No abstract

Bacteria use diverse immune systems to defend themselves from ubiquitous viruses termed bacteriophages (phages). Many anti-phage systems function by abortive infection to kill a phage-infected cell, raising the question of how these systems are regulated to avoid activation and cell killing outside the context of infection. Here, we identify a transcription factor associated with the widespread CBASS bacterial immune system, that we term CapW. CapW forms a homodimer and binds a palindromic DNA sequence in the CBASS promoter region. Two crystal structures of CapW reveal how the protein switches from a DNA binding-competent state to a ligand-bound state that cannot bind DNA due to misalignment of dimer-related DNA binding domains. We show that CapW strongly represses CBASS gene expression in uninfected cells, and that CapW disruption likely results in toxicity due to uncontrolled CBASS expression. Our results parallel recent findings with BrxR, a transcription factor associated with the BREX anti-phage system, and suggest that CapW and BrxR are the founding members of a family of universal anti-phage signaling proteins.

PurposeThe authors aimed to chronicle the evolution of the medical community's study of physician and surgeon pregnancy by investigating thematic trends in the literature in the context of pertinent sociopolitical events. MethodA scoping review was conducted in Cochrane Library, Google Scholar, Ovid MEDLINE, Ovid Embase, Scopus, and Web of Science Core Collection from inception through August 11, 2020, using vocabulary and terms for physicians (including surgeons), pregnancy, and family leave. Study populations were categorized by all physician specialties or exclusively surgical specialties as well as by all career levels or exclusively trainees.

To protect themselves from the constant threat of bacteriophage (phage) infection, bacteria have evolved diverse immune systems including restriction/modification, CRISPR/Cas, and many others. Here we describe the discovery of a two-protein transcriptional regulator module associated with hundreds of CBASS (Cyclic oligonucleotide Based Anti-phage Signaling System) immune systems, and demonstrate that this module drives expression of its associated CBASS system in response to DNA damage. We show that the helix-turn-helix transcriptional repressor CapH binds the promoter region of its associated CBASS system to repress transcription until it is cleaved by the metallopeptidase CapP. CapP is inactive except in the presence of singlestranded DNA, and CapP activity in cells is stimulated by DNA-damaging drugs. Together, CapH and CapP drive increased expression of their associated CBASS system in response to DNA damage. In both their structures and mechanisms, CapH and CapP resemble regulators that drive increased expression of DNA damage response genes in radiation-resistant Deinococcus, and control the mobilization of prophages and mobile elements in response to DNA damage. We also identify CapH and CapP-related proteins associated with diverse known and putative bacterial immune systems, including DISARM and two uncharacterized operons encoding proteins related to eukaryotic ubiquitin signaling pathways. Overall, our data highlight a mechanism by which bacterial immune systems can sense and respond to a universal stress signal, potentially enabling multiple immune systems to mount a coordinated defensive effort against an invading pathogen.

524 Background: The strategy of surgical extirpation of the primary tumor in the setting of metastatic disease has gained acceptance for a variety of solid tumors. The role of cytoreductive/consolidative radical cystectomy (CCRC) for metastatic urothelial cancer (UC) is unknown. We aimed to describe our institutional experience with CCRC for metastatic UC and to investigate clinicopathologic features predicting prolonged cancer specific survival (CSS) following CCRC. Methods: We performed IRB approved review of our bladder cancer database, and identified 32 patients with metastatic cancer originating from the lower urinary tract who underwent CCRC. Of these, two patients had non−UC histology. Baseline demographics, regimen of chemotherapy, clinicopathologic features, and perioperative complications were collected. Progression free survival (PFS) and cancer specific survival (CSS) were estimated from the time of CCRC. Univariate and multivariate Cox regression models were used to identify predictors of improved CSS after CCRC. Results: Of the 32 patients, 19 (59%) had clinical evidence of distant metastases, while 13 were found to harbor occult metastases on the surgical specimen. The most common site of metastasis was the retroperitoneal lymph nodes, found in 17 patients. Solitary metastases were found in 19 patients (59%). Twenty−eight (88%) patients received chemotherapy prior to CCRC. Disease progression was detected in 29 patients after CCRC (median PFS 4.5 mo), while 28 died of metastatic cancer (median CSS 11.7 mo). On multivariate analysis, patients with solitary metastases were found to have improved CSS compared to those with multiple metastases (HR 2.51, 95% CI 1.06−5.92, p = 0.04), with median CSS of 16.9 mo vs. 5.6 mo (p = 0.003). Median postoperative LOS was 10 days. Overall, 59% suffered postoperative complications, including one perioperative mortality. Conclusions: CCRC is feasible in the setting of metastatic UC, with comparable perioperative morbidity and mortality to RC with curative intent. Patients with solitary metastasis demonstrated longer CSS than those with multiple metastases, and should be considered candidates for future trials evaluating the role of CCRC for metastatic UC.