Oxygen radicals and reactive oxygen species in reproduction

Free radicals and reactive oxygen species play a number of significant and diverse roles in reproductive biology. In common with other biological systems, mechanisms have evolved to minimize the damaging effects that these highly reactive molecules can have on reproductive integrity. Conversely, however, recent findings illustrate the constructive roles that oxygen radicals and reactive oxygen species play in a number of important junctures in the development of germ cells and the obligate endocrine support they receive for the successful propagation of the species. Specifically addressed in this review are some aspects of sperm development and action, the uterine environment, oocyte maturation and ovulation, and corpus luteum function and regression.     

Social science methods for twins data: integrating causality, endowments, and heritability

Twins have been extensively used in economics, sociology, and behavioral genetics to investigate the role of genetic endowments on a broad range of social, demographic, and economic outcomes. However, the focus in these literatures has been distinct.: The economic literature has been primarily concerned with the need to control for unobserved endowments--including as an important subset, genetic endowments--in analyses that attempt to establish the impact of one variable, often schooling, on a variety of economic, demographic, and health outcomes. Behavioral genetic analyses have mostly been concerned with decomposing the variation in the outcomes of interest into genetic, shared environmental, and non-shared environmental components, with recent multivariate analyses investigating the contributions of genes and the environment to the correlation and causation between variables. Despite the fact that twins studies and the recognition of the role of endowments are central to both of these literatures, they have mostly evolved independently. In this paper we develop formally the relationship between the economic and behavioral genetic approaches to the analyses of twins, and we develop an integrative approach that combines the identification of causal effects, which dominates the economic literature, with the decomposition of variances and covariances into genetic and environmental factors that are the primary goal of behavioral genetic approaches. We apply this integrative ACE-beta approach to an illustrative investigation of the impact of schooling on several demographic outcomes such as fertility and nuptiality and health.     

Chemoresistance in prostate cancer cells is regulated by miRNAs and Hedgehog pathway

Many prostate cancers relapse due to the generation of chemoresistance rendering first-line treatment drugs like paclitaxel (PTX) ineffective. The present study aims to determine the role of miRNAs and Hedgehog (Hh) pathway in chemoresistant prostate cancer and to evaluate the combination therapy using Hh inhibitor cyclopamine (CYA). Studies were conducted on PTX resistant DU145-TXR and PC3-TXR cell lines and clinical prostate tissues. Drug sensitivity and apoptosis assays showed significantly improved cytotoxicity with combination of PTX and CYA. To distinguish the presence of cancer stem cell like side populations (SP), Hoechst 33342 flow cytometry method was used. PTX resistant DU145 and PC3 cells, as well as human prostate cancer tissue possess a distinct SP fraction. Nearly 75% of the SP cells are in the G0/G1 phase compared to 62% for non-SP cells and have higher expression of stem cell markers as well. SP cell fraction was increased following PTX monotherapy and treatment with CYA or CYA plus PTX effectively reduced their numbers suggesting the effectiveness of combination therapy. SP fraction cells were allowed to differentiate and reanalyzed by Hoechst staining and gene expression analysis. Post differentiation, SP cells constitute 15.8% of total viable cells which decreases to 0.6% on treatment with CYA. The expression levels of P-gp efflux protein were also significantly decreased on treatment with PTX and CYA combination. MicroRNA profiling of DU145-TXR and PC3-TXR cells and prostate cancer tissue from the patients showed decreased expression of tumor suppressor miRNAs such as miR34a and miR200c. Treatment with PTX and CYA combination restored the expression of miR200c and 34a, confirming their role in modulating chemoresistance. We have shown that supplementing mitotic stabilizer drugs such as PTX with Hh-inhibitor CYA can reverse PTX chemoresistance and eliminate SP fraction in androgen independent, metastatic prostate cancer cell lines.     

A gonadotropin-releasing hormone-binding inhibitor from bovine ovaries. Purification and identification as histone H2A

Bovine, ovine, rat, and human ovaries contain a protein defined as gonadotropin-releasing hormone (GnRH)-like because it reversibly inhibits the high affinity binding of GnRH to rat ovarian membranes, but these same tissues contain little, if any, detectable GnRH. In the present study this GnRH-binding inhibitor (GnRH-BI) was purified from bovine ovaries by a combination of reversed-phase high pressure liquid chromatography, cation-exchange, and gel filtration chromatography. Purification was monitored by analysis of GnRH-like activity in the highly specific rat ovarian membrane receptor assay. Amino acid composition and partial sequence analysis indicated that the purified ovarian GnRH-BI is histone H2A. Calf thymus histone H2A and the purified ovarian protein showed identical dose-dependent (ID50 = 2 microM), competitive, and reversible inhibitory effects on GnRH binding to rat ovarian membranes. The inhibitory effects could not be explained by charge interactions alone since spermine and spermidine at 10-fold higher concentrations did not inhibit GnRH binding. Furthermore, the effects showed specificity since EGF binding to rat ovarian membranes was not inhibited. It is possible that the inhibition of GnRH binding by the purified ovarian fraction was due to low level contamination by a highly active binding inhibitor. However, based on the variety of different purification procedures, the identical effects seen with histone H2A, and the absence of other proteins on gel electrophoresis, we conclude that the ovarian GnRH-BI is probably histone H2A.