Molecular mechanism for inhibition of twinfilin by phosphoinositides

Membrane phosphoinositides control organization and dynamics of the actin cytoskeleton by regulating the activities of several key actin-binding proteins. Twinfilin is an evolutionarily conserved protein that contributes to cytoskeletal dynamics by interacting with actin monomers, filaments, and the heterodimeric capping protein. Twinfilin also binds phosphoinositides, which inhibit its interactions with actin, but the underlying mechanism has remained unknown. Here, we show that the high-affinity binding site of twinfilin for phosphoinositides is located at the C-terminal tail region, whereas the two actin-depolymerizing factor (ADF)/cofilin-like ADF homology domains of twinfilin bind phosphoinositides only with low affinity. Mutagenesis and biochemical experiments combined with atomistic molecular dynamics simulations reveal that the C-terminal tail of twinfilin interacts with membranes through a multivalent electrostatic interaction with a preference toward phosphatidylinositol 3,5-bisphosphate (PI(3,5)P-2), PI(4,5)P-2, and PI(3,4,5)P-3. This initial interaction places the actin-binding ADF homology domains of twinfilin in close proximity to the membrane and subsequently promotes their association with the membrane, thus leading to inhibition of the actin interactions. In support of this model, a twinfilin mutant lacking the C-terminal tail inhibits actin filament assembly in a phosphoinositide-insensitive manner. Our mutagenesis data also reveal that the phosphoinositide-and capping protein-binding sites overlap in the C-terminal tail of twinfilin, suggesting that phosphoinositide binding additionally inhibits the interactions of twinfilin with the heterodimeric capping protein. The results demonstrate that the conserved C-terminal tail of twinfilin is a multifunctional binding motif, which is crucial for interaction with the heterodimeric capping protein and for tethering twinfilin to phosphoinositide-rich membranes.Peer reviewe

Circulating metabolites and the risk of type 2 diabetes : a prospective study of 11,896 young adults from four Finnish cohorts

Aims/hypothesis Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case-control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. Methods NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24-45 years). Associations between baseline metabolites and risk of developing diabetes during 8-15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. Results Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59-1.50; p Conclusions/interpretation Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk.Peer reviewe

Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts

Aims/hypothesis Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case-control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. Methods NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24-45 years). Associations between baseline metabolites and risk of developing diabetes during 8-15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. Results Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59-1.50; p< 0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31-1.33) and triacylglycerol within VLDL particles (OR 1.33-1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years). Conclusions/interpretation Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk

Examining the generalizability of research findings from archival data

This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability—for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples

Are coarse-grained models apt to detect protein thermal stability? The case of \OPEP\ force field

7th IDMRCS: Relaxation in Complex SystemsInternational audienceno abstrac

Entropic Analysis of Natural Language

38 σ.Εθνικό Μετσόβιο Πολυτεχνείο--Μεταπτυχιακή Εργασία. Διεπιστημονικό-Διατμηματικό Πρόγραμμα Μεταπτυχιακών Σπουδών (Δ.Π.Μ.Σ.) “Μαθηματική Προτυποποίηση σε Σύγχρονες Τεχνολογίες στην Οικονομία”Στην εργασία αυτή, στο πλαίσιο της μαθηματικής και υπολογιστικής ανάλυσης της φυσικής γλώσσας, διεξάγουμε και υλοποιούμε μία εντροπική ανάλυση γραπτών κειμένων σε μία αναπαράσταση χρονοσειρών μήκους λέξεων. Η εντροπία του Shannon και η γενίκευσή της με την μορφή των n-gram εντροπιών βρίσκονται να είναι μεγέθη ευαίσθητα στην αναγνώριση του είδους της γλώσσας (ελληνικά, αγγλικά, φιλανδικά κ.α.) και του είδους του κειμένου (πολιτικά και οικονομικά άρθρα, αθλητικά νέα και λογοτεχνία) για την εν λόγω αναπαράσταση. Η διαφορά στις εντροπίες αποδίδεται στην ομοιομορφία και την παρουσία πλατό στις κατανομές πιθανότητας των μηκών των λέξεων αλλά και στις διαφορετικές συσχετίσεις μεταξύ μηκών γειτονικών λέξεων στις υπό μελέτη χρονοσειρές. Με την σειρά της, η παρουσία των πλατό στις κατανομές πιθανότητας αντανακλά βασικές γλωσσολογικές ιδιότητες των διαφόρων γλωσσών, όπως τον πλούτο της κλιτικής μορφολογίας και την παραγωγικότητα της γλώσσας (μέσα από μηχανισμούς όπως είναι η παραγωγή, η σύνθεση και η σύμμειξη (blending)).In the present work and in the context of mathematical and computational study of natural language, we carry out an entropic analysis of natural language texts in a word-length representation. Shannon's entropy and its generalization in the form of n - gram entropy are found to be characteristic of the language (english, greek, finnish e.t.c.) as well as of the text genre (political and economical news, sports and literature). This is attributed to changes in the probability distribution of the lengths of single words (specifically the crucial role of the uniformity of probabilities of having words with length between five and ten) and the different word-length correlations in the studied symbolic series. On its behalf, the presence of the plateaus in the probability distributions reflects basic linguistic properties of the languages such as richness of inflectional morphology and productivity of a language through mechanisms like agglutination and synthesis of words.Μαρία Δ. Καλημέρ