Structural and ligand binding analyses of the periplasmic sensor domain of RsbU in Chlamydia trachomatis support a role in TCA cycle regulation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154297/1/mmi14401-sup-0001-Supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154297/2/mmi14401_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154297/3/mmi14401.pd

Coupled Simulations of Mechanical Deformation and Microstructural Evolution Using Polycrystal Plasticity and Monte Carlo Potts Models

The microstructural evolution of heavily deformed polycrystalline Cu is simulated by coupling a constitutive model for polycrystal plasticity with the Monte Carlo Potts model for grain growth. The effects of deformation on boundary topology and grain growth kinetics are presented. Heavy deformation leads to dramatic strain-induced boundary migration and subsequent grain fragmentation. Grain growth is accelerated in heavily deformed microstructures. The implications of these results for the thermomechanical fatigue failure of eutectic solder joints are discussed

Structure–activity relationship of ipglycermide binding to phosphoglycerate mutases

Catalysis of human phosphoglycerate mutase is dependent on a 2,3-bisphosphoglycerate cofactor (dPGM), whereas the nonhomologous isozyme in many parasitic species is cofactor independent (iPGM). This mechanistic and phylogenetic diversity offers an opportunity for selective pharmacologic targeting of glycolysis in disease-causing organisms. We previously discovered ipglycermide, a potent inhibitor of iPGM, from a large combinatorial cyclic peptide library. To fully delineate the ipglycermide pharmacophore, herein we construct a detailed structure–activity relationship using 280 substituted ipglycermide analogs. Binding affinities of these analogs to immobilized Caenorhabditis elegans iPGM, measured as fold enrichment relative to the index residue by deep sequencing of an mRNA display library, illuminated the significance of each amino acid to the pharmacophore. Using cocrystal structures and binding kinetics, we show that the high affinity of ipglycermide for iPGM orthologs, from Brugia malayi, Onchocerca volvulus, Dirofilaria immitis, and Escherichia coli, is achieved by a codependence between (1) the off-rate mediated by the macrocycle Cys14 thiolate coordination to an active-site Zn2+ in the iPGM phosphatase domain and (2) shape complementarity surrounding the macrocyclic core at the phosphotransferase–phosphatase domain interface. Our results show that the high-affinity binding of ipglycermide to iPGMs freezes these structurally dynamic enzymes into an inactive, stable complex

Modeling pore corrosion in normally open gold- plated copper connectors.

The goal of this study is to model the electrical response of gold plated copper electrical contacts exposed to a mixed flowing gas stream consisting of air containing 10 ppb H{sub 2}S at 30 C and a relative humidity of 70%. This environment accelerates the attack normally observed in a light industrial environment (essentially a simplified version of the Battelle Class 2 environment). Corrosion rates were quantified by measuring the corrosion site density, size distribution, and the macroscopic electrical resistance of the aged surface as a function of exposure time. A pore corrosion numerical model was used to predict both the growth of copper sulfide corrosion product which blooms through defects in the gold layer and the resulting electrical contact resistance of the aged surface. Assumptions about the distribution of defects in the noble metal plating and the mechanism for how corrosion blooms affect electrical contact resistance were needed to complete the numerical model. Comparisons are made to the experimentally observed number density of corrosion sites, the size distribution of corrosion product blooms, and the cumulative probability distribution of the electrical contact resistance. Experimentally, the bloom site density increases as a function of time, whereas the bloom size distribution remains relatively independent of time. These two effects are included in the numerical model by adding a corrosion initiation probability proportional to the surface area along with a probability for bloom-growth extinction proportional to the corrosion product bloom volume. The cumulative probability distribution of electrical resistance becomes skewed as exposure time increases. While the electrical contact resistance increases as a function of time for a fraction of the bloom population, the median value remains relatively unchanged. In order to model this behavior, the resistance calculated for large blooms has been weighted more heavily

Costameric integrin and sarcoglycan protein levels are altered in a Drosophila model for Limb-girdle muscular dystrophy type 2H

Mutations in two different domains of the ubiquitously expressed TRIM32 protein give rise to two clinically separate diseases, one of which is Limb-girdle muscular dystrophy type 2H (LGMD2H). Uncovering the muscle-specific role of TRIM32 in LGMD2H pathogenesis has proven difficult, as neurogenic phenotypes, independent of LGMD2H pathology, are present in TRIM32 KO mice. We previously established a platform to study LGMD2H pathogenesis using Drosophila melanogaster as a model. Here we show that LGMD2H disease-causing mutations in the NHL domain are molecularly and structurally conserved between fly and human TRIM32. Furthermore, transgenic expression of a subset of myopathic alleles (R394H, D487N, and 520fs) induce myofibril abnormalities, altered nuclear morphology, and reduced TRIM32 protein levels, mimicking phenotypes in patients afflicted with LGMD2H. Intriguingly, we also report for the first time that the protein levels of βPS integrin and sarcoglycan δ, both core components of costameres, are elevated in TRIM32 disease-causing alleles. Similarly, murine myoblasts overexpressing a catalytically inactive TRIM32 mutant aberrantly accumulate α- and β-dystroglycan and α-sarcoglycan. We speculate that the stoichiometric loss of costamere components disrupts costamere complexes to promote muscle degeneration

Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 2CL Protease

Human noroviruses are the primary causative agents of acute gastroenteritis and a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. Norovirus 3CL protease plays a vital role in viral replication by generating structural and nonstructural proteins via the cleavage of the viral polyprotein. Thus, molecules that inhibit the viral protease may have potential therapeutic value. We describe herein the structure-based design, synthesis, and in vitro and cell-based evaluation of the first class of oxadiazole-based, permeable macrocyclic inhibitors of norovirus 3CL protease

Surface softening in metal-ceramic sliding contacts: An experimental and numerical investigation

This study investigates the tribolayer properties at the interface of ceramic/metal (i.e., WC/W) sliding contacts using various experimental approaches and classical atomistic simulations. Experimentally, nanoindentation and micropillar compression tests, as well as adhesion mapping by means of atomic force microscopy, are used to evaluate the strength of tungsten?carbon tribolayers. To capture the influence of environmental conditions, a detailed chemical and structural analysis is performed on the worn surfaces by means of XPS mapping and depth profiling along with transmission electron microscopy of the debris particles. Experimentally, the results indicate a decrease in hardness and modulus of the worn surface compared to the unworn one. Atomistic simulations of nanoindentation on deformed and undeformed specimens are used to probe the strength of the WC tribolayer and despite the fact that the simulations do not include oxygen, the simulations correlate well with the experiments on deformed and undeformed surfaces, where the difference in behavior is attributed to the bonding and structural differences of amorphous and crystalline W-C. Adhesion mapping indicates a decrease in surface adhesion, which based on chemical analysis is attributed to surface passivation

Navigating through the r packages for movement

The advent of miniaturized biologging devices has provided ecologists with unprecedented opportunities to record animal movement across scales, and led to the collection of ever-increasing quantities of tracking data. In parallel, sophisticated tools have been developed to process, visualize and analyse tracking data; however, many of these tools have proliferated in isolation, making it challenging for users to select the most appropriate method for the question in hand. Indeed, within the r software alone, we listed 58 packages created to deal with tracking data or 'tracking packages'. Here, we reviewed and described each tracking package based on a workflow centred around tracking data (i.e. spatio-temporal locations (x, y, t)), broken down into three stages: pre-processing, post-processing and analysis, the latter consisting of data visualization, track description, path reconstruction, behavioural pattern identification, space use characterization, trajectory simulation and others. Supporting documentation is key to render a package accessible for users. Based on a user survey, we reviewed the quality of packages' documentation and identified 11 packages with good or excellent documentation. Links between packages were assessed through a network graph analysis. Although a large group of packages showed some degree of connectivity (either depending on functions or suggesting the use of another tracking package), one third of the packages worked in isolation, reflecting a fragmentation in the r movement-ecology programming community. Finally, we provide recommendations for users when choosing packages, and for developers to maximize the usefulness of their contribution and strengthen the links within the programming community

Structural comparison of oxidized and reduced FKBP13 from Arabidopsis thaliana

10.1002/prot.21108Proteins: Structure, Function and Genetics654789-795PSFG