Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures, and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing (snRNA-seq) and analyzed 50,708 high quality nuclei targeting the diencephalon, including the subthalamic nucleus and adjacent structures, from human post-mortem PSP brains with varying degrees of pathology compared to controls.

Master regulators governing protein abundance across ten human cancer types.

Protein abundance correlates only moderately with mRNA levels, and are modulated post-transcriptionally by a network of regulators including ribosomes, RNA-binding proteins (RBPs), and the proteasome. Here, we identified ster rotein abundance egulators (MaPRs) across ten cancer types by devising a new computational pipeline that jointly analyzed transcriptomes and proteomes from 1,305 tumor samples. We identified 232 to 1,394 MaPRs per cancer type, mediating up to 79% of post-transcriptional regulatory networks.

Multiscale protein networks systematically identify aberrant protein interactions and oncogenic regulators in seven cancer types.

Global proteomic data generated by advanced mass spectrometry (MS) technologies can help bridge the gap between genome/transcriptome and functions and hold great potential in elucidating unbiased functional models of pro-tumorigenic pathways. To this end, we collected the high-throughput, whole-genome MS data and conducted integrative proteomic network analyses of 687 cases across 7 cancer types including breast carcinoma (115 tumor samples; 10,438 genes), clear cell renal carcinoma (100 tumor samples; 9,910 genes), colorectal cancer (91 tumor samples; 7,362 genes), hepatocellular carcinoma (101 tumor samples; 6,478 genes), lung adenocarcinoma (104 tumor samples; 10,967 genes), stomach adenocarcinoma (80 tumor samples; 9,268 genes), and uterine corpus endometrial carcinoma UCEC (96 tumor samples; 10,768 genes). Through the protein co-expression network analysis, we identified co-expressed protein modules enriched for differentially expressed proteins in tumor as disease-associated pathways.

Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing and analyzed 45,559 high quality nuclei targeting the subthalamic nucleus and adjacent structures from human post-mortem PSP brains with varying degrees of pathology compared to controls.

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity.

Pathogenic tau accumulation fuels neurodegeneration in Alzheimer's disease (AD). Enhancing aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses.

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity.

Pathogenic tau accumulation fuels neurodegeneration in Alzheimer's disease (AD). Enhancing aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses.

Master Transcription Factor Reprogramming Unleashes Selective Translation Promoting Castration Resistance and Immune Evasion in Lethal Prostate Cancer.

Unlabelled: Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer unleashes eukaryotic initiation factor 3B (eIF3B)-dependent translation reprogramming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs.

Dysfunction of ubiquitin protein ligase leads to cell resilience in human breast cancers.

Breast cancer is the most common type of cancer among women worldwide, and it is estimated that 294 000 new diagnoses and 37 000 deaths will occur each year in the United States alone by 2030. Large-scale genomic studies have identified a number of genetic loci with alterations in breast cancer. However, identification of the genes that are critical for tumorgenicity still remains a challenge.

Plasma proteomics of SARS-CoV-2 infection and severity reveals impact on Alzheimer's and coronary disease pathways.

Identification of proteins dysregulated by COVID-19 infection is critically important for better understanding of its pathophysiology, building prognostic models, and identifying new targets. Plasma proteomic profiling of 4,301 proteins was performed in two independent datasets and tested for the association for three COVID-19 outcomes (infection, ventilation, and death). We identified 1,449 proteins consistently associated in both datasets with any of these three outcomes.

Multiscale network analysis identifies potential receptors for SARS-CoV-2 and reveals their tissue-specific and age-dependent expression.

The coronavirus disease 2019 (COVID-19) pandemic has affected tens of millions of individuals and caused hundreds of thousands of deaths worldwide. Here, we present a comprehensive, multiscale network analysis of the transcriptional response to the virus. In particular, we focused on key regulators, cell receptors, and host processes that were hijacked by the virus for its advantage.

Pseudo-temporal dynamics of chemoresistant triple negative breast cancer cells reveal EGFR/HER2 inhibition as synthetic lethal during mid-neoadjuvant chemotherapy.

In the absence of targetable hormonal axes, chemoresistance for triple-negative breast cancer (TNBC) often compromises patient outcomes. To investigate the underlying tumor dynamics, we performed trajectory analysis on the single-nuclei RNA-seq (snRNA-seq) of chemoresistant tumor clones during neoadjuvant chemotherapy (NAC). It revealed a common tumor trajectory across multiple patients with HER2-like expansions during NAC.

DDR2 coordinates EMT and metabolic reprogramming as a shared effector of FOXQ1 and SNAI1.

While multiple transcription factors (TFs) have been recognized to drive epithelial-mesenchymal transition (EMT) in cancer, their interdependence and context-dependent functions are poorly understood. In this study, we show that FOXQ1 and SNAI1 act as independent TFs within the EMT program with a shared ability to upregulate common EMT TFs without reciprocally impacting the expression of one another. Despite this independence, human mammary epithelial cells (HMLE) with ectopic expression of either FOXQ1 or SNAI1 share a common gene set that is enriched for a DDR2 coexpression signature.

Biopsy and blood-based molecular biomarker of inflammation in IBD.

Objective: IBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments.

Design: Transcriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn's disease, n=421 UC and 243 controls) in the Mount Sinai Crohn's and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis.

Plasma proteomics of SARS-CoV-2 infection and severity reveals impact on Alzheimer and coronary disease pathways.

Identification of the plasma proteomic changes of Coronavirus disease 2019 (COVID-19) is essential to understanding the pathophysiology of the disease and developing predictive models and novel therapeutics. We performed plasma deep proteomic profiling from 332 COVID-19 patients and 150 controls and pursued replication in an independent cohort (297 cases and 76 controls) to find potential biomarkers and causal proteins for three COVID-19 outcomes (infection, ventilation, and death). We identified and replicated 1,449 proteins associated with any of the three outcomes (841 for infection, 833 for ventilation, and 253 for death) that can be query on a web portal ( https://covid.

Culture shock: microglial heterogeneity, activation, and disrupted single-cell microglial networks in vitro.

Background: Microglia, the resident immune cells of the brain, play a critical role in numerous diseases, but are a minority cell type and difficult to genetically manipulate in vivo with viral vectors and other approaches. Primary cultures allow a more controlled setting to investigate these cells, but morphological and transcriptional changes upon removal from their normal brain environment raise many caveats from in vitro studies.

Methods: To investigate whether cultured microglia recapitulate in vivo microglial signatures, we used single-cell RNA sequencing (scRNAseq) to compare microglia freshly isolated from the brain to primary microglial cultures.

Guidelines for bioinformatics of single-cell sequencing data analysis in Alzheimer's disease: review, recommendation, implementation and application.

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. Extensive clinical and genomic studies have revealed biomarkers, risk factors, pathways, and targets of AD in the past decade. However, the exact molecular basis of AD development and progression remains elusive.

The landscape of human tissue and cell type specific expression and co-regulation of senescence genes.

Background: Cellular senescence is a complex stress response that impacts cellular function and organismal health. Multiple developmental and environmental factors, such as intrinsic cellular cues, radiation, oxidative stress, oncogenes, and protein accumulation, activate genes and pathways that can lead to senescence. Enormous efforts have been made to identify and characterize senescence genes (SnGs) in stress and disease systems.

Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development.

Background & Aims: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression.

Methods: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78).

Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease.

Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD-specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD.

Deep Analysis of the Peripheral Immune System in IBD Reveals New Insight in Disease Subtyping and Response to Monotherapy or Combination Therapy.

Background: Inflammatory bowel disease (IBD) is a complex disease with variable presentation, progression, and response to therapies. Current disease classification is based on subjective clinical phenotypes. The peripheral blood immunophenome can reflect local inflammation, and thus we measured 39 circulating immune cell types in a large cohort of IBD and control subjects and performed immunotype:phenotype associations.

Network models of primary melanoma microenvironments identify key melanoma regulators underlying prognosis.

Melanoma is the most lethal skin malignancy, driven by genetic and epigenetic alterations in the complex tumour microenvironment. While large-scale molecular profiling of melanoma has identified molecular signatures associated with melanoma progression, comprehensive systems-level modeling remains elusive. This study builds up predictive gene network models of molecular alterations in primary melanoma by integrating large-scale bulk-based multi-omic and single-cell transcriptomic data.