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Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients.

Marine encrusting communities play vital roles in benthic ecosystems and have major economic implications with regards to biofouling. However, their ability to persist under projected warming scenarios remains poorly understood and is difficult to study under realistic conditions. Here, using heated settlement panel technologies, we show that after 18 months Antarctic encrusting communities do not acclimate to either +1 °C or +2 °C above ambient temperatures. There is significant up-regulation of the cellular stress response in warmed animals, their upper lethal temperatures decline with increasing ambient temperature and population genetic analyses show little evidence of differential survival of genotypes with treatment. By contrast, biofilm bacterial communities show no significant differences in community structure with temperature. Thus, metazoan and bacterial responses differ dramatically, suggesting that ecosystem responses to future climate change are likely to be far more complex than previously anticipated. Genetic adaptation and physiological acclimation can potentially buffer species against climate change. Here, the authors perform a long-term warming experiment of Antarctic encrusting communities and show that focal animal species failed to acclimate and lacked genetic variation in tolerance to warming.

The mass customization (MC) toolkit is the major enabler ofrelational value for consumers.Not a new concept, but nascent in the context of the MC co-design experience, mixed reality (MR) merges the real and virtual world.While the literature extols the significance of MR components -augmented reality (AR) and virtual reality(VR)-in manufacturing, IT, education and, to a limited extent, retail, few if any studies address its relevance to MC and the consumer’s perceived value of the co-design experience.Is a mixed reality configurator viable as the enabler of relational benefit in the consumer co-design experience? With visual and feedback features critical to the structure of successful web-based configurators, what characteristics must a MR toolkit possess to deliver optimal experiential value to the MC consumer? What is the nature of the MR toolkitand its bearing upon perceived complexity, control and enjoyment of the co-design process?Are these perceptions the most relevant to consider in designing a MC toolkit utilizing MR technology?This conceptual paper attempts to define a mixed reality toolkit and explore its potential influence on the consumer’s perception of value ofthe MC co-design experiencein the mixed realitycontext.

SNP arrays are enabling tools for high-resolution studies of the genetic basis of complex traits in farmed and wild animals. Oysters are of critical importance in many regions from both an ecological and economic perspective, and oyster aquaculture forms a key component of global food security. The aim of our study was to design a combined-species, medium density SNP array for Pacific oyster (Crassostrea gigas) and European flat oyster (Ostrea edulis), and to test the performance of this array on farmed and wild populations from multiple locations, with a focus on European populations. SNP discovery was carried out by whole-genome sequencing (WGS) of pooled genomic DNA samples from eight C. gigas populations, and restriction site-associated DNA sequencing (RAD-Seq) of 11 geographically diverse O. edulis populations. Nearly 12 million candidate SNPs were discovered and filtered based on several criteria, including preference for SNPs segregating in multiple populations and SNPs with monomorphic flanking regions. An Affymetrix Axiom Custom Array was created and tested on a diverse set of samples (n = 219) showing ∼27 K high quality SNPs for C. gigas and ∼11 K high quality SNPs for O. edulis segregating in these populations. A high proportion of SNPs were segregating in each of the populations, and the array was used to detect population structure and levels of linkage disequilibrium (LD). Further testing of the array on three C. gigas nuclear families (n = 165) revealed that the array can be used to clearly distinguish between both families based on identity-by-state (IBS) clustering parental assignment software. This medium density, combined-species array will be publicly available through Affymetrix, and will be applied for genome-wide association and evolutionary genetic studies, and for genomic selection in oyster breeding programs.

The ability to learn progressively declines with age. Neural hyperactivity has been implicated in impairing cognitive plasticity with age, but the molecular mechanisms remain elusive. Here, we show that chronic excitation of the Caenorhabditis elegans O 2 -sensing neurons during ageing causes a rapid decline of experience-dependent plasticity in response to environmental O 2 concentration, whereas sustaining lower activity of O 2 -sensing neurons retains plasticity with age. We demonstrate that neural activity alters the ageing trajectory in the transcriptome of O 2 -sensing neurons, and our data suggest that high-activity neurons redirect resources from maintaining plasticity to sustaining continuous firing. Sustaining plasticity with age requires the K + -dependent Na + /Ca 2+ (NCKX) exchanger, whereas the decline of plasticity with age in high-activity neurons acts through calmodulin and the scaffold protein Kidins220. Our findings demonstrate directly that the activity of neurons alters neuronal homeostasis to govern the age-related decline of neural plasticity and throw light on the mechanisms involved.

Genomic data are lacking for most Antarctic marine invertebrates, predicating our ability to understand physiological adaptation and specific life-history traits, such as longevity. The environmental stress response of the Antarctic infaunal clam Laternula elliptica is much diminished in older adult animals compared with younger juvenile individuals. However, the mechanism underlying this reduced capacity is unknown. In this study, we describe and analyse the genome of L. elliptica and use it as a tool to understand transcriptomic responses to shell damage across different age cohorts. Gene expression data were combined with reduced representation enzymic methyl sequencing to identify if methylation was acting as an epigenetic mechanism driving age-dependent transcriptional profiles. Our transcriptomic results demonstrated a clear bipartite molecular response in L. elliptica , associated with a rapid growth phase in juveniles and a stabilization phase in reproductively mature adults. Genes active in the response to damage repair in juvenile animals are silent in adults but can be reactivated after several months following damage stimulus; however, these genes were not methylated. Hence, the trigger for this critical and imprinted change in physiological state is, as yet, unknown. While epigenetics is likely involved in this process, the mechanism is unlikely to be methylation.

In most studies aimed at localizing footprints of past selection, outliers at tails of the empirical distribution of a given test statistic are assumed to reflect locus-specific selective forces. Significance cutoffs are subjectively determined, rather than being related to a clear set of hypotheses. Here, we define an empirical p-value for the summary statistic by means of a permutation method that uses the observed SNP structure in the real data. To illustrate the methodology, we applied our approach to a panel of 2.9 million autosomal SNPs identified from re-sequencing a pool of 15 individuals from a brown egg layer line. We scanned the genome for local reductions in heterozygosity, suggestive of selective sweeps. We also employed a modified sliding window approach that accounts for gaps in the sequence and increases scanning resolution by moving the overlapping windows by steps of one SNP only, and suggest to call this a \"creeping window\" strategy. The approach confirmed selective sweeps in the region of previously described candidate genes, i.e. TSHR, PRL, PRLHR, INSR, LEPR, IGF1, and NRAMP1 when used as positive controls. The genome scan revealed 82 distinct regions with strong evidence of selection (genome-wide p-value<0.001), including genes known to be associated with eggshell structure and immune system such as CALB1 and GAL cluster, respectively. A substantial proportion of signals was found in poor gene content regions including the most extreme signal on chromosome 1. The observation of multiple signals in a highly selected layer line of chicken is consistent with the hypothesis that egg production is a complex trait controlled by many genes.

Background Skeletal damage is a challenge for laying hens because the physiological adaptations required for egg laying make them susceptible to osteoporosis. Previously, we showed that genetic factors explain 40% of the variation in end of lay bone quality and we detected a quantitative trait locus (QTL) of large effect on chicken chromosome 1. The aim of this study was to combine data from the commercial founder White Leghorn population and the F2 mapping population to fine-map this QTL and understand its function in terms of gene expression and physiology. Results Several single nucleotide polymorphisms on chromosome 1 between 104 and 110 Mb (galGal6) had highly significant associations with tibial breaking strength. The alternative genotypes of markers of large effect that flanked the region had tibial breaking strengths of 200.4 vs. 218.1 Newton (P < 0.002) and, in a subsequent founder generation, the higher breaking strength genotype was again associated with higher breaking strength. In a subsequent generation, cortical bone density and volume were increased in individuals with the better bone genotype but with significantly reduced medullary bone quality. The effects on cortical bone density were confirmed in a further generation and was accompanied by increased mineral maturity of the cortical bone as measured by infrared spectrometry and there was evidence of better collagen cross-linking in the cortical bone. Comparing the transcriptome of the tibia from individuals with good or poor bone quality genotypes indicated four differentially-expressed genes at the locus, one gene, cystathionine beta synthase ( CBS ), having a nine-fold higher expression in the genotype for low bone quality. The mechanism was cis -acting and although there was an amino-acid difference in the CBS protein between the genotypes, there was no difference in the activity of the enzyme. Plasma homocysteine concentration, the substrate of CBS, was higher in the poor bone quality genotype. Conclusions Validated markers that predict bone strength have been defined for selective breeding and a gene was identified that may suggest alternative ways to improve bone health in addition to genetic selection. The identification of how genetic variants affect different aspects of bone turnover shows potential for translational medicine.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the commonest cause of chronic liver disease worldwide and represents an unmet precision medicine challenge. We established a retrospective national cohort of 940 histologically defined patients (55.4% men, 44.6% women; median body mass index 31.3; 32% with type 2 diabetes) covering the complete MASLD severity spectrum, and created a secure, searchable, open resource (SteatoSITE). In 668 cases and 39 controls, we generated hepatic bulk RNA sequencing data and performed differential gene expression and pathway analysis, including exploration of gender-specific differences. A web-based gene browser was also developed. We integrated histopathological assessments, transcriptomic data and 5.67 million days of time-stamped longitudinal electronic health record data to define disease-stage-specific gene expression signatures, pathogenic hepatic cell subpopulations and master regulator networks associated with adverse outcomes in MASLD. We constructed a 15-gene transcriptional risk score to predict future hepatic decompensation events (area under the receiver operating characteristic curve 0.86, 0.81 and 0.83 for 1-, 3- and 5-year risk, respectively). Additionally, thyroid hormone receptor beta regulon activity was identified as a critical suppressor of disease progression. SteatoSITE supports rational biomarker and drug development and facilitates precision medicine approaches for patients with MASLD. SteatoSITE is an open resource that integrates histopathologic assessments, transcriptomic data and longitudinal electronic health records for a cohort of 940 patients with metabolic dysfunction-associated steatotic liver disease.

Background High density (HD) SNP genotyping arrays are an important tool for genetic analyses of animals and plants. Although the chicken is one of the most important farm animals, no HD array is yet available for high resolution genetic analysis of this species. Results We report here the development of a 600 K Affymetrix® Axiom® HD genotyping array designed using SNPs segregating in a wide variety of chicken populations. In order to generate a large catalogue of segregating SNPs, we re-sequenced 243 chickens from 24 chicken lines derived from diverse sources (experimental, commercial broiler and layer lines) by pooling 10–15 samples within each line. About 139 million (M) putative SNPs were detected by mapping sequence reads to the new reference genome ( Gallus_gallus_4.0 ) of which ~78 M appeared to be segregating in different lines. Using criteria such as high SNP-quality score, acceptable design scores predicting high conversion performance in the final array and uniformity of distribution across the genome, we selected ~1.8 M SNPs for validation through genotyping on an independent set of samples (n = 282). About 64% of the SNPs were polymorphic with high call rates (>98%), good cluster separation and stable Mendelian inheritance. Polymorphic SNPs were further analysed for their population characteristics and genomic effects. SNPs with extreme breach of Hardy-Weinberg equilibrium ( P  < 0.00001) were excluded from the panel. The final array, designed on the basis of these analyses, consists of 580,954 SNPs and includes 21,534 coding variants. SNPs were selected to achieve an essentially uniform distribution based on genetic map distance for both broiler and layer lines. Due to a lower extent of LD in broilers compared to layers, as reported in previous studies, the ratio of broiler and layer SNPs in the array was kept as 3:2. The final panel was shown to genotype a wide range of samples including broilers and layers with over 100 K to 450 K informative SNPs per line. A principal component analysis was used to demonstrate the ability of the array to detect the expected population structure which is an important pre-investigation step for many genome-wide analyses. Conclusions This Affymetrix® Axiom® array is the first SNP genotyping array for chicken that has been made commercially available to the public as a product. This array is expected to find widespread usage both in research and commercial application such as in genomic selection, genome-wide association studies, selection signature analyses, fine mapping of QTLs and detection of copy number variants.