Novel antibiotics are urgently needed to address the looming global crisis of antibiotic resistance. Historically, the primary source of clinically used antibiotics has been microbial secondary ...metabolism. Microbial genome sequencing has revealed a plethora of uncharacterized natural antibiotics that remain to be discovered. However, the isolation of these molecules is hindered by the challenge of linking sequence information to the chemical structures of the encoded molecules. Here, we present PRISM 4, a comprehensive platform for prediction of the chemical structures of genomically encoded antibiotics, including all classes of bacterial antibiotics currently in clinical use. The accuracy of chemical structure prediction enables the development of machine-learning methods to predict the likely biological activity of encoded molecules. We apply PRISM 4 to chart secondary metabolite biosynthesis in a collection of over 10,000 bacterial genomes from both cultured isolates and metagenomic datasets, revealing thousands of encoded antibiotics. PRISM 4 is freely available as an interactive web application at http://prism.adapsyn.com .
•We propose a Lode-dependent enhanced Lemaitre (LEL) model for fracture prediction.•Mechanical tests at different loading configurations are performed for 2 materials.•A J2–J2 plasticity criterion is ...proposed and identified by inverse analysis.•The LEL model predicts accurately fracture for the tests performed on 2 materials.
The present paper deals with a modification of the stress triaxiality-based Lemaitre damage model to predict the ductile fracture at low stress triaxiality and shear-dominated loadings. The influence of the third stress invariant on damage evolution is introduced through the Lode parameter to form the Lode-dependent Enhanced Lemaitre (LEL) model. The enhanced model is then employed to predict fracture at different loading configurations and for two materials. For each material, the hardening law is first identified using both J2 and J2–J3 plasticity criteria depending on material. A methodology to obtain the damage model parameters is then presented and applied to two different materials. Good agreement between the experimental and numerical results is obtained, which shows the interest of the proposed model to predict the ductile fracture for various loading configurations at both low and high stress triaxialities.
Abstract Diabetes mellitus (DM) adversely affects the number and function of circulating endothelial progenitor cells (EPCs). Consequently, there is also a reduction in the repair mechanism of these ...cells, which is a critical and initiating factor in the development of diabetic vascular disease. The aim of the present study was to analyze miR expression profiles in EPCs from patients with DM and choose the most significantly regulated miR to study its possible role on EPC dysfunction and elucidate its mechanism of action. EPCs were collected from subjects with Type II DM and non-diabetic control subjects. Total RNA was harvested from EPCs, and a total of 5 candidate miRNAs were identified by microarray screening and were quantified by TaqMan real-time PCR. Lentiviral vectors expressing miR-126 and miR-126 inhibitor (anti-miR-126) were transfected into EPCs, and the EPC colony-forming capacity, proliferation activity, migratory activity, differentiation capacity, and apoptotic susceptibility were determined and Western Blotting and mRNA real-time PCR analyses were performed. To study the mechanisms, lentiviral vectors expressing Spred-1 and a short interfering RNA (siRNA) targeting Spred-1 were prepared. Five miRs were aberrantly downregulated in EPCs from DM patients. These miRs included miR-126, miR-21, miR-27a, miR-27b and miR-130a. Anti-miR-126 inhibited EPC proliferation, migration, and enhanced apoptosis. Restored miR-126 expression in EPCs from DM promoted EPC proliferation, migration, and inhibited EPC apoptosis ability. Despite this, miR-126 had no effect on EPC differentiation. miR-126 overexpression significantly downregulated Spred-1 in EPCs. The knockdown of Spred-1 expression in EPCs from DM promoted proliferation, migration, and inhibited apoptosis of the cells. The signal pathway of miR-126 effecting on EPCs is partially mediated through Ras/ERK/VEGF and PI3K/Akt/eNOS regulation. This study provides the first evidence that miR-126 is downregulated in EPCs from diabetic patients, and impairs EPCs-mediated function via its target, Spred-1, and through Ras/ERK/VEGF and PI3K/Akt/eNOS signal pathway.
Ductile fracture at the high triaxiality regime is well-known to be controlled by void nucleation, growth and coalescence. However, under low stress triaxiality conditions and general three ...dimensional finite deformations, damage is still poorly predicted due to the complex loading state and microstructural changes under such a condition. Experimental results have revealed not only void growth, but also important void shape change and void rotation under shear-dominated loading. The ability of ductile damage models to predict both void growth with shape change and void rotation is thus crucial for complex loading applications. In the present study, a Gurson-like nonlinear homogenization-based model (namely GVAR) is proposed and compared with the constitutive models for elasto-plastic porous materials developed in Kailasam and Ponte Castañeda (1998) (VAR model) and Danas and Aravas (2012) (MVAR model). The proposed model is based on ad hoc modifications of the VAR model, to give sufficiently accurate results for void growth at both low and high stress triaxialities and keeping the functional form of the original Gurson model. The VAR and MVAR models were based on rigorous linear comparison composite (LCC) homogenization methods, which can describe the evolution of microstructure of porous materials, represented by the void volume fraction, the aspect ratios and the orientations of general ellipsoidal voids. The proposed GVAR model thus inherits these characteristics and provides a sufficiently accurate void growth formulation (and simple at the same time). In addition, the loading direction is not necessary aligned with the ellipsoidal void axes. These models are implemented in an object-oriented finite element (FE) code. The identification of model parameters and the assessment of the proposed model are then carried out via 3D periodic unit-cell computations subjected to different stress states. Comparative results show that the present model predicts relatively accurately the evolution of void volume fraction, void aspect ratios and void rotation for different initial void shapes, void volume fractions and under different stress triaxiality levels. A qualitative application to a tensile test on a notched round bar shows the efficiency of the model to predict microstructure evolution (i.e. voids volume, shape and orientation) in a real-scale model simulation. This model with few parameters to be identified is thus promising to predict damage under complex loading paths and ready to be applied to complex FE simulations.
Enhancer-mediated gene activation generally requires physical proximity between enhancers and their target gene promoters. However, the molecular mechanisms by which interactions between enhancers ...and promoters are formed are not well understood. Here, we investigate the function of the Mediator complex in the regulation of enhancer-promoter interactions, by combining rapid protein depletion and high-resolution MNase-based chromosome conformation capture approaches. We show that depletion of Mediator leads to reduced enhancer-promoter interaction frequencies, which are associated with a strong decrease in gene expression. In addition, we find increased interactions between CTCF-binding sites upon Mediator depletion. These changes in chromatin architecture are associated with a redistribution of the Cohesin complex on chromatin and a reduction in Cohesin occupancy at enhancers. Together, our results indicate that the Mediator and Cohesin complexes contribute to enhancer-promoter interactions and provide insights into the molecular mechanisms by which communication between enhancers and promoters is regulated.
Damage to fracture transition has become a popular topic in the ductile fracture scientific community. Indeed, the transition from a damage continuous approach to a discontinuous fracture is not ...straightforward both from mechanical and numerical points of view. In the present study, a new improved Lode dependent phenomenological coupled damage model is used to investigate the ductile fracture in different mechanical tests. The remeshing and elements erosion techniques are employed to propagate the ductile cracks in 3D models using Forge® finite element code. This code is based on a mixed velocity–pressure formulation using the MINI element P1+/P1. In addition, the plasticity behavior is modeled by a Lode-dependent plasticity criterion. Applications to different mechanical tests at different loading configurations, using identified damage model parameters, show good agreement in terms of fracture prediction between experimental and numerical results.
Highlights ► Morphologically activated microglia seen up to 28 days after diffuse brain injury. ► Inflammatory genes acutely elevated in thalamus & cortex after diffuse TBI. ► Anti-inflammatory genes ...acutely elevated after diffuse TBI. ► Translocator protein 18 kDa receptor binding validated qPCR results. ► Acute ibuprofen administration attenuated classical inflammatory genes in the VPM.
Intestinal IgA, which is regulated by gut microbiota, has a crucial role in maintenance of intestinal homeostasis and in protecting the intestines from inflammation. However, the means by which ...microbiota promotes intestinal IgA responses remain unclear. Emerging evidence suggests that the host can sense gut bacterial metabolites in addition to pathogen-associated molecular patterns and that recognition of these small molecules influences host immune response in the intestines and beyond. We reported here that microbiota metabolite short-chain fatty acid acetate promoted intestinal IgA responses, which was mediated by "metabolite-sensing" GPR43. GPR43
mice demonstrated lower levels of intestinal IgA and IgA
gut bacteria compared with those in wild type (WT) mice. Feeding WT but not GPR43
mice acetate but not butyrate promoted intestinal IgA response independent of T cells. Acetate promoted B-cell IgA class switching and IgA production in vitro in the presence of WT but not GPR43
dendritic cells (DCs). Mechanistically, acetate-induced DC expression of Aldh1a2, which converts Vitamin A into its metabolite retinoic acid (RA). Moreover, blockade of RA signaling inhibited the acetate induction of B-cell IgA production. Our studies thus identified a new pathway by which microbiota promotes intestinal IgA response through its metabolites.
•In situ micro-tomography tensile tests are used to quantify ductile damage.•We identify the GTN model using both micro- and macroscopic mechanical tests.•We propose an improvement for the nucleation ...law in the GTN model.•We implement and identify the modified GTN proposed by Xue 47.•All fractures in experimental tests can be predicted by the identified model.
The present paper deals with the identification of the parameters of a generalized GTN model and the characterization of ductile damage for a high carbon steel by both X-ray micro-tomography and “macroscopic” mechanical tests. First, in situ X-ray micro-tomography tensile tests are performed and the results are used for the modeling of ductile damage mechanisms (voids nucleation, growth and coalescence) using analytical formulations. Interrupted in situ SEM tensile test is also carried out to examine the microstructure evolution. The damage process during in situ X-ray micro-tomography tensile tests is the result of continuous nucleation of small voids and significant growth of large voids; whereas the coalescence takes place locally. In addition, tomography results combined with the results of macroscopic mechanical tests at different loading configurations are used to identify the Gurson–Tvergaard–Needleman model extended for shear loading by Xue (2008). It proved necessary to propose an improvement to account for the influence of the stress triaxiality level on the nucleation formulation of the GTN model. This new formulation is then identified via experimental tests. The results show that, with the parameters obtained from both microstructure measurements and macroscopic considerations, the modified GTN model can reproduce quite accurately the experimental results for different loading configurations.
Biocompatible antimicrobial coatings may enhance the function of many orthopedic implants by combating infection. Hydroxyapatite is a choice mineral for such a coating as it is native to bone and ...silver would be a possible antimicrobial agent as it is also commonly used in biomedical applications. The aim of the research is to develop a silver-containing calcium phosphate (Ag/Ca-P) coating via electrochemical deposition on titanium substrates as this allows for controlled coating buildup on complex shapes and porous surfaces. Two different deposition approaches are explored: one-step Ag/Ca-P(1) deposition coatings, containing silver ions as microsized silver phosphate particles embedded in the Ca-P matrix; and via a two-step method (Ag/Ca-P(2)) where silver is deposited as metallic silver nanoparticle on the Ca-P coating. The Ag/Ca-P(1) coating displays a bacterial reduction of 76.1 ± 8.3% via Ag-ion leaching. The Ag/Ca-P(2) coating displays a bacterial reduction of 83.7 ± 4.5% via contact killing. Interestingly, by preincubation in phosphate-buffered saline solution, bacterial reduction improves to 97.6 ± 2.7 and 99.7 ± 0.4% for Ag/Ca-P(1) and Ag/Ca-P(2) coatings, respectively, due to leaching of formed AgCl x (x–1)– species. The biocompatibility evaluation indicates that the Ag/Ca-P(1) coating is cytotoxic towards osteoblasts while the Ag/Ca-P(2) coating shows excellent compatibility. The electrochemical deposition of highly bactericidal coatings with excellent biocompatibility will enable us to coat future bone implants even with complex or porous structures.
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