Publications by authors named "Ayshwarya Subramanian"

T helper (Th) 17 cells encompass a spectrum of cell states, including cells that maintain homeostatic tissue functions and pro-inflammatory cells that can drive autoimmune tissue damage. Identifying regulators that determine Th17 cell states can identify ways to control tissue inflammation and restore homeostasis. Here, we found that interleukin (IL)-23, a cytokine critical for inducing pro-inflammatory Th17 cells, decreased transcription factor T cell factor 1 (TCF1) expression.

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  • The study investigates how the balance between T helper type 1 (T1) and other T cell types is maintained, which is crucial for effective antiviral and anti-tumor responses.
  • Researchers utilized a specialized culture system and CRISPR screens to uncover regulators that influence T cell differentiation, focusing on the role of RAMP3 and its interactions with the neuropeptide CGRP.
  • Findings reveal that after viral infection, neuron-produced CGRP enhances T1 and CD8 T cell responses via RAMP3, creating a neuroimmune circuit that aids in controlling acute viral infections.
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  • - Diabetic kidney disease (DKD) is a major cause of kidney failure linked to diabetes and obesity, but effective treatments to slow its progression are currently unavailable.
  • - Research on single-cell transcriptomic profiles from DKD patients and mouse models reveals a growing population of macrophages expressing TREM2 in mice fed a high-fat diet, which correlates with obesity and diabetes.
  • - In mice lacking TREM2, increased kidney damage and cell injury were observed, indicating that boosting TREM2 macrophages could be a promising therapeutic approach for DKD.
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B cells can express pro-inflammatory cytokines that promote a wide variety of immune responses. Here we show that B cells expressing the phosphatidylserine receptor TIM-4, preferentially express IL-17A, as well as IL-22, IL-6, IL-1β, and GM-CSF - a collection of cytokines reminiscent of pathogenic Th17 cells. Expression of this proinflammatory module requires IL-23R signaling and selective expression of RORγt and IL-17A by TIM-4 B cells.

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Microglia play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA-155 (miR-155), enriched in immune cells, critically regulates MGnD.

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  • - The study examines how genetic diversity in 240 mammals impacts their resilience and risk of extinction, linking it to historical population sizes.
  • - It finds that species with smaller historical populations tend to have more harmful genetic mutations, increasing their extinction risk.
  • - Genomic data was shown to effectively predict conservation status, indicating its usefulness for assessing extinction risk when ecological information is lacking.
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Background: Quality control (QC) of cells, a critical first step in single-cell RNA sequencing data analysis, has largely relied on arbitrarily fixed data-agnostic thresholds applied to QC metrics such as gene complexity and fraction of reads mapping to mitochondrial genes. The few existing data-driven approaches perform QC at the level of samples or studies without accounting for biological variation.

Results: We first demonstrate that QC metrics vary with both tissue and cell types across technologies, study conditions, and species.

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The molecular underpinnings of organ dysfunction in acute COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we performed single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents. We identified hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells.

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  • * Genetic research points to the involvement of KIR and HLA genes in FGR, but identifying specific risk alleles is challenging due to various genetic and research constraints.
  • * This study reveals that the interaction between maternal KIR2DL1 and paternal HLA-C*0501 can cause FGR in a humanized mouse model, affecting uterine blood vessel remodeling and NK cell function, which leads to downstream impacts on maternal-fetal communication.
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  • Disruption of microbial communities and their bioactive compounds is linked to inflammatory bowel diseases (IBD), with many microbial proteins remaining uncharacterized despite their potential bioactivity.
  • Researchers identified over 340,000 protein families possibly involved in gut inflammation related to IBD, with a significant portion previously uncharacterized, using a combination of metagenomic techniques.
  • The new methodology, called MetaWIBELE, helped validate findings and revealed that specific microbial proteins could influence host immune responses, offering insights into potential therapeutic targets for chronic diseases like IBD.
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Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profiles, which we integrated across tissues, donors, and laboratory methods with a conditional variational autoencoder. Using the resulting cross-tissue atlas, we highlight shared and tissue-specific features of tissue-resident cell populations; identify cell types that might contribute to neuromuscular, metabolic, and immune components of monogenic diseases and the biological processes involved in their pathology; and determine cell types and gene modules that might underlie disease mechanisms for complex traits analyzed by genome-wide association studies.

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High-resolution spatial transcriptomics enables mapping of RNA expression directly from intact tissue sections; however, its utility for the elucidation of disease processes and therapeutically actionable pathways remains unexplored. We applied Slide-seqV2 to mouse and human kidneys, in healthy and distinct disease paradigms. First, we established the feasibility of Slide-seqV2 in tissue from nine distinct human kidneys, which revealed a cell neighborhood centered around a population of macrophages.

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Dendritic cells (DCs) sense environmental cues and adopt either an immune-stimulatory or regulatory phenotype, thereby fine-tuning immune responses. Identifying endogenous regulators that determine DC function can thus inform the development of therapeutic strategies for modulating the immune response in different disease contexts. Tim-3 plays an important role in regulating immune responses by inhibiting the activation status and the T cell priming ability of DC in the setting of cancer.

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It is challenging to associate features such as human health outcomes, diet, environmental conditions, or other metadata to microbial community measurements, due in part to their quantitative properties. Microbiome multi-omics are typically noisy, sparse (zero-inflated), high-dimensional, extremely non-normal, and often in the form of count or compositional measurements. Here we introduce an optimized combination of novel and established methodology to assess multivariable association of microbial community features with complex metadata in population-scale observational studies.

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Charting an organs' biological atlas requires us to spatially resolve the entire single-cell transcriptome, and to relate such cellular features to the anatomical scale. Single-cell and single-nucleus RNA-seq (sc/snRNA-seq) can profile cells comprehensively, but lose spatial information. Spatial transcriptomics allows for spatial measurements, but at lower resolution and with limited sensitivity.

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  • This study examines the pathophysiology of COVID-19 by analyzing single-cell and spatial atlases from various organ autopsy samples of individuals who died from the virus.
  • Findings revealed significant changes in lung tissue, including impaired tissue regeneration and inflammation, indicating how SARS-CoV-2 affects different cell types.
  • The research provides crucial insights into the biological impact of severe COVID-19, aiding in the development of potential new treatments.
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  • The SARS-CoV-2 pandemic has led to over 1 million deaths worldwide, primarily due to severe lung injuries and multiple organ failures, but there is limited understanding of the immune responses involved in COVID-19.
  • Researchers collected and analyzed over 420 tissue samples from various organs of 17 COVID-19 victims, utilizing advanced techniques like RNA sequencing to map out cellular changes related to their illness.
  • Significant findings include alterations in lung tissue cell types, such as the increase of specific progenitor cells and myofibroblasts, indicating impaired tissue repair and failed regenerative processes in severely damaged lungs.
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Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology.

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Drug repurposing has the advantage of identifying potential treatments on a shortened timescale. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high-content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. Elevated MUC1 levels predict the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and correlate with poor clinical outcomes.

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Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice.

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Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance.

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Human iPSC-derived kidney organoids have the potential to revolutionize discovery, but assessing their consistency and reproducibility across iPSC lines, and reducing the generation of off-target cells remain an open challenge. Here, we profile four human iPSC lines for a total of 450,118 single cells to show how organoid composition and development are comparable to human fetal and adult kidneys. Although cell classes are largely reproducible across time points, protocols, and replicates, we detect variability in cell proportions between different iPSC lines, largely due to off-target cells.

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Background: In high-throughput studies, hundreds to millions of hypotheses are typically tested. Statistical methods that control the false discovery rate (FDR) have emerged as popular and powerful tools for error rate control. While classic FDR methods use only p values as input, more modern FDR methods have been shown to increase power by incorporating complementary information as informative covariates to prioritize, weight, and group hypotheses.

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