CD39 is an ectonucleotidase that initiates conversion of extracellular nucleotides into immunosuppressive adenosine. CD39 is expressed by regulatory T (Treg)-cells, where it mediates immunosuppression, and by a subset of T-helper (Th) 17-cells, where it limits pathogenicity. CD39 is regulated via single-nucleotide-polymorphisms and upon activation of aryl-hydrocarbon-receptor and oxygen-mediated pathways. Here we report a mechanism of CD39 regulation that relies on…
The authors investigated the pathways hijacked by the SARS-CoV-2 cells in human alveolar cells during this respiratory infection. Unlike the transformed cell studies reported this year, this study highlights physiologically relevant pathways targeted by the virus that are uniquely important to lung pathogenesis, revealing fundamental mechanisms supporting viral replication in the distal lung, and unexpected clinically actionable therapeutic targets.
Mutagenic translesion synthesis (TLS) allows cells to increase their survival after DNA damage by bypassing lesions that normally block DNA replication but at the cost of introducing mutations. Interfering with this TLS pathway genetically or with the small molecule inhibitor JH-RE-06 has been shown to improve cisplatin chemotherapy by suppressing tumor growth and enhancing survival in mouse xenograft tumor models.…
Recent large-scale sequencing efforts have enabled the detection of millions of missense variants. Elucidating their functional effect is of crucial importance but challenging. We approach this problem by performing a wide-scale characterization of missense variants from 1,330 disease-associated genes using >14,000 protein structures. We identify 3D features associated with pathogenic and benign variants that unveiled the mutations’ effect at the…
Cell differentiation and function are regulated across multiple layers of gene regulation, including modulation of gene expression by changes in chromatin accessibility. However, differentiation is an asynchronous process precluding a temporal understanding of regulatory events leading to cell fate commitment. Here we developed simultaneous high-throughput ATAC and RNA expression with sequencing (SHARE-seq), a highly scalable approach for measurement of chromatin…
Cryptosporidium is a leading cause of diarrhea and death in young children and untreated AIDS patients in resource-poor settings, and of waterborne outbreaks of disease in developed countries. However, there is no consistently effective treatment for vulnerable populations. Progress towards development of therapeutics for cryptosporidiosis has been hampered by lack of optimal culture systems to study it. New advances in organoid/enteroid technology have…
This study identified a unique lipid signature in human post-mortem Parkinson’s disease brain, wherein lipids accumulated in the dopaminergic neurons most vulnerable in the disease, and in adjacent immune cells (microglia). Concurrently, lipid content was dramatically reduced in neighboring astrocytes – a specialized class of glia that among other functions are involved in neutralizing potentially harmful lipid substrates that accumulate in neurons.
In pursuit of mechanistically novel modulators of androgen receptor, the authors have discovered a potent, ultra-selective CDK9 inhibitor. They describe the most selective inhibitors of CDK9 known to date, and provide compelling preclinical support in vitro and in vivo for targeting CDK9 as a therapeutic strategy in castration resistant prostate cancer and other transcriptionally addicted tumor types.
In collaboration with the NIH’s Pediatric Cardiac Genomics Consortium, the authors sequenced thousands of children who were born with a heart defect and identified causal gene mutations. They used CRISPR/Cas9 gene editing to introduce GATA6 mutations in hiPSC lines and followed the transcriptional changes that occur in normal and mutated stem cells during differentiation into cardiomyocytes.
Emergency granulopoiesis, or the de novo generation of neutrophils in response to a systemic infection through proliferation of myeloid progenitor cells, is an important fundamental host response to severe infections. The authors demonstrate that bone marrow mesenchymal stromal cells, known to support the hematopoietic niche, secrete paracrine factors that can augment emergency granulopoiesis.