Winkelguthrie5468

Therapeutic approaches to combat type 1 diabetes (T1D) include donor pancreas transplantation, exogenous insulin administration and immunosuppressive therapies. However, these clinical applications are limited due to insufficient tissue compatible donors, side effects of exogenous insulin administration and/or increased onset of opportunistic infections attributable to induced global immunosuppression. An alternative approach to alleviate disease states is to utilize insulin-producing pancreatic islets seeded in a bioscaffold for implantation into diabetic recipients. The present studies now report that a newly developed cationic polymer biomaterial serves as an efficient bioscaffold for delivery of donor syngeneic pancreatic islet cells to reverse hyperglycemia in murine streptozotocin induced- or non-obese diabetic mouse models of T1D. Intraperitoneal implantation of pancreatic islets seeded within the copolymer bioscaffold supports long-term cell viability, response to extracellular signaling cues and ability to produce soluble factors into the microenvironment. Elevated insulin levels were measured in recipient diabetic mice upon implantation of the islet-seeded biomaterial coupled with reduced blood glucose levels, collectively resulting in increased survival and stabilization of metabolic indices. Importantly, the implanted islet-seeded biomaterial assembled into a solid organoid substructure that reorganized the extracellular matrix compartment and recruited endothelial progenitors for neovascularization. This allowed survival of the graft long-term in vivo and access to the blood for monitoring glucose levels. These results highlight the novelty, simplicity and effectiveness of this biomaterial for tissue regeneration and in vivo restoration of organ functions.The two vasoactive hormones, angiotensin II (ANG II; vasoconstrictive) and atrial natriuretic peptide (ANP; vasodilatory) antagonize the biological actions of each other. ANP acting through natriuretic peptide receptor-A (NPRA) lowers blood pressure and blood volume. We tested hypothesis that ANG II plays critical roles in the transcriptional repression of Npr1 (encoding NPRA) and receptor function. ANG II significantly decreased NPRA mRNA and protein levels and cGMP accumulation in cultured mesangial cells and attenuated ANP-mediated relaxation of aortic rings ex vivo. The transcription factors, cAMP-response element-binding protein (CREB) and heat-shock factor-4a (HSF-4a) facilitated the ANG II-mediated repressive effects on Npr1 transcription. Tyrosine kinase (TK) inhibitor, genistein and phosphatidylinositol 3-kinase (PI-3K) inhibitor, wortmannin reversed the ANG II-dependent repression of Npr1 transcription and receptor function. ANG II enhanced the activities of Class I histone deacetylases (HDACs 1/2), thereby decreased histone acetylation of H3K9/14ac and H4K8ac. The repressive effect of ANG II on Npr1 transcription and receptor signaling seems to be transduced by TK and PI-3K pathways and modulated by CREB, HSF-4a, HDACs, and modified histones. The current findings suggest that ANG II-mediated repressive mechanisms of Npr1 transcription and receptor function may provide new molecular targets for treatment and prevention of hypertension and cardiovascular diseases.A refined risk assessment was conducted to evaluate the efficacy of different glove materials in reducing the potential hazards associated with using paint strippers containing N-methylpyrrolidone (NMP) under the scenarios defined by USEPA's TSCA risk assessment. Three categories of gloves were identified based on measured permeation rates for NMP (1) minimal protection; (2) moderate protection; and (3) maximal protection. Simulations for eight acute and chronic occupational exposure scenarios identified by USEPA as having a potential hazard (i.e., margins of exposure, MOE, less then 30) were reassessed for each glove category using PBPK modeling to predict peak (Cmax) and cumulative (AUC) internal doses of NMP. For the acute assessment, the refined MOE values were ≥30 for half of the scenarios for gloves from the moderate protection group category, and all of the scenarios for gloves from the maximal protection category. For the chronic assessment, the refined MOE values were ≥30 for all scenarios except one for gloves from the maximal protection category. The results of this assessment indicate that (1) the degree of protection provided by gloves from NMP permeation can vary widely depending upon the glove material, NMP formulation, and internal dose measure (with calculated glove protection factors ranging from 1.1 to 1900); and (2) NMP-containing paint strippers can be used safely when appropriate PPE are used. As such, these results can be used to support risk-reduction methods (e.g., product labeling, MSDS instructions on use of appropriate glove materials) as alternatives to banning NMP use under TSCA.Human exposure to particulate matter and other environmental species is difficult to estimate in large populations. Individuals can encounter significant and acute variations in exposure over small spatiotemporal scales. Exposure is strongly tied to both the environmental and activity contexts that individuals experience. Here we present the development of an agent-based model to simulate human exposure at high spatiotemporal resolutions. The model is based on simulated activity and location trajectories on a per-person basis for large geographical areas. read more We demonstrate that the model can successfully estimate trajectories and that activity patterns have been validated against traffic patterns and that can be integrated with exposure-agent geographical distributions to estimate total human exposure.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Stevens - Johnson syndrome (SJS) has manifestation through the exfoliation of epidermis and mucosal tissue. Ocular surface is usually affected in acute and chronic stage. The patients are usually suffered from chronic ocular sequelae including symblepharon, limbal stem cell deficiency, etc. Furthermore, ocular microbiome may also be altered in SJS. This is prospective, age and sex matched analytical study which including 20 chronic SJS patients and 20 healthy subjects for specimen collection from inferior conjunctiva for microbiome analysis by conventional cultures and Next-Generation Sequencing (NGS) methods. Significant higher proportion of positive-cultured specimen was demonstrated in SJS group (SJS group 60%, healthy 10%, p-value = 0.001). In addition, NGS which providing high-throughput sequencing has demonstrated the greater diversity of microbial species. The higher proportion of pathogenic microorganisms including Pseudomonas spp., Staphylococcus spp., Streptococcus spp., Acinetobacter spp. was shown in SJS group. Ocular surface in SJS is usually occupied by more diverse microorganisms with increased proportion of pathogenic species. This condition may affect chronic inflammation and opportunistic infections in SJS group. In order to prevent and treat infection in these patients, appropriate antibiotics based on bacterial examination should be considered as the first-line treatment in the SJS patients.The majority of anaerobic biogeochemical cycling occurs within marine sediments. To understand these processes, quantifying the distribution of active cells and gross metabolic activity is essential. We present an isotope model rooted in thermodynamics to draw quantitative links between cell-specific sulfate reduction rates and active sedimentary cell abundances. This model is calibrated using data from a series of continuous culture experiments with two strains of sulfate reducing bacteria (freshwater bacterium Desulfovibrio vulgaris strain Hildenborough, and marine bacterium Desulfovibrio alaskensis strain G-20) grown on lactate across a range of metabolic rates and ambient sulfate concentrations. We use a combination of experimental sulfate oxygen isotope data and nonlinear regression fitting tools to solve for unknown kinetic, step-specific oxygen isotope effects. This approach enables identification of key isotopic reactions within the metabolic pathway, and defines a new, calibrated framework for understanding oxygen isotope variability in sulfate. This approach is then combined with porewater sulfate/sulfide concentration data and diagenetic modeling to reproduce measured 18O/16O in porewater sulfate. From here, we infer cell-specific sulfate reduction rates and predict abundance of active cells of sulfate reducing bacteria, the result of which is consistent with direct biological measurements.Although the microbiota is known to affect host development, metabolism, and immunity, its impact on host behavior is only beginning to be understood. In order to better characterize behavior modulation by host-associated microorganisms, we investigated how bacteria modulate complex behaviors in the nematode model organism Pristionchus pacificus. This nematode is a predator that feeds on the larvae of other nematodes, including Caenorhabditis elegans. By growing P. pacificus on different bacteria and testing their ability to kill C. elegans, we reveal large differences in killing efficiencies, with a Novosphingobium species showing the strongest enhancement. This enhanced killing was not accompanied by an increase in feeding, which is a phenomenon known as surplus killing, whereby predators kill more prey than necessary for sustenance. Our RNA-seq data demonstrate widespread metabolic rewiring upon exposure to Novosphingobium, which facilitated screening of bacterial mutants with altered transcriptional responses. We identified bacterial production of vitamin B12 as an important cause of such enhanced predatory behavior. Although vitamin B12 is an essential cofactor for detoxification and metabolite biosynthesis, shown previously to accelerate development in C. elegans, supplementation with this enzyme cofactor amplified surplus killing in P. pacificus, whereas mutants in vitamin B12-dependent pathways reduced surplus killing. By demonstrating that production of vitamin B12 by host-associated microbiota can affect complex host behaviors, we reveal new connections between animal diet, microbiota, and nervous system.The present work studied the effect of temperature on the corrosion behavior of API X120 steel in a saline solution saturated with CO2 in absence and presence of polyethyleneimine (PEI) as an environmentally safe green inhibitor. The effect of PEI on the corrosion behavior of API X120 steel was investigated using destructive and non-destructive electrochemical techniques. The overall results revealed that PEI significantly decreases the corrosion rate of API X120 steel with inhibition efficiency of 94% at a concentration of 100 μmol L-1. The adsorption isotherm, activation energy and the thermodynamic parameters were deduced from the electrochemical results. It is revealed that the adsorption of PEI on API X120 steel surface follows Langmuir adsorption isotherm adopting a Physi-chemisorption mechanism. Finally, the samples were characterized using scanning electron microscopy (SEM) and atomic force microscopy (AFM) techniques to elucidate the effect of aggressiveness of corrosive media on the surface morphology and the corrosion performance of API X120 steel.