Evolutionary Implications of Environmental Toxicant Exposure

Homo sapiens have been exposed to various toxins and harmful compounds that change according to various phases of human evolution. Population genetics studies showed that such exposures lead to adaptive genetic changes; while observing present exposures to different toxicants, the first molecular mechanism that confers plasticity is epigenetic remodeling and, in particular, DNA methylation variation, a molecular mechanism proposed for medium-term adaptation. A large amount of scientific literature from clinical and medical studies revealed the high impact of such exposure on human biology; thus, in this review, we examine and infer the impact that different environmental toxicants may have in shaping human evolution. We first describe how environmental toxicants shape natural human variation in terms of genetic and epigenetic diversity, and then we describe how DNA methylation may influence mutation rate and, thus, genetic variability. We describe the impact of these substances on biological fitness in terms of reproduction and survival, and in conclusion, we focus on their effect on brain evolution and physiology

Transcriptomic analysis reveals an association of FCGBP with Parkinson’s disease

Transcriptomics in Parkinson’s disease (PD) offers new insights into the molecular mechanism of PD pathogenesis. Several pathways, such as inflammation and protein degradation, have been identified by differential gene expression analysis. Our aim was to identify gene expression differences underlying the disease etiology and the discovery of pre-symptomatic risk biomarkers for PD from a multicenter study in the context of the PROPAG-AGEING project. We performed RNA sequencing from 47 patients with de novo PD, 10 centenarians, and 65 healthy controls. Using identified differentially expressed genes, functional annotations were assigned using gene ontology to unveil significant enriched biological processes. The expression of 16 selected genes was validated using OpenArray® assays and samples from independent cohorts of 201 patients with advanced PD, 340 healthy siblings of PD patients, and 177 healthy controls. Differential gene expression analysis identified higher FCGBP expression in patients with de novo PD compared with healthy controls and compared with centenarians. Furthermore, FCGBP showed no differences in terms of population origin or aging process. The increased FCGBP expression was validated in patients with advanced PD and their siblings. Thus, we provided evidence for an upregulation of FCGBP mRNA levels not only in patients with PD but also in individuals at putative higher risk of PD, suggesting that it could be important in gut–brain PD interaction, mediating the connection between microbiota and intestinal inflammatory processes, as well as neuroinflammation and neurodegeneration

No association between frailty index and epigenetic clocks in Italian semi-supercentenarians

Centenarians experience successful ageing, although they still present high heterogeneity in their health status. The frailty index is a biomarker of biological age, able to capture such heterogeneity, even at extreme old age. At the same time, other biomarkers (e.g., epigenetic clocks) may be informative the biological age of the individual and potentially describe the ageing status in centenarians. In this article, we explore the relationship between epigenetic clocks and frailty index in a cohort of Italian centenarians. No association was reported, suggesting that these two approaches may describe different aspects of the same ageing process

Erythropoietin (EPO) haplotype associated with all-cause mortality in a cohort of Italian patients with Type-2 Diabetes

Type-2 Diabetes (T2D), diabetic complications, and their clinical risk factors harbor a substantial genetic component but the genetic factors contributing to overall diabetes mortality remain unknown. Here, we examined the association between genetic variants at 21 T2D-susceptibility loci and all-cause mortality in an elderly cohort of 542 Italian diabetic patients who were followed for an average of 12.08 years. Univariate Cox regression analyses detected age, waist-to-hip ratio (WHR), glycosylated haemoglobin (HbA1c), diabetes duration, retinopathy, nephropathy, chronic kidney disease (CKD), and anaemia as predictors of all-cause mortality. When Cox proportional hazards multivariate models adjusted for these factors were run, three erythropoietin (EPO) genetic variants in linkage disequilibrium (LD) with each other (rs1617640-T/G, rs507392-T/C and rs551238-A/C) were significantly (False Discovery Rate < 0.1) associated with mortality. Haplotype multivariate analysis revealed that patients carrying the G-C-C haplotype have an increased probability of survival, while an opposite effect was observed among subjects carrying the T-T-A haplotype. Our findings provide evidence that the EPO gene is an independent predictor of mortality in patients with T2D. Thus, understanding the mechanisms by which the genetic variability of EPO affects the mortality of T2D patients may provide potential targets for therapeutic interventions to improve the survival of these patients

Spatial and temporal variability in summer snow pack in Dronning Maud Land, Antarctica

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Comparative analysis of molecular signatures suggests the use of gabapentin for the management of endometriosis-associated pain

Background: It has been repetitively shown that the transcription factors DLX5 and DLX6 are drastically downregulated in endometriotic lesions when compared with eutopic endometrium. These findings suggest that regulatory cascades involving DLX5/6 might be at the origin of endometriosis symptoms such as chronic pelvic pain (CPP). We have shown that inactivation of Dlx5 and Dlx5/6 in the mouse uterus results in an endometrial phenotype reminiscent of endometriosis. Methods: We focused on genes that present a similar deregulation in endometriosis and in Dlx5/6-null mice in search of new endometriosis targets. Results: We confirmed a strong reduction of DLX5 expression in endometriosis implants. We identified a signature of 30 genes similarly deregulated in human endometriosis implants and in Dlx5/6-null mouse uteri, reinforcing the notion that the downregulation of Dlx5/6 is an early event in the progress of endometriosis. CACNA2D3, a component of the \u3b12\u3b4 family of voltagedependent calcium channel complex, was strongly overexpressed both in mutant mouse uteri and in endometriosis implants, were also CACNA2D1 and CACNA2D2, other members of the \u3b12\u3b4 family involved in nociception, are upregulated. Conclusion: Comparative analysis of gene expression signatures from endometriosis and mouse models showed that calcium channel subunits \u3b12\u3b4 involved in nociception can be targets for the treatment of endometriosis-associated pain. CACNA2D3 has been associated with pain sensitization and heat nociception in animal models. In patients, CACNA2D3 variants were associated with reduced sensitivity to acute noxious stimuli. As \u3b12\u3b4s were targets of gabapentinoid analgesics, the results suggested the use of these drugs for the treatment of endometriosis-associated pain. Indeed, recent small-scale clinical studies have shown that gabapentin could be effective in women with CPP. The findings of this study reinforce the need for a large definitive trial

Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels compared to protease inhibitor-based therapy

Background: It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress human immunodeficiency virus (HIV) replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Methods: CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n = 100, n = 124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically measured adherence to ART. Results: In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho = 0.70 and rho = 0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj = 0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj = 0.048 and padj = 0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals. Conclusions: All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size

Overview of the MOSAiC expedition-Atmosphere INTRODUCTION

With the Arctic rapidly changing, the needs to observe, understand, and model the changes are essential. To support these needs, an annual cycle of observations of atmospheric properties, processes, and interactions were made while drifting with the sea ice across the central Arctic during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition from October 2019 to September 2020. An international team designed and implemented the comprehensive program to document and characterize all aspects of the Arctic atmospheric system in unprecedented detail, using a variety of approaches, and across multiple scales. These measurements were coordinated with other observational teams to explore crosscutting and coupled interactions with the Arctic Ocean, sea ice, and ecosystem through a variety of physical and biogeochemical processes. This overview outlines the breadth and complexity of the atmospheric research program, which was organized into 4 subgroups: atmospheric state, clouds and precipitation, gases and aerosols, and energy budgets. Atmospheric variability over the annual cycle revealed important influences from a persistent large-scale winter circulation pattern, leading to some storms with pressure and winds that were outside the interquartile range of past conditions suggested by long-term reanalysis. Similarly, the MOSAiC location was warmer and wetter in summer than the reanalysis climatology, in part due to its close proximity to the sea ice edge. The comprehensiveness of the observational program for characterizing and analyzing atmospheric phenomena is demonstrated via a winter case study examining air mass transitions and a summer case study examining vertical atmospheric evolution. Overall, the MOSAiC atmospheric program successfully met its objectives and was the most comprehensive atmospheric measurement program to date conducted over the Arctic sea ice. The obtained data will support a broad range of coupled-system scientific research and provide an important foundation for advancing multiscale modeling capabilities in the Arctic.Peer reviewe