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The sodium (Na+) leak channel (NALCN) is a member of the four-domain voltage-gated cation channel family that includes the prototypical voltage-gated sodium and calcium channels (NaVs and CaVs, respectively). Unlike NaVs and CaVs, which have four lateral fenestrations that serve as routes for lipophilic compounds to enter the central cavity to modulate channel function, NALCN has bulky residues (W311, L588, M1145, and Y1436) that block these openings. Structural data suggest that occluded fenestrations underlie the pharmacological resistance of NALCN, but functional evidence is lacking. To test this hypothesis, we unplugged the fenestrations of NALCN by substituting the four aforementioned residues with alanine (AAAA) and compared the effects of NaV, CaV, and NALCN blockers on both wild-type (WT) and AAAA channels. Most compounds behaved in a similar manner on both channels, but phenytoin and 2-aminoethoxydiphenyl borate (2-APB) elicited additional, distinct responses on AAAA channels. Further experiments using single alanine mutants revealed that phenytoin and 2-APB enter the inner cavity through distinct fenestrations, implying structural specificity to their modes of access. Using a combination of computational and functional approaches, we identified amino acid residues critical for 2-APB activity, supporting the existence of drug binding site(s) within the pore region. Intrigued by the activity of 2-APB and its analogues, we tested compounds containing the diphenylmethane/amine moiety on WT channels. We identified clinically used drugs that exhibited diverse activity, thus expanding the pharmacological toolbox for NALCN. While the low potencies of active compounds reiterate the pharmacological resistance of NALCN, our findings lay the foundation for rational drug design to develop NALCN modulators with refined properties. [ABSTRACT FROM AUTHOR]

Rationale: A silver phosphate reference material (Ag3PO4) for the measurement of stable oxygen isotope compositions is much needed; however, it is not available from the authorities distributing reference materials. This study aims to fill this gap by calibrating a new Ag3PO4 stable isotope comparison material produced by the University of Natural Resources and Life Sciences (BOKU). Methods: Aliquots of Ag3PO4 were distributed to four laboratories who frequently measure the δ18O value in Ag3PO4; the University of Natural Resources and Life Sciences (BOKU), the University of Western Australia (UWA), the University of Helsinki (UH), and the Helmholtz Centre for Environmental Research (UFZ). The instruments used to perform the measurements were high‐temperature conversion elemental analysers coupled with continuous flow isotope ratio mass spectrometers. The working gas δ18O value was set to 0‰ and the normalization was done by a three‐point linear regression using the reference materials IAEA‐601, IAEA‐602, and NBS127. Results: The mean δ18O value of the new BOKU Ag3PO4 comparison material on the VSMOW‐SLAP scale is 13.71‰ and the combined uncertainty is estimated as ±0.34‰. This estimated uncertainty is within the range typical for comparison materials of phosphates and sulphates. Consistent results from the different laboratories probably derived from similar instrumentation, and use of the same reference materials and normalization procedure. The matrix effect of the different reference materials used in this study was deemed negligible. Conclusions: The BOKU Ag3PO4 can be used as an alternative comparison material for stable oxygen isotope analysis and is available for stable isotope research laboratories to facilitate calibration. [ABSTRACT FROM AUTHOR]

Problem: Vaginal bleeding during early pregnancy is estimated to occur in 20% of all pregnancies and it is often difficult to predict who will ultimately miscarry. The role of immune cells in early pregnancy loss is poorly understood. Method of Study: In this prospective cohort study, 28 pregnant women presenting with first‐trimester vaginal bleeding donated vaginal blood, peripheral venous blood, and saliva during their initial emergency room visit, and at a follow‐up. The composition, frequency, and phenotype of immune cells in the vaginal blood were determined using flow cytometry. The proteome of serum and saliva was analyzed with OLINK proximity extension assay and correlated to vaginal immune cell phenotype and outcome of pregnancy. The course and outcome of pregnancies were followed and recorded. Results: Vaginal blood contained all main immune cell lineages including B cells, NK cells, T cells, and monocytes/macrophages. Notably, vaginal blood immune cells expressed tissue residency markers including CD49a. Women who subsequently miscarried had a higher frequency of vaginal blood CD49a+ NK cells compared to those who did not miscarry, and this correlated with serum levels of granzyme A and H, as well as CSF1, CAIX, and TWEAK. Women in the miscarriage group also had a higher frequency of peripheral blood T cells expressing CD49a. Conclusions: Our study provides novel insight into human reproductive immunology in relation to miscarriage. Tissue‐resident NK cells in vaginal blood alone or in combination with serological biomarkers hold potential as prognostic factors in the prediction of pregnancy outcome in women with early pregnancy bleedings. [ABSTRACT FROM AUTHOR]

The Austrian network of isotopes in rivers comprises about 15 sampling locations and has been operated since 1976. The Danube isotope time series goes back to 1963. The isotopic composition of river water in Central Europe is mainly governed by the isotopic composition of precipitation in the catchment area; evaporation effects play only a minor role. Short-term and long-term isotope signals in precipitation are thus transmitted through the whole catchment. The influence of climatic changes has become observable in the long-term stable isotope time series of precipitation and surface waters. Environmental 3H values were around 8 TU in 2015, short-term 3H pulses up to about 80 TU in the rivers Danube and March were a consequence of releases from nuclear power plants. The complete isotope data series of this network will be included in the Global Network of Isotopes in Rivers database of the International Atomic Energy Agency (IAEA) in 2017. This article comprises a review of 50 years isotope monitoring on rivers and is also intended to provide base information on the (isotope-)hydrological conditions in Central Europe specifically for the end-users of these data, e.g. for modelling hydrological processes. Furthermore, this paper includes the 2006-2015 supplement adding to the Danube isotope set published earlier. [ABSTRACT FROM AUTHOR]

Results of stable isotope measurements (δ2H, δ18O) of daily grab samples, taken from the Danube River at Tulln (river km 1963) during 2012, show seasonal and short-term variations depending on the climatic/hydrological conditions and changes in the catchment area (temperature changes, heavy rains and snow melt processes). Isotope ratios in river water clearly reflect the isotopic composition of precipitation water in the catchment area since evaporation influences play a minor role. Average δ2H and δ18O values in 2012 are−78‰ and−11.0‰, respectively, deuterium excess averages 10‰. The entire variation amounts to 1.8‰ in δ18O and 15‰ in δ2H. Quick changes of the isotopic composition within a few days emphasise the necessity of daily sampling for the investigation of hydrological events, while monthly grab sampling seems sufficient for the investigation of long-term hydro-climatic trends.3H results show peaks (half-width 1–2 days, up to about 150 TU) exceeding the regional environmental level of about 9 TU, probably due to releases from nuclear power plants. [ABSTRACT FROM PUBLISHER]

The hydrological application of isotope-ratio measurements is based upon variations of ²H, ³H and 18O in the natural water cycle. Main targets of isotope-hydrological projects are the investigation of hydrological relationships, the hydrogeological situation, the residence times of groundwater, and the possible transport of pollutants. Isotope-hydrological data also play an important role in climate research. A good knowledge of the "isotopic environment" is necessary for the interpretation of isotope data. For this purpose, basic isotope data of all parts of the hydrological cycle have been gathered at the Vienna Arsenal for nearly fifty years. The emphasis was on the isotope ratios in precipitation as they represent the input values for isotopic investigations in the terrestrial part of the water cycle. The influence of climatic changes has become observable in the long-term isotope time series of precipitation and surface waters. This influence must also be taken into account when using isotope data from a longer time period in hydrology. Environmental 3H values were around 10 TU in 2010, while slightly higher values can be observed in hydrological systems which still contain significant water portions from the sixties and seventies. Aside from a survey of the development of the "isotopic environment" in the last decades and a few key results, which helped to understand (isotope)hydrological processes, this paper includes some data sets meant for application purposes. [ABSTRACT FROM AUTHOR]