RESUMEN
The COVID-19 pandemic demands assimilation of all biomedical knowledge to decode mechanisms of pathogenesis. Despite the recent renaissance in neural networks, a platform for the real-time synthesis of the exponentially growing biomedical literature and deep omics insights is unavailable. Here, we present the nferX platform for dynamic inference from over 45 quadrillion possible conceptual associations from unstructured text, and triangulation with insights from single-cell RNA-sequencing, bulk RNA-seq and proteomics from diverse tissue types. A hypothesis-free profiling of ACE2 suggests tongue keratinocytes, olfactory epithelial cells, airway club cells and respiratory ciliated cells as potential reservoirs of the SARS-CoV-2 receptor. We find the gut as the putative hotspot of COVID-19, where a maturation correlated transcriptional signature is shared in small intestine enterocytes among coronavirus receptors (ACE2, DPP4, ANPEP). A holistic data science platform triangulating insights from structured and unstructured data holds potential for accelerating the generation of impactful biological insights and hypotheses.
Asunto(s)
Infecciones por Coronavirus/virología , Bibliotecas Médicas , Neumonía Viral/virología , Receptores Virales/metabolismo , Animales , Betacoronavirus/genética , Betacoronavirus/metabolismo , COVID-19 , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/patología , Perfilación de la Expresión Génica , Humanos , Descubrimiento del Conocimiento , Ratones , Pandemias , Neumonía Viral/metabolismo , Neumonía Viral/patología , Receptores de Coronavirus , Receptores Virales/química , Receptores Virales/genética , SARS-CoV-2RESUMEN
G-protein-coupled receptors (GPCRs) are physiologically important membrane proteins that sense signalling molecules such as hormones and neurotransmitters, and are the targets of several prescribed drugs. Recent exciting developments are providing unprecedented insights into the structure and function of several medically important GPCRs. Here, through a systematic analysis of high-resolution GPCR structures, we uncover a conserved network of non-covalent contacts that defines the GPCR fold. Furthermore, our comparative analysis reveals characteristic features of ligand binding and conformational changes during receptor activation. A holistic understanding that integrates molecular and systems biology of GPCRs holds promise for new therapeutics and personalized medicine.