How single-cell multi-omics builds relationships Nature Methods, 2022

AlphaThera Highlighted in Nature Methods Article: “How single-cell multi-omics builds relationships” Dr. Tsourkas, co-founder of AlphaThera, and Dr. Yu, Scientific Director at the company, were recently interviewed for a Technology Feature article in Nature Methods titled, ‘How single-cell multi-omics builds relationships’.  The article, written by Vivian Marx, takes a look at approaches to analyze single-cell changes, and specifically reviews inCITE-seq as a way to multiplex measurements of a protein...



Oxygen and mechanical ventilation impede the functional properties of... PLoS One, 2020

Abstract Resident/endogenous mesenchymal stromal cells function to promote the normal development, growth, and repair of tissues. Following premature birth, the effects of routine neonatal care (e.g. oxygen support and mechanical ventilation) on the biological properties of lung endogenous mesenchymal stromal cells is (L-MSCs) is poorly understood. New Zealand white preterm rabbits were randomized into the following groups: (i) sacrificed at birth (Fetal), (ii) spontaneously breathing with 50% O2 for 4 hours (SB), or (iii) mechanical venti...



CRISPR loss of function screening to identify genes involved in human... Cold Spring Harbor Press, 2022

Abstract Despite our increasing knowledge of molecular mechanisms guiding various aspects of human reproduction, those underlying human primordial germ cell (PGC) development remain largely unknown. Here, we conducted custom CRISPR screening in an in vitro system of hPGC-like cells (hPGCLCs) to identify genes required for acquisition and maintenance of PGC fate in humans. Amongst our candidates, we identified TCL1A, an AKT coactivator. Functional assessment in our in vitro hPGCLCs system revealed that TCL1A played a critical role in later...



Cannabidiol inhibits SARS-CoV-2 replication through induction of the h... Science Advances, 2022

Abstract The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ongoing coronavirus disease 2019 (COVID-19) pandemic underscores the need for new treatments. Here, we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcr...



Combining selective inhibitors of nuclear export (SINEs) with chimeric... Oncology Reports, 2021

Abstract Chimeric antigen receptor (CAR) T cells directed against CD19 (CD19.CAR T cells) have yielded impressive clinical responses in the treatment of patients with lymphoid malignancies. However, resistance and/or relapse can limit treatment outcome. Risk of tumor escape can be reduced by combining treatment strategies. Selective inhibitors of nuclear export (SINEs) directed against nuclear exportin‑1 (XPO1) have demonstrated anti‑tumor efficacy in several hematological malignancies. The aim of the present study was to evaluate the comb...



RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pa... Cancer Cell, 2018

Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in...



SARS-CoV-2 variants with reduced infectivity and varied sensitivity to... PLOS PATHOGENS, 2022

Abstract In-depth analysis of SARS-CoV-2 quasispecies is pivotal for a thorough understating of its evolution during infection. The recent deployment of COVID-19 vaccines, which elicit pro- tective anti-spike neutralizing antibodies, has stressed the importance of uncovering and characterizing SARS-CoV-2 variants with mutated spike proteins. Sequencing databases have allowed...



The nucleolus functions as a phase-separated protein quality control c... Science, 2019

Abstract The nuclear proteome is rich in stress-sensitive proteins, which suggests that effective protein quality control mechanisms are in place to ensure conformational maintenance. We investigated the role of the nucleolus in this process. In mammalian tissue culture cells under stress conditions, misfolded proteins entered the granular component (GC) phase of the nucleolus. Transient associations with nucleolar proteins such as NPM1 conferred low mobility to misfolded proteins within the liquid-like GC phase, avoiding irreversible aggr...



Mechanosensitive smooth muscle cell phenotypic plasticity emerging fro... Cell Reports, 2021

Abstract THIS WEEK: Reversible differentiation of vascular smooth muscle cells (VSMCs) plays a critical role in vascular biology and disease. Changes in VSMC differentiation correlate with stiffness of the arterial extracellular matrix (ECM), but causal relationships remain unclear. We show that VSMC plasticity is mechanosensitive and that both the de-differentiated and differentiated fates are promoted by the same ECM stiffness. Differential equations developed to model this behavior predicted that a null VSMC state generat...



Mapping molecular subtype specific alterations in breast cancer brain... Mapping molecular subtype specific alterations in breast cancer brain...

Abstract The molecular events and transcriptional plasticity driving brain metastasis in clinically relevant breast tumor subtypes has not been determined. Here we comprehensively dissect genomic, transcriptomic and clinical data in patient-matched longitudinal tumor samples, and unravel distinct transcriptional programs enriched in brain metastasis. We report on subtype specific hub genes and functional processes, central to disease-affected networks in brain metastasis. Importantly, in luminal brain metastases we identify homologous recomb...