Extracellular DNAses Facilitate Antagonism and Coexistence in Bacterial Competitor-Sensing Interference Competition.

Over the last 4 decades, the rate of discovery of novel antibiotics has decreased drastically, ending the era of fortuitous antibiotic discovery. A better understanding of the biology of bacteriogenic toxins potentially helps to prospect for new antibiotics. To initiate this line of research, we quantified antagonists from two different sites at two different depths of soil and found the relative number of antagonists to correlate with the bacterial load and carbon-to-nitrogen (C/N) ratio of the soil. Consecutive studies show the importance of antagonist interactions between soil isolates and the lack of a predicted role for nutrient availability and, therefore, support an in situ role in offense for the production of toxins in environments of high bacterial loads. In addition, the production of extracellular DNAses (exDNases) and the ability to antagonize correlate strongly. Using an in domum-developed probabilistic cellular automaton model, we studied the consequences of exDNase production for both coexistence and diversity within a dynamic equilibrium. Our model demonstrates that exDNase-producing isolates involved in amensal interactions act to stabilize a community, leading to increased coexistence within a competitor-sensing interference competition environment. Our results signify that the environmental and biological cues that control natural-product formation are important for understanding antagonism and community dynamics, structure, and function, permitting the development of directed searches and the use of these insights for drug discovery. IMPORTANCE Ever since the first observation of antagonism by microorganisms by Ernest Duchesne (E. Duchesne, Contribution à l'étude de la concurrence vitale chez les microorganisms. Antagonism entre les moisissures et les microbes, These pour obtenir le grade de docteur en medicine, Lyon, France, 1897), many scientists successfully identified and applied bacteriogenic bioactive compounds from soils to cure infection. Unfortunately, overuse of antibiotics and the emergence of clinical antibiotic resistance, combined with a lack of discovery, have hampered our ability to combat infections. A deeper understanding of the biology of toxins and the cues leading to their production may elevate the success rate of the much-needed discovery of novel antibiotics. We initiated this line of research and discovered that bacterial reciprocal antagonism is associated with exDNase production in isolates from environments with high bacterial loads, while diversity may increase in environments of lower bacterial loads.

Assessment for Learning: Investigating the Utility of the Family Medicine and Emergency Medicine Self-assessments for Subject Examination Preparation.

INTRODUCTION: Medical students use self-assessments to assess their knowledge and identify areas for additional study before taking a summative examination at the end of their clinical education segment. This study extended previous research on the NBME Clinical Science Mastery Series self-assessments to investigate the utility of recently released self-assessments for students completing Family Medicine clerkships and Emergency Medicine sub-internships and preparing for summative assessments. MATERIALS: The dataset included 12,200 Family Medicine and 3919 Emergency Medicine students who took the self-assessment and corresponding subject examination from the implementation of the self-assessments in 2017 through January 2020. RESULTS: Like other self-assessments, students typically took the self-assessment within a week of their Family Medicine or Emergency Medicine subject examination using the standard-paced testing mode. The proportion of variance in subject examination scores explained by self-assessment scores was slightly higher for the standard-paced group than for the self-paced group for Family Medicine, (R 2 = .26 and .23, respectively); however, the pattern was reversed for Emergency Medicine (R 2 = .29 and .32). Further, the two pacing groups had significantly different sets of regression parameter estimates. CONCLUSION: The Family Medicine and Emergency Medicine self-assessments allow students to prepare for their summative subject examinations using formative assessments that mirror the content and pacing of the subject examinations. Students can also opt to use the self-paced mode to leverage the self-assessment as an educational tool. Although the standard-paced mode often provides better prediction of subsequent subject examination scores, the self-paced mode is also consistent with an assessment for learning framework.

Chemopreventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and ß-catenin.

Analysis of the Polyp Prevention Trial showed an association between an isorhamnetin-rich diet and a reduced risk of advanced adenoma recurrence; however, the mechanism behind the chemoprotective effects of isorhamnetin remains unclear. Here, we show that isorhamnetin prevents colorectal tumorigenesis of FVB/N mice treated with the chemical carcinogen azoxymethane and subsequently exposed to colonic irritant dextran sodium sulfate (DSS). Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively. MRI, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than the control diet. Isorhamnetin inhibited AOM/DSS-induced oncogenic c-Src activation and ß-catenin nuclear translocation, while promoting the expression of C-terminal Src kinase (CSK), a negative regulator of Src family of tyrosine kinases. Similarly, in HT-29 colon cancer cells, isorhamnetin inhibited oncogenic Src activity and ß-catenin nuclear translocation by inducing expression of csk, as verified by RNA interference knockdown of csk. Our observations suggest the chemoprotective effects of isorhamnetin in colon cancer are linked to its anti-inflammatory activities and its inhibition of oncogenic Src activity and consequential loss of nuclear ß-catenin, activities that are dependent on CSK expression.

STAT2 contributes to promotion of colorectal and skin carcinogenesis.

Signal transducer and activator of transcription 2 (STAT2) is an essential transcription factor in the type I IFN (IFN-alpha/beta) signal transduction pathway and known for its role in mediating antiviral immunity and cell growth inhibition. Unlike other members of the STAT family, IFNs are the only cytokines known to date that can activate STAT2. Given the inflammatory and antiproliferative dual nature of IFNs, we hypothesized that STAT2 prevents inflammation-induced colorectal and skin carcinogenesis by altering the inflammatory immune response. Contrary to our hypothesis, deletion of STAT2 inhibited azoxymethane/dextran sodium sulfate-induced colorectal carcinogenesis as measured by prolonged survival, lower adenoma incidence, smaller polyps, and less chronic inflammation. STAT2 deficiency also inhibited 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin carcinogenesis as indicated by reduced papilloma multiplicity. A potential mechanism by which STAT2 promotes carcinogenesis is through activation of proinflammatory mediators. Deletion of STAT2 decreased azoxymethane/dextran sodium sulfate-induced expression and release of proinflammatory mediators, such as interleukin-6 and CCL2, and decreased interleukin-6 release from skin carcinoma cells, which then decreased STAT3 activation. Our findings identify STAT2 as a novel contributor to colorectal and skin carcinogenesis that may act to increase the gene expression and secretion of proinflammatory mediators, which in turn activate the oncogenic STAT3 signaling pathway.