferentially interact with CD8 T cells. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcomes, distinct from mature tertiary lymphoid structures, and enriched for stem-like TCF7+PD-1+ CD8 T cells and activated CCR7 + LAMP3 + dendritic cells, as well as chemokines that organize these cells. These results elucidate the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular 'immunity hubs' defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens, and found that they were associated with beneficial responses to PD-1-blockade. Immunity hubs were enriched for many interferon-stimulated genes, T cells in multiple differentiation states, and CXCL9/10/11 + macrophages that preferentially interact with CD8 T cells. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcomes, distinct from mature tertiary lymphoid structures, and enriched for stem-like TCF7+PD-1+ CD8 T cells and activated CCR7 + LAMP3 + dendritic cells, as well as chemokines that organize these cells. These results elucidate the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.