Molecular determinants of desensitization in an ENaC/degenerin channel.

Epithelial Na(+) channel (ENaC)/degenerin family members are involved in mechanosensation, blood pressure control, pain sensation, and the expression of fear. Several of these channel types display a form of desensitization that allows the channel to limit Na(+) influx during prolonged stimulation. We used site-directed mutagenesis and chemical modification, functional analysis, and molecular dynamics simulations to investigate the role of the lower palm domain of the acid-sensing ion channel 1, a member of the ENaC/degenerin family. The lower palm domains of this trimeric channel are arranged around a central vestibule, at ∼20 Å above the plasma membrane and are covalently linked to the transmembrane channel parts. We show that the lower palm domains approach one another during desensitization. Residues in the palm co-determine the pH dependence of desensitization, its kinetics, and the stability of the desensitized state. Mutations of palm residues impair desensitization by preventing the closing movement of the palm. Overexpression of desensitization-impaired channel mutants in central neurons allowed--in contrast to overexpression of wild type--a sustained signaling response to rapid pH fluctuations. We identify and describe here the function of an important regulatory domain that most likely has a conserved role in ENaC/degenerin channels.

Multiscale determinants of tree frog (Hyla arborea L.) calling ponds in western Switzerland

A tree frog (Hyla arborea L., 1758) metapopulation in western Switzerland was studied during spring 2001. All potential calling ponds in an area of 350 km(2) were searched for tree frog calling males. Twenty-nine out of 111 ponds sheltered between 1 and 250 callers. Most ponds were occupied by less than 12 males. Pond parameters were measured at three different levels using field analysis and a Geographical Information System (GIS). The first level was water chemistry and pond-associated measures. The second level was the surrounding land use in a 30 m buffer around the pond. The third level consisted of landscape indices on a broader scale (up to 2 km). Logistic regression was applied to identify parameters that can predict the presence of calling males in a pond. Response variable was the presence or absence of callers. Four significant parameters allowed us to explain about 40% of the total deviance of the observed occupational pattern. Urbanization around the pond had a highly negative impact on the probability of presence of calling males. Hours of direct sunlight on the pond was positively correlated with callers. Higher water conductivity was associated with a lesser probability of species presence. Finally, the further the closest two-lane road, the higher the probability of callers presence. Our results show that presence or absence of callers is influenced by factors acting at various geographical scales.

Frequency and determinants of urgent requests to home care agencies for community-dwelling elderly.

We analyzed a one-year case series and performed a longitudinal (4 month) cohort analysis of urgent requests made to home care agencies by and for their > or = 65 years old clients in order to estimate the frequency of unscheduled services delivered by home care agencies and to identify risk factors. All 40 home care agencies located in a Swiss region were included in the study and we registered 3,816 urgent requests (75/1,000 > or = 65 years residents per year). Among home care users, the presence of a urinary catheter, incontinence and the need for assistance in bathing were predictors of unscheduled services. Resources should be planned in order to help home care teams to handle unexpected, disruptive clusters of urgent requests that may compromise their scheduled activities.

Determinants of brain cell metabolic phenotypes and energy substrate utilization unraveled with a modeling approach.

Although all brain cells bear in principle a comparable potential in terms of energetics, in reality they exhibit different metabolic profiles. The specific biochemical characteristics explaining such disparities and their relative importance are largely unknown. Using a modeling approach, we show that modifying the kinetic parameters of pyruvate dehydrogenase and mitochondrial NADH shuttling within a realistic interval can yield a striking switch in lactate flux direction. In this context, cells having essentially an oxidative profile exhibit pronounced extracellular lactate uptake and consumption. However, they can be turned into cells with prominent aerobic glycolysis by selectively reducing the aforementioned parameters. In the case of primarily oxidative cells, we also examined the role of glycolysis and lactate transport in providing pyruvate to mitochondria in order to sustain oxidative phosphorylation. The results show that changes in lactate transport capacity and extracellular lactate concentration within the range described experimentally can sustain enhanced oxidative metabolism upon activation. Such a demonstration provides key elements to understand why certain brain cell types constitutively adopt a particular metabolic profile and how specific features can be altered under different physiological and pathological conditions in order to face evolving energy demands.

Determinants of Corporate Disclosure : A Multicountry, Multilevel Model

Abstract The complexity of the current business world is making corporate disclosure more and more important for information users. These users, including investors, financial analysts, and government authorities rely on the disclosed information to make their investment decisions, analyze and recommend shares, and to draft regulation policies. Moreover, the globalization of capital markets has raised difficulties for information users in understanding the differences incorporate disclosure across countries and across firms. Using a sample of 797 firms from 34 countries, this thesis advances the literature on disclosure by illustrating comprehensively the disclosure determinants originating at firm systems and national systems based on the multilevel latent variable approach. Under this approach, the overall variation associated with the firm-specific variables is decomposed into two parts, the within-country and the between-country part. Accordingly, the model estimates the latent association between corporate disclosure and information demand at two levels, the within-country and the between-country level. The results indicate that the variables originating from corporate systems are hierarchically correlated with those from the country environment. The information demand factor indicated by the number of exchanges listed and the number of analyst recommendations can significantly explain the variation of corporate disclosure for both "within" and "between" countries. The exogenous influences of firm fundamentals-firm size and performance-are exerted indirectly through the information demand factor. Specifically, if the between-country variation in firm variables is taken into account, only the variables of legal systems and economic growth keep significance in explaining the disclosure differences across countries. These findings strongly support the hypothesis that disclosure is a response to both corporate systems and national systems, but the influence of the latter on disclosure reflected significantly through that of the former. In addition, the results based on ADR (American Depositary Receipt) firms suggest that the globalization of capital markets is harmonizing the disclosure behavior of cross-boundary listed firms, but it cannot entirely eliminate the national features in disclosure and other firm-specific characteristics.

Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study.

PURPOSE: To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. METHODS: Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. RESULTS: Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. CONCLUSION: Cannabis use and higher methadone doses in MMT could in part be a response to-or a cause of-more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

Seasonality and cyclic tendency of mortality in a Pyrenean population

Las características de la mortalidad Influyen decisivamente en la estructura demográfica de las poblaciones, regida por diferentes factores: internos (rasgos específicos genéticos y culturales), externos (características del ecosistema) e intermedios (capacidad de la población de autoajustarse al ambiente). El estudio de la distribución estacional de las 3313 defunciones registradas en la Villa de El Pont de Suert (Alta Ribagorça, Cataluña) desde 1664 evidencia la importancia de todos estos factores. Los patrones de distribución muestran el Influjo de las condiciones climáticas, de los ambientes epidemiológicos, así como de las transformaciones socioeconómicas y demográficas. El modelo de tendencia cíclica en la mortalidad, común a muchas poblaciones ibéricas de montaña, no se evidencia en esta población.

Entry and transcription as key determinants of differences in CD4 T-cell permissiveness to human immunodeficiency virus type 1 infection.

Isolated primary human cells from different donors vary in their permissiveness-the ability of cells to be infected and sustain the replication of human immunodeficiency virus type 1 (HIV-1). We used replicating HIV-1 and single-cycle lentivirus vectors in a population approach to identify polymorphic steps during viral replication. We found that phytohemagglutinin-stimulated CD4(+) CD45RO(+) CD57(-) T cells from healthy blood donors (n = 128) exhibited a 5.2-log-unit range in virus production. For 20 selected donors representing the spectrum of CD4 T-cell permissiveness, we could attribute up to 42% of the total variance in virus production to entry factors and 48% to postentry steps. Efficacy at key intracellular steps of the replicative cycle (reverse transcription, integration, transcription and splicing, translation, and budding and release) varied from 0.71 to 1.45 log units among donors. However, interindividual differences in transcription efficiency alone accounted for 64 to 83% of the total variance in virus production that was attributable to postentry factors. While vesicular stomatitis virus G protein-mediated fusion was more efficacious than CCR5/CD4 entry, the latter resulted in greater transcriptional activity per proviral copy. The phenotype of provirus transcription was stable over time, indicating that it represents a genetic trait.

Identifying the socioeconomic determinants of crime in Spanish provinces

In this paper we study, having as theoretical reference the economic model of crime (Becker, 1968; Ehrlich, 1973), which are the socioeconomic and demographic determinants of crime in Spain paying attention on the role of provincial peculiarities. We estimate a crime equation using a panel dataset of Spanish provinces (NUTS3) for the period 1993 to 1999 employing the GMMsystem estimator. Empirical results suggest that lagged crime rate and clear-up rate are correlated to all typologies of crime rate considered. Property crimes are better explained by socioeconomic variables (GDP per capita, GDP growth rate and percentage of population with high school and university degree), while demographic factors reveal important and significant influences, in particular for crimes against the person. These results are obtained using an instrumental variable approach that takes advantage of the dynamic properties of our dataset to control for both measurement errors in crime data and joint endogeneity of the explanatory variables

Socioeconomic determinants of dietary patterns in low- and middle-income countries : a systematic review

BACKGROUND: In high-income countries, high socioeconomic status (SES) is generally associated with a healthier diet, but whether social differences in dietary intake are also present in low- and middle-income countries (LMICs) remains to be established. OBJECTIVE: We performed a systematic review of studies that assessed the relation between SES and dietary intake in LMICs. DESIGN: We carried out a systematic review of cohort and cross-sectional studies in adults in LMICs and published between 1996 and 2013. We assessed associations between markers of SES or urban and rural settings and dietary intake. RESULTS: A total of 33 studies from 17 LMICs were included (5 low-income countries and 12 middle-income countries; 31 cross-sectional and 2 longitudinal studies). A majority of studies were conducted in Brazil (8), China (6), and Iran (4). High SES or living in urban areas was associated with higher intakes of calories; protein; total fat; cholesterol; polyunsaturated, saturated, and monounsaturated fatty acids; iron; and vitamins A and C and with lower intakes of carbohydrates and fiber. High SES was also associated with higher fruit and/or vegetable consumption, diet quality, and diversity. Although very few studies were performed in low-income countries, similar patterns were generally observed in both LMICs except for fruit intake, which was lower in urban than in rural areas in low-income countries. CONCLUSIONS: In LMICs, high SES or living in urban areas is associated with overall healthier dietary patterns. However, it is also related to higher energy, cholesterol, and saturated fat intakes. Social inequalities in dietary intake should be considered in the prevention and control of noncommunicable diseases in LMICs.

The determinants of industrial location in Spain, 1856-1929

Durant el segle XIX, l'economia espanyola va transitar per les primeres etapes de la industrialització. Aquest procés es va donar en paral·lel a la integració del mercat domèstic de béns i factors, en un moment en què les reformes liberals i la construcció de la xarxa ferroviària, entre d'altres, van generar una important caiguda en els costos detransport. Al mateix temps que es donava aquesta progressiva integració del mercat domèstic espanyol, es van produir canvis significatius en la pauta de localització industrial. D'una banda, hi hagué un augment considerable de la concentració espacial de la indústria des de mitjans de segle XIX i fins a la Guerra Civil, i d¿altra, un increment de l'especialització regional. Ara bé, quines van ser les forces que van generar aquests canvis? Des d¿un punt de vista teòric, el model de Heckscher-Ohlin suggereix que la distribució a l'espai de l¿activitat econòmica ve determinada per l'avantatge comparativa dels territoris en funció de la dotació relativa de factors. Al seu torn, els models de Nova Geografia Econòmica (NEG) mostren l'existència d'una relació en forma de campana entre el procés d'integració econòmica i el grau de concentració geogràfica de l'activitat industrial. Aquest article examina empíricament els determinants de la localització industrial a Espanya entre 1856 i 1929, mitjançant l'estimació d¿un model que combina els elements de tipus Heckscher-Ohlin i els factors apuntats des de la NEG, amb l'objectiu de contrastar la força relativa dels arguments vinculats a aquestes dues interpretacions a l'hora de modular la localització de la indústria a Espanya. L'anàlisi dels resultats obtinguts mostra que tant la dotació de factors com els mecanismes de tipus NEG van ser elements determinants que expliquen la distribució geogràfica de la indústria des del segle XIX, tot i que la seva força relativa va anar variant amb el temps.

The determinants of social spending in Spain (1880-1960): Is Lindert right?

[spa] El principal objetivo de este artículo se centra en analizar los orígenes del Estado de Bienestar en España a partir del marco teórico elaborado por Peter Lindert. Con este fin, se ofrece un análisis econométrico de los factores que determinaron la evolución del gasto social público en este país entre 1880 y 1960. Utilizando nueva evidencia cuantitativa, se construyó un panel de datos por quinquenios con el porcentaje de gasto social respecto al PIB desagregado en tres partidas: sanidad, seguridad social y beneficencia. El análisis permite insertar el caso español en el debate internacional y los resultados revelan interesantes singularidades de este país.

Geographical determinants of the creation of manufacturing firms: The regions of Spain

La complexitat dels mecanismes que determinen l'entrada i la sortida de signatures augmenta quan diferències geogràfiques de l'estructura de producció, la capital humana i l'atur són considerades. Variacions interregionals en la tarifa de les noves de signatures dintre de cada activitat industrial persisteixen durant els períodes llargs de temps, una circumstància que indica que hi ha determinants no-conjunturals en la capacitat de regions per a crear nous projectes industrials. Aquest estudi està preocupat amb l'establiment d'influència variables geogràfiques sobre la fundació de nous establiments de la fabricació. Les indústries (NEIX la R 25) en les regions espanyoles (el BOIG 2) han estat preses com les unitats d'anàlisis per al període 1980-1992