Probing the biophysical properties of the murine voltage dependent anion channel (mVDAC1) structure: Insight from continuum electrostatics and Markov state models

The voltage-dependent anion channel (VDAC) is the major pathway mediating the transfer of metabolites and ions across the mitochondrial outer membrane. The open state of the channel passes millions of ATP molecules per second and is anion selective, while the closed state exhibits no detectable ATP flux and is cation selective. The high-resolution structure of VDAC1 revealed a 19 stranded β-barrel with an α-helix occupying the pore. To probe VDAC1’s biophysical properties, we first carried out continuum electrostatics calculations on the murine VDAC1 (mVDAC1) structure. Poisson-Boltzmann (PB) calculations show that the ion transfer free energy through the channel is favorable for anions, suggesting that mVDAC1 represents the open state. This claim is buttressed by Poisson–Nernst–Planck calculations that predict a high single-channel conductance indicative of the open state and an anion selectivity of 1.75, nearly a two-fold selectivity for anions over cations. These calculations were then repeated on mutant channels and gave selectivity changes in accord with experimental observations. We next investigated two proposals for how the channel gates between the open and the closed state. Both models involve the movement of the N-terminal helix, but neither motion produced the observed voltage sensitivity, nor did either motion result in a cation-selective channel, which is observed experimentally. Thus, we were able to rule out certain models for channel gating, but the true motion is yet to be determined. Finally, to understand ATP permeation through VDAC, our collaborators solved the structure of mVDAC1 in the presence of ATP revealing a low-occupancy binding site. We first carried out long, unbiased, multi-microsecond simulations of mVDAC1 in the presence of ATP on the Anton Supercomputer. Guided by the mVDAC1-ATP co-crystal coordinates, we then initiated hundreds of molecular dynamics (MD) simulations to construct a Markov state model (MSM) of ATP permeation. These MSM results show a high ATP flux generated from multiple pathways through the channel, consistent with our structural data and previously reported physiological rates. Continuum calculations and fully atomistic MSM both demonstrate that the solved structures are indicative of an open state of the channel

Oxidation Kinetics of some Lower Oxyacids of Phosphorus by Picolinium Chlorochromate: Determination of Reactive Reducing Species

Picolinium chlorochromate (PICC) in dimethylsuloxide (DMSO) oxidizes lower oxyacids of phosphorus, forming matching oxyacids with phosphorus in a higher oxidation state. The reaction shows a stoichiometry of 1:1. In relation to PICC, the response is first order. Regarding the reductants, a kinetics of the Michaelis-Menten type was noticed. Acrylonitrile does not undergo polymerization as a result of the reaction. Hydrogen ions function as catalysts for reactions. The form of the hydrogen-ion dependency is: kobs = a + b[H+]. Deuterated phosphinic and phenylphosphinic acids showed a significant primary kinetic isotope impact during oxidation. Nineteen different organic solvents were used to study the oxidation. The multiparametric equations of Taft and Swain were used to analyze the solvent effects. The influence of the solvent shows that the polarity of the solvent is crucial to the process. The penta-coordinated tautomer of the phosphorus oxyacid has been shown to be the reactive reductant, and it has been determined that the tricoordinated forms of phosphorus oxyacids do not take part in the oxidation process. It has been hypothesized that the rate-determining phase involves the transfer of a hydride ion

Polarization Sensitive Optical Coherence Tomography for Blood Glucose Monitoring in Human Subjects

A device based on Polarization sensitive optical coherence tomography is developed to monitor blood glucose levels in human subjects. The device was initially tested with tissue phantom. The measurements with human subjects for various glucose concentration levels are found to be linearly dependent on the degree of circular polarization obtainable from the PS-OCT.Comment: 12 pages, 5 figure

Interactive effects of rice-residue biochar and N-fertilizer on soil functions and crop biomass in contrasting soils

There is limited understanding of the effects of rice residue biochar, particularly when applied in combination with nitrogen (N) fertilizer on soil fertility, soil C sequestration and crop productivity. A one-year pot experiment was established to examine effects of rice residue biochar (0, 10, 20 and 40 t ha-1) and N (0, 60, 90, 120 and 150 kg N ha-1) in soils with contrasting texture (loamy sand and sandy clay loam) in a wheat(maize cropping sequence. Biochar was only applied once before sowing wheat. Biochar alone or in combination with N did not significantly increase wheat biomass in both soils, whereas biomass of maize (next crop) was significantly increased from the residual effect of biochar, alone or in combination with N fertilizer. In both soils, electrical conductivity (EC) and pH, oxidisable organic carbon (OC), microbial biomass carbon (MBC), dissolved organic carbon (DOC) and available nutrients (NPK) increased with increasing rates of biochar addition. However, addition of N with biochar (cf. biochar alone) did not change pH and oxidisable OC values but increased EC significantly. After one year, the soil organic carbon (SOC) stocks increased beyond the input of biochar-C, that is, by 0.1-2.1 t ha-1 and 1.8-4.8 t ha-1 in loamy sand and sandy clay loam, respectively, across all treatments. It may be concluded that the potential benefits of rice residue biochar to soil functions and crop production may encourage growers to minimise open field burning of straw, which is a common practice in the region

Osteometric and topographic measurement of the skull and mandible of Siirt colored Mohair goat with three-dimensional (3D) modeling technique

Siirt-colored Mohair goat is one of the breeds that contributed significantly to the existence of Mohair goats reared in Turkey. Morphological and morphometric characteristics of the Siirt-colored Mohair goat remained vague owing to a lack of studies. Recent advances in high-tech imaging have replaced conventional two-dimensional anatomical structures with three-dimensional (3D) models. In our study, morphometric features were determined by 3D modeling from computed tomography images obtained from the skull and mandibular bones of Siirt-colored Mohair goats. For this purpose, the skulls and mandibular bones of 20 Siirt-colored Mohair goats (10 females and 10 males) were used. The images were reconstructed with the help of a particular software program. The craniometric data were analyzed in terms of sexual dimorphism, and statistically significant difference was found in the A5, A18, and A31 measurement parameters (P<0.05) and Skull index (P<0.01) parameters. In the mandible measurements, there was a statistically significant difference between the sexes in C5, C10 measurement points (P<0.05), C2, C8, C12, C18, C21 measurement points (P<0.001) and surface area parameter (P<0.01). The morphometric data obtained is a resource in the fields of zoo archaeology, anatomy, forensics, anesthesia, surgery, and treatment

Mechanism of Werner DNA Helicase: POT1 and RPA Stimulates WRN to Unwind beyond Gaps in the Translocating Strand

WRN belongs to the RecQ family of DNA helicases and it plays a role in recombination, replication, telomere maintenance and long-patch base excision repair. Here, we demonstrate that WRN efficiently unwinds DNA substrates containing a 1-nucleotide gap in the translocating DNA strand, but when the gap size is increased to 3-nucleotides unwinding activity significantly declines. In contrast, E. coli UvrD (3′→5′ helicase), which recognizes nicks in DNA to initiate unwinding, does not unwind past a 1-nucleotide gap. This unique ability of WRN to bypass gaps supports its involvement in DNA replication and LP-BER where such gaps can be produced by glycosylases and the apurinic/apyrimidinic endonuclease 1 (APE1). Furthermore, we tested telomere repeat binding factor 2 (TRF2), both variants 1 and 2 of protector of telomeres 1 (POT1v1 and POT1v2) and RPA on telomeric DNA substrates containing much bigger gaps than 3-nucleotides in order to determine whether unwinding could be facilitated through WRN-protein interaction. Interestingly, POT1v1 and RPA are capable of stimulating WRN helicase on gapped DNA and 5′-overhang substrates, respectively

APBSmem: A Graphical Interface for Electrostatic Calculations at the Membrane

Electrostatic forces are one of the primary determinants of molecular interactions. They help guide the folding of proteins, increase the binding of one protein to another and facilitate protein-DNA and protein-ligand binding. A popular method for computing the electrostatic properties of biological systems is to numerically solve the Poisson-Boltzmann (PB) equation, and there are several easy-to-use software packages available that solve the PB equation for soluble proteins. Here we present a freely available program, called APBSmem, for carrying out these calculations in the presence of a membrane. The Adaptive Poisson-Boltzmann Solver (APBS) is used as a back-end for solving the PB equation, and a Java-based graphical user interface (GUI) coordinates a set of routines that introduce the influence of the membrane, determine its placement relative to the protein, and set the membrane potential. The software Jmol is embedded in the GUI to visualize the protein inserted in the membrane before the calculation and the electrostatic potential after completing the computation. We expect that the ease with which the GUI allows one to carry out these calculations will make this software a useful resource for experimenters and computational researchers alike. Three examples of membrane protein electrostatic calculations are carried out to illustrate how to use APBSmem and to highlight the different quantities of interest that can be calculated

The population of merging compact binaries inferred using gravitational waves through GWTC-3

We report on the population properties of 76 compact binary mergers detected with gravitational waves below a false alarm rate of 1 per year through GWTC-3. The catalog contains three classes of binary mergers: BBH, BNS, and NSBH mergers. We infer the BNS merger rate to be between 10 $\rm{Gpc^{-3} yr^{-1}}$ and 1700 $\rm{Gpc^{-3} yr^{-1}}$ and the NSBH merger rate to be between 7.8 $\rm{Gpc^{-3}\, yr^{-1}}$ and 140 $\rm{Gpc^{-3} yr^{-1}}$ , assuming a constant rate density versus comoving volume and taking the union of 90% credible intervals for methods used in this work. Accounting for the BBH merger rate to evolve with redshift, we find the BBH merger rate to be between 17.9 $\rm{Gpc^{-3}\, yr^{-1}}$ and 44 $\rm{Gpc^{-3}\, yr^{-1}}$ at a fiducial redshift (z=0.2). We obtain a broad neutron star mass distribution extending from $1.2^{+0.1}_{-0.2} M_\odot$ to $2.0^{+0.3}_{-0.3} M_\odot$. We can confidently identify a rapid decrease in merger rate versus component mass between neutron star-like masses and black-hole-like masses, but there is no evidence that the merger rate increases again before 10 $M_\odot$. We also find the BBH mass distribution has localized over- and under-densities relative to a power law distribution. While we continue to find the mass distribution of a binary's more massive component strongly decreases as a function of primary mass, we observe no evidence of a strongly suppressed merger rate above $\sim 60 M_\odot$. The rate of BBH mergers is observed to increase with redshift at a rate proportional to $(1+z)^{\kappa}$ with $\kappa = 2.9^{+1.7}_{-1.8}$ for $z\lesssim 1$. Observed black hole spins are small, with half of spin magnitudes below $\chi_i \simeq 0.25$. We observe evidence of negative aligned spins in the population, and an increase in spin magnitude for systems with more unequal mass ratio

Diverse definitions of the early course of schizophrenia - a targeted literature review

Schizophrenia is a debilitating psychiatric disorder and patients experience significant comorbidity, especially cognitive and psychosocial deficits, already at the onset of disease. Previous research suggests that treatment during the earlier stages of disease reduces disease burden, and that a longer time of untreated psychosis has a negative impact on treatment outcomes. A targeted literature review was conducted to gain insight into the definitions currently used to describe patients with a recent diagnosis of schizophrenia in the early course of disease ('early' schizophrenia). A total of 483 relevant English-language publications of clinical guidelines and studies were identified for inclusion after searches of MEDLINE, MEDLINE In-Process, relevant clinical trial databases and Google for records published between January 2005 and October 2015. The extracted data revealed a wide variety of terminology and definitions used to describe patients with 'early' or 'recent-onset' schizophrenia, with no apparent consensus. The most commonly used criteria to define patients with early schizophrenia included experience of their first episode of schizophrenia or disease duration of less than 1, 2 or 5 years. These varied definitions likely result in substantial disparities of patient populations between studies and variable population heterogeneity. Better agreement on the definition of early schizophrenia could aid interpretation and comparison of studies in this patient population and consensus on definitions should allow for better identification and management of schizophrenia patients in the early course of their disease