Rooneypetty3645

AIM Glucagon-like peptide-1 (GLP1) produces pleiotropic effects binding to the GLP1 receptor (GLP1-R) potentiating insulin secretion in the pancreas. GLP1-R is expressed in peripheral tissues and evidence for its role in reproduction came from knockout mice, although the relationship between GLP1 and male fertility needs to be clarified. Given that human sperm is an insulin-sensitive and insulin-secreting cell, we hypothesized that GLP-1/GLP1-R axis may be expressed and functional in these cells. RESULTS and discussion We evidenced GLP1-R presence by Western blotting and immunofluorescence analyses. Since Exendin-4 (Ex-4) displays similar functional properties to native GLP-1 we used this agonist to perform a dose-response study on progressive motility and cholesterol efflux, showing that 300 pM Ex-4 was the most effective treatment. These actions are mediated by GLP1-R and independent from sperm-secreted insulin. The exposure to Ex-4 fueled the PI3K/AKT signaling and reversed by H89, indicating a PKA-dependence of GLP1/GLP1-R signaling. It emerged that in sperm, insulin secretion regulated by Ex-4 did not occur in a strictly glucose-dependent manner. A stimulatory action of Ex-4/GLP1-R on LDH and G6PDH activities was observed. The Ex-4/GLP1-R decreased triglycerides content concomitantly to an enhanced lipase and Acyl-CoA dehydrogenase activities, addressing a lipolytic effect. CONCLUSION Collectively, we discovered that human sperm is a new GLP1 incretin target broadening our knowledge about the effects of the GLP1-R agonist in male reproductive field. Further findings in humans should be conducted in the future to confirm it and to improve the translational aspect of this study. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations, and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive due to the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multi-'omics' analysis of 74 CP and BC samples using whole genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. see more While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our datasets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called 'epigenetic switching', while PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. Based on these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP. Copyright © 2020 American Society of Hematology.Space radiation is characterized by high-linear energy transfer (LET) ionizing radiation. The relationships between the early biological effects of space radiation and the probability of cancer in humans are poorly understood. Bcl2 not only functions as a potent antiapoptotic molecule but also as an oncogenic protein that induces DNA replication stress. To test the role and mechanism of Bcl2 in high-LET space radiation-induced lung carcinogenesis, we created lung-targeting Bcl2 transgenic C57BL/6 mice using the CC10 promoter to drive Bcl2 expression selectively in lung tissues. Intriguingly, lung-targeting transgenic Bcl2 inhibits ribonucleotide reductase activity, reduces dNTP pool size and retards DNA replication fork progression in mouse bronchial epithelial cells. After exposure of mice to space radiation derived from 56iron, 28silicon or protons, the incidence of lung cancer was significantly higher in lung-targeting Bcl2 transgenic mice than in wild type mice, indicating that Bcl2-induced DNA replication stress promotes lung carcinogenesis in response to space radiation. The findings provide some evidence for the relative effectiveness of space radiation and Bcl-2 at inducing lung cancer in mice. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email journals.permissions@oup.com.The objective of this study was to determine the impact of quality grade and steak location on color stability of semitendinosus (ST) steaks during a 9-d refrigerated study. Twenty-one ST muscles (12 Choice and 9 Select) were purchased from a commercial beef packing plant and fabricated into twelve 2.54-cm thick steaks per muscle. Steaks 1, 6, and 12 were designated for immunohistochemistry while remaining steak locations of proximal (steaks 2 to 4), middle (5 to 8), and distal (9 to 11) were randomly assigned to 0, 4 or 9 d of simulated retail display. Surface color attributes of d-9 steaks were recorded daily by a visual color panel and spectrophotometer. On d 0, 4 and 9 of display, steaks were analyzed for metmyoglobin reducing ability (MRA) and oxygen consumption (OC). Grade × DOD interactions were detected for L*, a*, surface oxymyoglobin (OMb) and metmyoglobin (MMb) percentages, and visual panel surface redness and discoloration scores (P ≤ 0.02); however, no Grade × DOD interactions were observed for MRA or OC (P > 0.