The Toll/interleukin-1 receptor (TIR) domain is the signature signaling domain of Toll-like receptors (TLRs) and their adaptors, serving as a scaffold for the assembly of protein complexes for innate immune signaling [1, 2]. TIR domain proteins are also expressed in plants, where they mediate disease resistance [3, 4], and in bacteria, where they have been associated with virulence [5-9]. In pursuing our work on axon degeneration [10], we made the surprising discovery that the TIR domain of SARM1 (sterile alpha and TIR motif containing 1), a TLR adaptor protein, has enzymatic activity [11]. Upon axon injury, the SARM1 TIR domain cleaves nicotinamide adenine dinucleotide (NAD), destroying this essential metabolic co-factor to trigger axon destruction [11, 12]. Whereas current studies of TIR domains focus on their scaffolding function, our findings with SARM1 inspired us to ask whether this enzymatic activity is the primordial function of the TIR domain. Here we show that ancestral prokaryotic TIR domains constitute a new family of NADase enzymes. Using purified proteins from a cell-free translation system, we find that TIR domain proteins from both bacteria and archaea cleave NAD into nicotinamide and ADP-ribose (ADPR), with catalytic cleavage executed by a conserved glutamic acid. A subset of bacterial and archaeal TIR domains generates a non-canonical variant cyclic ADPR (cADPR) molecule, and the full-length TIR domain protein from pathogenic Staphylococcus aureus induces NAD loss in mammalian cells. These findings suggest that the primordial function of the TIR domain is the enzymatic cleavage of NAD and establish TIR domain proteins as a new class of metabolic regulatory enzymes.
An HDM genome draft produced from genomic, transcriptomic, and proteomic experiments revealed allergen genes and a diverse endosymbiotic microbiome, providing a tool for further identification and characterization of HDM allergens and development of diagnostics and immunotherapeutic vaccines.
Introduction: The emergence of anovel coronavirus identified in patients with unknown cause of acute respiratory disease in Wuhan, China at the end of 2019 has caused aglobal outbreak. The causative coronavirus was later named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease caused by SARS-CoV-2 was named as Coronavirus Disease-2019 (COVID-19). As of 10 August 2020, more than 19,718,030 confirmed cases and 728,013 deaths have been reported. COVID-19 is spread via respiratory droplets which are inhaled into the lungs. Areas covered: In this article, we summarized the knowledge about the causative pathogen of COVID-19 and various diagnostic methods in this pandemic for better understanding of the limitations and the nuances of virus testing for COVID-19. Expert opinion: In this pandemic, rapid and accurate identification of COVID-19 patients are critical to break the chain of infection in the community. RT-PCR provides a rapid and reliable identification of SARS-CoV-2 infection. In the future, molecular diagnostics will still be the gold standard and nextgeneration sequencing can help us to understand more on the pathogenesis and detect novel mutations. It is believed that more sophisticated detection methods will be introduced to detect SARS-CoV-2 as earliest as possible.
Purpose To determine if sex differences in abdominal visceral fat composition, measured by using computed tomography (CT), and tumor glucose metabolism, measured by gene expression, can help predict outcomes in patients with clear cell renal cell carcinoma (RCC). Materials and Methods This retrospective cohort study included 222 patients with clear cell RCC from The Cancer Imaging Atlas. By using CT, body fat was segmented into subcutaneous fat and visceral fat areas (VFAs) and normalized to total fat to obtain the relative VFA (rVFA) and relative subcutaneous fat area. Multivariate Cox proportional hazard regression models were performed to identify effects of rVFA on sex-specific survival. Expression profiles for 39 glycolytic genes in tumors from these patients were obtained from The Cancer Genome Atlas to determine sex differences in metabolism and compared with rVFA. Key mutations in clear cell RCC were analyzed for association with rVFA and tumor glycolytic profiles. Results Women with rVFA greater than 30.9% had an increased risk of death (hazard ratio, 3.66 [95% confidence interval: 1.64, 8.19]) for women vs 1.13 ([95% confidence interval: 0.58, 2.18] for men, P = .028). Glycolytic gene expression stratified both men and women, and the combination of low rVFA and low glycolysis identified 19 women with excellent overall survival (P < .001). SETD2 and BAP1 mutations were uniquely enriched in female tumors with high glycolysis (P = .036 and .001, respectively). No significant differences were identified in tumor mutations between patients with high and low rVFA. Conclusion Sex differences in visceral fat and tumor glucose metabolism may provide a new risk-stratification system for patients with clear cell RCC. RSNA, 2018 Online supplemental material is available for this article.
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