Background: Cladribine (CdA), an oral prodrug approved for the treatment of relapsing multiple sclerosis, selectively depletes lymphocytes. CdA passes the blood-brain barrier suggesting a potential effect on CNS resident cells. Objective: We examined, if CdA modifies the phenotype and function of naïve and activated primary mouse microglia, when applied in different concentrations including 0.1-1 µM that putatively overlaps human CSF concentrations. Methods: Primary microglia cultures without stimulation or in the presence of proinflammatory lipopolysaccharide (LPS) or anti-inflammatory IL-4 were co-treated with different concentrations of CdA for 24 hours. Viability was assessed by MTT assay. Phagocytotic ability and morphology were examined by flow cytometry, and random migration by IncuCyte Zoom and TrackMate. Change in gene expression was examined by qPCR, and protein secretion by Meso Scale Discovery. Results: LPS and IL-4 upregulated deoxycytidine kinase (DCK) expression. Only activated microglia were affected by CdA, and this was unrelated to viability. CdA 0.1-1 µM significantly reduced granularity, phagocytotic ability and random migration of activated microglia. CdA 10 µM increased the IL-4-induced gene expression of Arg1 and LPS-induced expression of IL-1beta, TNF, iNOS, and Arg1, but protein secretion remained unaffected. CdA 10 µM potentiated the increased expression of anti-inflammatory TNFR2 but not TNFR1 induced by LPS. Conclusion: Microglia acquire a less activated phenotype when treated with 0.1–1 µM CdA that putatively overlaps human CSF concentrations. This may be related to the upregulated gene expression of DCK upon activation and suggests a potential alternative mechanism of CdA with direct effect on CNS resident cells.

Carbon dioxide has attracted considerable attention owing to its physics and abundant polymorphs. Despite decades of extensive experiments and theoretical simulations, the structure and properties of carbon dioxide under extreme pressures and temperatures are yet to be properly understood. Particularly, the intermediate phase IV of solid carbon dioxide, which separates the molecular phases at low pressures from the non-molecular phases at high pressures, has not been fully investigated, and its structure remains controversial. Here, based on the second-order Møller−Plesset perturbation (MP2) theory and the embedded fragment method, we study the crystal structure, equation of state, and Raman spectra of solid carbon dioxide phase IV at high pressures and temperatures. We demonstrate that the solid carbon dioxide phase IV is a molecular structure that remains in a molecular state rather than the bent state shown in other literatures, which is consistent with the experimental work by Datchi et al. and denies the observed results by Park et al. The proposed work is of great significance in determining the structure of the high-pressure phases of carbon dioxide and further exploring the new phase of molecular crystals.

The ab initio molecular dynamics simulations are performed to study the atomic structures of Co92-xBxTa8 (x = 30, 32.5, 35, 37.5, at.%) glassy alloys. The result shows that the local packing of B-centered clusters is more efficient than that for Co- and Ta-centered clusters. It is also found that B-centered clusters are the primary structure-forming clusters. The Kasper polyhedra with a Voronoi index of <0 3 6 0> and <0 2 8 0> are dominant in B-centered clusters. Specially, the <0 3 6 0> clusters can form a robust network structure, which plays a key role in mechanical properties. Such a network structure has a higher activation barrier for structural rearrangement and a better resist to plastic flow. Thus, the increase in the fraction of <0 3 6 0> with B content would result in an increase in yield strength as well as a sharp decrease in compression plasticity.

Background and purpose: Amphetamine use disorder is a serious health concern, but surprisingly little is known about the vulnerability to the moderate and compulsive use of this psychostimulant and its underlying mechanisms. Previous research showed that inherited serotonin transporter (SERT) down-regulation increases the motor response to cocaine, as well as moderate and compulsive intake of this psychostimulant. Here we sought to investigate whether these findings generalize to amphetamine and the underlying mechanisms in the nucleus accumbens. Experimental Approach: In serotonin transporter knockout (SERT−/−) and wild-type control (SERT+/+) rats we assessed the locomotor response to acute amphetamine (AMPH) and intravenous AMPH self-administration under short access (ShA: 1 hr daily sessions) and long access (LgA: 6 hr daily sessions) conditions. 24 hrs after AMPH self-administration we analysed the expression of glutamate system components in the nucleus accumbens shell and core. Key results: We found that SERT−/− animals displayed an increased AMPH-induced locomotor response and increased AMPH self-administration under LgA, but not ShA conditions. Further, we observed changes in the vesicular and glial glutamate transporters, NMDA and AMPA receptor subunits and their respective postsynaptic scaffolding proteins as function of serotonin transporter genotype, AMPH exposure (baseline, ShA and LgA) and nucleus accumbens sub region. Conclusion and implications: We demonstrate that SERT gene deletion increases the psychomotor and reinforcing effects of AMPH, and that the latter is potentially mediated, at least in part, by homeostatic changes in the glutamatergic synapse of the nucleus accumbens shell and/or core.

In this paper we consider a class of chemotaxis models with two arbitrary constitutive functions g(u) and f(v). After having performed a complete symmetry group classification with respect to them the reduced systems are derived. By considering g(u) of the logistic form wide classes of exact solutions are found.

This paper analyzes a SIS model for infectious diseases with two classes of individuals with different susceptibilities. It focuses in a transition function between both classes of susceptible individuals depending on the density of the infected population. A classification of all the possible bifurcation diagrams that the model can present is done. Specifically, some conditions for the simultaneous existence of backward bifurcation and multiple endemic states are shown.

In this paper, we define a non-iterative transformation method for an Extended Blasius Problem. The original non-iterative transformation method, which is based on scaling invariance properties, was defined for the classical Blasius problem by T\”opfer in 1912. This method allows us to solve numerically a boundary value problem by solving a related initial value problem and then rescaling the obtained numerical solution. In recent years, we have seen applications of the non-iterative transformation method to several problems of interest. The obtained numerical results are improved by both a mesh refinement strategy and Richardson’s extrapolation technique. In this way, we can be confident that the computed six decimal places are correct.

in this work, we introduce an efficient meshless technique for solving the two-dimensional variable-order time-fractional mobile/immobile advection-diffusion model with Dirichlet boundary conditions. The main advantage of this scheme is to obtain a global approximation for this problem which reduces such problems to a system of algebraic equations. To approximate the first and fractional variable-order against the time, we use the finite difference relations. The proposed method is based on the Moving Kriging (MK) interpolation shape functions. To discretization this model in space variables, we use the MK interpolation. Duo to the fact that the shape functions of MK have Kronecker’s delta property, boundary conditions are imposed directly and easily. To illustrate the capability of the proposed technique on regular and irregular domains, several examples are presented in different kinds of domains and with uniform and nonuniform nodes. Also, we use this scheme to simulating anomalous contaminant diffusion in underground reservoirs.

The current work is devoted for operating the Lie symmetry approach, to coupled complex short pulse equation. The method reduces the coupled complex short pulse equation to a system of ordinary differential equations with the help of suitable similarity transformations. Consequently, these systems of nonlinear ordinary differential equations under each subalgeras are solved for traveling wave solutions. Further, with the help of similarity variable, similarity solutions and traveling wave solutions of nonlinear ordinary differential equation, complex soliton solutions of the coupled complex short pulse equation are obtained which are in form of sinh, cosh, sin and cos functions.

Inflammatory breast cancer (IBC), a rare form of breast cancer associated with increased angiogenesis and metastasis, is largely driven by tumor-stromal interactions with the vasculature and the extracellular matrix (ECM). However, there is currently a lack of understanding of the role these interactions play in initiation and progression of the disease. In this study, we developed the first three-dimensional, in vitro, vascularized, IBC platform to quantify the spatial and temporal dynamics of tumor-vasculature and tumor-ECM interactions specific to IBC. Platforms consisting of collagen type 1 ECM with an endothelialized blood vessel were cultured with IBC cells, MDA-IBC3 (HER2+) or SUM149 (triple negative), and for comparison to non-IBC cells, MDA-MB-231 (triple negative). An acellular collagen platform with an endothelial blood vessel served as control. SUM149 and MDA-MB-231 platforms exhibited a significantly (p<0.05) higher vessel permeability and decreased endothelial coverage of the vessel lumen compared to the control. Both IBC platforms, MDA-IBC3 and SUM149, expressed higher levels of VEGF (p<0.05) and increased collagen ECM porosity compared to non-IBC MDA-MB-231 (p<0.05) and control (p<0.01) platforms. Additionally, unique to the MDA-IBC3 platform, we observed progressive sprouting of the endothelium over time resulting in viable vessels with lumen. The newly sprouted vessels encircled clusters of MDA-IBC3 cells replicating a feature of in vivo IBC. The IBC in vitro vascularized platforms introduced in this study model well-described in vivo and clinical IBC phenotypes and provide an adaptable, high throughout tool for systematically and quantitatively investigating tumor-stromal mechanisms and dynamics of tumor progression.

Background and Purpose. Despite widespread abuse of cocaine, there are no approved treatments for cocaine use disorder. Chronic cocaine use is associated with upregulated dopamine D3 receptor (D3R) expression in the brain, and therefore, most D3R-based medication development has focused on D3R antagonists. However, D3R antagonists do not attenuate cocaine intake under “easy” self-administration conditions when response requirements are low. Here we evaluated a novel, highly selective and metabolically stable D3R partial agonist, VK4-40, for its efficacy in reducing cocaine intake and relapse to drug seeking. Experimental Approach. The impact of VK4-40 on cocaine intake and relapse were evaluated using intravenous self-administration procedures under a fixed-ratio 2 reinforcement schedule and cocaine-primed reinstatement conditions in rats. Optogenetic brain-stimulation reward procedures were used to evaluate the interaction of VK4-40 and cocaine in the mesolimbic dopamine system. Sucrose self-administration and a conditioned place preference paradigm was used to evaluate the abuse potential of VK4-40 alone and other unwanted effects. Key Results. VK4-40 dose-dependently reduced cocaine self-administration and cocaine-primed reinstatement of drug-seeking behavior. In addition, VK4-40 inhibited cocaine-enhanced brain-stimulation reward caused by optogenetic stimulation of dopamine neurons in the ventral tegmental area. VK4-40 alone decreased brain-stimulation reward, and produced neither conditioned place preference nor place aversion. This new D3R partial agonist also failed to alter oral sucrose self-administration. Conclusions and Implications. The novel D3R partial agonist, VK4-40, attenuates cocaine reward and relapse in rodents, without significant unwanted effects. These findings support further investigation of D3R partial agonists as putative treatments for cocaine use disorder.

Nitrogen (N) and phosphorus (P) additions to grasslands increase aboveground plant biomass and modify plant community composition, thereby affect plant-derived organic carbon inputting to soil and soil C cycling and storage. However, the effects of nutrient additions on SOC decomposition and soil C sequestration have no census and their underlying mechanisms are poorly understood. This study aimed to explore the mechanisms underlying SOC decomposition and SOC content decline in the topsoil of Tibetan alpine meadows after nine-year field N and P additions. Soil and microbial stoichiometric characteristics were measured and priming effects (PEs), substrate decomposition, as well as microbial C use efficiency (CUE) by adding 13C labeled substrate (glucose or vanillin) were analyzed. N and P additions differentially affected the magnitude and direction of PEs and SOC decomposition, accelerated substrate mineralization of glucose by 33-45% and that of vanillin by 11-45%, but decreased microbial CUE of glucose by 9-15% and that of vanillin by 11-48%. This was associated with the N and P additions-induced lower soil ecological stoichiometric ratios and higher microbial C:N:P ratios compared with Control. Therefore, these comprehensive effects of N and P additions on decomposition of SOC and plant-derived C substrates reduced SOC sequestration and thus SOC content. Long-term N and P additions would weaken soil functioning as C pool of Tibetan alpine meadows.

Sequential model-based design of experiments (MBDoE) uses information from previous experiments to select run conditions for new experiments. Computation of the objective functions for popular MBDoE can be impossible due to a non-invertible Fisher Information Matrix (FIM). Previously, we evaluated a leave-out (LO) approach that design experiments by removing problematic model parameters from the design process. However, the LO approach can be computationally expensive due to its iterative nature and some model parameters are ignored. In this study, we propose a simple Bayesian approach that makes the FIM invertible by accounting for prior parameter information. We compare the proposed Bayesian approach to the LO approach for designing sequential A-optimal experiments. Results from a pharmaceutical case study show that the Bayesian approach is superior, on average, to the LO approach for design of experiments. However, for subsequent parameter estimation, a subset-selection-based LO approach gives better parameter values than the Bayesian approach.

Recently, numerous synthetic small molecular peptidomimetics have been designed to overcome the shortcomings of antimicrobial peptides (AMPs), such as protease instability and high production cost. TZP4 is a triazine-based amphipathic polymer designed to mimic the amphipathic structure found in AMPs. Compared to melittin, TZP4 showed superior antimicrobial activity against antibiotic-resistant pathogens, such as methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa. Results of membrane depolarization, SYTOX Green uptake, flow cytometry, and gel retardation assays suggested that the mechanism of antimicrobial action of TZP4 involved an intracellular target rather than the bacterial cell membrane. Furthermore, TZP4 suppressed the mRNA levels of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α) and inhibited the release of NO and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. BODIPY-TR-cadaverine displacement and dissociation of Fluorescein isothiocyanate (FITC) labelled lipopolysaccharides (LPS) assays revealed that TZP4 strongly bound to Escherichia coli-derived LPS and disaggregated the LPS oligomers. Additionally, flow cytometric analysis revealed that TZP4 inhibited the binding of FITC-conjugated LPS to RAW264.7 cells. These observations indicate that TZP4 may exert its anti-endotoxin activity by directly binding with LPS and inhibiting the interaction between LPS and CD14+ cells. Thus, we propose that TZP4 is a promising drug candidate for the treatment of endotoxic shock and sepsis caused by gram-negative bacterial infections.

Experimental results on pressure drop and flow patterns for gas-liquid flow through packed beds obtained in the International Space Station with two types of packing are presented and analyzed. It is found that the pressure drop depends on the packing wettability in the viscous-capillary (V-C) regime and this dependence is compared with previously published results developed using short duration low-gravity aircraft tests. Within the V-C regime, the capillary contribution is the dominant force contributing to the pressure drop for the wetting case (glass) versus the viscous contribution dominating for the non-wetting case (Teflon). Outside of the V-C regime, it is also found that hysteresis effects that are often strong in normal gravity gas-liquid flows are greatly diminished in microgravity and pressure drop is nearly independent of packing wettability. A flow pattern transition map from bubble to pulse flow is also compared with the earlier aircraft data.

Predator-prey interactions are critical to understand how communities function. However, we need to describe intraspecific variation in diet to accurately depict those interactions. Harbor seals (Phoca vitulina, Linnaeus 1758) are an abundant marine predator that prey on species of conservation concern. We estimated intrapopulation feeding diversity of harbor seals in the Salish Sea relative to sex, time, and location with a novel approach that combined molecular techniques, repeated cross-sectional sampling of scat, and a specialization metric (within-individual consistency in diet). Based on 1,083 scat samples collected from five haul-out sites during four non-sequential years, we quantified diet using metabarcoding techniques, and determined the sex of the scat depositor using a molecular assay. Results suggest that intrapopulation feeding diversity was pervasive. Specialization was high over short periods (24 - 48 hours,〖PS〗_i = 0.392, 95% CI = 0.013, R = 100,000) and variable in time and space. Females showed more specialization than males, particularly during summer and fall, and demersal and benthic prey species were correlated with more specialized diets. The latter finding suggests that this type of prey likely require specific foraging strategies and that there are trade-offs between pelagic and benthic foraging styles for harbor seals. This differential feeding on prey species, as well as between sexes of harbor seals, indicate that predator-prey interactions in harbor seals are complex and that each sex may have a different impact on species of conservation concern. As such, describing intraspecific variation in diet may unravel hitherto unknown complex predator-prey interactions in the community.

Soil pH is strongly associated with soil biogeochemical cycles and biodiversity in terrestrial ecosystems. GE has been widely adopted as an effective practice to restore degraded grasslands. However, the effect of GE on soil pH is still poorly understood and remains inconclusive. We synthesized data from 63 sites in the literature and 43 additional field sites and investigated the dynamics of soil pH following GE across China’s grasslands. Mean pH decreased 0.13 units with GE (mean pH was 8.15 and 8.02 for grazed and GE groups, respectively, p < 0.001). The pH of surface soil (0–20 cm) showed greatest decrease rates in GE grasslands, whereas that of deep soil (20–100 cm) had limited responses to GE. In general, the largest decrease in the rates of soil pH occurred after medium-term periods (5–15 years) of GE, whereas a smaller rate of change was found over short- (≤5 years) and long-term periods (≥15 years) of GE. Of the factors examined, the rate of soil pH change was negatively correlated to MAP, but had no significant relationship with MAT. The rate of soil pH change decreased linearly with RCC, RNC, RAC and RBC. Sedge-dominated grassland had higher pH decrease rates at 0–10 cm soil depth than grass-dominated grassland, whereas grassland dominated by forbs and shrub species showed the highest decrease in pH at 20–30 cm. Our results indicate that GE causes significant soil acidification, especially in surface soil and humid areas, which provides an important reference for future management of China’s grasslands.

In this investigation, CO2 capture performance of zeolite 13X monoliths with 600 and 800 cpsi in presence of SO2/NO impurities under dry and humid conditions were evaluated and compared with that of 13X beads. Dynamic breakthrough tests demonstrated a drastic reduction in CO2 capture capacity and deterioration of kinetics under dry-clean conditions, whereas, upon switching the feed from a clean gas to contaminated gas which contained SO2 and NO, different adsorption performance was observed. Specifically, in dry-contaminated mode, the adsorbents retained their capture capacities with comparable kinetics to that of dry-clean feed conditions, however, in humid-contaminated mode, the adsorbents experienced improved CO2 uptake and CO2/N2 selectivity, albeit at the expense of deteriorated kinetics. These findings indicate that the presence of SO2 and NO contaminants, especially SO2 contaminants, lead to dramatic changes in the adsorption performance of zeolite 13X monoliths, indicating the importance of evaluating adsorbent materials under realistic conditions.