Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 50 end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development

Analysis of Rabies in China: Transmission Dynamics and Control

Human rabies is one of the major public-health problems in China. The number of human rabies cases has increased dramatically in the last 15 years, partially due to the poor understanding of the transmission dynamics of rabies and the lack of effective control measures of the disease. In this article, in order to explore effective control and prevention measures we propose a deterministic model to study the transmission dynamics of rabies in China. The model consists of susceptible, exposed, infectious, and recovered subpopulations of both dogs and humans and describes the spread of rabies among dogs and from infectious dogs to humans. The model simulations agree with the human rabies data reported by the Chinese Ministry of Health. We estimate that the basic reproduction number for the rabies transmission in China and predict that the number of the human rabies is decreasing but may reach another peak around 2030. We also perform some sensitivity analysis of in terms of the model parameters and compare the effects of culling and immunization of dogs. Our study demonstrates that (i) reducing dog birth rate and increasing dog immunization coverage rate are the most effective methods for controlling rabies in China; and (ii) large scale culling of susceptible dogs can be replaced by immunization of them

Btk regulates macrophage polarization in response to lipopolysaccharide

Bacterial Lipopolysaccharide (LPS) is a strong inducer of inflammation and does so by inducing polarization of macrophages to the classic inflammatory M1 population. Given the role of Btk as a critical signal transducer downstream of TLR4, we investigated its role in M1/M2 induction. In Btk deficient (Btk (−\−)) mice we observed markedly reduced recruitment of M1 macrophages following intraperitoneal administration of LPS. Ex vivo analysis demonstrated an impaired ability of Btk(−/−) macrophages to polarize into M1 macrophages, instead showing enhanced induction of immunosuppressive M2-associated markers in response to M1 polarizing stimuli, a finding accompanied by reduced phosphorylation of STAT1 and enhanced STAT6 phosphorylation. In addition to STAT activation, M1 and M2 polarizing signals modulate the expression of inflammatory genes via differential activation of transcription factors and regulatory proteins, including NF-κB and SHIP1. In keeping with a critical role for Btk in macrophage polarization, we observed reduced levels of NF-κB p65 and Akt phosphorylation, as well as reduced induction of the M1 associated marker iNOS in Btk(−/−) macrophages in response to M1 polarizing stimuli. Additionally enhanced expression of SHIP1, a key negative regulator of macrophage polarisation, was observed in Btk(−/−) macrophages in response to M2 polarizing stimuli. Employing classic models of allergic M2 inflammation, treatment of Btk (−/−) mice with either Schistosoma mansoni eggs or chitin resulted in increased recruitment of M2 macrophages and induction of M2-associated genes. This demonstrates an enhanced M2 skew in the absence of Btk, thus promoting the development of allergic inflammation

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genome-Wide Association Study Singles Out SCD and LEPR as the Two Main Loci Influencing Intramuscular Fat Content and Fatty Acid Composition in Duroc Pigs

[EN] Intramuscular fat (IMF) content and fatty acid composition affect the organoleptic quality and nutritional value of pork. A genome-wide association study was performed on 138 Duroc pigs genotyped with a 60k SNP chip to detect biologically relevant genomic variants influencing fat content and composition. Despite the limited sample size, the genome-wide association study was powerful enough to detect the association between fatty acid composition and a known haplotypic variant in SCD (SSC14) and to reveal an association of IMF and fatty acid composition in the LEPR region (SSC6). The association of LEPR was later validated with an independent set of 853 pigs using a candidate quantitative trait nucleotide. The SCD gene is responsible for the biosynthesis of oleic acid (C18:1) from stearic acid. This locus affected the stearic to oleic desaturation index (C18:1/C18:0), C18: 1, and saturated (SFA) and monounsaturated (MUFA) fatty acids content. These effects were consistently detected in gluteus medius, longissimus dorsi, and subcutaneous fat. The association of LEPR with fatty acid composition was detected only in muscle and was, at least in part, a consequence of its effect on IMF content, with increased IMF resulting in more SFA, less polyunsaturated fatty acids (PUFA), and greater SFA/PUFA ratio. Marker substitution effects estimated with a subset of 65 animals were used to predict the genomic estimated breeding values of 70 animals born 7 years later. Although predictions with the whole SNP chip information were in relatively high correlation with observed SFA, MUFA, and C18: 1/C18: 0 (0.48-0.60), IMF content and composition were in general better predicted by using only SNPs at the SCD and LEPR loci, in which case the correlation between predicted and observed values was in the range of 0.36 to 0.54 for all traits. Results indicate that markers in the SCD and LEPR genes can be useful to select for optimum fatty acid profiles of pork.This research was funded by the Spanish Ministry of Economy and Competitiveness (MINECO; grants AGL2012-33529 and AGL2015-65846-R).Ros-Freixedes, R.; Gol, S.; Pena, R.; Tor, M.; Ibañez Escriche, N.; Dekkers, J.; Estany, J. (2016). Genome-Wide Association Study Singles Out SCD and LEPR as the Two Main Loci Influencing Intramuscular Fat Content and Fatty Acid Composition in Duroc Pigs. PLoS ONE. 11(3). https://doi.org/10.1371/journal.pone.0152496S113Cameron, N. ., Enser, M., Nute, G. ., Whittington, F. ., Penman, J. ., Fisken, A. ., … Wood, J. . (2000). Genotype with nutrition interaction on fatty acid composition of intramuscular fat and the relationship with flavour of pig meat. Meat Science, 55(2), 187-195. doi:10.1016/s0309-1740(99)00142-4Christophersen, O. A., & Haug, A. (2011). 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Journal of Heredity, 97(5), 535-537. doi:10.1093/jhered/esl026Sanchez, M.-P., Iannuccelli, N., Basso, B., Bidanel, J.-P., Billon, Y., Gandemer, G., … Le Roy, P. (2007). Identification of QTL with effects on intramuscular fat content and fatty acid composition in a Duroc × Large White cross. BMC Genetics, 8(1), 55. doi:10.1186/1471-2156-8-55Guo, T., Ren, J., Yang, K., Ma, J., Zhang, Z., & Huang, L. (2009). Quantitative trait loci for fatty acid composition in longissimus dorsi and abdominal fat: results from a White Duroc × Erhualian intercross F2population. Animal Genetics, 40(2), 185-191. doi:10.1111/j.1365-2052.2008.01819.xC.M. Dekkers, J. (2012). Application of Genomics Tools to Animal Breeding. Current Genomics, 13(3), 207-212. doi:10.2174/138920212800543057Uemoto, Y., Nakano, H., Kikuchi, T., Sato, S., Ishida, M., Shibata, T., … Suzuki, K. (2011). 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Identification of signatures of selection for intramuscular fat and backfat thickness in two Duroc populations1. Journal of Animal Science, 93(7), 3292-3302. doi:10.2527/jas.2015-8879Bosch, L., Tor, M., Reixach, J., & Estany, J. (2009). Estimating intramuscular fat content and fatty acid composition in live and post-mortem samples in pigs. Meat Science, 82(4), 432-437. doi:10.1016/j.meatsci.2009.02.013AOAC. 1997. Supplement to AOAC Official Method 996.06: Fat (total, saturated, and monounsaturated) in foods hydrolytic extraction gas chromatographic method. Page 18 in Official Methods of Analysis (16th ed). Association of Official Analytical Chemists, Arlington, VA.ÓVILO, C., FERNÁNDEZ, A., NOGUERA, J. L., BARRAGÁN, C., LETÓN, R., RODRÍGUEZ, C., … TORO, M. (2005). Fine mapping of porcine chromosome 6 QTL and LEPR effects on body composition in multiple generations of an Iberian by Landrace intercross. 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Joint analysis of additive, dominant and first-order epistatic effects of four genes (IGF2,MC4R,PRKAG3andLEPR) with known effects on fat content and fat distribution in pigs. Animal Genetics, 45(1), 133-137. doi:10.1111/age.12091Mackowski, M., Szymoniak, K., Szydlowski, M., Kamyczek, M., Eckert, R., Rozycki, M., & Switonski, M. (2005). Missense mutations in exon 4 of the porcine LEPR gene encoding extracellular domain and their association with fatness traits. Animal Genetics, 36(2), 135-137. doi:10.1111/j.1365-2052.2005.01247.xLi, X., Kim, S.-W., Choi, J.-S., Lee, Y.-M., Lee, C.-K., Choi, B.-H., … Kim, K.-S. (2010). Investigation of porcine FABP3 and LEPR gene polymorphisms and mRNA expression for variation in intramuscular fat content. Molecular Biology Reports, 37(8), 3931-3939. doi:10.1007/s11033-010-0050-1Tyra, M., & Ropka-Molik, K. (2011). Effect of the FABP3 and LEPR gene polymorphisms and expression levels on intramuscular fat (IMF) content and fat cover degree in pigs. 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Mycobacterium vaccae as Adjuvant Therapy to Anti-Tuberculosis Chemotherapy in Never-Treated Tuberculosis Patients: A Meta-Analysis

OBJECTIVE: To evaluate the effectiveness and safety of heat-killed M. vaccae added to chemotherapy of never-treated tuberculosis (TB) patients. METHODS: The databases of Medline, Embase, Biosis, Cochrane Central Register of Controlled Trials, SCI, CBM, VIP and CNKI were searched. Randomized controlled trials (RCT) and Controlled clinical trials (CCT) comparing M. vaccae with or without a placebo-control injection as adjuvant therapy in the chemotherapy of never-treated TB patients were included. Two reviewers independently performed data extraction and quality assessment. Data were analyzed using RevMan 5.0 software by The Cochrane Collaboration. RESULTS: Fifty four studies were included. At the end of the follow-up period, Pooled RR (Risk Ratio) and its 95% CI of sputum smear conversion rate were 1.07 (1.04, 1.10) in TB patients without complications, 1.17 (0.92, 1.49) in TB patients with diabetes mellitus, 1.02 (0.94, 1.10) in TB patients with hepatitis B, and 1.46 (0.21, 10.06) in TB patients with pneumosilicosis. In elderly TB patients the RR was 1.22 (1.13, 1.32). Analysis of each time point during the follow-up period showed that M. vaccae could help to improve the removal of acid-fast bacilli from the sputum, and promote improvement of radiological focal lesions and cavity closure. Compared with the control group, the differences in levels of immunological indicators of Th1 such as IL-2 and TNF-α were not statistical significant (P = 0.65 and 0.31 respectively), and neither was that of IL-6 produced by Th2 (P = 0.52). An effect of M. vaccae of prevention of liver damage was found in TB patients with hepatitis B (RR 0.20 and 95% CI (0.12, 0.33). No systemic adverse events were reported. CONCLUSION: Added to chemotherapy, M. vaccae is helpful in the treatment of never-treated TB patients in terms of improving both sputum conversion and X-ray appearances

Traumatic Brain Injury in Precariously Housed Persons: Incidence and Risks

Background Homeless and precarious housed persons are particularly prone to traumatic brain injuries (TBIs), but existent incidence rates are hampered by poor case acquisition. We rigorously documented TBIs in precariously housed persons transitioning in and out of homelessness. Methods Between December 2016 and May 2018, 326 precariously housed participants enrolled in a longitudinal study in Vancouver, Canada were assessed monthly for TBI occurrences after education on sequelae. Over one participant-year, 2433 TBI screenings were acquired for 326 person-years and variables associated with odds of incident TBI were evaluated. Findings One hundred participants acquired 175 TBIs, yielding an observed incidence proportion of 30¢7% and event proportion of 53¢7%. Of the injured, 61% reported one TBI and 39% reported multiple injuries. Acute intoxication was present for more than half of the TBI events assessed. Additionally, 9¢7% of TBI events occurred in the context of a drug overdose. Common injury mechanisms were falls (45¢1%), assaults (25¢1%), and hitting one’s head on an object (13¢1%). In this community-based but non-randomly recruited sample, exploratory analyses identified factors associated with odds of an incident TBI over one year of follow-up, including: schizophrenia disorders (odds ratio (OR) = 0¢43, 95% confidence interval (CI) 0¢19, 0¢94), role functioning (OR = 0¢69, 95% CI 0¢52, 0¢91), opioid dependence (OR = 2¢17, 95% CI 1¢27, 3¢72) and those reporting past TBIs (OR = 1¢99, 95% CI 1¢13, 3¢52). Interpretation Given the ubiquity of TBIs revealed in this precariously housed sample, we identify an underappreciated and urgent healthcare priority. Several factors modified the odds of incident TBI, which can facilitate investigations into targeted prevention efforts