A framework for application of metabolic modeling in yeast to predict the effects of nsSNV in human orthologs

Background We have previously suggested a method for proteome wide analysis of variation at functional residues wherein we identified the set of all human genes with nonsynonymous single nucleotide variation (nsSNV) in the active site residue of the corresponding proteins. 34 of these proteins were shown to have a 1:1:1 enzyme:pathway:reaction relationship, making these proteins ideal candidates for laboratory validation through creation and observation of specific yeast active site knock-outs and downstream targeted metabolomics experiments. Here we present the next step in the workflow toward using yeast metabolic modeling to predict human metabolic behavior resulting from nsSNV. Results For the previously identified candidate proteins, we used the reciprocal best BLAST hits method followed by manual alignment and pathway comparison to identify 6 human proteins with yeast orthologs which were suitable for flux balance analysis (FBA). 5 of these proteins are known to be associated with diseases, including ribose 5-phosphate isomerase deficiency, myopathy with lactic acidosis and sideroblastic anaemia, anemia due to disorders of glutathione metabolism, and two porphyrias, and we suspect the sixth enzyme to have disease associations which are not yet classified or understood based on the work described herein. Conclusions Preliminary findings using the Yeast 7.0 FBA model show lack of growth for only one enzyme, but augmentation of the Yeast 7.0 biomass function to better simulate knockout of certain genes suggested physiological relevance of variations in three additional proteins. Thus, we suggest the following four proteins for laboratory validation: delta-aminolevulinic acid dehydratase, ferrochelatase, ribose-5 phosphate isomerase and mitochondrial tyrosyl-tRNA synthetase. This study indicates that the predictive ability of this method will improve as more advanced, comprehensive models are developed. Moreover, these findings will be useful in the development of simple downstream biochemical or mass-spectrometric assays to corroborate these predictions and detect presence of certain known nsSNVs with deleterious outcomes. Results may also be useful in predicting as yet unknown outcomes of active site nsSNVs for enzymes that are not yet well classified or annotated

Exploratory genome-wide analyses of cortical inhibition, facilitation, and plasticity in late-life depression

Late-life depression (LLD) is a heterogenous mood disorder influenced by genetic factors. Cortical physiological processes such as cortical inhibition, facilitation, and plasticity may be markers of illness that are more strongly associated with genetic factors than the clinical phenotype. Thus, exploring the relationship between genetic factors and these physiological processes may help to characterize the biological mechanisms underlying LLD and improve diagnosis and treatment selection. Transcranial magnetic stimulation (TMS) combined with electromyography was used to measure short interval intracortical inhibition (SICI), cortical silent period (CSP), intracortical facilitation (ICF), and paired associative stimulation (PAS) in 79 participants with LLD. We used exploratory genome-wide association and gene-based analyses to assess for genetic correlations of these TMS measures. MARK4 (which encodes microtubule affinity-regulating kinase 4) and PPP1R37 (which encodes protein phosphatase 1 regulatory subunit 37) showed genome-wide significant association with SICI. EGFLAM (which encodes EGF-like fibronectin type III and laminin G domain) showed genome-wide significant association with CSP. No genes met genome-wide significant association with ICF or PAS. We observed genetic influences on cortical inhibition in older adults with LLD. Replication with larger sample sizes, exploration of clinical phenotype subgroups, and functional analysis of relevant genotypes is warranted to better characterize genetic influences on cortical physiology in LLD. This work is needed to determine whether cortical inhibition may serve as a biomarker to improve diagnostic precision and guide treatment selection in LLD

Association of molecular senescence markers in late-life depression with clinical characteristics and treatment outcome

Importance: Many older adults with depression do not experience remission with antidepressant treatment, and markers of cellular senescence in late-life depression (LLD) are associated with greater severity of depression, greater executive dysfunction, and higher medical illness burden. Since these clinical characteristics are associated with remission in LLD, molecular and cellular senescence abnormalities could be a possible biological mechanism underlying poor treatment response in this population. Objective: To examine whether the senescence-associated secretory phenotype (SASP) index was associated with the likelihood of remission from a depressive episode in older adults. Design, Setting, and Participants: A nonrandomized, open-label clinical trial was conducted between August 2009 and August 2014 in Pittsburgh, Pennsylvania; St Louis, Missouri; and Toronto, Ontario, Canada, with older adults in a current major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnostic criteria. Data from biomarker analyses were reported according to the clinical trial archived plasma samples run in March 2021. Data were analyzed from June to November 2021. Exposure: Venlafaxine extended release (dose ranging from 37.5 mg to 300 mg daily) for up to 12 weeks. Main Outcomes and Measures: The association between a composite biomarker-based index (SASP index) and treatment remission in older adults with major depression was measured using clinical data and blood samples. Results: There were 416 participants with a mean (SD) age of 60.02 (7.13) years; 64% (265 participants) were self-reported female, and the mean (SD) Montgomery-Asberg Depression Rating Scale score was 26.6 (5.7). Higher SASP index scores were independently associated with higher rates of nonremission, with an increase of 1 unit in the SASP index score increasing the odds of nonremission by 19% (adjusted odds ratio, 1.19; 95% CI, 1.05-1.35; P = .006). In contrast, no individual SASP factors were associated with remission in LLD. Conclusions and Relevance: Using clinical data and blood samples from a nonrandomized clinical trial, the results of this study suggest that molecular and cellular senescence, as measured with the SASP index, is associated with worse treatment outcomes in LLD. Combining this index score reflecting interrelated biological processes with other molecular, clinical, and neuroimaging markers may be useful in evaluating antidepressant treatment outcomes. These findings inform a path forward for geroscience-guided interventions targeting senescence to improve remission rates in LLD. Trial Registration: ClinicalTrials.gov Identifier: NCT00892047

Understanding the pathways from biodiversity to agro-ecological outcomes: A new, interactive approach

The adoption of agro-ecological practices in agricultural systems worldwide can contribute to increased food production without compromising future food security, especially under the current biodiversity loss and climate change scenarios. Despite the increase in publications on agro-ecological research and practices during the last 35 years, a weak link between that knowledge and changed farmer practices has led to few examples of agro-ecological protocols and effective delivery systems to agriculturalists. In an attempt to reduce this gap, we synthesised the main concepts related to biodiversity and its functions by creating a web-based interactive spiral (www.biodiversityfunction.com). This tool explains and describes a pathway for achieving agro-ecological outcomes, starting from the basic principle of biodiversity and its functions to enhanced biodiversity on farms. Within this pathway, 11 key steps are identified and sequentially presented on a web platform through which key players (farmers, farmer networks, policy makers, scientists and other stakeholders) can navigate and learn. Because in many areas of the world the necessary knowledge needed for achieving the adoption of particular agro-ecological techniques is not available, the spiral approach can provide the necessary conceptual steps needed for obtaining and understanding such knowledge by navigating through the interactive pathway. This novel approach aims to improve our understanding of the sequence from the concept of biodiversity to harnessing its power to improve prospects for ‘sustainable intensification’ of agricultural systems worldwide

Models of natural pest control : Towards predictions across agricultural landscapes

Natural control of invertebrate crop pests has the potential to complement or replace conventional insecticide based practices, but its mainstream application is hampered by predictive unreliability across agroecosystems. Inconsistent responses of natural pest control to changes in landscape characteristics have been attributed to ecological complexity and system-specific conditions. Here, we review agroecological models and their potential to provide predictions of natural pest control across agricultural landscapes. Existing models have used a multitude of techniques to represent specific crop-pest-enemy systems at various spatiotemporal scales, but less wealthy regions of the world are underrepresented. A realistic representation of natural pest control across systems appears to be hindered by a practical trade-off between generality and realism. Nonetheless, observations of context-sensitive, trait-mediated responses of natural pest control to land-use gradients indicate the potential of ecological models that explicitly represent the underlying mechanisms. We conclude that modelling natural pest control across agroecosystems should exploit existing mechanistic techniques towards a framework of contextually bound generalizations. Observed similarities in causal relationships can inform the functional grouping of diverse agroecosystems worldwide and the development of the respective models based on general, but context-sensitive, ecological mechanisms. The combined use of qualitative and quantitative techniques should allow the flexible integration of empirical evidence and ecological theory for robust predictions of natural pest control across a wide range of agroecological contexts and levels of knowledge availability. We highlight challenges and promising directions towards developing such a general modelling framework.Peer reviewe

Topological and geometrical restrictions, free-boundary problems and self-gravitating fluids

Let (P1) be certain elliptic free-boundary problem on a Riemannian manifold (M,g). In this paper we study the restrictions on the topology and geometry of the fibres (the level sets) of the solutions f to (P1). We give a technique based on certain remarkable property of the fibres (the analytic representation property) for going from the initial PDE to a global analytical characterization of the fibres (the equilibrium partition condition). We study this analytical characterization and obtain several topological and geometrical properties that the fibres of the solutions must possess, depending on the topology of M and the metric tensor g. We apply these results to the classical problem in physics of classifying the equilibrium shapes of both Newtonian and relativistic static self-gravitating fluids. We also suggest a relationship with the isometries of a Riemannian manifold.Comment: 36 pages. In this new version the analytic representation hypothesis is proved. Please address all correspondence to D. Peralta-Sala

Accelerating the Translation of Nanomaterials in Biomedicine

Due to their size and tailorable physicochemical properties, nanomaterials are an emerging class of structures utilized in biomedical applications. There are now many prominent examples of nanomaterials being used to improve human health, in areas ranging from imaging and diagnostics to therapeutics and regenerative medicine. An overview of these examples reveals several common areas of synergy and future challenges. This Nano Focus discusses the current status and future potential of promising nanomaterials and their translation from the laboratory to the clinic, by highlighting a handful of successful examples

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies. Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny

Bird and bat predation services in tropical forests and agroforestry landscapes

Understanding distribution patterns and multitrophic interactions is critical for managing batâ and birdâ mediated ecosystem services such as the suppression of pest and nonâ pest arthropods. Despite the ecological and economic importance of bats and birds in tropical forests, agroforestry systems, and agricultural systems mixed with natural forest, a systematic review of their impact is still missing. A growing number of bird and bat exclosure experiments has improved our knowledge allowing new conclusions regarding their roles in food webs and associated ecosystem services. Here, we review the distribution patterns of insectivorous birds and bats, their local and landscape drivers, and their effects on trophic cascades in tropical ecosystems. We report that for birds but not bats community composition and relative importance of functional groups changes conspicuously from forests to habitats including both agricultural areas and forests, here termed â forestâ agriâ habitats, with reduced representation of insectivores in the latter. In contrast to previous theory regarding trophic cascade strength, we find that birds and bats reduce the density and biomass of arthropods in the tropics with effect sizes similar to those in temperate and boreal communities. The relative importance of birds versus bats in regulating pest abundances varies with season, geography and management. Birds and bats may even suppress tropical arthropod outbreaks, although positive effects on plant growth are not always reported. As both bats and birds are major agents of pest suppression, a better understanding of the local and landscape factors driving the variability of their impact is needed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134094/1/brv12211_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134094/2/brv12211.pd