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© 2017 The Author 2017. Published by Oxford University Press. Systems medicine holds many promises, but has so far provided only a limited number of proofs of principle. To address this road block, possible barriers and challenges of translating systems medicine into clinical practice need to be identified and addressed. The members of the European Cooperation in Science and Technology COST) Action CA15120 Open Multiscale Systems Medicine OpenMultiMed) wish to engage the scientific community of systems medicine and multiscale modelling, data science and computing, to provide their feedback in a structured manner. This will result in follow-up white papers and open access resources to accelerate the clinical translation of systems medicine. Austrian Science Fund: Special Research Program SFB-F54. The European Cooperation in Science and Technology (COST) Action CA15120 OpenMultiMed (http://openmultimed.net).

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SRY, a sex-determining gene, induces testis development in chromosomally female (XX) individuals. However, mouse XX Sertoli cells carrying Sry (XX/Sry Sertoli cells) are incapable of fully supporting germ cell development, even when the karyotype of the germ cells is XY. While it has therefore been assumed that XX/Sry Sertoli cells are not functionally equivalent to XY Sertoli cells, it has remained unclear which specific functions are affected. To elucidate the functional difference, we compared the gene expression of XY and XX/Sry Sertoli cells. Lactate and cholesterol metabolisms, essential for nursing the developing germ cells, were down-regulated in XX/Sry cells, which appears to be caused at least in part by the differential expression of histone modification enzymes SMCX/SMCY (H3K4me3 demethylase) and UTX/UTY (H3K27me3 demethylase) encoded by the sex chromosomes. We suggest that down-regulation of lactate and cholesterol metabolism that may be due to altered epigenetic modification affects the nursing functions of XX/Sry Sertoli cells., This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 21249018 and 16H05142 (K. Mo.), Ministry of Education, Culture, Sports, Science, and Technology, Japan (MEXT) KAKENHI Grant Number 22132002 (K. Mo.), the Uehara Memorial Foundation, and Takeda Science Foundation (T.B.).

A collaborative effort of clinicians, infectologists, molecular biologists, pharmacologists, veterinarians, bioinformaticians, management and education specialists is united in order to develop novel strategies of detecting early stages of chronic and infective diseases, their prevention and therapy. CODI-STRAT integrates 15 centers conducting leading–edge research of chronic inflammatory/infective diseases from seven European (five Mediterranean) countries and the USA, with specific aims to: i) establish long-standing partner center cross-disciplinary collaborations for clinical studies and research, ii) provide young investigators with broad and content-driven training and employability and iii) promote scientists up-skilled in genomics, transcriptomics, tissue expression, human serological and genetic studies, bioinformatics, chip technology, cell cultures and animal models, all directed toward clinical translation and chronic/infective disease management. This manuscript outlines the goals, partner roles and development of CODI-STRAT and its programme., peer-reviewed

Sexual differentiation is a carefully regulated process that ultimately results in a development of the male or female phenotype. Proper development of the male phenotype is dependent upon the action of testosterone, produced by Leydig cells, and antimullerian hormone, produced by Sertoli cells. Leydig cells start to produce testosterone around day 12.5 in the fetal mouse testis, and continue to produce high levels of testosterone throughout the gestation. In the present study we examined whether expression of two enzymes, lanosterol 14α -demethylase (cyp51) and cytochrome P450 NADPH reductase, involved in the cholesterol production, occurs simultaneously with proteins required for the production of steroid hormones. Immunocytochemical staining with antibodies against lanosterol 14α -demethylase , cytochrome P450 NADPH reductase, steroidogenic acute regulatory protein (StAR) and 3beta- hydroxysteroid dehydrogenase I (3β -HSD I) was used to determine the ontogeny of expression of these four proteins. As expected, 3β -HSD I and StAR proteins were detected on day 12.5 p.c., while expression of cyp51 and NADPH cytochrome P450 reductase appeared one day later, on day 13.5. Thereafter, the expression of all four proteins remained strong throughout the gestation. In human fetal testes, all four proteins were expressed in the Leydig cells at all ages studied, although very young samples from the time of initial Leydig cell development were not examined as they were not available. Results of this study suggest that initial steps of steroid hormone production in murine Leydig cells are dependent on exogenously derived cholesterol. Later on (from day 13.5 onwards), murine and human Leydig cells are able to synthesize cholesterol and are therefore not dependent on exogenous cholesterol resources.

The data show for the first time that cell type-specific mechanisms and post-translational modifications may infleunce trafficking of cytochrome P450 proteins

Superfamily of cytochromoes P450 (CYP) have been extensively investigated in xenobiotic metabolism studies but only a handful of these genes (e.g., Cyp19al and Cpy7al) have been associated with obesity. Examining these associations in animal models is relevant since obesity and metabolic syndrome in humans have become a prevalent health problem. In previous studies we identified four loci affecting obesity in mouse lines selected for high (Fat line) or low (Lean line) body fat content. Here we developed a Congenic line carrying a chromosome 15 obesity segment from the Lean line and compared its liver transcriptome and obesity traits with the original Fat line. Congenic segment exibited therapeutic effect on several obesity-related parameters such as lowering fat depot size by up to 29% and lowering fasting glucose levels. Using the Steroltalk microrray focused on cytochromes P450 and cholesterol metabolism, we identified 9 differentially expressed genes including two Cyp genes (Cyp 26al, Cyp2a4). Given the scacity of literature reporting associations between obesity and Cyps, our results auggest that these genes might play a more pronounced role in regulating obesity than previously thought. Further functional studies are needed to explain the mechanism by which pertubations in these Cyps affect obesity in our polygenic model. Proteini naddružine citokromov P450 (CYP) so dobro proučeni predvsem v povezavi s presnovo ksenobiotikov, le malo pa je znanega o vlogi genov te naddružine (npr. Cyp19al in Cyp7al) pri pojavu debelosti. Zaradi vse večjega števila bolezni, povezanih z debelostjo in metabolnim sindromom pri ljudeh, je preučevanje takih povezav na živalskih modelih v vzponu. V naših predhodnih genetskih študijah smo določili štiri lokuse, ki vplivjo na nalaganje maščevja v linijah miši, ki so bile selekcionirane na visok (debela linija) ali nizek odstotek telesnih maščob (suha linija). V tej študiji smo razvili kongeno linijo, ki vsebuje samo genomski segment kromosoma 15 iz suhe linije in primerjali njen transkriptom in druge fenotipske podatke z izvorno debelo linijo. Ugotovili smo, da ima kongeni odsek terapevtski učinek na večino z debelostjo poezanih lastnosti, kot so zmanjšanje količine posameznih maščobnih depojev ali zniževanje koncentracije glukoze v plazmi. Z uporabo Steroltalk mikromreže, ki je osredotočena na gene Cyp in gene v presnovi holesterola, smo uspeli določiti 9 diferencialno izraženih genov, ki vkljkučujejo tudi dva citokroma P450 (Cyp26al, Cyp2a4). Naši rezultati nakazuujejo, da imajo ti geni pomembno vlogo pri uravnavanju debelosti, kar dosedaj še ni bilo opisano. Da bi lahko razložili, kako so motnje v delovanju genov Cyp povezane z uravnavanjem debelosti v našem živalskem modelu, bodo potrebne nadaljnje funkcijske študije.