Modelling the structural evolution of ternary phosphate glasses from melts to solid amorphous materials

The local and medium-range structural properties of phosphate-based melts and glasses have been characterized by means of first principles (density functional theory) and classical (shell-model) molecular dynamics simulations. The structure of glasses with biomedically active molecular compositions, (P2O5)0.45(CaO)x(Na2O)0.55−x (x = 0.30, 0.35 and 0.40), have been generated using first principles molecular dynamics simulations for the full melt-and-quench procedure and the changes in the structural properties as the 3000 K melt is cooled down to room temperature have been compared extensively with those of the final glasses. The melts are characterized by a significant fraction of threefold (P3c) and fivefold (P5c) phosphorus atoms, but structural defects rapidly decrease during the cooling phase and for temperatures lower than 1800 K the system is free of under- and over-coordinated species. The analysis of the structures of the glasses at 300 K shows a prevalence of the metaphosphate Q2 and pyrophosphate Q1 species, whereas the number of Q3 units, which constitute the three-dimensional phosphate network, significantly decreases with the increase of calcium content in the glass. The radial and angular distribution functions indicate that higher calcium concentration in the glass leads to an increase of the rigidity of the phosphate tetrahedral network, which has been explained in terms of the calcium's higher field strength compared to that of sodium. The structural characterization of the melts and glasses obtained from first principles simulations was used to assess and validate a recently developed interatomic shell-model forcefield for phosphate-based materials. For all three compositions, our potential model is in good agreement with the first principles data. In the glass network, the forcefield provides a very good description of the split between the shorter distances of phosphorus to non-bonded oxygen and the longer distances of the phosphorus to bonded oxygen; the phosphorus–phosphorus medium-range distribution; and the coordination environment around the Na and Ca glass modifiers. Moreover, the distribution of the Qn species in the melts and glasses is in excellent agreement with the values extracted from the first principles simulations. In contrast, simulations using standard rigid ion potentials do not provide a satisfactory description of the local short-range structure of phosphate-based glasses and are therefore less suitable to model this class of multicomponent amorphous system

Adapted block hybrid method for the numerical solution of duffing equations and related problems

Problems of non-linear equations to model real-life phenomena have a long history in science and engineering. One of the popular of such non-linear equations is the Duffing equation. An adapted block hybrid numerical integrator that is dependent on a fixed frequency and fixed step length is proposed for the integration of Duffing equations. The stability and convergence of the method are demonstrated; its accuracy and efficiency are also established

Prognostic markers of ferroptosis-related long non-coding RNA in lung adenocarcinomas

Ferroptosis is a recently established type of iron-dependent programmed cell death. Growing studies have focused on the function of ferroptosis in cancers, including lung adenocarcinoma (LUAD). However, the factors involved in the regulation of ferroptosis-related genes are not fully understood. In this study, we collected data from lung adenocarcinoma datasets of the Cancer Genome Atlas (TCGA-LUAD). The expression profiles of 60 ferroptosis-related genes were screened, and two differentially expressed ferroptosis subtypes were identified. We found the two ferroptosis subtypes can predict clinical outcomes and therapeutic responses in LUAD patients. Furthermore, key long non-coding RNAs (lncRNAs) were screened by single factor Cox and least absolute shrinkage and selection operator (LASSO) based on which co-expressed with the 60 ferroptosis-related genes. We then established a risk score model which included 13 LUAD ferroptosis-related lncRNAs with a multi-factor Cox regression. The risk score model showed a good performance in evaluating the outcome of LUAD. What’s more, we divided TCGA-LUAD tumor samples into two groups with high- and low-risk scores and further explored the differences in clinical characteristics, tumor mutation burden, and tumor immune cell infiltration among different LUAD tumor risk score groups and evaluate the predictive ability of risk score for immunotherapy benefit. Our findings provide good support for immunotherapy in LUAD in the future

Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1

Introduction We have previously reported that induction of epidermal growth factor receptor and ErbB2 in response to antihormonal agents may provide an early mechanism to allow breast cancer cells to evade the growth-inhibitory action of such therapies and ultimately drive resistant cell growth. More recently, the other two members of the ErbB receptor family, ErbB3 and ErbB4, have been implicated in antihormone resistance in breast cancer. In the present study, we have investigated whether induction of ErbB3 and/or ErbB4 may provide an alternative resistance mechanism to antihormonal action in a panel of four oestrogen receptor (ER)-positive breast cancer cell lines. Methods MCF-7, T47D, BT474 and MDAMB361 cell lines were exposed to fulvestrant (100 nM) for seven days, and effects on ErbB3/4 expression and signalling, as well as on cell growth, were assessed. Effects of heregulin β1 (HRGβ1) were also examined in the absence and presence of fulvestrant to determine the impact of ER blockade on the capacity of this ErbB3/4 ligand to promote signalling and cell proliferation. Results Fulvestrant potently reduced ER expression and transcriptional activity and significantly inhibited growth in MCF-7, T47D, BT474 and MDAMB361 cells. However, alongside this inhibitory activity, fulvestrant also consistently induced protein expression and activity of ErbB3 in MCF-7 and T47D cells and ErbB4 in BT474 and MDAMB361 cell lines. Consequently, fulvestrant treatment sensitised all cell lines to the actions of the ErbB3/4 ligand HRGβ1 with enhanced ErbB3/4-driven signalling activity, reexpression of cyclin D1 and significant increases in cell proliferation being observed when compared to untreated cells. Indeed, in T47D and MDAMB361 HRGβ1 was converted from a ligand having negligible or suppressive growth activity into one that potently promoted cell proliferation. Consequently, fulvestrant-mediated growth inhibition was completely overridden by HRGβ1 in all four cell lines. Conclusions These findings suggest that although antihormones such as fulvestrant may have potent acute growth-inhibitory activity in ER-positive breast cancer cells, their ability to induce and sensitise cells to growth factors may serve to reduce and ultimately limit their inhibitory activity

Glycogen Synthase Kinase 3 Beta (GSK3β) Phosphorylates the RNAase III Enzyme Drosha at S300 and S302

The canonical microRNA (miRNA) pathway commences with the enzymatic cleavage of the primary gene transcript (pri-miRNA) by the RNAase III enzyme Drosha in the nucleus into shorter pre-miRNA species that are subsequently exported to the cytoplasm for further processing into shorter, mature miRNA molecules. Using a series of reporter constructs, we have previously demonstrated that phosphorylation of Drosha at Ser 300 and 302 was required for its nuclear localization. Here, we identify GSK3β as the culprit kinase. We demonstrate that Drosha is unable to selectively localize to the nucleus in cells deficient in GSK3β. These findings expand the substrate base of GSK3β to include a central component of the miRNA biogenesis pathway

Ischemic Stroke Caused by Paradoxical Embolism After an Unsuccessful Transcatheter Atrial Septal Defect Closure Procedure: A Word of Caution

Transcatheter device closure of atrial septal defect (ASD) has become a well-accepted alternative to surgical repair. Serious complications of transcatheter ASD closure are rare, but when they occur, devastating consequences may result. Herein, we present the case of a 4-year-old girl who had an ischemic stroke caused by a presumptive paradoxical embolism after an unsuccessful transcatheter ASD procedure and in whom subsequent venous color Doppler showed deep venous thrombosis (DVT) of the right lower extremity. The risk factors that predisposed to paradoxical cerebral embolism and DVT in this patient are discussed, and the literature is reviewed

Microbial soil respiration and its dependency on carbon inputs, soil temperature and moisture

This experiment was designed to study three determinant factors in decomposition patterns of soil organic matter (SOM): temperature, water and carbon (C) inputs. The study combined field measurements with soil lab incubations and ends with a modelling framework based on the results obtained. Soil respiration was periodically measured at an oak savanna woodland and a ponderosa pine plantation. Intact soils cores were collected at both ecosystems, including soils with most labile C burnt off, soils with some labile C gone and soils with fresh inputs of labile C. Two treatments, dry-field condition and field capacity, were applied to an incubation that lasted 111 days. Short-term temperature changes were applied to the soils periodically to quantify temperature responses. This was done to prevent confounding results associated with different pools of C that would result by exposing treatments chronically to different temperature regimes. This paper discusses the role of the above-defined environmental factors on the variability of soil C dynamics. At the seasonal scale, temperature and water were, respectively, the main limiting factors controlling soil CO2 efflux for the ponderosa pine and the oak savanna ecosystems. Spatial and seasonal variations in plant activity (root respiration and exudates production) exerted a strong influence over the seasonal and spatial variation of soil metabolic activity. Mean residence times of bulk SOM were significantly lower at the Nitrogen (N)-rich deciduous savanna than at the N-limited evergreen dominated pine ecosystem. At shorter time scales (daily), SOM decomposition was controlled primarily by temperature during wet periods and by the combined effect of water and temperature during dry periods. Secondary control was provided by the presence/absence of plant derived C inputs (exudation). Further analyses of SOM decomposition suggest that factors such as changes in the decomposer community, stress-induced changes in the metabolic activity of decomposers or SOM stabilization patterns remain unresolved, but should also be considered in future SOM decomposition studies. Observations and confounding factors associated with SOM decomposition patterns and its temperature sensitivity are summarized in the modeling framework

Conformational changes in a pore-forming region underlie voltage-dependent “loop gating” of an unapposed connexin hemichannel

The structure of the pore is critical to understanding the molecular mechanisms underlying selective permeation and voltage-dependent gating of channels formed by the connexin gene family. Here, we describe a portion of the pore structure of unapposed hemichannels formed by a Cx32 chimera, Cx32*Cx43E1, in which the first extracellular loop (E1) of Cx32 is replaced with the E1 of Cx43. Cysteine substitutions of two residues, V38 and G45, located in the vicinity of the border of the first transmembrane (TM) domain (TM1) and E1 are shown to react with the thiol modification reagent, MTSEA–biotin-X, when the channel resides in the open state. Cysteine substitutions of flanking residues A40 and A43 do not react with MTSEA–biotin-X when the channel resides in the open state, but they react with dibromobimane when the unapposed hemichannels are closed by the voltage-dependent “loop-gating” mechanism. Cysteine substitutions of residues V37 and A39 do not appear to be modified in either state. Furthermore, we demonstrate that A43C channels form a high affinity Cd2+ site that locks the channel in the loop-gated closed state. Biochemical assays demonstrate that A43C can also form disulfide bonds when oocytes are cultured under conditions that favor channel closure. A40C channels are also sensitive to micromolar Cd2+ concentrations when closed by loop gating, but with substantially lower affinity than A43C. We propose that the voltage-dependent loop-gating mechanism for Cx32*Cx43E1 unapposed hemichannels involves a conformational change in the TM1/E1 region that involves a rotation of TM1 and an inward tilt of either each of the six connexin subunits or TM1 domains