Permeation of CO2 and N2 through glassy poly(dimethyl phenylene) oxide under steady- and presteady-state conditions

Glassy polymers are often used for gas separations because of their high selectivity. Although the dual-mode permeation model correctly fits their sorption and permeation isotherms, its physical interpretation is disputed, and it does not describe permeation far from steady state, a condition expected when separations involve intermittent renewable energy sources. To develop a more comprehensive permeation model, we combine experiment, molecular dynamics, and multiscale reaction–diffusion modeling to characterize the time-dependent permeation of N2 and CO2 through a glassy poly(dimethyl phenylene oxide) membrane, a model system. Simulations of experimental time-dependent permeation data for both gases in the presteady-state and steady-state regimes show that both single- and dual-mode reaction–diffusion models reproduce the experimental observations, and that sorbed gas concentrations lag the external pressure rise. The results point to environment-sensitive diffusion coefficients as a vital characteristic of transport in glassy polymers

Temperature controlled martensitic phase transformations in a model NiAl alloy

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The Archaeology of Yukon Ice Patches: New Artifacts, Observations, and Insights

Since 1997, more than 207 archaeological objects and 1700 faunal remains have been recovered from 43 melting ice patches in the southern Yukon. The artifacts range in age from a 9000-year-old (calendar) dart shaft to a 19th-century musket ball. This paper provides an update on Yukon ice patch research and summary data on select areas of research conducted since 2003. More than 200 radiocarbon dates have been run on ice patch archaeological and faunal materials, and these data allow us to observe and comment on apparent temporal trends. Analysis undertaken since 2003 has improved our understanding of the development and maintenance of hunting technologies, including dart shaft design, wood selection, and point styles. Of particular interest is the description of three different techniques for the construction of throwing darts and the observation of stability in the hunting technology employed in the study area over seven millennia. Radiocarbon chronologies indicate that this period of stability was followed by an abrupt technological replacement of the throwing dart by the bow and arrow after 1200 BP.Depuis 1997, plus de 350 objets archéologiques et de 1 700 restes fauniques ont été récupérés dans 43 névés en fusion dans le sud du Yukon. L’âge de ces artefacts varie, allant d’une tige de propulseur de 9 000 ans (années civiles) à une balle de mousquet du XIXe siècle. Dans cet article, nous faisons la mise à jour des données sommaires et des travaux de recherche effectués dans les névés de régions choisies du Yukon depuis 2003. Plus de 200 dates au carbone 14 ont été établies pour le matériel faunique et archéologique des névés. Ces données nous permettent d’observer les tendances temporales apparentes et de formuler des commentaires à leur sujet. Les analyses qui ont été effectuées depuis 2003 nous ont permis de mieux comprendre l’évolution et le maintien des techniques de chasse, notamment en matière de conception des tiges de propulseurs, de choix du bois et des types de pointes. La description de trois techniques différentes de fabrication de tirs au propulseur de même que l’observation de la stabilité entourant la technique de chasse employée au cours de la période visée par l’étude, soit plus de sept millénaires, revêtent un intérêt particulier. Les chronologies au carbone 14 indiquent que cette période de stabilité a été suivie d’un remplacement technique abrupt, qui est passé du tir au propulseur aux arcs et aux flèches après 1200 BP

18F-Labelled exendin to image GLP-1 receptor-expressing tissues: from niche to blockbuster?

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GTP binding and intramolecular regulation by the ROC domain of Death Associated Protein Kinase 1

The ROCO proteins are a family of large, multidomain proteins characterised by the presence of a Ras of complex proteins (ROC) domain followed by a COR, or C-terminal of ROC, domain. It has previously been shown that the ROC domain of the human ROCO protein Leucine Rich Repeat Kinase 2 (LRRK2) controls its kinase activity. Here, the ability of the ROC domain of another human ROCO protein, Death Associated Protein Kinase 1 (DAPK1), to bind GTP and control its kinase activity has been evaluated. In contrast to LRRK2, loss of GTP binding by DAPK1 does not result in loss of kinase activity, instead acting to modulate this activity. These data highlight the ROC domain of DAPK1 as a target for modifiers of this proteins function, and casts light on the role of ROC domains as intramolecular regulators in complex proteins with implications for a broad range of human diseases

Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.

A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined)=2.1 × 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb)=1.9 × 10(-6), rs281377; p(comb)=2.1 × 10(-6) and rs601338; p(comb)=2.7 × 10(-6)) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC.Norwegian PSC Research Center German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN) Integrated Research and Treatment Center - Transplantation 01EO0802 PopGen biobank NIH DK 8496

A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.

Mutations in LRRK2 are a common cause of genetic Parkinson's disease (PD). LRRK2 is a multi-domain Roco protein, harbouring kinase and GTPase activity. In analogy with a bacterial homologue, LRRK2 was proposed to act as a GTPase activated by dimerization (GAD), while recent reports suggest LRRK2 to exist under a monomeric and dimeric form in vivo. It is however unknown how LRRK2 oligomerization is regulated. Here, we show that oligomerization of a homologous bacterial Roco protein depends on the nucleotide load. The protein is mainly dimeric in the nucleotide-free and GDP-bound states, while it forms monomers upon GTP binding, leading to a monomer-dimer cycle during GTP hydrolysis. An analogue of a PD-associated mutation stabilizes the dimer and decreases the GTPase activity. This work thus provides insights into the conformational cycle of Roco proteins and suggests a link between oligomerization and disease-associated mutations in LRRK2

The cell adhesion protein CAR is a negative regulator of synaptic transmission

The Coxsackievirus and adenovirus receptor (CAR) is essential for normal electrical conductance in the heart, but its role in the postnatal brain is largely unknown. Using brain specific CAR knockout mice (KO), we discovered an unexpected role of CAR in neuronal communication. This includes increased basic synaptic transmission at hippocampal Schaffer collaterals, resistance to fatigue, and enhanced long-term potentiation. Spontaneous neurotransmitter release and speed of endocytosis are increased in KOs, accompanied by increased expression of the exocytosis associated calcium sensor synaptotagmin 2. Using proximity proteomics and binding studies, we link CAR to the exocytosis machinery as it associates with syntenin and synaptobrevin/VAMP2 at the synapse. Increased synaptic function does not cause adverse effects in KO mice, as behavior and learning are unaffected. Thus, unlike the connexin-dependent suppression of atrioventricular conduction in the cardiac knockout, communication in the CAR deficient brain is improved, suggesting a role for CAR in presynaptic processes