‘Free’ inhibin α subunit is expressed by bovine ovarian theca cells and its knockdown suppresses androgen production

Inhibins are ovarian dimeric glycoprotein hormones that suppress pituitary FSH production. They are synthesised by follicular granulosa cells as α plus βA/βB subunits (encoded by INHA, INHBA, INHBB, respectively). Inhibin concentrations are high in follicular fluid (FF) which is also abundant in ‘free’ α subunit, presumed to be of granulosal origin, but its role(s) remains obscure. Here, we report the unexpected finding that bovine theca cells show abundant INHA expression and ‘free’ inhibin α production. Thus, theca cells may contribute significantly to the inhibin α content of FF and peripheral blood. In vitro, knockdown of thecal INHA inhibited INSL3 and CYP17A1 expression and androgen production while INSL3 knockdown reduced INHA and inhibin α secretion. These findings suggest a positive role of thecal inhibin α on androgen production. However, exogenous inhibin α did not raise androgen production. We hypothesised that inhibin α may modulate the opposing effects of BMP and inhibin on androgen production. However, this was not supported experimentally. Furthermore, neither circulating nor intrafollicular androgen concentrations differed between control and inhibin α-immunized heifers, casting further doubt on thecal inhibin α subunit having a significant role in modulating androgen production. Role(s), if any, played by thecal inhibin α remain elusive

New Developments in Brief Interventions to Treat Problem Drinking in Nonspecialty Health Care Settings

The delivery of brief interventions (BIs) in health care settings to reduce problematic alcohol consumption is a key preventive strategy for public health. However, evidence of effectiveness beyond primary care is inconsistent. Patient populations and intervention components are heterogeneous. Also, evidence for successful implementation strategies is limited. In this article, recent literature is reviewed covering BI effectiveness for patient populations and subgroups, and design and implementation of BIs. Support is evident for short-term effectiveness in hospital settings, but long-term effects may be confounded by changes in control groups. Limited evidence suggests effectiveness with young patients not admitted as a consequence of alcohol, dependent patients, and binge drinkers. Influential BI components include high-quality change plans and provider characteristics. Health professionals endorse BI and feel confident in delivering it, but training and support initiatives continue to show no significant effects on uptake, prompting calls for systematic approaches to implementing BI in health care

Downregulation of Homologous Recombination DNA Repair Genes by HDAC Inhibition in Prostate Cancer Is Mediated through the E2F1 Transcription Factor

Histone deacetylase inhibitors (HDACis) re-express silenced tumor suppressor genes and are currently undergoing clinical trials. Although HDACis have been known to induce gene expression, an equal number of genes are downregulated upon HDAC inhibition. The mechanism behind this downregulation remains unclear. Here we provide evidence that several DNA repair genes are downregulated by HDAC inhibition and provide a mechanism involving the E2F1 transcription factor in the process.Applying Analysis of Functional Annotation (AFA) on microarray data of prostate cancer cells treated with HDACis, we found a number of genes of the DNA damage response and repair pathways are downregulated by HDACis. AFA revealed enrichment of homologous recombination (HR) DNA repair genes of the BRCA1 pathway, as well as genes regulated by the E2F1 transcription factor. Prostate cancer cells demonstrated a decreased DNA repair capacity and an increased sensitization to chemical- and radio-DNA damaging agents upon HDAC inhibition. Recruitment of key HR repair proteins to the site of DNA damage, as well as HR repair capacity was compromised upon HDACi treatment. Based on our AFA data, we hypothesized that the E2F transcription factors may play a role in the downregulation of key repair genes upon HDAC inhibition in prostate cancer cells. ChIP analysis and luciferase assays reveal that the downregulation of key repair genes is mediated through decreased recruitment of the E2F1 transcription factor and not through active repression by repressive E2Fs.Our study indicates that several genes in the DNA repair pathway are affected upon HDAC inhibition. Downregulation of the repair genes is on account of a decrease in amount and promoter recruitment of the E2F1 transcription factor. Since HDAC inhibition affects several pathways that could potentially have an impact on DNA repair, compromised DNA repair upon HDAC inhibition could also be attributed to several other pathways besides the ones investigated in this study. However, our study does provide insights into the mechanism that governs downregulation of HR DNA repair genes upon HDAC inhibition, which can lead to rationale usage of HDACis in the clinics

Efflux in Fungi: La Pièce de Résistance

Pathogens must be able to overcome both host defenses and antimicrobial treatment in order to successfully infect and maintain colonization of the host. One way fungi accomplish this feat and overcome intercellular toxin accumulation is efflux pumps, in particular ATP-binding cassette transporters and transporters of the major facilitator superfamily. Members of these two superfamilies remove many toxic compounds by coupling transport with ATP hydrolysis or a proton gradient, respectively. Fungal genomes encode a plethora of members of these families of transporters compared to other organisms. In this review we discuss the role these two fungal superfamilies of transporters play in virulence and resistance to antifungal agents. These efflux transporters are responsible not only for export of compounds involved in pathogenesis such as secondary metabolites, but also export of host-derived antimicrobial compounds. In addition, we examine the current knowledge of these transporters in resistance of pathogens to clinically relevant antifungal agents

Protein tyrosine phosphatases expression during development of mouse superior colliculus

Protein tyrosine phosphatases (PTPs) are key regulators of different processes during development of the central nervous system. However, expression patterns and potential roles of PTPs in the developing superior colliculus remain poorly investigated. In this study, a degenerate primer-based reverse transcription-polymerase chain reaction (RT-PCR) approach was used to isolate seven different intracellular PTPs and nine different receptor-type PTPs (RPTPs) from embryonic E15 mouse superior colliculus. Subsequently, the expression patterns of 11 PTPs (TC-PTP, PTP1C, PTP1D, PTP-MEG2, PTP-PEST, RPTPJ, RPTPε, RPTPRR, RPTPσ, RPTPκ and RPTPγ) were further analyzed in detail in superior colliculus from embryonic E13 to postnatal P20 stages by quantitative real-time RT-PCR, Western blotting and immunohistochemistry. Each of the 11 PTPs exhibits distinct spatiotemporal regulation of mRNAs and proteins in the developing superior colliculus suggesting their versatile roles in genesis of neuronal and glial cells and retinocollicular topographic mapping. At E13, additional double-immunohistochemical analysis revealed the expression of PTPs in collicular nestin-positive neural progenitor cells and RC-2-immunoreactive radial glia cells, indicating the potential functional importance of PTPs in neurogenesis and gliogenesis

A competitive integration model of exogenous and endogenous eye movements

We present a model of the eye movement system in which the programming of an eye movement is the result of the competitive integration of information in the superior colliculi (SC). This brain area receives input from occipital cortex, the frontal eye fields, and the dorsolateral prefrontal cortex, on the basis of which it computes the location of the next saccadic target. Two critical assumptions in the model are that cortical inputs are not only excitatory, but can also inhibit saccades to specific locations, and that the SC continue to influence the trajectory of a saccade while it is being executed. With these assumptions, we account for many neurophysiological and behavioral findings from eye movement research. Interactions within the saccade map are shown to account for effects of distractors on saccadic reaction time (SRT) and saccade trajectory, including the global effect and oculomotor capture. In addition, the model accounts for express saccades, the gap effect, saccadic reaction times for antisaccades, and recorded responses from neurons in the SC and frontal eye fields in these tasks. © The Author(s) 2010