The ether-Ã -go-go -related gene (erg) K + channels are known to be crucial for life in Caenorhabditis elegans (mating), Drosophila melanogaster (seizure), and humans (LQT syndrome). The erg genes ...known to date ( erg1 , erg2 , and erg3 ) are highly expressed in various areas of the rat and mouse central nervous system (CNS), and ERG channel blockers alter
firing accommodation. To assign physiological roles to each isoform, it is necessary to design pharmacological strategies
to distinguish individual currents. To this purpose, we have investigated the blocking properties of specific peptide inhibitors
of hERG1 channels on the human and rat isoforms. In particular, we have tested ErgTx1 (from the scorpion Centruroides noxious ), BeKm-1 (from the scorpion Buthus eupeus ), and APETx1 (from the sea anemone Anthopleura elegantissima ). Because these peptides had different species-specific effects on the six different channels, we have also carried out a
biophysical characterization of hERG2 and hERG3 channels that turned out to be different from the rat homologs. It emerged
that APETx1 is exquisitely selective for ERG1 and does not compete with the other two toxins. BeKm-1 discriminates well among
the three rat members. ErgTx1 is unable to block hERG2, but blocks rERG2 and has the lowest K D for hERG3. BeKm-1 and ErgTx1 compete for hERG3 but not for rERG2 blockade. Our findings should be helpful for structure-function
studies and for novel CNS ERG-specific drug design.
We report here the results of a nonrelativistic effective field theory (EFT) WIMP search analysis using LUX data. We build upon previous LUX analyses by extending the search window to include nuclear ...recoil energies up to ∼ 180 keVnr, requiring a reassessment of data quality criteria and background models. In order to use an unbinned profile likelihood statistical framework, the development of new analysis techniques to account for higher-energy backgrounds was required. With a 3.14 × 104 kg ⋅ day exposure using data collected between 2014 and 2016, we find our data is compatible with the background expectation and set 90% C.L. exclusion limits on nonrelativistic EFT WIMP-nucleon couplings, improving upon previous LUX results and providing constraints on a EFT WIMP interactions using the { neutron , proton } interaction basis. Additionally, we report exclusion limits on inelastic EFT WIMP-isoscalar recoils that are competitive and world-leading for several interaction operators.
The isolation of the peptide inhibitor of M-type K+ current, BeKm-1, from the venom of the Central Asian scorpion Buthus eupeus has been described previously (Fillipov A. K., Kozlov, S. A., ...Pluzhnikov, K. A., Grishin, E. V., and Brown, D. A. (1996) FEBS Lett. 384, 277–280). Here we report the cloning, expression, and selectivity of BeKm-1. A full-length cDNA of 365 nucleotides encoding the precursor of BeKm-1 was isolated using the rapid amplification of cDNA ends polymerase chain reaction technique from mRNA obtained from scorpion telsons. Sequence analysis of the cDNA revealed that the precursor contains a signal peptide of 21 amino acid residues. The mature toxin consists of 36 amino acid residues. BeKm-1 belongs to the family of scorpion venom potassium channel blockers and represents a new subgroup of these toxins. The recombinant BeKm-1 was produced as a Protein A fusion product in the periplasm of Escherichia coli. After cleavage and high performance liquid chromatography purification, recombinant BeKm-1 displayed the same properties as the native toxin. Three BeKm-1 mutants (R27K, F32K, and R27K/F32K) were generated, purified, and characterized. Recombinant wild-type BeKm-1 and the three mutants partly inhibited the native M-like current in NG108-15 at 100 nm. The effect of the recombinant BeKm-1 on different K+ channels was also studied. BeKm-1 inhibited hERG1 channels with an IC50 of 3.3 nm, but had no effect at 100 nm on hEAG, hSK1, rSK2, hIK, hBK, KCNQ1/KCNE1, KCNQ2/KCNQ3, KCNQ4 channels, and minimal effect on rELK1. Thus, BeKm-1 was shown to be a novel specific blocker of hERG1 potassium channels.
AF276623
We present the results of a direct detection search for mirror dark matter interactions, using data collected from the Large Underground Xenon experiment during 2013, with an exposure of 95 ...live−days×118 kg. Here, the calculations of the mirror electron scattering rate in liquid xenon take into account the shielding effects from mirror dark matter captured within the Earth. Annual and diurnal modulation of the dark matter flux and atomic shell effects in xenon are also accounted for. Having found no evidence for an electron recoil signal induced by mirror dark matter interactions we place an upper limit on the kinetic mixing parameter over a range of local mirror electron temperatures between 0.1 and 0.9 keV. This limit shows significant improvement over the previous experimental constraint from orthopositronium decays and significantly reduces the allowed parameter space for the model. We exclude mirror electron temperatures above 0.3 keV at a 90% confidence level, for this model, and constrain the kinetic mixing below this temperature.
Nicotinic acetylcholine receptors (nAChRs) play an important role in the functioning of the central and peripheral nervous systems, and other organs of living creatures. There are several subtypes of ...nAChRs, and almost all of them are considered as pharmacological targets in different pathological states. The crude venom of the sea anemone
showed the ability to interact with nAChRs. Four novel peptides (Ms11a-1-Ms11a-4) with nAChR binding activity were isolated. These peptides stabilized by three disulfide bridges have no noticeable homology with any known peptides. Ms11a-1-Ms11a-4 showed different binding activity towards the muscle-type nAChR from the
ray. The study of functional activity and selectivity for the most potent peptide (Ms11a-3) revealed the highest antagonism towards the heterologous rat α9α10 nAChR compared to the muscle and α7 receptors. Structural NMR analysis of two toxins (Ms11a-2 and Ms11a-3) showed that they belong to a new variant of the inhibitor cystine knot (ICK) fold but have a prolonged loop between the fifth and sixth cysteine residues. Peptides Ms11a-1-Ms11a-4 could represent new pharmacological tools since they have structures different from other known nAChRs inhibitors.
We estimate the amount of Ar37 produced in natural xenon via cosmic-ray-induced spallation, an inevitable consequence of the transportation and storage of xenon on the Earth’s surface. We then ...calculate the resulting Ar37 concentration in a 10-tonne payload (similar to that of the LUX-ZEPLIN experiment) assuming a representative schedule of xenon purification, storage, and delivery to the underground facility. Using the spallation model by Silberberg and Tsao, the sea-level production rate of Ar37 in natural xenon is estimated to be 0.024 atoms/kg/day. Assuming the xenon is successively purified to remove radioactive contaminants in 1-tonne batches at a rate of 1 tonne/month, the average Ar37 activity after 10 tons are purified and transported underground is 0.058-0.090 μBq/kg, depending on the degree of argon removal during above-ground purification. Such cosmogenic Ar37 will appear as a noticeable background in the early science data, while decaying with a 35-day half-life. This newly noticed production mechanism of Ar37 should be considered when planning for future liquid-xenon-based experiments.
We present the results from combining machine learning with the profile likelihood fit procedure, using data from the Large Underground Xenon (LUX) dark matter experiment. This approach demonstrates ...reduction in computation time by a factor of 30 when compared with the previous approach, without loss of performance on real data. We establish its flexibility to capture non-linear correlations between variables (such as smearing in light and charge signals due to position variation) by achieving equal performance using pulse areas with and without position-corrections applied. Its efficiency and scalability furthermore enables searching for dark matter using additional variables without significant computational burden. We demonstrate this by including a light signal pulse shape variable alongside more traditional inputs such as light and charge signal strengths. Furthermore, this technique can be exploited by future dark matter experiments to make use of additional information, reduce computational resources needed for signal searches and simulations, and make inclusion of physical nuisance parameters in fits tractable.
We report here the results of a nonrelativistic effective field theory (EFT) WIMP search analysis using LUX data. We build upon previous LUX analyses by extending the search window to include nuclear ...recoil energies up to ~180 keVnr, requiring a reassessment of data quality criteria and background models. In order to use an unbinned profile likelihood statistical framework, the development of new analysis techniques to account for higher-energy backgrounds was required. With a 3.14×104 kg·day exposure using data collected between 2014 and 2016, we find our data is compatible with the background expectation and set 90% C.L. exclusion limits on nonrelativistic EFT WIMP-nucleon couplings, improving upon previous LUX results and providing constraints on a EFT WIMP interactions using the {neutron,proton} interaction basis. Additionally, we report exclusion limits on inelastic EFT WIMP-isoscalar recoils that are competitive and world-leading for several interaction operators.
The Large Underground Xenon (LUX) dark matter search was a 250-kg active mass dual-phase time projection chamber that operated by detecting light and ionization signals from particles incident on a ...xenon target. In December 2015, LUX reported a minimum 90% upper C.L. of 6 x 10-46 cm2 on the spin-independent WIMP-nucleon elastic scattering cross section based on a 1.4 x 104 kg ∙ day exposure in its first science run. Tension between experiments and the absence of a definitive positive detection suggest it would be prudent to search for WIMPs outside the standard spin-independent/spin-dependent paradigm. Recent theoretical work has identified a complete basis of 14 independent effective field theory (EFT) operators to describe WIMP-nucleon interactions. In addition to spin-independent and spin-dependent nuclear responses, these operators can produce novel responses such as angular-momentum-dependent and spin-orbit couplings. Here we report on a search for all 14 of these EFT couplings with data from LUX's first science run. Limits are placed on each coupling as a function of WIMP mass.
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