Structural determinants for membrane association and dynamic organization of the hepatitis C virus NS3-4A complex.

Hepatitis C virus (HCV) NS3-4A is a membrane-associated multifunctional protein harboring serine protease and RNA helicase activities. It is an essential component of the HCV replication complex and a prime target for antiviral intervention. Here, we show that membrane association and structural organization of HCV NS3-4A are ensured in a cooperative manner by two membrane-binding determinants. We demonstrate that the N-terminal 21 amino acids of NS4A form a transmembrane alpha-helix that may be involved in intramembrane protein-protein interactions important for the assembly of a functional replication complex. In addition, we demonstrate that amphipathic helix alpha(0), formed by NS3 residues 12-23, serves as a second essential determinant for membrane association of NS3-4A, allowing proper positioning of the serine protease active site on the membrane. These results allowed us to propose a dynamic model for the membrane association, processing, and structural organization of NS3-4A on the membrane. This model has implications for the functional architecture of the HCV replication complex, proteolytic targeting of host factors, and drug design.

Neurally Adjusted Ventilatory Assist (NAVA) improves the matching of diaphragmatic electrical activity and tidal volume in comparison to pressure support (PS) under non invasive ventilation

INTRODUCTION. Patient-ventilator asynchrony is a frequent issue in non invasivemechanical ventilation (NIV) and leaks at the patient-mask interface play a major role in itspathogenesis. NIV algorithms alleviate the deleterious impact of leaks and improve patient-ventilator interaction. Neurally adusted ventilatory assist (NAVA), a neurally triggered modethat avoids interferences between leaks and the usual pneumatic trigger, could further improvepatient-ventilator interaction in NIV patients.OBJECTIVES. To evaluate the feasibility ofNAVAin patients receiving a prophylactic postextubationNIV and to compare the respective impact ofPSVandNAVAwith and withoutNIValgorithm on patient-ventilator interaction.METHODS. Prospective study conducted in 16 beds adult critical care unit (ICU) in a tertiaryuniversity hospital. Over a 2 months period, were included 17 adult medical ICU patientsextubated for less than 2 h and in whom a prophylactic post-extubation NIV was indicated.Patients were randomly mechanically ventilated for 10 min with: PSV without NIV algorithm(PSV-NIV-), PSV with NIV algorithm (PSV-NIV+),NAVAwithout NIV algorithm (NAVANIV-)and NAVA with NIV algorithm (NAVA-NIV+). Breathing pattern descriptors, diaphragmelectrical activity, leaks volume, inspiratory trigger delay (Tdinsp), inspiratory time inexcess (Tiexcess) and the five main asynchronies were quantified. Asynchrony index (AI) andasynchrony index influenced by leaks (AIleaks) were computed.RESULTS. Peak inspiratory pressure and diaphragm electrical activity were similar in thefour conditions. With both PSV and NAVA, NIV algorithm significantly reduced the level ofleak (p\0.01). Tdinsp was not affected by NIV algorithm but was shorter in NAVA than inPSV (p\0.01). Tiexcess was shorter in NAVA and PSV-NIV+ than in PSV-NIV- (p\0.05).The prevalence of double triggering was significantly lower in PSV-NIV+ than in NAVANIV+.As compared to PSV,NAVAsignificantly reduced the prevalence of premature cyclingand late cycling while NIV algorithm did not influenced premature cycling. AI was not affectedby NIV algorithm but was significantly lower in NAVA than in PSV (p\0.05). AIleaks wasquasi null with NAVA and significantly lower than in PSV (p\0.05).CONCLUSIONS. NAVA is feasible in patients receiving a post-extubation prophylacticNIV. NAVA and NIV improve patient-ventilator synchrony in different manners. NAVANIV+offers the best patient-ventilator interaction. Clinical studies are required to assess thepotential clinical benefit of NAVA in patients receiving NIV.

Contrasting spatio-temporal climatic niche dynamics during the eastern and western invasions of spotted knapweed in North America

Aim The spotted knapweed (Centaurea stoebe), a plant native to south-east and central Europe, is highly invasive in North America. We investigated the spatio-temporal climatic niche dynamics of the spotted knapweed in North America along two putative eastern and western invasion routes. We then considered the patterns observed in the light of historical, ecological and evolutionary factors. Location Europe and North America. Methods The niche characteristics of the east and west invasive populations of spotted knapweed in North America were determined from documented occurrences over 120 consecutive years (1890-2010). The 2.5 and 97.5 percentiles of values along temperature and precipitation gradients, as given by the two first axes of a principal component axis (PCA), were then calculated. We additionally measured the climatic dissimilarity between invaded and native niches using a multivariate environmental similarity surface (MESS) analysis. Results Along both invasion routes, the species established in regions with climatic conditions that were similar to those in the native range in Europe. An initial spread in ruderal habitats always preceded spread in (semi-)natural habitats. In the east, the niche gradually increased over time until it reached limits similar to the native niche. Conversely, in the west the niche abruptly expanded after an extended time lag into climates not occupied in the native range; only the native cold niche limit was conserved. Main conclusions Our study reveals that different niche dynamics have taken place during the eastern and western invasions. This pattern indicates different combinations of historical, ecological and evolutionary factors in the two ranges. We hypothesize that the lack of a well-developed transportation network in the west at the time of the introduction of spotted knapweed confined the species to a geographically and climatically isolated region. The invasion of dry rangelands may have been favoured during the agricultural transition in the 1930s by release from natural enemies, local adaptation and less competitive vegetation, but further experimental and molecular studies are needed to explain these contrasting niche patterns fully. Our study illustrates the need and benefit of applying large-scale, temporally explicit approaches to understanding biological invasions.

Work and health conditions of sugar cane workers in Brazil

This is an exploratory research, with a quantitative approach, developed with the objective of analyzing the work and of life situations that can offer risks to the workers' health involved in the manual and automated cut of the sugar cane. The sample was composed by 39 sugar cane cutters and 16 operators of harvesters. The data collection occurred during the months of July and August of 2006, by the technique of direct observation of work situations and workers' homes and through interviews semi-structured. The interviews were recorded and later transcribed. Data were analyzed according to Social Ecological Theory. It was observed that the workers deal with multiple health risk situations, predominantly to the risks of occurrence of respiratory, musculoskeletal and psychological problems and work-related accidents due to the work activities. The interaction of individual, social and environmental factors can determine the workers' tendency to falling ill.

Interobserver and intraobserver variability of the apparent diffusion coefficient in treated malignant hepatic lesions on a 3.0T machine: measurements in the whole lesion versus in the area with the most restricted diffusion.

PURPOSE: To assess the inter/intraobserver variability of apparent diffusion coefficient (ADC) measurements in treated hepatic lesions and to compare ADC measurements in the whole lesion and in the area with the most restricted diffusion (MRDA). MATERIALS AND METHODS: Twenty-five patients with treated malignant liver lesions were examined on a 3.0T machine. After agreeing on the best ADC image, two readers independently measured the ADC values in the whole lesion and in the MRDA. These measurements were repeated 1 month later. The Bland-Altman method, Spearman correlation coefficients, and the Wilcoxon signed-rank test were used to evaluate the measurements. RESULTS: Interobserver variability for ADC measurements in the whole lesion and in the MRDA was 0.17 x 10(-3) mm(2)/s [-0.17, +0.17] and 0.43 x 10(-3) mm(2)/s [-0.45, +0.41], respectively. Intraobserver limits of agreement could be as low as [-0.10, +0.12] 10(-3) mm(2)/s and [-0.20, +0.33] 10(-3) mm(2)/s for measurements in the whole lesion and in the MRDA, respectively. CONCLUSION: A limited variability in ADC measurements does exist, and it should be considered when interpreting ADC values of hepatic malignancies. This is especially true for the measurements of the minimal ADC.

The effects of employment uncertainty and wealth shocks on the labor supply and claiming behavior of older American workers

Unemployment rates in developed countries have recently reached levels not seenin a generation, and workers of all ages are facing increasing probabilities of losingtheir jobs and considerable losses in accumulated assets. These events likely increasethe reliance that most older workers will have on public social insurance programs,exactly at a time that public finances are suffering from a large drop in contributions.Our paper explicitly accounts for employment uncertainty and unexpectedwealth shocks, something that has been relatively overlooked in the literature, butthat has grown in importance in recent years. Using administrative and householdlevel data we empirically characterize a life-cycle model of retirement and claimingdecisions in terms of the employment, wage, health, and mortality uncertainty facedby individuals. Our benchmark model explains with great accuracy the strikinglyhigh proportion of individuals who claim benefits exactly at the Early RetirementAge, while still explaining the increased claiming hazard at the Normal RetirementAge. We also discuss some policy experiments and their interplay with employmentuncertainty. Additionally, we analyze the effects of negative wealth shocks on thelabor supply and claiming decisions of older Americans. Our results can explainwhy early claiming has remained very high in the last years even as the early retirementpenalties have increased substantially compared with previous periods, andwhy labor force participation has remained quite high for older workers even in themidst of the worse employment crisis in decades.

Retirement incentives, individual heterogeneity and labour transitions of employed and unemployed workers

In this paper we analyze the sensitivity of the labour market decisions of workers close toretirement with respect to the incentives created by public regulations. We improve upon the extensiveprior literature on the effect of pension incentives on retirement in two ways. First, bymodeling the transitions between employment, unemployment and retirement in a simultaneousmanner, paying special attention to the transition from unemployment to retirement (which is particularlyimportant in Spain). Second, by considering the influence of unobserved heterogeneity inthe estimation of the effect of our (carefully constructed) incentive variables.Using administrative data, we find that, when properly defined, economic incentives have astrong impact on labour market decisions in Spain. Unemployment regulations are shown to be particularlyinfluential for retirement behaviour, along with the more traditional determinants linked tothe pension system. Pension variables also have a major bearing on both workers reemploymentdecisions and on the strategic actions of employers. The quantitative impact of the incentives, however,is greatly affected by the existence of unobserved heterogeneity among workers. Its omissionleads to sizable biases in the assessment of the sensitivity to economic incentives, a finding thathas clear consequences for the credibility of any model-based policy analysis. We confirm theimportance of this potential problem in one especially interesting instance: the reform of earlyretirement provisions undertaken in Spain in 2002. We use a difference-in-difference approach tomeasure the behavioural reaction to this change, finding a large overestimation when unobservedheterogeneity is not taken into account.

Morphological and physiological variation between queens and workers of Protonectarina sylveirae (de Saussure) (Hymenoptera, Vespidae, Epiponini)

Morphological and physiological variation between queens and workers of Protonectarina sylveirae (de Saussure) (Hymenoptera, Vespidae, Epiponini). The Neotropical swarm-founding wasps, Epiponini, range from the absence of morphological differentiation between castes to highly distinct castes. We measured eight body parts of females of two colonies of Protonectarina sylveirae (de Saussure, 1854). ANOVA and Discriminant Analysis evidenced significant differences between castes, as previously observed by other authors for other species of Epiponini. However, some females previously categorized as queens, were actually workers, supported by our statistic analyses. These individuals showed intermediate morphological features between queens and workers, having distinct patterns of hairs and clypeal spots. The castes of P. sylveirae are distinct, however intermediate individuals may be found in colonies promoting social flexibility.