The question of how genomic information is expressed to determine phenotypes is of central importance for basic and translational life science research and has been studied by transcriptomic and ...proteomic profiling. Here, we review the relationship between protein and mRNA levels under various scenarios, such as steady state, long-term state changes, and short-term adaptation, demonstrating the complexity of gene expression regulation, especially during dynamic transitions. The spatial and temporal variations of mRNAs, as well as the local availability of resources for protein biosynthesis, strongly influence the relationship between protein levels and their coding transcripts. We further discuss the buffering of mRNA fluctuations at the level of protein concentrations. We conclude that transcript levels by themselves are not sufficient to predict protein levels in many scenarios and to thus explain genotype-phenotype relationships and that high-quality data quantifying different levels of gene expression are indispensable for the complete understanding of biological processes.
Genomic information becomes translated into phenotypes via the complex and highly regulated process of gene expression and translation. Here, we review the relationship between mRNA and protein levels under various scenarios and conclude that transcript abundance by itself is not always sufficient to predict protein levels, emphasizing the complexity of the genotype-phenotype relationships.
•This paper uses market-based asset prices from a liquid market (i.e., CDS market).•We estimate recursively a vector-autoregressive model with exogenous common factors.•The time-varying feature ...allows to compare with developments around previous events.•Tracking the systemic contribution of variables can be regarded as a risk assessment tool for financial stability.•The model incorporates feedback effects and it is able to track the evolution of the sovereign–bank nexus.
In this paper we modify and extend the framework of Diebold and Yilmaz (2011) to quantify spillovers between sovereign credit markets and banks in the euro area. Spillovers are estimated recursively from a vector autoregressive model of daily changes in credit default swap (CDS) spreads with exogenous common factors. We account for interdependencies between sovereign and bank CDS spreads and derive generalized impulse response functions. Specifically, we assess the systemic effect of an unexpected shock to the creditworthiness of a sovereign or country-specific bank index on other sovereigns and bank CDSs between October 2009 and July 2012. Channels of shock transmission from or to sovereigns and banks are summarized in a Contagion Index and its four components: (i) among sovereigns, (ii) among banks, (iii) from sovereigns to banks, and (iv) from banks to sovereigns. We also highlight the impact of policy-related events on the Contagion Index.
Globally, cardiovascular disease (CVD) and cancer are leading causes of morbidity and mortality. While having different etiologies, CVD and cancer are linked by multiple shared risk factors, the ...presence of which exacerbate adverse outcomes for individuals with either disease. For both pathologies, factors such as poverty, lack of physical activity (PA), poor dietary intake, and climate change increase risk of adverse outcomes. Prior research has shown that greenspaces and other nature-based interventions (NBIs) contribute to improved health outcomes and climate change resilience.
To summarize evidence on the impact of greenspaces or NBIs on cardiovascular health and/or cancer-related outcomes and identify knowledge gaps to inform future research.
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and Peer Review of Electronic Search Strategies (PRESS) guidelines, we searched five databases: Web of Science, Scopus, Medline, PsycINFO and GreenFile. Two blinded reviewers used Rayyan AI and a predefined criteria for article inclusion and exclusion. The risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale (NOS). This review is registered with PROSPERO, ID # CRD42021231619.
Of 2565 articles retrieved, 31 articles met the inclusion criteria, and overall had a low risk of bias. 26 articles studied cardiovascular related outcomes and 5 studied cancer-related outcomes. Interventions were coded into 4 categories: forest bathing, green exercise, gardening, and nature viewing. Outcomes included blood pressure (BP), cancer-related quality of life (QoL) and (more infrequently) biomarkers of CVD risk. Descriptions of findings are presented as well as visual presentations of trends across the findings using RAW graphs. Overall studies included have a low risk of bias; and alluvial chart trends indicated that NBIs may have beneficial effects on CVD and cancer-related outcomes.
(1) Clinical implication: Healthcare providers should consider the promotion of nature-based programs to improve health outcomes. (2) Policy implication: There is a need for investment in equitable greenspaces to improve health outcomes and build climate resilient neighborhoods. (3) Research or academic implication: Research partnerships with community-based organizations for a comprehensive study of benefits associated with NBIs should be encouraged to reduce health disparities and ensure intergenerational health equity. There is a need for investigation of the mechanisms by which NBIs impact CVD and exploration of the role of CVD biological markers of inflammation among cancer survivors.
Expanding a statistical approach called Mendelian randomization to include multiple variables may help researchers to identify new molecular causes of specific traits.
Insulin and its receptor are critical for the regulation of metabolic functions, but the mechanisms underlying insulin receptor (IR) trafficking to the plasma membrane are not well understood. Here, ...we show that Bardet Biedl Syndrome (BBS) proteins are necessary for IR localization to the cell surface. We demonstrate that the IR interacts physically with BBS proteins, and reducing the expression of BBS proteins perturbs IR expression in the cell surface. We show the consequence of disrupting BBS proteins for whole body insulin action and glucose metabolism using mice lacking different BBS genes. These findings demonstrate the importance of BBS proteins in underlying IR cell surface expression. Our data identify defects in trafficking and localization of the IR as a novel mechanism accounting for the insulin resistance commonly associated with human BBS. This is supported by the reduced surface expression of the IR in fibroblasts derived from patients bearing the M390R mutation in the BBS1 gene.
Vascular autophagy in health and disease Hughes, William E.; Beyer, Andreas M.; Gutterman, David D.
Basic research in cardiology,
07/2020, Letnik:
115, Številka:
4
Journal Article
Recenzirano
Homeostasis is maintained within organisms through the physiological recycling process of autophagy, a catabolic process that is intricately involved in the mobilization of nutrients during ...starvation, recycling of cellular cargo, as well as initiation of cellular death pathways. Specific to the cardiovascular system, autophagy responds to both chemical (e.g. free radicals) and mechanical stressors (e.g. shear stress). It is imperative to note that autophagy is not a static process, and measurement of autophagic flux provides a more comprehensive investigation into the role of autophagy. The overarching themes emerging from decades of autophagy research are that basal levels of autophagic flux are critical, physiological stressors may increase or decrease autophagic flux, and more importantly, aberrant deviations from basal autophagy may elicit detrimental effects. Autophagy has predominantly been examined within cardiac or vascular smooth muscle tissue within the context of disease development and progression. Autophagic flux within the endothelium holds an important role in maintaining vascular function, demonstrated by the necessary role for intact autophagic flux for shear-induced release of nitric oxide however the underlying mechanisms have yet to be elucidated. Within this review, we theorize that autophagy itself does not solely control vascular homeostasis, rather, it works in concert with mitochondria, telomerase, and lipids to maintain physiological function. The primary emphasis of this review is on the role of autophagy within the human vasculature, and the integrative effects with physiological processes and diseases as they relate to the vascular structure and function.
The accurate mapping of causal variants in genome-wide association studies requires the consideration of both, confounding factors (for example, population structure) and nonlinear interactions ...between individual genetic variants. Here, we propose a method termed 'mixed random forest' that simultaneously accounts for population structure and captures nonlinear genetic effects. We test the model in simulation experiments and show that the mixed random forest approach improves detection power compared with established approaches. In an application to data from an outbred mouse population, we find that mixed random forest identifies associations that are more consistent with prior knowledge than competing methods. Further, our approach allows predicting phenotypes from genotypes with greater accuracy than any of the other methods that we tested. Our results show that approaches that simultaneously account for both, confounding due to population structure and epistatic interactions, are important to fully explain the heritable component of complex quantitative traits.
Network propagation refers to a class of algorithms that integrate information from input data across connected nodes in a given network. These algorithms have wide applications in systems biology, ...protein function prediction, inferring condition-specifically altered sub-networks, and prioritizing disease genes. Despite the popularity of network propagation, there is a lack of comparative analyses of different algorithms on real data and little guidance on how to select and parameterize the various algorithms. Here, we address this problem by analyzing different combinations of network normalization and propagation methods and by demonstrating schemes for the identification of optimal parameter settings on real proteome and transcriptome data. Our work highlights the risk of a 'topology bias' caused by the incorrect use of network normalization approaches. Capitalizing on the fact that network propagation is a regularization approach, we show that minimizing the bias-variance tradeoff can be utilized for selecting optimal parameters. The application to real multi-omics data demonstrated that optimal parameters could also be obtained by either maximizing the agreement between different omics layers (e.g. proteome and transcriptome) or by maximizing the consistency between biological replicates. Furthermore, we exemplified the utility and robustness of network propagation on multi-omics datasets for identifying ageing-associated genes in brain and liver tissues of rats and for elucidating molecular mechanisms underlying prostate cancer progression. Overall, this work compares different network propagation approaches and it presents strategies for how to use network propagation algorithms to optimally address a specific research question at hand.
The microcirculation is responsible for orchestrating adjustments in vascular tone to match local tissue perfusion with oxygen demand. Beyond this metabolic dilation, the microvasculature plays a ...critical role in modulating vascular tone by endothelial release of an unusually diverse family of compounds including nitric oxide, other reactive oxygen species, and arachidonic acid metabolites. Animal models have provided excellent insight into mechanisms of vasoregulation in health and disease. However, there are unique aspects of the human microcirculation that serve as the focus of this review. The concept is put forth that vasculoparenchymal communication is multimodal, with vascular release of nitric oxide eliciting dilation and preserving normal parenchymal function by inhibiting inflammation and proliferation. Likewise, in disease or stress, endothelial release of reactive oxygen species mediates both dilation and parenchymal inflammation leading to cellular dysfunction, thrombosis, and fibrosis. Some pathways responsible for this stress-induced shift in mediator of vasodilation are proposed. This paradigm may help explain why microvascular dysfunction is such a powerful predictor of cardiovascular events and help identify new approaches to treatment and prevention.
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