Metformin alleviates lung-endothelial hyperpermeability by regulating cofilin-1/PP2AC pathway

Background: Microvascular endothelial hyperpermeability is an earliest pathological hallmark in Acute Lung Injury (ALI), which progressively leads to Acute Respiratory Distress Syndrome (ARDS). Recently, vascular protective and anti-inflammatory effect of metformin, irrespective of glycemic control, has garnered significant interest. However, the underlying molecular mechanism(s) of metformin’s barrier protective benefits in lung-endothelial cells (ECs) has not been clearly elucidated. Many vascular permeability-increasing agents weakened adherens junctions (AJ) integrity by inducing the reorganization of the actin cytoskeleton and stress fibers formation. Here, we hypothesized that metformin abrogated endothelial hyperpermeability and strengthen AJ integrity via inhibiting stress fibers formation through cofilin-1-PP2AC pathway.Methods: We pretreated human lung microvascular ECs (human-lung-ECs) with metformin and then challenged with thrombin. To investigate the vascular protective effects of metformin, we studied changes in ECs barrier function using electric cell-substrate impedance sensing, levels of actin stress fibers formation and inflammatory cytokines IL-1β and IL-6 expression. To explore the downstream mechanism, we studied the Ser3-phosphorylation-cofilin-1 levels in scramble and PP2AC-siRNA depleted ECs in response to thrombin with and without metformin pretreatment.Results: In-vitro analyses showed that metformin pretreatment attenuated thrombin-induced hyperpermeability, stress fibers formation, and the levels of inflammatory cytokines IL-6 and IL-β in human-lung-ECs. We found that metformin mitigated Ser3-phosphorylation mediated inhibition of cofilin-1 in response to thrombin. Furthermore, genetic deletion of PP2AC subunit significantly inhibited metformin efficacy to mitigate thrombin-induced Ser3-phosphorylation cofilin-1, AJ disruption and stress fibers formation. We further demonstrated that metformin increases PP2AC activity by upregulating PP2AC-Leu309 methylation in human-lung-ECs. We also found that the ectopic expression of PP2AC dampened thrombin-induced Ser3-phosphorylation-mediated inhibition of cofilin-1, stress fibers formation and endothelial hyperpermeability.Conclusion: Together, these data reveal the unprecedented endothelial cofilin-1/PP2AC signaling axis downstream of metformin in protecting against lung vascular endothelial injury and inflammation. Therefore, pharmacologically enhancing endothelial PP2AC activity may lead to the development of novel therapeutic approaches for prevention of deleterious effects of ALI on vascular ECs

Caveolin-1–eNOS signaling promotes p190RhoGAP-A nitration and endothelial permeability

Caveolin-1–mediated inhibition of endothelial nitric oxide synthase signaling is essential for adherens junction integrity and endothelial permeability homeostasis

Plasmodium vivax Tryptophan-Rich Antigen PvTRAg33.5 Contains Alpha Helical Structure and Multidomain Architecture

Tryptophan-rich proteins from several malarial parasites have been identified where they play an important role in host-parasite interaction. Structural characterization of these proteins is needed to develop them as therapeutic targets. Here, we describe a novel Plasmodium vivax tryptophan-rich protein named PvTRAg33.5. It is expressed by blood stage(s) of the parasite and its gene contains two exons. The exon 1 encodes for a 23 amino acids long putative signal peptide which is likely to be cleaved off whereas the exon 2 encodes for the mature protein of 252 amino acids. The mature protein contains B-cell epitopes which were recognized by the human immune system during P.vivax infection. The PvTRAg33.5 contains 24 (9.5%) tryptophan residues and six motifs whose patterns were similar among tryptophan-rich proteins. The modeled structure of the PvTRAg33.5 consists of a multidomain architecture which is stabilized by the presence of large number of tryptophan residues. The recombinant PvTRAg33.5 showed predominantly α helical structure and alpha helix to beta sheet transition at pH below 4.5. Protein acquires an irreversible non-native state at temperature more than 50°C at neutral pH. Its secondary and tertiary structures remain stable in the presence of 35% alcohol but these structures are destabilized at higher alcohol concentrations due to the disturbance of hydrophobic interactions between tryptophanyl residues. These structural changes in the protein might occur during its translocation to interact with other proteins at its final destination for biological function such as erythrocyte invasion

Consumer trust and confidence in the compliance of Islamic banks

Islamic banks compete with traditional (non-Islamic) banks for customers. This article aims to provide insight into why some Muslims choose to bank with Islamic banks in Pakistan, while others do not. Specifically, it addresses the questions: to what extent are trust and confidence active influencers in the decision-making process, are they differentiated or are they one of the same? Also how does the Pakistani collective cultural context further complicate the application of these concepts? For the purposes of this article trust refers to people and their interpersonal or social relations whereas confidence concerns institutions such as banks. Drawing on interviews with Muslim consumers in Pakistan, this study provides further insight into consumer behaviour within financial services and specifically Islamic banking and contributes to our theoretical understanding of the concepts of trust and confidence

Affective interpersonal touch in close relationships: a cross-cultural perspective

Interpersonal touch behavior differs across cultures, yet no study to date has systematically tested for cultural variation in affective touch, nor examined the factors that might account for this variability. Here, over 14,000 individuals from 45 countries were asked whether they embraced, stroked, kissed, or hugged their partner, friends, and youngest child during the week preceding the study. We then examined a range of hypothesized individual-level factors (sex, age, parasitic history, conservatism, religiosity, and preferred interpersonal distance) and cultural-level factors (regional temperature, parasite stress, regional conservatism, collectivism, and religiosity) in predicting these affective-touching behaviors. Our results indicate that affective touch was most prevalent in relationships with partners and children, and its diversity was relatively higher in warmer, less conservative, and religious countries, and among younger, female, and liberal people. This research allows for a broad and integrated view of the bases of cross-cultural variability in affective touch

Sex differences in mate preferences across 45 countries: A large-scale replication

Considerable research has examined human mate preferences across cultures, finding universal sex differences in preferences for attractiveness and resources as well as sources of systematic cultural variation. Two competing perspectives—an evolutionary psychological perspective and a biosocial role perspective—offer alternative explanations for these findings. However, the original data on which each perspective relies are decades old, and the literature is fraught with conflicting methods, analyses, results, and conclusions. Using a new 45-country sample (N = 14,399), we attempted to replicate classic studies and test both the evolutionary and biosocial role perspectives. Support for universal sex differences in preferences remains robust: Men, more than women, prefer attractive, young mates, and women, more than men, prefer older mates with financial prospects. Cross-culturally, both sexes have mates closer to their own ages as gender equality increases. Beyond age of partner, neither pathogen prevalence nor gender equality robustly predicted sex differences or preferences across countries

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Synthesis and electrical behaviour of poly(chlorotrifluoroethylene)

170-172The synthesis of poly (chlorotrifluoroethylene) [PCTFE) and its electrical measurements are reported here. A linear increase in current with voltage up to 400 V, and an exponential increase thereafter, is observed at all the studied temperatures. This is an indication of the Schottky or Poole Frankel conduction mechanisms to be operative. The variation of dielectric constant and dielectric loss with frequency at the studied temperatures suggests the contribution of electronic and ionic polarization to this effect.</span