Atomistic Insight into the Lipid Nanodomains of Synaptic Vesicles

Membrane curvature, once regarded as a passive consequence of membrane composition and cellular architecture, has been shown to actively modulate various properties of the cellular membrane. These changes could also lead to segregation of the constituents of the membrane, generating nanodomains with precise biological properties. Proteins often linked with neurodegeneration (e.g., tau, alpha-synuclein) exhibit an unintuitive affinity for synaptic vesicles in neurons, which are reported to lack distinct, ordered nanodomains based on their composition. In this study, all-atom molecular dynamics simulations are used to study a full-scale synaptic vesicle of realistic Gaussian curvature and its effect on the membrane dynamics and lipid nanodomain organization. Compelling indicators of nanodomain formation, from the perspective of composition, surface areas per lipid, order parameter, and domain lifetime, are identified in the vesicle membrane, which are absent in a flat bilayer of the same lipid composition. Therefore, our study supports the idea that curvature may induce phase separation in an otherwise fluid, disordered membrane

El Diario de Pontevedra : periódico liberal: Ano L Número 15777 - 1936 maio 13

Additional file 4: Figure S4. Comparison of standardized differences (A, B) and propensity scores (C, D) in unmatched and matched samples. A, C: propensity score matching in overall dataset; B, D: propensity score matching of dataset excluding deaths with other reasons

Hepatotoxicity induced by intragastrically administrated with Gardenia decoction in mice

<p>The study was to investigate the potential hepatotoxicity of Gardenia decoction induced by intragastrically administrated mice. Mice were randomly divided into four groups. Intragastric administration of the respective treatments was provided continuously for seven days and the body weight was recorded everyday. The activity levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum were recorded. In addition, changes in liver morphology and organ coefficients were evaluated. Compared with the mice in the control group, GD increased the activities of ALT and AST in a dose-dependent manner (<i>P</i> < 0.05). However, there were no significant differences in the weight between the GD-treated groups and the control group (<i>P</i> > 0.05). The liver coefficient was significantly higher (<i>P</i> < 0.05) in the mice in the medium- and high-dose GD groups and there were significant pathological changes in the lives. In conclusion, the high-dose GD has the potential to induce hepatotoxicity in mice.</p

Impact of the Unstirred Water Layer on the Permeation of Small-Molecule Drugs

Over the last two decades, numerous molecular dynamics (MD) simulation-based investigations have attempted to predict the membrane permeability to small-molecule drugs as indicators of their bioavailability, a majority of which utilize the inhomogeneous solubility diffusion (ISD) model. However, MD-based membrane permeability is routinely 3–4 orders of magnitude larger than the values measured with the intestinal perfusion technique. There have been contentious discussions on the sources of the large discrepancies, and the two indisputable, potentially dominant ones are the fixed protonation state of the permeant and the neglect of the unstirred water layer (UWL). Employing six small-molecule drugs of different biopharmaceutical classification system classes, the current MD study relies on the ISD model but introduces the (de)protonation of the permeant by characterizing the permeation free energy of both neutral and charged states. In addition, the role of the UWL as a potential resistance against permeation is explored. The new MD protocol closely mimics the nature of small-molecule permeation and yields estimates that agree well with in vivo intestinal permeability

Impact of the Unstirred Water Layer on the Permeation of Small-Molecule Drugs

Over the last two decades, numerous molecular dynamics (MD) simulation-based investigations have attempted to predict the membrane permeability to small-molecule drugs as indicators of their bioavailability, a majority of which utilize the inhomogeneous solubility diffusion (ISD) model. However, MD-based membrane permeability is routinely 3–4 orders of magnitude larger than the values measured with the intestinal perfusion technique. There have been contentious discussions on the sources of the large discrepancies, and the two indisputable, potentially dominant ones are the fixed protonation state of the permeant and the neglect of the unstirred water layer (UWL). Employing six small-molecule drugs of different biopharmaceutical classification system classes, the current MD study relies on the ISD model but introduces the (de)protonation of the permeant by characterizing the permeation free energy of both neutral and charged states. In addition, the role of the UWL as a potential resistance against permeation is explored. The new MD protocol closely mimics the nature of small-molecule permeation and yields estimates that agree well with in vivo intestinal permeability

Theoretical Studies on F^– + NH₂Cl Reaction: Nucleophilic Substitution at Neutral Nitrogen

The S_N2 reactions at N center, denoted as S_N2@N, has been recognized to play a significant role in carcinogenesis, although they are less studied and less understood. The potential energy profile for the model reaction of S_N2@N, chloramine (NH₂Cl) with fluorine anion (F^–), has been characterized by extensive electronic structure calculations. The back-side S_N2 channel dominates the reaction with the front-side S_N2 channel becoming feasible at higher energies. The minimum energy pathway shows a resemblance to the well-known double-well potential model for S_N2 reactions at carbon. However, the complexes involving nitrogen on both sides of the reaction barrier are characterized by NH---X (X = F or Cl) hydrogen bond and possess C₁ symmetry, in contrast to the more symmetric ion-dipole carbon analogues. In the F^– + NH₂Cl system, the proton transfer pathway is found to become more competitive with the S_N2 pathway than in the F^– + CH₃Cl system. The calculations reported here indicate that stationary point properties on the F^– + NH₂Cl potential energy surface are slightly perturbed by the theories employed. The MP2 and CAM-B3LYP, as well as M06-2X and MPW1K functionals give overall best agreement with the benchmark CCSD­(T)/CBS energies for the major S_N2 reaction channel, and are recommended as the preferred methods for the direct dynamics simulations to uncover the dynamic behaviors of the title reaction

Highly Frustrated Poly(ionic liquid) ABC Triblock Terpolymers with Exceptionally High Morphology Factors

In this work, we report the successful synthesis of 17 unique compositions of a poly(ionic liquid) (PIL) ABC triblock terpolymer, poly(S-b-VBMIm-TFSI-b-HA), where S is styrene, VBMIm-TFSI is vinylbenzyl methylimidazolium bis(trifluoromethanesulfonyl)imide, and HA is hexyl acrylate. Nine distinct morphologies were observed, including two-phase and three-phase disordered microphase separated (D2 and D3), two-phase hexagonally packed cylinders (C2), core–shell hexagonally packed cylinders (CCS), three-phase lamellae (L3), two-phase lamellae (L2), core–shell double gyroid (Q230), spheres-in-lamellae (LSI), and a three-phase hexagonal superlattice of cylinders (CSL). The LSI morphology was unambiguously confirmed using small-angle X-ray scattering and transmission electron microscopy. Morphology type significantly impacted the ion conductivity of the PIL ABC triblock terpolymers, where remarkable changes in morphology factor (normalized ion conductivity) were observed with only small changes in the conducting volume fraction, i.e., PIL block composition. An exceptionally high morphology factor of 2.0 was observed from the PIL ABC triblock terpolymer with a hexagonal superlattice morphology due to the three-dimensional narrow, continuous PIL nanodomains that accelerate ion conduction. Overall, this work demonstrates the first systematic study of highly frustrated single-ion conducting ABC triblock terpolymers with a diverse set of morphologies and exceptionally high morphology factors, enabling the exploration of transport–morphology relationships to guide the future design of highly conductive polymer electrolytes

Data_Sheet_1_Progressive 3D biomedical image registration network based on deep self-calibration.PDF

Three dimensional deformable image registration (DIR) is a key enabling technique in building digital neuronal atlases of the brain, which can model the local non-linear deformation between a pair of biomedical images and align the anatomical structures of different samples into one spatial coordinate system. And thus, the DIR is always conducted following a preprocessing of global linear registration to remove the large global deformations. However, imperfect preprocessing may leave some large non-linear deformations that cannot be handled well by existing DIR methods. The recently proposed cascaded registration network gives a primary solution to deal with such large non-linear deformations, but still suffers from loss of image details caused by continuous interpolation (information loss problem). In this article, a progressive image registration strategy based on deep self-calibration is proposed to deal with the large non-linear deformations without causing information loss and introducing additional parameters. More importantly, we also propose a novel hierarchical registration strategy to quickly achieve accurate multi-scale progressive registration. In addition, our method can implicitly and reasonably implement dynamic dataset augmentation. We have evaluated the proposed method on both optical and MRI image datasets with obtaining promising results, which demonstrate the superior performance of the proposed method over several other state-of-the-art approaches for deformable image registration.</p

Diurnal and Seasonal Variations in Carbon Dioxide Exchange in Ecosystems in the Zhangye Oasis Area, Northwest China

<div><p>Quantifying carbon dioxide exchange and understanding the response of key environmental factors in various ecosystems are critical to understanding regional carbon budgets and ecosystem behaviors. For this study, CO₂ fluxes were measured in a variety of ecosystems with an eddy covariance observation matrix between June 2012 and September 2012 in the Zhangye oasis area of Northwest China. The results show distinct diurnal variations in the CO₂ fluxes in vegetable field, orchard, wetland, and maize cropland. Diurnal variations of CO₂ fluxes were not obvious, and their values approached zero in the sandy desert, desert steppe, and Gobi ecosystems. Additionally, daily variations in the Gross Primary Production (<i>GPP</i>), Ecosystem Respiration (<i>R_eco</i>) and Net Ecosystem Exchange (<i>NEE</i>) were not obvious in the sandy desert, desert steppe, and Gobi ecosystems. In contrast, the distributions of the <i>GPP</i>, <i>R_eco</i>, and <i>NEE</i> show significant daily variations, that are closely related to the development of vegetation in the maize, wetland, orchard, and vegetable field ecosystems. All of the ecosystems are characterized by their carbon absorption during the observation period. The ability to absorb CO₂ differed significantly among the tested ecosystems. We also used the Michaelis-Menten equation and exponential curve fitting methods to analyze the impact of Photosynthetically Active Radiation (<i>PAR</i>) on the daytime CO₂ flux and impact of air temperature on <i>R_eco</i> at night. The results show that <i>PAR</i> is the dominant factor in controlling photosynthesis with limited solar radiation, and daytime CO₂ assimilation increases rapidly with <i>PAR</i>. Additionally, the carbon assimilation rate was found to increase slowly with high solar radiation. The light response parameters changed with each growth stage for all of the vegetation types, and higher light response values were observed during months or stages when the plants grew quickly. Light saturation points are different for different species. Nighttime <i>R_eco</i> increases exponentially with air temperature. High Q₁₀ values were observed when the vegetation coverage was relatively low, and low Q₁₀ values occurred when the vegetables grew vigorously.</p></div

Figure S2. Mislocalized Sdt variants do not displace endogenous PATJ or PAR-6

(A-D) Sdt-GFP was ubiquitous expressed in wild type embryos and distribution of GFP, PATJ and PAR-6 was analyzed in stage 11-12 embryos. Scale bars = 5µm