Sex hormone-binding globulin regulation of androgen bioactivity in vivo : validation of the free hormone hypothesis

Sex hormone-binding globulin (SHBG) is the high-affinity binding protein for androgens and estrogens. According to the free hormone hypothesis, SHBG modulates the bioactivity of sex steroids by limiting their diffusion into target tissues. Still, the in vivo physiological role of circulating SHBG remains unclear, especially since mice and rats lack circulating SHBG post-natally. To test the free hormone hypothesis in vivo, we examined total and free sex steroid concentrations and bioactivity on target organs in mice expressing a human SHBG transgene. SHBG increased total androgen and estrogen concentrations via hypothalamic-pituitary feedback regulation and prolonged ligand half-life. Despite markedly raised total sex steroid concentrations, free testosterone was unaffected while sex steroid bioactivity on male and female reproductive organs was attenuated. This occurred via a liganddependent, genotype-independent mechanism according to in vitro seminal vesicle organ cultures. These results provide compelling support for the determination of free or bioavailable sex steroid concentrations in medicine, and clarify important comparative differences between translational mouse models and human endocrinology

Large-area femtosecond laser milling of silicon employing trench analysis

A femtosecond laser is a powerful tool for micromachining of silicon. In this work, large-area laser ablation of crystalline silicon is comprehensively studied using a laser source of pulse width 300 fs at two wavelengths of 343 nm and 1030 nm. We develop a unique approach to gain insight into the laser milling process by means of detailed analysis of trenches. Laser scribed trenches and milled areas are characterized using optical profilometry to extract dimensional and roughness parameters with accuracy and repeatability. In a first step, multiple measures of the trench including the average depth, the volume of recast material, the average longitudinal profile roughness, the inner trench width and the volume removal rate are studied. This allows for delineation of ablation regimes and associated characteristics allowing to determine the impact of fluence and repetition rate on laser milling. In a second step, additional factors of debris formation and material redeposition that come into play during laser milling are further elucidated. These results are utilized for processing large-area (up to few mm2) with milling depths up to 200 {\mu}m to enable the fabrication of cavities with low surface roughness at high removal rates of up to 6.9 {\mu}m3 {\mu}s-1. Finally, laser processing in combination with XeF2 etching is applied on SOI-CMOS technology in the fabrication of radio-frequency (RF) functions standing on suspended membranes. Performance is considerably improved on different functions like RF switch (23 dB improvement in 2nd harmonic), inductors (near doubling of Q-factor) and LNA (noise figure improvement of 0.1 dB) demonstrating the applicability of milling to radio-frequency applications.Comment: 23 pages, 16 figure

Androgen receptor uses relaxed response element stringency for selective chromatin binding and transcriptional regulation in vivo

Peer reviewe

The logic of transcriptional regulator recruitment architecture at cis-regulatory modules controlling liver functions.

Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis-regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic, and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs. Different combinations of TRMs add to a core TRM, broadly found across the whole landscape of CRMs, to discriminate promoters from enhancers. These combinations also specify distinct sets of CRM differentially organized along the genome and involved in regulation of either housekeeping/cellular maintenance genes or liver-specific functions. In addition to these TRMs which we define as obligatory, we show that facultative TRMs, such as one comprising core circadian TRs, are further recruited to selective subsets of CRMs to modulate their activities. TRMs transcend TR classification into ubiquitous versus liver-identity factors, as well as TR grouping into functional families. Hence, hierarchical superimpositions of obligatory and facultative TRMs bring about independent transcriptional regulatory inputs defining different sets of CRMs with logical connection to regulation of specific gene sets and biological pathways. Altogether, our study reveals novel principles of concerted transcriptional regulation by multiple TRs at CRMs

Chain length affects pancreatic lipase activity and the extent and pH–time profile of triglyceride lipolysis

Triglycerides (TG) are one of the most common excipients used in oral lipid-based formulations. The chain length of the TG plays an important role in the oral bioavailability of the co-administered drug. Fatty acid (FA) chain-length specificity of porcine pancreatic lipase was studied by means of an in vitro lipolysis model under bio-relevant conditions at pH 6.80. In order to determine the total extent of lipolysis, back-titration experiments at pH 11.50 were performed. Results suggest that there is a specific chain length range (C2–C8) for which pancreatic lipase shows higher activity. This specificity could result from a combination of physicochemical properties of TGs, 2-monoglycerides (2-MGs) and FAs, namely the droplet size of the TGs, the solubility of 2-MGs within mixed micelles, and the relative stability of the FAs as leaving groups in the hydrolysis reaction. During experimentation, it was evident that an optimisation of lipolysis conditions was needed for tighter control over pH levels so as to better mimic in vivo conditions. 1 M NaOH, 3.5 mL/min maximum dosing rate, and 3 μL/min minimum dosing rate were the optimised set of conditions that allowed better pH control, as well as the differentiation of the lipolysis of different lipid loads

Food Patterns According to Sociodemographics, Physical Activity, Sleeping and Obesity in Portuguese Children

Our study aimed to describe the association between food patterns and gender, parental education, physical activity, sleeping and obesity in 1976 children aged 5−10 years old. Dietary intake was measured by a semi quantitative food frequency questionnaire; body mass index was calculated and categorized according to the IOTF classification. Factor analysis and generalized linear models were applied to identify food patterns and their associations. TV viewing and male gender were significant positive predictors for fast-food, sugar sweetened beverages and pastry pattern, while a higher level of maternal education and longer sleeping duration were positively associated with a dietary patterns that included fruit and vegetables