Voltage-gated sodium channels initiate action potentials in nerve, muscle, and other electrically excitable cells. Voltage-gated calcium channels are activated by depolarization during action ...potentials, and calcium influx through them is the key second messenger of electrical signaling, initiating secretion, contraction, neurotransmission, gene transcription, and many other intracellular processes. Drugs that block sodium channels are used in local anesthesia and the treatment of epilepsy, bipolar disorder, chronic pain, and cardiac arrhythmia. Drugs that block calcium channels are used in the treatment of epilepsy, chronic pain, and cardiovascular disorders, including hypertension, angina pectoris, and cardiac arrhythmia. The principal pore-forming subunits of voltage-gated sodium and calcium channels are structurally related and likely to have evolved from ancestral voltage-gated sodium channels that are widely expressed in prokaryotes. Determination of the structure of a bacterial ancestor of voltage-gated sodium and calcium channels at high resolution now provides a three-dimensional view of the binding sites for drugs acting on sodium and calcium channels. In this minireview, we outline the different classes of sodium and calcium channel drugs, review studies that have identified amino acid residues that are required for their binding and therapeutic actions, and illustrate how the analogs of those key amino acid residues may form drug-binding sites in three-dimensional models derived from bacterial channels.
Permeability (P m) across biological membranes is of fundamental importance and a key factor in drug absorption, distribution, and development. Although the majority of drugs will be charged at some ...point during oral delivery, our understanding of membrane permeation by charged species is limited. The canonical model assumes that only neutral molecules partition into and passively permeate across membranes, but there is mounting evidence that these processes are also facile for certain charged species. However, it is unknown whether such ionizable permeants dynamically neutralize at the membrane surface or permeate in their charged form. To probe protonation-coupled permeation in atomic detail, we herein apply continuous constant-pH molecular dynamics along with free energy sampling to study the permeation of a weak base propranolol (PPL), and evaluate the impact of including dynamic protonation on P m. The simulations reveal that PPL dynamically neutralizes at the lipid–tail interface, which dramatically influences the permeation free energy landscape and explains why the conventional model overestimates the assigned intrinsic permeability. We demonstrate how fixed-charge-state simulations can account for this effect, and propose a revised model that better describes pH-coupled partitioning and permeation. Our results demonstrate how dynamic changes in protonation state may play a critical role in the permeation of ionizable molecules, including pharmaceuticals and drug-like molecules, thus requiring a revision of the standard picture.
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We present constraints on extensions of the minimal cosmological models dominated by dark matter and dark energy, ΛCDM and wCDM, by using a combined analysis of galaxy clustering and weak ...gravitational lensing from the first-year data of the Dark Energy Survey (DES Y1) in combination with external data. We consider four extensions of the minimal dark energy-dominated scenarios: (1) nonzero curvature Ωk, (2) number of relativistic species Neff different from the standard value of 3.046, (3) time-varying equation-of-state of dark energy described by the parameters w0 and wa (alternatively quoted by the values at the pivot redshift, wp, and wa), and (4) modified gravity described by the parameters μ0 and Σ0 that modify the metric potentials. We also consider external information from Planck cosmic microwave background measurements; baryon acoustic oscillation measurements from SDSS, 6dF, and BOSS; redshift-space distortion measurements from BOSS; and type Ia supernova information from the Pantheon compilation of datasets. Constraints on curvature and the number of relativistic species are dominated by the external data; when these are combined with DES Y1, we find Ωk=0.0020−0.0032+0.0037 at the 68% confidence level, and the upper limit Neff<3.28(3.55) at 68% (95%) confidence, assuming a hard prior Neff>3.0. For the time-varying equation-of-state, we find the pivot value (wp,wa)=(−0.91−0.23+0.19,−0.57−1.11+0.93) at pivot redshift zp=0.27 from DES alone, and (wp,wa)=(−1.01−0.04+0.04,−0.28−0.48+0.37) at zp=0.20 from DES Y1 combined with external data; in either case we find no evidence for the temporal variation of the equation of state. For modified gravity, we find the present-day value of the relevant parameters to be Σ0=0.43−0.29+0.28 from DES Y1 alone, and (Σ0,μ0)=(0.06−0.07+0.08,−0.11−0.46+0.42) from DES Y1 combined with external data. These modified-gravity constraints are consistent with predictions from general relativity.
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Despite considerable interest in the forces shaping the relationship between brain size and cognitive abilities, it remains controversial whether larger-brained animals are, indeed, better ...problem-solvers. Recently, several comparative studies have revealed correlations between brain size and traits thought to require advanced cognitive abilities, such as innovation, behavioral flexibility, invasion success, and self-control. However, the general assumption that animals with larger brains have superior cognitive abilities has been heavily criticized, primarily because of the lack of experimental support for it. Here, we designed an experiment to inquire whether specific neuroanatomical or socioecological measures predict success at solving a novel technical problem among species in the mammalian order Carnivora. We presented puzzle boxes, baited with food and scaled to accommodate body size, to members of 39 carnivore species from nine families housed in multiple North American zoos. We found that species with larger brains relative to their body mass were more successful at opening the boxes. In a subset of species, we also used virtual brain endocasts to measure volumes of four gross brain regions and show that some of these regions improve model prediction of success at opening the boxes when included with total brain size and body mass. Socioecological variables, including measures of social complexity and manual dexterity, failed to predict success at opening the boxes. Our results, thus, fail to support the social brain hypothesis but provide important empirical support for the relationship between relative brain size and the ability to solve this novel technical problem.
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As galaxy surveys become larger and more complex, keeping track of the completeness, magnitude limit and other survey parameters as a function of direction on the sky becomes an increasingly ...challenging computational task. For example, typical angular masks of the Sloan Digital Sky Survey contain about N= 300 000 distinct spherical polygons. Managing masks with such large numbers of polygons becomes intractably slow, particularly for tasks that run in time with a naive algorithm, such as finding which polygons overlap each other. Here we present a ‘divide-and-conquer’ solution to this challenge: we first split the angular mask into pre-defined regions called ‘pixels’, such that each polygon is in only one pixel, and then perform further computations, such as checking for overlap, on the polygons within each pixel separately. This reduces tasks to , and also reduces the important task of determining in which polygon(s) a point on the sky lies from to , resulting in significant computational speedup. Additionally, we present a method to efficiently convert any angular mask to and from the popular healpix format. This method can be generically applied to convert to and from any desired spherical pixelization. We have implemented these techniques in a new version of the mangle software package, which is freely available at http://space.mit.edu/home/tegmark/mangle/, along with complete documentation and example applications. These new methods should prove quite useful to the astronomical community, and since mangle is a generic tool for managing angular masks on a sphere, it has the potential to benefit terrestrial mapmaking applications as well.
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The zinc finger antiviral protein (ZAP) is a broad inhibitor of virus replication. Its best-characterized function is to bind CpG dinucleotides present in viral RNAs and, through the recruitment of ...TRIM25, KHNYN and other cofactors, target them for degradation or prevent their translation. The long and short isoforms of ZAP (ZAP-L and ZAP-S) have different intracellular localization and it is unclear how this regulates their antiviral activity against viruses with different sites of replication. Using ZAP-sensitive and ZAP-insensitive human immunodeficiency virus type I (HIV-1), which transcribe the viral RNA in the nucleus and assemble virions at the plasma membrane, we show that the catalytically inactive poly-ADP-ribose polymerase (PARP) domain in ZAP-L is essential for CpG-specific viral restriction. Mutation of a crucial cysteine in the C-terminal CaaX box that mediates S-farnesylation and, to a lesser extent, the residues in place of the catalytic site triad within the PARP domain, disrupted the activity of ZAP-L. Addition of the CaaX box to ZAP-S partly restored antiviral activity, explaining why ZAP-S lacks antiviral activity for CpG-enriched HIV-1 despite conservation of the RNA-binding domain. Confocal microscopy confirmed the CaaX motif mediated localization of ZAP-L to vesicular structures and enhanced physical association with intracellular membranes. Importantly, the PARP domain and CaaX box together jointly modulate the interaction between ZAP-L and its cofactors TRIM25 and KHNYN, implying that its proper subcellular localisation is required to establish an antiviral complex. The essential contribution of the PARP domain and CaaX box to ZAP-L antiviral activity was further confirmed by inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, which replicates in double-membrane vesicles derived from the endoplasmic reticulum. Thus, compartmentalization of ZAP-L on intracellular membranes provides an essential effector function in ZAP-L-mediated antiviral activity against divergent viruses with different subcellular replication sites.
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We describe perturbation theory (PT) models of galaxy bias for applications to photometric galaxy surveys. We model the galaxy-galaxy and galaxy-matter correlation functions in configuration space ...and validate against measurements from mock catalogs designed for the Dark Energy Survey (DES). We find that an effective PT model with five galaxy bias parameters provides a good description of the 3D correlation functions above scales of 4 Mpc /h and z < 1 . Our tests show that at the projected precision of the DES Year 3 analysis, two of the nonlinear bias parameters can be fixed to their coevolution values, and a third (the k2 term for higher derivative bias) set to zero. The agreement is typically at the 2% level over scales of interest, which is the statistical uncertainty of our simulation measurements. To achieve this level of agreement, our fiducial model requires using the full nonlinear matter power spectrum (rather than the one-loop PT one). We also measure the relationship between the nonlinear and linear bias parameters and compare them to their expected coevolution values. We use these tests to motivate the galaxy bias model and scale cuts for the cosmological analysis of the Dark Energy Survey; our conclusions are generally applicable to all photometric surveys.
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Proton transport in aqueous media is ubiquitously important in chemical and biological processes. Although ab initio molecular dynamics (AIMD) simulations have made great progress in characterizing ...proton transport, there has been a long-standing challenge in defining and tracking the excess proton, or more properly, the center of excess charge (CEC) created when a hydrogen nucleus distorts the electron distributions of water molecules in a delocalized and highly dynamic nature. Yet, defining (and biasing) such a CEC is essential when combining AIMD with enhanced sampling methods to calculate the relevant macroscopic properties via free-energy landscapes, which is the standard practice for most processes of interest. Several CEC formulas have been proposed and used, but none have yet been systematically tested or rigorously derived. In this paper, we show that the CEC can be used as a computational tool to disentangle IR features of the solvated excess proton from its surrounding solvent, and in turn, how correlating the features in the excess charge spectrum with the behavior of CEC in simulations enables a systematic evaluation of various CEC definitions. We present a new definition of CEC and show how it overcomes the limitations of those currently available both from a spectroscopic point of view and from a practical perspective of performance in enhanced sampling simulations.
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