Analysis of the Caenorhabditis elegans innate immune response to Coxiella burnetii

The nematode Caenorhabditis elegans is well established as a system for characterization and discovery of molecular mechanisms mediating microbe-specific inducible innate immune responses to human pathogens. Coxiella burnetii is an obligate intracellular bacterium that causes a flu-like syndrome in humans (Q fever), as well as abortions in domesticated livestock, worldwide. Initially, when wild type C. elegans (N2 strain) was exposed to mCherry-expressing C. burnetii (CCB) a number of overt pathological manifestations resulted, including intestinal distension, deformed anal region and a decreased lifespan. However, nematodes fed autoclave-killed CCB did not exhibit these symptoms. Although vertebrates detect C. burnetii via TLRs, pathologies in tol-1(-) mutant nematodes were indistinguishable from N2, and indicate nematodes do not employ this orthologue for detection of C. burnetii. sek-1(-) MAP kinase mutant nematodes succumbed to infection faster, suggesting that this signaling pathway plays a role in immune activation, as previously shown for orthologues in vertebrates during a C. burnetii infection. C. elegans daf-2(-) mutants are hyper-immune and exhibited significantly reduced pathological consequences during challenge. Collectively, these results demonstrate the utility of C. elegans for studying the innate immune response against C. burnetii and could lead to discovery of novel methods for prevention and treatment of disease in humans and livestock

Computational and experimental investigation of the strain rate sensitivity of small punch testing of the high-entropy alloy CoCrFeMnNi

The suitability of determining the strain rate sensitivity (SRS) of the CoCrFeMnNi high-entropy alloy (HEA) by small punch (SP) testing has been assessed at displacement rates ranging from 0.2 to 2 mm∙min−1. The stress was found to increase as the displacement rate was raised from 0.2 to 2 mm∙min−1, whereas the plastic strain distributions were similar in all cases. However, for a higher displacement rate of 10 mm∙min−1, the sample was found to exhibit a drop in strength and ductility attributed to casting defects. The strain-rate sensitivity exponent (m) was found to be 0.1387 whilst the Finite Element Analysis (FEA) simulations predicted a slightly smaller value of 0.1313. This latter value is closer to m = 0.091 obtained from nanoindentation strain rate jump tests since the results are insensitive to the presence of small casting defects. The relationship between the experimental and the empirically derived predicted properties from the SP tests revealed a high level of agreement for maximum stress properties. The properties predicted at 2 mm∙min−1 (R2 = 0.96) offered a stronger fit than at 0.5 mm∙min−1 (R2 = 0.92)

Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens

Investigation of the diversity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human malaria parasite, Plasmodium falciparum, have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global diversity and population structure of leading vaccine candidate antigens of P. falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. A stringent variant calling pipeline was used to extract high quality antigen gene 'haplotypes' from the global dataset and a new R-package named VaxPack was used to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp, trap, eba175, ama1, rh5, and CelTOS. Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. High levels of diversity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptation to different human host or mosquito vector populations. This study provides an essential framework for the diversity of P. falciparum antigens to be considered in the design of the next generation of malaria vaccines

Computational and experimental investigation of the strain rate sensitivity of small punch testing of the high-entropy alloy CoCrFeMnNi

The suitability of determining the strain rate sensitivity (SRS) of the CoCrFeMnNi high-entropy alloy (HEA) by small punch (SP) testing has been assessed at displacement rates ranging from 0.2 to 2mm∙min-1. The stress was found to increase as the displacement rate was raised from 0.2 to 2mm∙min-1, whereas the plastic strain distributions were similar in all cases. However, for a higher displacement rate of 10mm∙min-1, the sample was found to exhibit a drop in strength and ductility attributed to casting defects. The strain-rate sensitivity exponent (m) was found to be 0.1387 whilst the Finite Element Analysis (FEA) simulations predicted a slightly smaller value of 0.1313. This latter value is closer to m = 0.091 obtained from nanoindentation strain rate jump tests since the results are insensitive to the presence of small casting defects. The relationship between the experimental and the empirically derived predicted properties from the SP tests revealed a high level of agreement for maximum stress properties. The properties predicted at 2mm∙min-1 (R2 = 0.96) offered a stronger fit than at 0.5mm∙min-1 (R2 = 0.92)

VIVID: A web application for variant interpretation and visualization in multi-dimensional analyses

Large-scale comparative genomics- and population genetic studies generate enormous amounts of polymorphism data in the form of DNA variants. Ultimately, the goal of many of these studies is to associate genetic variants to phenotypes or fitness. We introduce VIVID, an interactive, user-friendly web application that integrates a wide range of approaches for encoding genotypic to phenotypic information in any organism or disease, from an individual or population, in three-dimensional (3D) space. It allows mutation mapping and annotation, calculation of interactions and conservation scores, prediction of harmful effects, analysis of diversity and selection, and 3D visualization of genotypic information encoded in Variant Call Format on AlphaFold2 protein models. VIVID enables the rapid assessment of genes of interest in the study of adaptive evolution and the genetic load, and it helps prioritizing targets for experimental validation. We demonstrate the utility of VIVID by exploring the evolutionary genetics of the parasitic protist Plasmodium falciparum, revealing geographic variation in the signature of balancing selection in potential targets of functional antibodies

Investigation of the strain rate sensitivity of CoCrFeMnNiTix (x = 0, 0.3) high-entropy alloys using the shear punch test

High entropy alloys (HEAs) are a novel class of metallic materials that exhibit a unique blend of properties due to their chemical composition and atomic arrangement. This research aims to investigate the strain rate sensitivity (SRS) of two HEA CoCrFeMnNiTix (x = 0, 0.3) alloy compositions through the use of shear punch testing. This method has been proven to provide reliable results for both HEA materials, including the CoCrFeMnNiTi0.3 HEA composition which was found to be inherently brittle and contained both σ-phase and Laves phase compounds with a hardness close to 14 GPa and a soft FCC phase. Among all the testing temperatures (room temperature to 400 °C) and deflection rates (0.2, 2 and 10 mm.min−1) used, only the CoCrFeMnNi HEA alloy was found to exhibit SRS at room temperature (m = 0.0333), while for the other HEA alloy variant and testing conditions, the SRS was found to be zero. From empirical correlations and finite element analysis (FEA), the calculated value for m ranged from 0.0333 to 0.0359, thus evidencing that the FEA simulations provide an accurate and suitable means of capturing the deformation behaviour of such alloys when subjected to shearing