These results demonstrate that mRNA and protein for TRPM8 exist in multiple genitourinary organs in the rat and human, and it may be considered a possible new target, as is TRPV1, for the pharmacological treatment of detrusor overactivity or other urological disorders.

Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. Here we performed a genome-wide CRISPR screen with SARS-CoV-2 and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex and key components of the TGF-β signaling pathway. Small molecule inhibitors of these pathways prevented SARS-CoV-2-induced cell death. We also revealed that the alarmin HMGB1 is critical for SARS-CoV-2 replication. In contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death. Together this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 , represents the greatest public health threat in a century. More than 7,500,000 people have been infected with more than 420,000 deaths globally (1). Novel therapeutics and vaccines are desperately needed. Coronaviruses are enveloped, positive-sense RNA viruses with genomes of approximately 30 kb that exhibit broad host-range among birds and mammals and are typically transmitted via the respiratory route (2, 3). There are four circulating seasonal coronaviruses in humans (NL63, OC43, 229E, and HKU1) and three highly pathogenic zoonotic coronaviruses (SARS-CoV, MERS, and SARS-CoV-2), none of which have effective antiviral drugs or vaccines (4-7).Viral entry, the first stage of the SARS-CoV-2 life cycle, is mediated by the viral spike protein. The receptor binding domain of spike binds to the cell surface receptor angiotensinconverting enzyme 2 (ACE2), a major determinant of host range and cell tropism (8,9). The coronavirus spike protein requires two proteolytic processing steps prior to entry. The first cleavage event occurs at the interface of the S1 and S2 domains of the spike protein (10, 11). This can occur in the producer cell, the extracellular environment, or in the endosome and can be mediated by several proteases including furin and the plasma membrane protease TMPRSS2 (12)(13)(14). A second proteolytic event is required within S2 to expose the viral fusion peptide and enable membrane fusion. This second cleavage event can occur at the target cell plasma membrane by TMPRSS2 or in the endosome by Cathepsin L (14,15). Upon viral membrane fusion, the viral RNA is released into the cytoplasm where it is translated and establishes viral replication and transcription complexes before assembling and budding (16)(17)(18). The host genes that mediate these processes largely remain elusive.Identification of host factors essential for infection is critical to inform mechanisms of COVID-19 pathogenesis, reveal variation in host susceptibility, and identify novel host-directed therapies, which may have efficacy against current and future pand...

volume > 30 mL) into the prostate transperineally under transrectal ultrasonography guidance. Study exclusion criteria were confirmed or suspected malignancy, previous pelvic surgery or trauma and previous invasive treatment for BPH. The clinical effects were evaluated at baseline and at 1, 3 and 6 months after treatment. RESULTSThere were no significant local or systemic side-effects in any men. LUTS and QoL indices improved by > 30% in 31 of the 41 men (76%), and four of five men with urinary retention for > 1 month could void spontaneously at 1 week to 1 month after the BoNT-A injection. In 12 of 41 men (29%) there was no change in prostate volume, yet seven of these men still had a > 30% improvement in maximum flow rate, LUTS and QoL. The efficacy was sustained at 12 months. CONCLUSIONBoNT-A injected into the prostate is safe and effective for men with symptomatic BPH. The mechanisms of relief of symptoms might not depend totally on the volume shrinkage; the inhibitory effect on the smooth muscle tone and aberrant sensory function might also be important.

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