Role of PCSK5 Expression in Mouse Ovarian Follicle Development: Identification of the Inhibin α- and β-Subunits as Candidate Substrates

Inhibin and activin are essential dimeric glycoproteins belonging to the transforming growth factor-beta (TGFβ) superfamily. Inhibin is a heterodimer of α- and β-subunits, whereas activin is a homodimer of β-subunits. Production of inhibin is regulated during the reproductive cycle and requires the processing of pro-ligands to produce mature hormone. Furin is a subtilisin-like proprotein convertase (proconvertase) that activates precursor proteins by cleavage at basic sites during their transit through the secretory pathway and/or at the cell surface. We hypothesized that furin-like proconvertases are central regulators of inhibin α- and β-subunit processing within the ovary. We analyzed the expression of the proconvertases furin, PCSK5, PCSK6, and PCSK7 in the developing mouse ovary by real-time quantitative RT-PCR. The data showed that proconvertase enzymes are temporally expressed in ovarian cells. With the transition from two-layer secondary to pre-antral follicle, only PCSK5 mRNA was significantly elevated. Activin A selectively enhanced expression of PCSK5 mRNA and decreased expression of furin and PCSK6 in cultured two-layer secondary follicles. Inhibition of proconvertase enzyme activity by dec-RVKR-chloromethylketone (CMK), a highly specific and potent competitive inhibitor of subtilisin-like proconvertases, significantly impeded both inhibin α- and β-subunit maturation in murine granulosa cells. Overexpression of PC5/6 in furin-deficient cells led to increased inhibin α- and βB-subunit maturation. Our data support the role of proconvertase PCSK5 in the processing of ovarian inhibin subunits during folliculogenesis and suggest that this enzyme may be an important regulator of inhibin and activin bioavailability

Identifying and characterizing COPD patients in US managed care. A retrospective, cross-sectional analysis of administrative claims data

<p>Abstract</p> <p>Background</p> <p>Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death among US adults and is projected to be the third by 2020. In anticipation of the increasing burden imposed on healthcare systems and payers by patients with COPD, a means of identifying COPD patients who incur higher healthcare utilization and costs is needed.</p> <p>Methods</p> <p>This retrospective, cross-sectional analysis of US managed care administrative claims data describes a practical way to identify COPD patients. We analyze 7.79 million members for potential inclusion in the COPD cohort, who were continuously eligible during a 1-year study period. A younger commercial population (7.7 million) is compared with an older Medicare population (0.115 million). We outline a novel approach to stratifying COPD patients using "complexity" of illness, based on occurrence of claims for given comorbid conditions. Additionally, a unique algorithm was developed to identify and stratify COPD exacerbations using claims data.</p> <p>Results</p> <p>A total of 42,565 commercial (median age 56 years; 51.4% female) and 8507 Medicare patients (median 75 years; 53.1% female) were identified as having COPD. Important differences were observed in comorbidities between the younger commercial versus the older Medicare population. Stratifying by complexity, 45.0%, 33.6%, and 21.4% of commercial patients and 36.6%, 35.8%, and 27.6% of older patients were low, moderate, and high, respectively. A higher proportion of patients with high complexity disease experienced multiple (≥2) exacerbations (61.7% commercial; 49.0% Medicare) than patients with moderate- (56.9%; 41.6%), or low-complexity disease (33.4%; 20.5%). Utilization of healthcare services also increased with an increase in complexity.</p> <p>Conclusion</p> <p>In patients with COPD identified from Medicare or commercial claims data, there is a relationship between complexity as determined by pulmonary and non-pulmonary comorbid conditions and the prevalence of exacerbations and utilization of healthcare services. Identification of COPD patients at highest risk of exacerbations using complexity stratification may facilitate improved disease management by targeting those most in need of treatment.</p

The plight of the sense-making ape

This is a selective review of the published literature on object-choice tasks, where participants use directional cues to find hidden objects. This literature comprises the efforts of researchers to make sense of the sense-making capacities of our nearest living relatives. This chapter is written to highlight some nonsensical conclusions that frequently emerge from this research. The data suggest that when apes are given approximately the same sense-making opportunities as we provide our children, then they will easily make sense of our social signals. The ubiquity of nonsensical contemporary scientific claims to the effect that humans are essentially--or inherently--more capable than other great apes in the understanding of simple directional cues is, itself, a testament to the power of preconceived ideas on human perception

Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP

The Demographic and Socioeconomic Factors Predictive for Populations at High-Risk for La Crosse Virus Infection in West Virginia

Although a large body of literature exists for the environmental risk factors for La Crosse virus (LACV) transmission, the demographic and socioeconomic risk factors for developing LACV infection have not been investigated. Therefore, this study investigated the demographic and socioeconomic risk factors for LACV infection in West Virginia from 2003 to 2007, using two forward stepwise discriminant analyses. The discriminant analyses were used to evaluate a number of demographic and socioeconomic factors for their ability to predict: 1) those census tracts with at least one reported case of LACV infection versus those census tracts with no reported cases of LACV infection and 2) to evaluate significantly high-risk clusters for LACV infection versus significantly low-risk clusters for LACV infection. In the first model, a high school education diploma or a general education diploma or less and a lower housing densit

Interpreting household survey data intended to measure insecticide-treated bednet coverage: results from two surveys in Eritrea

BACKGROUND: As efforts are currently underway to roll-out insecticide-treated bednets (ITNs) to populations within malarious areas in Africa, there is an unprecedented need for data to measure the effectiveness of such programmes in terms of population coverage. This paper examines methodological issues to using household surveys to measure core Roll Back Malaria coverage indicators of ITN possession and use. METHODS: ITN coverage estimates within Anseba and Gash Barka Provinces from the 2002 Eritrean Demographic and Health Survey, implemented just prior to a large-scale ITN distribution programme, are compared to estimates from the same area from a sub-national Bednet Survey implemented 18 months later in 2003 after the roll-out of the ITN programme. RESULTS: Measures of bednet possession were dramatically higher in 2003 compared to 2002. In 2003, 82.2% (95% confidence interval (CI) 77.4–87.0) of households in Anseba and Gash Barka possessed at least one ITN. RBM coverage indicators for ITN use were also dramatically higher in 2003 as compared to 2002, with 76.1% (95% CI 69.9–82.2) of children under five years old and 52.4% (95% CI 38.2–66.6) of pregnant women sleeping under ITNs. The ITN distribution programme resulted in a gross increase in ITN use among children and pregnant women of 68.3% and 48% respectively. CONCLUSION: Eritrea has exceeded the Abuja targets of 60% coverage for ITN household possession and use among children under five years old within two malarious provinces. Results point to several important potential sources of bias that must be considered when interpreting data for ITN coverage over time, including: disparate survey universes and target populations that may include non-malarious areas; poor date recall of bednet procurement and treatment; and differences in timing of surveys with respect to malaria season

Post-democracy and institutionalized austerity in France:budgetary politics during François Hollande’s presidency

This paper applies the concept of post-democracy coined by Crouch to shed light on the emerging political dynamics of macro-economic policy coordination in the Eurozone as they applied to France during Hollande’s presidency. Firstly, the paper explains the nature of EMU reform, characterized here as post-democratic by institutional design, before analysing its impact on France’s budgetary politics. Finally, the French case involving Hollande’s balancing act between supranational rules and domestic spending preferences is used as a way to reflect on the stability of this post-democratic arrangement for rescuing the Euro. The 2017 presidential election pitting Macron against Le Pen showed that post-democracy by design is sustainable only if the supply side of politics remains supportive of EMU – a condition undermined by the institutionalization of austerity, at least in France

The Re-Emerging Role of the State in Contemporary Russia

I examine ownership structure of Russian firms during the 1998-2006 period, where a greater emphasis is placed on motivations behind increased government ownership in the latter years, when oligarchs' opportunistic influence on the firm diminished as state ownership correspondingly increased. As this phenomenon is also correlated with improved corporate growth during the period, I argue that state participation in corporate governance acted as an effective substitute mechanism to constrain wealth-tunnelling behaviour of corporate insiders and local bureaucrats in a country defined by a weak property rights system. © 2012 Springer-Verlag

Term birth weight and ambient air pollutant concentrations during pregnancy, among women living in Monroe County, New York

Increased ambient air pollutant concentrations during pregnancy have been associated with reduced birth weight, but the etiologically relevant pregnancy time window(s) is/are unclear. In 76,500 singleton births in Monroe County, NY (2005–2016), who were 37–42 gestational weeks at delivery, we used generalized linear models to regress term birth weight against mean gestational month pollutant concentrations, adjusting for mean temperature, and maternal, infant, and medical service use characteristics. Overall, there were no clear patterns of term birth weight change associated with increased concentrations of any pollutant across gestational months. However, among Hispanic women only, increases in all pollutants, except O3, in multiple gestational months, were associated with decreased term birth weight. Each 3.25 µg/m3 increase in PM2.5 concentration in the 6th gestational month was associated with a −20.4 g (95% CI = −34.0, −6.8) reduction in term birth weight among Hispanic women, but a 4.1 g (95% CI = −2.5, 10.8) increase among non-Hispanic mothers (p for interaction &lt; 0.001). Although ambient air pollutant concentrations during pregnancy were not associated with reduced term birth weight among women of all ethnicities living in Monroe County, this observed association in Hispanic mothers may be a result of less exposure misclassification and bias (due to closer residential proximity to the monitoring site)