Sequence-Based Analysis of Thermal Adaptation and Protein Energy Landscapes in an Invasive Blue Mussel (Mytilus galloprovincialis).

Adaptive responses to thermal stress in poikilotherms plays an important role in determining competitive ability and species distributions. Amino acid substitutions that affect protein stability and modify the thermal optima of orthologous proteins may be particularly important in this context. Here, we examine a set of 2,770 protein-coding genes to determine if proteins in a highly invasive heat tolerant blue mussel (Mytilus galloprovincialis) contain signals of adaptive increases in protein stability relative to orthologs in a more cold tolerant M. trossulus. Such thermal adaptations might help to explain, mechanistically, the success with which the invasive marine mussel M. galloprovincialis has displaced native species in contact zones in the eastern (California) and western (Japan) Pacific. We tested for stabilizing amino acid substitutions in warm tolerant M. galloprovincialis relative to cold tolerant M. trossulus with a generalized linear model that compares in silico estimates of recent changes in protein stability among closely related congeners. Fixed substitutions in M. galloprovincialis were 3,180.0 calories per mol per substitution more stabilizing at genes with both elevated dN/dS ratios and transcriptional responses to heat stress, and 705.8 calories per mol per substitution more stabilizing across all 2,770 loci investigated. Amino acid substitutions concentrated in a small number of genes were more stabilizing in M. galloprovincialis compared with cold tolerant M. trossulus. We also tested for, but did not find, enrichment of a priori GO terms in genes with elevated dN/dS ratios in M. galloprovincialis. This might indicate that selection for thermodynamic stability is generic across all lineages, and suggests that the high change in estimated protein stability that we observed in M. galloprovincialis is driven by selection for extra stabilizing substitutions, rather than by higher incidence of selection in a greater number of genes in this lineage. Nonetheless, our finding of more stabilizing amino acid changes in the warm adapted lineage is important because it suggests that adaption for thermal stability has contributed to M. galloprovincialis' superior tolerance to heat stress, and that pairing tests for positive selection and tests for transcriptional response to heat stress can identify candidates of protein stability adaptation

Petőfi Sándor levele Arany Jánosnak

BackgroundComparative genomics studies investigating the signals of positive selection among groups of closely related species are still rare and limited in taxonomic breadth. Such studies show great promise in advancing our knowledge about the proportion and the identity of genes experiencing diversifying selection. However, methodological challenges have led to high levels of false positives in past studies. Here, we use the well-annotated genome of the purple sea urchin, Strongylocentrotus purpuratus, as a reference to investigate the signals of positive selection at 6520 single-copy orthologs from nine sea urchin species belonging to the family Strongylocentrotidae paying careful attention to minimizing false positives.ResultsWe identified 1008 (15.5%) candidate positive selection genes (PSGs). Tests for positive selection along the nine terminal branches of the phylogeny identified 824 genes that showed lineage-specific adaptive diversification (1.67% of branch-sites tests performed). Positively selected codons were not enriched at exon borders or near regions containing missing data, suggesting a limited contribution of false positives caused by alignment or annotation errors. Alignments were validated at 10 loci with re-sequencing using Sanger methods. No differences were observed in the rates of synonymous substitution (d S), GC content, and codon bias between the candidate PSGs and those not showing positive selection. However, the candidate PSGs had 68% higher rates of nonsynonymous substitution (d N) and 33% lower levels of heterozygosity, consistent with selective sweeps and opposite to that expected by a relaxation of selective constraint. Although positive selection was identified at reproductive proteins and innate immunity genes, the strongest signals of adaptive diversification were observed at extracellular matrix proteins, cell adhesion molecules, membrane receptors, and ion channels. Many candidate PSGs have been widely implicated as targets of pathogen binding, inactivation, mimicry, or exploitation in other groups (notably mammals).ConclusionsOur study confirmed the widespread action of positive selection across sea urchin genomes and allowed us to reject the possibility that annotation and alignment errors (including paralogs) were responsible for creating false signals of adaptive molecular divergence. The candidate PSGs identified in our study represent promising targets for future research into the selective agents responsible for their adaptive diversification and their contribution to speciation

Minority Stress and Leukocyte Gene Expression In Sexual Minority Men Living With Treated HIV Infection

Sexual minority (i.e., non-heterosexual) individuals experience poorer mental and physical health, accounted for in part by the additional burden of sexual minority stress occurring from being situated in a culture favoring heteronormativity. Informed by previous research, the purpose of this study was to identify the relationship between sexual minority stress and leukocyte gene expression related to inflammation, cancer, immune function, and cardiovascular function. Sexual minority men living with HIV who were on anti-retroviral medication, had viral load \u3c 200 copies/mL, and had biologically confirmed, recent methamphetamine use completed minority stress measures and submitted blood samples for RNA sequencing on leukocytes. Differential gene expression and pathway analyses were conducted comparing those with clinically elevated minority stress (n = 18) and those who did not meet the clinical cutoff (n = 20), covarying reactive urine toxicology results for very recent stimulant use. In total, 90 differentially expressed genes and 138 gene set pathways evidencing 2-directional perturbation were observed at false discovery rate (FDR) \u3c 0.10. Of these, 41 of the differentially expressed genes and 35 of the 2-directionally perturbed pathways were identified as functionally related to hypothesized mechanisms of inflammation, cancer, immune function, and cardiovascular function. The neuroactive-ligand receptor pathway (implicated in cancer development) was identified using signaling pathway impact analysis. Our results suggest several potential biological pathways for future work investigating the relationship between sexual minority stress and health

Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors.

Paclitaxel is a common chemotherapy drug associated with the development of chronic paclitaxel-induced peripheral neuropathy (PIPN). PIPN is associated with neuroinflammatory mechanisms in pre-clinical studies. Here, we evaluated for differential gene expression (DGE) in peripheral blood between breast cancer survivors with and without PIPN and for neuroinflammatory (NI) related signaling pathways and whole-transcriptome profiles from other experiments. Pathway impact analysis identified 8 perturbed NI related pathways. Expression profile analysis found 15 experiments having similar whole-transcriptome profiles of DGE related to neuroinflammation and PIPN. These findings suggest that perturbations in pathways associated with neuroinflammation are found in cancer survivors with PIPN

The HIV Genomic Incidence Assay Meets False Recency Rate and Mean Duration of Recency Infection Performance Standards.

HIV incidence is a primary metric for epidemic surveillance and prevention efficacy assessment. HIV incidence assay performance is evaluated via false recency rate (FRR) and mean duration of recent infection (MDRI). We conducted a meta-analysis of 438 incident and 305 chronic specimens' HIV envelope genes from a diverse global cohort. The genome similarity index (GSI) accurately characterized infection stage across diverse host and viral factors. All except one chronic specimen had GSIs below 0.67, yielding a FRR of 0.33 [0-0.98] %. We modeled the incidence assay biomarker dynamics with a logistic link function assuming individual variabilities in a Beta distribution. The GSI probability density function peaked close to 1 in early infection and 0 around two years post infection, yielding MDRI of 420 [361, 467] days. We tested the assay by newly sequencing 744 envelope genes from 59 specimens of 21 subjects who followed from HIV negative status. Both standardized residuals and Anderson-Darling tests showed that the test dataset was statistically consistent with the model biomarker dynamics. This is the first reported incidence assay meeting the optimal FRR and MDRI performance standards. Signatures of HIV gene diversification can allow precise cross-sectional surveillance with a desirable temporal range of incidence detection

Patterns and rates of viral evolution in HIV-1 subtype B infected females and males.

Biological sex differences affect the course of HIV infection, with untreated women having lower viral loads compared to their male counterparts but, for a given viral load, women have a higher rate of progression to AIDS. However, the vast majority of data on viral evolution, a process that is clearly impacted by host immunity and could be impacted by sex differences, has been derived from men. We conducted an intensive analysis of HIV-1 gag and env-gp120 evolution taken over the first 6-11 years of infection from 8 Women's Interagency HIV Study (WIHS) participants who had not received combination antiretroviral therapy (ART). This was compared to similar data previously collected from men, with both groups infected with HIV-1 subtype B. Early virus populations in men and women were generally homogenous with no differences in diversity between sexes. No differences in ensuing nucleotide substitution rates were found between the female and male cohorts studied herein. As previously reported for men, time to peak diversity in env-gp120 in women was positively associated with time to CD4+ cell count below 200 (P = 0.017), and the number of predicted N-linked glycosylation sites generally increased over time, followed by a plateau or decline, with the majority of changes localized to the V1-V2 region. These findings strongly suggest that the sex differences in HIV-1 disease progression attributed to immune system composition and sensitivities are not revealed by, nor do they impact, global patterns of viral evolution, the latter of which proceeds similarly in women and men

Network analysis of the multidimensional symptom experience of oncology

Oncology patients undergoing cancer treatment experience an average of fifteen unrelieved symptoms that are highly variable in both their severity and distress. Recent advances in Network Analysis (NA) provide a novel approach to gain insights into the complex nature of co-occurring symptoms and symptom clusters and identify core symptoms. We present findings from the first study that used NA to examine the relationships among 38 common symptoms in a large sample of oncology patients undergoing chemotherapy. Using two different models of Pairwise Markov Random Fields (PMRF), we examined the nature and structure of interactions for three different dimensions of patients’ symptom experience (i.e., occurrence, severity, distress). Findings from this study provide the first direct evidence that the connections between and among symptoms differ depending on the symptom dimension used to create the network. Based on an evaluation of the centrality indices, nausea appears to be a structurally important node in all three networks. Our findings can be used to guide the development of symptom management interventions based on the identification of core symptoms and symptom clusters within a network

Congruence between latent class and k-modes analyses in the identification of oncology patients with distinct symptom experiences

CONTEXT: Risk profiling of oncology patients based on their symptom experience assists clinicians to provide more personalized symptom management interventions. Recent findings suggest that oncology patients with distinct symptom profiles can be identified using a variety of analytic methods. OBJECTIVES: The objective of this study was to evaluate the concordance between the number and types of subgroups of patients with distinct symptom profiles using latent class analysis and K-modes analysis. METHODS: Using data on the occurrence of 25 symptoms from the Memorial Symptom Assessment Scale, that 1329 patients completed prior to their next dose of chemotherapy (CTX), Cohen's kappa coefficient was used to evaluate for concordance between the two analytic methods. For both latent class analysis and K-modes, differences among the subgroups in demographic, clinical, and symptom characteristics, as well as quality of life outcomes were determined using parametric and nonparametric statistics. RESULTS: Using both analytic methods, four subgroups of patients with distinct symptom profiles were identified (i.e., all low, moderate physical and lower psychological, moderate physical and higher Psychological, and all high). The percent agreement between the two methods was 75.32%, which suggests a moderate level of agreement. In both analyses, patients in the all high group were significantly younger and had a higher comorbidity profile, worse Memorial Symptom Assessment Scale subscale scores, and poorer QOL outcomes. CONCLUSION: Both analytic methods can be used to identify subgroups of oncology patients with distinct symptom profiles. Additional research is needed to determine which analytic methods and which dimension of the symptom experience provide the most sensitive and specific risk profile