Mcleodle6850

Copyright ©2020, American Association for Cancer Research.Integration of spacers into CRISPR loci requires the Cas1/Cas2 integrase complex, frequently in combination with Cas4 exonuclease. However, several CRISPR-Cas systems lack Cas4. Whether Cas4-like activity is dispensable in these systems or provided by an unidentified actor was not known. In this issue of the Journal of Biological Chemistry, Ramachandran et al. show that in subtype I-E systems, Cas4-like activity is supplied by DnaQ-superfamily exonucleases, providing a beautiful example of cellular machinery moonlighting in support of CRISPR-Cas adaptive immunity. © 2020 Lawrence.Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease mediated by the inflammatory cytokine, IL-1β. Although IL-1β is known as the key driver of bone lesions in CRMO, the signaling events leading to pathogenic levels of the cytokine are not fully understood. Using a genetic mouse model of CRMO, Dasari et al. find a role for the nonreceptor spleen tyrosine kinase (SYK) in upstream signaling leading to IL-1β up-regulation. Their findings suggest that SYK may constitute a new therapeutic target for CRMO. © 2020 Hartland.BACKGROUND We explored who actually provides most admission care in hospitals offering supervised experiential training to graduating clinicians in a high mortality setting where practices deviate from guideline recommendations. METHODS We used a large observational data set from 13 Kenyan county hospitals from November 2015 through November 2018 where patients were linked to admitting clinicians. We explored guideline adherence after creating a cumulative correctness of Paediatric Admission Quality of Care (cPAQC) score on a 5-point scale (0-4) in which points represent correct, sequential progress in providing care perfectly adherent to guidelines comprising admission assessment, diagnosis and treatment. At the point where guideline adherence declined the most we dichotomised the cPAQC score and used multilevel logistic regression models to explore whether clinician and patient-level factors influence adherence. RESULTS There were 1489 clinicians who could be linked to 53 003 patients over a period of 3 yea of paediatric rotations. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.OBJECTIVES This study explored unintentional fatal drowning among children and adolescents (0-19 years) diagnosed with autism spectrum disorder (ASD) in Australia. DESIGN This total population, cross-sectional audit used data from the Royal Life Saving National Fatal Drowning Database to explore demographic and causal factors in ASD drowning cases between 1 July 2002 and 30 June 2018. Rates and relative risk (RR) with a 95% confidence interval (CI) were calculated for drowning cases with and without ASD, using estimated population-level prevalence data. RESULTS Of the 667 cases of drowning among 0-19 year olds with known medical history, 27 children and adolescents (4.0%) who drowned had an ASD diagnosis. Children and adolescents with ASD were three times more likely to drown than those without ASD (RR=2.85; CI 0.61 to 13.24). Among those with ASD, 0-4 year olds record the highest rate (11.60/100 000 diagnosed). Children and adolescents with ASD were significantly more likely to drown when compared with those without ASD if aged 5-9 years (44.4% of ASD-yes cases; 13.3% of ASD-no cases); in a lake or dam (25.9% vs 10.0%) and during winter (37.0% vs 13.1%). CONCLUSION Heightened awareness of drowning risk for children and adolescents with ASD is required, including adult supervision and barriers restricting water access. Further evaluation of the effectiveness of personal alarms to alert caregivers to an unsupervised child is warranted. Challenges exist regarding accurate estimates of population-level ASD prevalence and identification of ASD in coronial files. As the diagnosis of ASD does not often occur until age five, results may be an underestimate. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Autoimmune diseases are a physiological state that immune responses are directed against and damage the body's own tissues. Numerous studies have demonstrated promising therapeutic effects in certain autoimmune diseases by targeting IL-23/IL-17 axis, mostly through using Abs against IL-23 or IL-17A. Pyrrole-imidazole polyamides are nuclease-resistant compounds that inhibit gene expression through binding to the minor groove of DNA. To develop a novel gene-silencing agent that targets IL-23/IL-17 axis, we designed polyamide that specifically binds to the transcription factor c-Rel-binding site located in the promoter of IL-23p19 subunit. Our study showed that this polyamide is capable of entering into nucleus with high efficiency in dendritic cells and macrophage. In addition, it prevented the binding of c-Rel to the promoter of IL-23p19 in vivo and specifically inhibited the expression of IL-23. More importantly, we demonstrated that this polyamide is therapeutically effective using both the imiquimod-induced psoriasis and experimental autoimmune uveitis mouse models. Taken together, these results indicate that pyrrole-imidazole polyamide targeting IL-23p19 could be a novel and feasible therapeutic strategy for patients with autoimmune diseases. Copyright © 2020 by The American Association of Immunologists, Inc.Neutrophils promote tumor growth and metastasis at multiple stages of cancer progression. One mechanism through which this occurs is via release of neutrophil extracellular traps (NETs). ZK53 We have previously shown that NETs trap tumor cells in both the liver and the lung, increasing their adhesion and metastasis following postoperative complications. Multiple studies have since shown that NETs play a role in tumor progression and metastasis. NETs are composed of nuclear DNA-derived web-like structures decorated with neutrophil-derived proteins. However, it is unknown which, if any, of these NET-affiliated proteins is responsible for inducing the metastatic phenotype. In this study, we identify the NET-associated carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) as an essential element for this interaction. Indeed, blocking CEACAM1 on NETs, or knocking it out in a murine model, leads to a significant decrease in colon carcinoma cell adhesion, migration and metastasis. Thus, this work identifies NET-associated CEACAM1 as a putative therapeutic target to prevent the metastatic progression of colon carcinoma.