Epigenetic regulation of 5α reductase-1 underlies adaptive plasticity of reproductive function and pubertal timing

Women facing increased energetic demands in childhood commonly have altered adult ovarian activity and shorter reproductive lifespan, possibly comprising a strategy to optimize reproductive success. Here we sought to understand the mechanisms of early-life programming of reproductive function, by integrating analysis of reproductive tissues in an appropriate mouse model with methylation analysis of proxy tissue DNA in a well-characterized population of Bangladeshi migrants in the UK. Bangladeshi women whose childhood was in Bangladesh were found to have later pubertal onset and lower age-matched ovarian reserve than Bangladeshi women who grew-up in England. Subsequently we aimed to explore the potential relevance to the altered reproductive phenotype of one of the genes that emerged from the screens. Results: Of the genes associated with differential methylation in the Bangladeshi women whose childhood was in Bangladesh as compared to Bangladeshi women who grew up in the UK, 13 correlated with altered expression of the orthologous gene in the mouse model ovaries. These mice had delayed pubertal onset and a smaller ovarian reserve compared to controls. The most relevant of these genes for reproductive function appeared to be SRD5A1, which encodes the steroidogenic enzyme 5α reductase-1. SRD5A1 was more methylated at the same transcriptional enhancer in mice ovaries as in the women’s buccal DNA, and its expression was lower in the hypothalamus of the mice as well, suggesting a possible role in the central control of reproduction. The expression of Kiss1 and Gnrh was also lower in these mice compared to controls, and inhibition of 5α reductase-1 reduced Kiss1 and Gnrh mRNA levels and blocked GnRH release in GnRH neuronal cell cultures. Crucially, we show that inhibition of this enzyme in female mice in vivo delayed pubertal onset. Conclusions: SRD5A1/5α reductase-1 responds epigenetically to the environment and its down-regulation appears to alter the reproductive phenotype. These findings help to explain diversity in reproductive characteristics and how they are shaped by early-life environment, and reveal novel pathways that might be targeted to mitigate health issues caused by life-history trade-offs

Local and macroscopic tunneling spectroscopy of Y(1-x)CaxBa2Cu3O(7-d) films: evidence for a doping dependent is or idxy component in the order parameter

Tunneling spectroscopy of epitaxial (110) Y1-xCaxBa2Cu3O7-d films reveals a doping dependent transition from pure d(x2-y2) to d(x2-y2)+is or d(x2-y2)+idxy order parameter. The subdominant (is or idxy) component manifests itself in a splitting of the zero bias conductance peak and the appearance of subgap structures. The splitting is seen in the overdoped samples, increases systematically with doping, and is found to be an inherent property of the overdoped films. It was observed in both local tunnel junctions, using scanning tunneling microscopy (STM), and in macroscopic planar junctions, for films prepared by either RF sputtering or laser ablation. The STM measurements exhibit fairly uniform splitting size in [110] oriented areas on the order of 10 nm2 but vary from area to area, indicating some doping inhomogeneity. U and V-shaped gaps were also observed, with good correspondence to the local faceting, a manifestation of the dominant d-wave order parameter

Tunneling spectroscopy measurement of the superconductor gap parameter of MgB_2

Cryogenic scanning tunneling microscopy and magnetization measurements were used to study the superconducting properties of MgB_2. The magnetization measurements show a sharp superconductor transition onset at T_c = 38.5 K, in agreement with previous works. The tunneling spectra exhibit BCS gap structures, with gap parameters in the range of 5 to 7 meV, yielding a ratio of 2delat/KT_c ~ 3-4. This suggests that MgB_2 is a conventional BCS (s-wave) superconductor, either in the weak-coupling or in the `intermediate-coupling` regimeComment: accepted to PRB, revised versio