Tetrahydrolipstatin (THL) is bactericidal but its precise target spectrum is poorly characterized. Here, we used a THL analog and activity-based protein profiling to identify target proteins after enrichment from whole cell lysates of Mycobacterium bovis Bacillus Calmette-Gué rin cultured under replicating and non-replicating conditions. THL targets ␣/␤-hydrolases, including many lipid esterases (LipD, G, H, I, M, N, O, V, W, and TesA). Target protein concentrations and total esterase activity correlated inversely with cellular triacylglycerol upon entry into and exit from non-replicating conditions. Cellular overexpression of lipH and tesA led to decreased THL susceptibility thus providing functional validation. Our results define the target spectrum of THL in a biological species with particularly diverse lipid metabolic pathways. We furthermore derive a conceptual approach that demonstrates the use of such THL probes for the characterization of substrate recognition by lipases and related enzymes. Molecular & Cellular

Chromosome arm aneuploidies (CAAs) are pervasive in cancers. However, how they affect cancer development, prognosis and treatment remains largely unknown. Here, we analyse CAA profiles of 23,427 tumours, identifying aspects of tumour evolution including probable orders in which CAAs occur and CAAs predicting tissue-specific metastasis. Both haematological and solid cancers initially gain chromosome arms, while only solid cancers subsequently preferentially lose multiple arms. 72 CAAs and 88 synergistically co-occurring CAA pairs multivariately predict good or poor survival for 58% of 6977 patients, with negligible impact of whole-genome doubling. Additionally, machine learning identifies 31 CAAs that robustly alter response to 56 chemotherapeutic drugs across cell lines representing 17 cancer types. We also uncover 1024 potential synthetic lethal pharmacogenomic interactions. Notably, in predicting drug response, CAAs substantially outperform mutations and focal deletions/amplifications combined. Thus, CAAs predict cancer prognosis, shape tumour evolution, metastasis and drug response, and may advance precision oncology.

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Background Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration. Results We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10−3). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10−4), and estimated bone mineral density (eBMD, P< 2× 10−5). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10−24) or eBMD (SPP1, P=6× 10−20) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2Y228X/Y228X mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1P160X/P160X mutants predominantly showed mineralisation defects. Conclusion We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease.

Chromosomal translocations drive the development of many hematological and some solid cancers. Several factors have been identified to explain the non-random occurrence of translocation breakpoints in the genome. These include chromatin density, gene density and CCCTC-binding factor (CTCF)/cohesin binding site density. However, such factors are at least partially interdependent. Using 13,844 and 1563 karyotypes from human blood and solid cancers, respectively, our multiple regression analysis only identified chromatin density as the primary statistically significant predictor. Specifically, translocation breakpoints preferentially occur in open chromatin. Also, blood and solid tumors show markedly distinct translocation signatures. Strikingly, translocation breakpoints occur significantly more frequently in acrocentric chromosomes than in non-acrocentric chromosomes. Thus, translocations are probably often generated around nucleoli in the inner nucleoplasm, away from the nuclear envelope. Importantly, our findings remain true both in multivariate analyses and after removal of highly recurrent translocations. Finally, we applied pairwise probabilistic co-occurrence modeling. In addition to well-known highly prevalent translocations, such as those resulting in BCR-ABL1 (BCR-ABL) and RUNX1-RUNX1T1 (AML1-ETO) fusion genes, we identified significantly underrepresented translocations with putative fusion genes, which are probably subject to strong negative selection during tumor evolution. Taken together, our findings provide novel insights into the generation and selection of translocations during cancer development.

Blunt trauma abdomen is a very common entity but traumatic abdominal wall hernia is not that common. Herniation through abdominal wall usually occurs following trauma with seat belt, motor cycle, bicycle handle bar etc. Handlebar hernia is a less known variety of traumatic abdominal wall hernia as a consequence of injury with handlebar of a bicycle. It is difficult to diagnose and one should have high index of suspicion. Management in traumatic abdominal wall hernia is individualized based on various factors. We herein present an interesting case of a14-year-old boy, who sustained blunt trauma abdomen from bicycle handlebar leading to triple herniation and perforation of the small bowel and hematoma of the mesentery. Patient was resuscitated and operated with a favorable outcome. Blunt trauma abdomen is a very common and the possibility of traumatic abdominal wall hernia should always be borne in mind.

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From retrospective studies, we have observed that from past few decades the industrialization growing very fast in developed as well as developing countries. This introduced many kinds of products which stamped their deleterious effect on environment, flora and fauna much more efficiently than their useful one. One of them which are recently hot topic for researchers is plastic. Plastic pollution is the major headache and concerning topic for researchers in various aspects like its production and commercial use. The major concern is its efficient as well as harmless disposal because of its harmful chemical composition, which are released during recycling and disposal and are deleterious for environment and living creatures, both. One of such chemicals is bisphenol A (BPA), a phenol group containing organic compound most widely used in industries like polycarbonate plastic, plastic canned food and epoxy resins. It is responsible for many kinds of physiological acute as well as chronic disorders in humans and animals but have the major effect on reproductive system and endocrine disrupter. Effect on bovine reproduction and fertility is of major concern because India became highest milk producer in the world with 198.4 million tones, which is increased by 35.61% from last 6 years. It affects the bovine reproductive system in many ways like affecting the cellular functions and morphology (granulose, theca, cumulus complex etc.) as well as embryonic level too. To maintain such type of high production level it is necessary to properly manage the reproductive performance of bovines. Reproduction is composed of different interconnected cellular and molecular events; such processis badly affected at different levels by bisphenol A because of its deleterious effect some country restricted its use and industries become shifted to use bisphenol S (bisphenol A substitute) but after various studies it is proven that it is a "regrettable substitute" rather than substitute. There are many few researches on that field, so there is a urge of more and more studies regarding their effect on bovine fertility. By this review we want to make awareness among the people about the dangerous and unwanted effects of such elements on cattle as well as other living organisms also and request researchers to go for future studies and experiments on its other type of unwanted effects not only on the cattle but other living creatures also to prevent further harm to our ecosystem by spreading knowledge and minimizing the use of plastic based products.