Proton block and voltage gating are potassium-dependent in the cardiac leak channel Kcnk3.

Potassium leak conductances were recently revealed to exist as independent molecular entities. Here, the genomic structure, cardiac localization, and biophysical properties of a murine example are considered. Kcnk3 subunits have two pore-forming P domains and unique functional attributes. At steady state, Kcnk3 channels behave like open, potassium-selective, transmembrane holes that are inhibited by physiological levels of proton. With voltage steps, Kcnk3 channels open and close in two phases, one appears to be immediate and one is time-dependent (tau = approximately 5 ms). Both proton block and gating are potassium-sensitive; this produces an anomalous increase in outward flux as external potassium levels rise because of decreased proton block. Single Kcnk3 channels open across the physiological voltage range; hence they are "leak" conductances; however, they open only briefly and rarely even after exposure to agents that activate other potassium channels

Pedigree analysis of Czech Holstein calves with schistosoma reflexum

<p>Abstract</p> <p>Background</p> <p>Schistosoma reflexum (SR) is congenital syndrome briefly characterized by visceral eventration, severe dorsoflexion and ankylosis of the spine and arthrogryposis. A genetic etiology has been proposed, but conclusive evidence has not yet been provided.</p> <p>Methods</p> <p>Pedigree analysis was carried out in 29 cases of SR in Czech Holsteins and Holstein crosses. Genetic relationship was evaluated and inbreeding coefficients calculated. Pedigrees of 15 Czech Holsteins fathering non-SR affected calves were used for comparison.</p> <p>Results</p> <p>Twenty-one cases occurred in one pedigree founded by three sires while three SR calves occurred in another pedigree with a common grandfather. The sex ratio between affected males and females was 11:6. Affected calves shared common ancestors different from those shared by the unaffected calves. The inbreeding coefficient in the SR affected calves was not increased compared to unaffected calves.</p> <p>Conclusions</p> <p>The findings are consistent with SR being inherited autosomal recessively. Further studies are however needed to confirm this and therefore a breeding trial is recommended where a suspected heterozygous sire is mated to closely related females.</p

Empowering employees with chronic diseases: process evaluation of an intervention aimed at job retention

Purpose Employees with a chronic disease may experience work-related problems that contribute to the risk of job loss. We developed a group-based intervention programme aimed at clarifying problems, making these a subject of discussion at work, and realizing solutions. This process evaluation investigates the intervention's feasibility and the satisfaction of 64 participants in eight groups. Methods Data were collected through process evaluation forms and self-report questionnaires. Results The recruitment of participants was time-consuming. Highly educated women working in the service sector were overrepresented. The programme was administered as planned, although components were sometimes only discussed briefly, due to lack of time. Satisfaction with the overall programme among participants was high; it was perceived as effective and there were only three dropouts. In particular, the focus on feelings and thoughts about having a chronic disease was highly valued, as were the exchange of experiences and role-playing directed at more assertive communication. Conclusions A vocational rehabilitation programme aimed at job retention is feasible and is perceived to be effective. Such a programme should address psychosocial aspects of working with a chronic disease beside practical problems. The recruitment of participants is time-consuming. Cooperation with outpatient clinics is necessary in order to reach all groups of employees with a chronic disease that might benefit from job retention programmes. Trial registration: ISRCTN77240155

Improved ChIP-chip analysis by a mixture model approach

<p>Abstract</p> <p>Background</p> <p>Microarray analysis of immunoprecipitated chromatin (ChIP-chip) has evolved from a novel technique to a standard approach for the systematic study of protein-DNA interactions. In ChIP-chip, sites of protein-DNA interactions are identified by signals from the hybridization of selected DNA to tiled oligomers and are graphically represented as peaks. Most existing methods were designed for the identification of relatively sparse peaks, in the presence of replicates.</p> <p>Results</p> <p>We propose a data normalization method and a statistical method for peak identification from ChIP-chip data based on a mixture model approach. In contrast to many existing methods, including methods that also employ mixture model approaches, our method is more flexible by imposing less restrictive assumptions and allowing a relatively large proportion of peak regions. In addition, our method does not require experimental replicates and is computationally efficient. We compared the performance of our method with several representative existing methods on three datasets, including a spike-in dataset. These comparisons demonstrate that our approach is more robust and has comparable or higher power than the other methods, especially in the context of abundant peak regions.</p> <p>Conclusion</p> <p>Our data normalization and peak detection methods have improved performance to detect peak regions in ChIP-chip data.</p

Normal X-inactivation mosaicism in corneas of heterozygous FlnaDilp2/+ female mice--a model of human Filamin A (FLNA) diseases

<p>Abstract</p> <p>Background</p> <p>Some abnormalities of mouse corneal epithelial maintenance can be identified by the atypical mosaic patterns they produce in X-chromosome inactivation mosaics and chimeras. Human <it>FLNA</it>/+ females, heterozygous for X-linked, filamin A gene (<it>FLNA</it>) mutations, display a range of disorders and X-inactivation mosaicism is sometimes quantitatively unbalanced. <it>Flna</it>^{<it>Dilp2/+ </it>}mice, heterozygous for an X-linked filamin A (<it>Flna</it>) nonsense mutation have variable eye, skeletal and other abnormalities, but X-inactivation mosaicism has not been investigated. The aim of this study was to determine whether X-inactivation mosaicism in the corneal epithelia of <it>Flna</it>^{<it>Dilp2/+ </it>}mice was affected in any way that might predict abnormal corneal epithelial maintenance.</p> <p>Results</p> <p>X-chromosome inactivation mosaicism was studied in the corneal epithelium and a control tissue (liver) of <it>Flna</it>^{<it>Dilp2/+ </it>}and wild-type (WT) female X-inactivation mosaics, hemizygous for the X-linked, <it>LacZ </it>reporter H253 transgene, using β-galactosidase histochemical staining. The corneal epithelia of <it>Flna</it>^{<it>Dilp2/+ </it>}and WT X-inactivation mosaics showed similar radial, striped patterns, implying epithelial cell movement was not disrupted in <it>Flna</it>^{<it>Dilp2/+ </it>}corneas. Corrected stripe numbers declined with age overall (but not significantly for either genotype individually), consistent with previous reports suggesting an age-related reduction in stem cell function. Corrected stripe numbers were not reduced in <it>Flna</it>^{<it>Dilp2/+ </it>}compared with WT X-inactivation mosaics and mosaicism was not significantly more unbalanced in the corneal epithelia or livers of <it>Flna</it>^{<it>Dilp2/+ </it>}than wild-type <it>Flna^+/+</it>X-inactivation mosaics.</p> <p>Conclusions</p> <p>Mosaic analysis identified no major effect of the mouse <it>Flna^Dilp2</it>mutation on corneal epithelial maintenance or the balance of X-inactivation mosaicism in the corneal epithelium or liver.</p

The deuteron: structure and form factors

A brief review of the history of the discovery of the deuteron in provided. The current status of both experiment and theory for the elastic electron scattering is then presented.Comment: 80 pages, 33 figures, submited to Advances in Nuclear Physic

Fluctuation-Driven Flocking Movement in Three Dimensions and Scale-Free Correlation

Recent advances in the study of flocking behavior have permitted more sophisticated analyses than previously possible. The concepts of “topological distances” and “scale-free correlations” are important developments that have contributed to this improvement. These concepts require us to reconsider the notion of a neighborhood when applied to theoretical models. Previous work has assumed that individuals interact with neighbors within a certain radius (called the “metric distance”). However, other work has shown that, assuming topological interactions, starlings interact on average with the six or seven nearest neighbors within a flock. Accounting for this observation, we previously proposed a metric-topological interaction model in two dimensions. The goal of our model was to unite these two interaction components, the metric distance and the topological distance, into one rule. In our previous study, we demonstrated that the metric-topological interaction model could explain a real bird flocking phenomenon called scale-free correlation, which was first reported by Cavagna et al. In this study, we extended our model to three dimensions while also accounting for variations in speed. This three-dimensional metric-topological interaction model displayed scale-free correlation for velocity and orientation. Finally, we introduced an additional new feature of the model, namely, that a flock can store and release its fluctuations

Role of the Lateral Paragigantocellular Nucleus in the Network of Paradoxical (REM) Sleep: An Electrophysiological and Anatomical Study in the Rat

The lateral paragigantocellular nucleus (LPGi) is located in the ventrolateral medulla and is known as a sympathoexcitatory area involved in the control of blood pressure. In recent experiments, we showed that the LPGi contains a large number of neurons activated during PS hypersomnia following a selective deprivation. Among these neurons, more than two-thirds are GABAergic and more than one fourth send efferent fibers to the wake-active locus coeruleus nucleus. To get more insight into the role of the LPGi in PS regulation, we combined an electrophysiological and anatomical approach in the rat, using extracellular recordings in the head-restrained model and injections of tracers followed by the immunohistochemical detection of Fos in control, PS-deprived and PS-recovery animals. With the head-restrained preparation, we showed that the LPGi contains neurons specifically active during PS (PS-On neurons), neurons inactive during PS (PS-Off neurons) and neurons indifferent to the sleep-waking cycle. After injection of CTb in the facial nucleus, the neurons of which are hyperpolarized during PS, the largest population of Fos/CTb neurons visualized in the medulla in the PS-recovery condition was observed in the LPGi. After injection of CTb in the LPGi itself and PS-recovery, the nucleus containing the highest number of Fos/CTb neurons, moreover bilaterally, was the sublaterodorsal nucleus (SLD). The SLD is known as the pontine executive PS area and triggers PS through glutamatergic neurons. We propose that, during PS, the LPGi is strongly excited by the SLD and hyperpolarizes the motoneurons of the facial nucleus in addition to local and locus coeruleus PS-Off neurons, and by this means contributes to PS genesis

The Twin-Arginine Translocation Pathway in α-Proteobacteria Is Functionally Preserved Irrespective of Genomic and Regulatory Divergence

The twin-arginine translocation (Tat) pathway exports fully folded proteins out of the cytoplasm of Gram-negative and Gram-positive bacteria. Although much progress has been made in unraveling the molecular mechanism and biochemical characterization of the Tat system, little is known concerning its functionality and biological role to confer adaptive skills, symbiosis or pathogenesis in the α-proteobacteria class. A comparative genomic analysis in the α-proteobacteria class confirmed the presence of tatA, tatB, and tatC genes in almost all genomes, but significant variations in gene synteny and rearrangements were found in the order Rickettsiales with respect to the typically described operon organization. Transcription of tat genes was confirmed for Anaplasma marginale str. St. Maries and Brucella abortus 2308, two α-proteobacteria with full and partial intracellular lifestyles, respectively. The tat genes of A. marginale are scattered throughout the genome, in contrast to the more generalized operon organization. Particularly, tatA showed an approximately 20-fold increase in mRNA levels relative to tatB and tatC. We showed Tat functionality in B. abortus 2308 for the first time, and confirmed conservation of functionality in A. marginale. We present the first experimental description of the Tat system in the Anaplasmataceae and Brucellaceae families. In particular, in A. marginale Tat functionality is conserved despite operon splitting as a consequence of genome rearrangements. Further studies will be required to understand how the proper stoichiometry of the Tat protein complex and its biological role are achieved. In addition, the predicted substrates might be the evidence of role of the Tat translocation system in the transition process from a free-living to a parasitic lifestyle in these α-proteobacteria

Quantifying children's aggregate (dietary and residential) exposure and dose to permethrin: application and evaluation of EPA's probabilistic SHEDS-Multimedia model

Reliable, evaluated human exposure and dose models are important for understanding the health risks from chemicals. A case study focusing on permethrin was conducted because of this insecticide's widespread use and potential health effects. SHEDS-Multimedia was applied to estimate US population permethrin exposures for 3- to 5-year-old children from residential, dietary, and combined exposure routes, using available dietary consumption data, food residue data, residential concentrations, and exposure factors. Sensitivity and uncertainty analyses were conducted to identify key factors, pathways, and research needs. Model evaluation was conducted using duplicate diet data and biomonitoring data from multiple field studies, and comparison to other models. Key exposure variables were consumption of spinach, lettuce, and cabbage; surface-to-skin transfer efficiency; hand mouthing frequency; fraction of hand mouthed; saliva removal efficiency; fraction of house treated; and usage frequency. For children in households using residential permethrin, the non-dietary exposure route was most important, and when all households were included, dietary exposure dominated. SHEDS-Multimedia model estimates compared well to real-world measurements data; this exposure assessment tool can enhance human health risk assessments and inform children's health research. The case study provides insights into children's aggregate exposures to permethrin and lays the foundation for a future cumulative pyrethroid pesticides risk assessment