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nditions.<br />Gametes are highly differentiated cells specialized to carry and protect the parental genetic information. During male germ cell maturation, histone proteins undergo distinct changes that result in a highly compacted chromatin organization. Technical difficulties exclude comprehensive analysis of precise histone mutations during mammalian spermatogenesis. The model organism Saccharomyces cerevisiae possesses a differentiation pathway termed sporulation which exhibits striking similarities to mammalian spermatogenesis. This study took advantage of this yeast pathway to first perform systematic mutational and proteomics screens on histones, revealing amino acid residues which are essential for the formation of spores.<br />A systematic mutational screen has been performed on the histones H2A and H2B, generating ~ 250 mutants using two genetic backgrounds and assessing their ability to form spores. In addition, histones were purified at key stages of sporulation and post-translational modifications analyzed by mablishing conservation during mammalian spermatogenesis.<br />Our results demonstrate that a combination of genetic and proteomic approaches applied to yeast sporulation can reveal new aspects of chromatin signaling pathways during mammalian spermatogenesis.<br />Our results demonstrate that a combination of genetic and proteomic approaches applied to yeast sporulation can reveal new aspects of chromatin signaling pathways during mammalian spermatogenesis.<br />The control of schistosomiasis has been centered to date on a single drug, praziquantel, with shortcomings including treatment failure, reinfection, and emergence of drug resistance. Drug repurposing, combination therapy or nanotechnology were explored to improve antischistosomal treatment. The aim of the present study was to utilize a novel combination of the three strategies to improve the therapeutic profile of praziquantel. This was based on a fixed-dose nanocombination of praziquantel and miltefosine, an antischistosomal repurposing candidate, co-loaded at reduced doses into lipid nanocapsules, for single dose oral therapy.<br />Two nanocombinations were prepared to provide 250mg praziquantel-20mg miltefosine/kg (higher fixed-dose) or 125mg praziquantel-10mg miltefosine/kg (lower fixed-dose), respectively. Their antischistosomal efficacy in comparison with a non-treated control and their praziquantel or miltefosine singly loaded counterparts was assessed in murine schistosomiasis mansoni. A single oral doocombination safety and explore its prophylactic activity and potential to hinder the onset of resistance to the drug components.<br />Irrational prescribing has received increasing attention among policy-makers to improve drug safety and effectiveness while avoiding economic waste. The policies intended to rationalise prescribing have been grouped by WHO under a taxonomy, classifying them into two types of strategies - (1) targeted approaches (micro level) and (2) system-oriented approaches (macro level). The extent to which countries implement strategies and the existing types is currently unknown. This paper explores the following research question via expert opinions to what extent have European countries implemented strategies to support rational prescribing (targeted and system oriented) and what are the types implemented?<br />We assessed the available information on policies intended to promote rational prescribing. We used the WHO taxonomy to explore our research question as the basis for a standardised questionnaire. The data were collected between August 2018 and April 2019. [https://www.selleckchem.com/products/bromoenol-lactone.html Metabolism inhibitor] The questionnaire consisted of questions that solicited tal mechanisms in place for enhancing rational prescribing in primary care on both the micro and macro levels. With respect to the extent of mechanisms being in place, two groups of countries were identified. This initial mapping of strategies forms a basis for more in-depth research to be able to assess the impact of bundles of strategies on system and targeted level on rational drug prescribing in primary care in Europe.<br />The data reported by the experts suggests that all 13 countries included in our study have several mechanisms in place for enhancing rational prescribing in primary care on both the micro and macro levels. With respect to the extent of mechanisms being in place, two groups of countries were identified. This initial mapping of strategies forms a basis for more in-depth research to be able to assess the impact of bundles of strategies on system and targeted level on rational drug prescribing in primary care in Europe.<br />The three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, hitherto there is no comprehensive survey of genome-wide CTCF binding patterns across different human cancers.<br />To dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions, partially with DNA methylation changes, and rarely with sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events exhibit enhancer activities and are induced by oncogenic transcription factors. We validate these findings in T cell acute lymphoblastic leukemia cell lines and patient samples and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena.<br />Specific CTCF binding events occur in human cancers. Cancer-specific CTCF binding can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.<br />Specific CTCF binding events occur in human cancers. Cancer-specific CTCF binding can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.