Broad Repertoire of T Cell Autoreactivity Directly from Islets of Donors with Type 1 Diabetes (T1D)

Type 1 diabetes (T1D) is an autoimmune disease characterized by the infiltration of lymphocytes into the insulin-producing β-cells in the pancreas. We have isolated live T cells sorted or grown directly from the isolated, handpicked islets of human donors with T1D. We received ~500 islet equivalent EQ of variable purity (10-90%) from 12 donors with T1D (disease duration 0.42-20 years) and from seven control donors and two donors with type 2 diabetes (T2D). A total of 321 T cell lines and clones were derived from the islets of donors with T1D (3 lines from the 9 control donors). These are 131 CD4+ lines and clones, 47 CD8+ lines and 143 lines that contain both CD4+ and CD8+ T cells. From 50 lines and clones examined to date, we have determined the autoreactivity of 19 and have seen a broad repertoire of T cell autoreactivity in the islets, including characterized targets and post-translationally modified targets. Autoreactivity of CD4+ T cell lines was to three different peptides from glutamic acid decarboxylase 65 (GAD; GAD115-127, GAD274-286, GAD555-567), proinsulin76-90, and to chromogranin A or proinsulin expressed by DR4+DQ8+ B cells transduced with lentivirus containing constructs with the open reading frames corresponding to whole autoantigens. Reactivity to modified peptides included the glucose-regulated protein 78 and islet amyloid polypeptide with arginine to citrulline modifications (GRP78292-305(Arg-Cit297) and IAPP65-84(Arg-Cit 73, 81)), deaminations (IA-2545-562(Gln-Glu 548, 551, 556), and to several insulin hybrid peptides. These autoreactive CD4+ T cell lines and clones secreted only pro-inflammatory cytokines (IFN-γ, TNFα) upon peptide stimulation. For CD8+ T cells from islets, from one donor with T1D, we saw binding of a pool of HLA-A2 pentamers loaded with insulin B10-18, IA-2797-805 and insulin specific glucose-6-phosphatase catalytic subunit related protein, IGRP265-273. These results have implications for the development of successful prevention and reversal therapeutic strategies in T1D

Stanniocalcin-1 Regulates Re-Epithelialization in Human Keratinocytes

Stanniocalcin-1 (STC1), a glycoprotein hormone, is believed to be involved in various biological processes such as inflammation, oxidative responses and cell migration. Riding on these emerging evidences, we hypothesized that STC1 may participate in the re-epithelialization during wound healing. Re-epithelialization is a critical step that involves keratinocyte lamellipodia (e-lam) formation, followed by cell migration. In this study, staurosporine (STS) treatment induced human keratinocyte (HaCaT) e-lam formation on fibronectin matrix and migration via the activation of focal adhesion kinase (FAK), the surge of intracellular calcium level [Ca2+]i and the inactivation of Akt. In accompanied with these migratory features, a time- and dose-dependent increase in STC1 expression was detected. STC1 gene expression was found not the downstream target of FAK-signaling as illustrated by FAK inhibition using PF573228. The reduction of [Ca2+]i by BAPTA/AM blocked the STS-mediated keratinocyte migration and STC1 gene expression. Alternatively the increase of [Ca2+]i by ionomycin exerted promotional effect on STS-induced STC1 gene expression. The inhibition of Akt by SH6 and GSK3β by lithium chloride (LiCl) could respectively induce and inhibit the STS-mediated e-lam formation, cell migration and STC1 gene expression. The STS-mediated e-lam formation and cell migration were notably hindered or induced respectively by STC1 knockdown or overexpression. This notion was further supported by the scratched wound assay. Collectively the findings provide the first evidence that STC1 promotes re-epithelialization in wound healing

Pandemic Boredom: Little Evidence That Lockdown-Related Boredom Affects Risky Public Health Behaviors Across 116 Countries

Some public officials have expressed concern that policies mandating collective public health behaviors (e.g., national/regional "lockdown ") may result in behavioral fatigue that ultimately renders such policies ineffective. Boredom, specifically, has been singled out as one potential risk factor for noncompliance. We examined whether there was empirical evidence to support this concern during the COVID-19 pandemic in a large cross-national sample of 63,336 community respondents from 116 countries. Although boredom was higher in countries with more COVID-19 cases and in countries that instituted more stringent lockdowns, such boredom did not predict longitudinal within-person decreases in social distancing behavior (or vice versa; n = 8,031) in early spring and summer of 2020. Overall, we found little evidence that changes in boredom predict individual public health behaviors (handwashing, staying home, self-quarantining, and avoiding crowds) over time, or that such behaviors had any reliable longitudinal effects on boredom itself. In summary, contrary to concerns, we found little evidence that boredom posed a public health risk during lockdown and quarantine

Conceptual replication and extension of health behavior theories' predictions in the context of COVID-19: Evidence across countries and over time

Virus mitigation behavior has been and still is a powerful means to fight the COVID-19 pandemic irrespective of the availability of pharmaceutical means (e.g., vaccines). We drew on health behavior theories to predict health-protective (coping-specific) responses and hope (coping non-specific response) from health-related cognitions (vulnerability, severity, self-assessed knowledge, efficacy). In an extension of this model, we proposed orientation to internal (problem-focused coping) and external (country capability) coping resources as antecedents of health protection and hope; health-related cognitions were assumed as mediators of this link. We tested these predictions in a large multi-national multi-wave study with a cross-sectional panel at T1 (Baseline, March-April 2020; N = 57,631 in 113 countries) and a panel subsample at two later time points, T2 (November 2020; N = 3097) and T3 (April 2021; N = 2628). Multilevel models showed that health-related cognitions predicted health-protective responses and hope. Problem-focused coping was mainly linked to health-protective behaviors (T1-T3), whereas country capability was mainly linked to hope (T1-T3). These relationships were partially mediated by health-related cognitions. We conceptually replicated predictions of health behavior theories within a real health threat, further suggesting how different coping resources are associated with qualitatively distinct outcomes. Both patterns were consistent across countries and time

Trust in government regarding COVID-19 and its associations with preventive health behaviour and prosocial behaviour during the pandemic: A cross-sectional and longitudinal study

Background The effective implementation of government policies and measures for controlling the coronavirus disease 2019 (COVID-19) pandemic requires compliance from the public. This study aimed to examine cross-sectional and longitudinal associations of trust in government regarding COVID-19 control with the adoption of recommended health behaviours and prosocial behaviours, and potential determinants of trust in government during the pandemic. Methods This study analysed data from the PsyCorona Survey, an international project on COVID-19 that included 23 733 participants from 23 countries (representative in age and gender distributions by country) at baseline survey and 7785 participants who also completed follow-up surveys. Specification curve analysis was used to examine concurrent associations between trust in government and self-reported behaviours. We further used structural equation model to explore potential determinants of trust in government. Multilevel linear regressions were used to examine associations between baseline trust and longitudinal behavioural changes. Results Higher trust in government regarding COVID-19 control was significantly associated with higher adoption of health behaviours (handwashing, avoiding crowded space, self-quarantine) and prosocial behaviours in specification curve analyses (median standardised beta = 0.173 and 0.229, p < 0.001). Government perceived as well organised, disseminating clear messages and knowledge on COVID-19, and perceived fairness were positively associated with trust in government (standardised beta = 0.358, 0.230, 0.056, and 0.249, p < 0.01). Higher trust at baseline survey was significantly associated with lower rate of decline in health behaviours over time (p for interaction = 0.001). Conclusions These results highlighted the importance of trust in government in the control of COVID-19

Trust in government and its associations with health behaviour and prosocial behaviour during the COVID-19 pandemic

Previous studies suggested that public trust in government is vital for implementations of social policies that rely on public's behavioural responses. This study examined associations of trust in government regarding COVID-19 control with recommended health behaviours and prosocial behaviours. Data from an international survey with representative samples (N=23,733) of 23 countries were analysed. Specification curve analysis showed that higher trust in government was significantly associated with higher adoption of health and prosocial behaviours in all reasonable specifications of multilevel linear models (median standardised β=0.173 and 0.244, P<0.001). We further used structural equation modelling to explore potential determinants of trust in government regarding pandemic control. Governments perceived as well organised, disseminating clear messages and knowledge on COVID-19, and perceived fairness were positively associated with trust in government (standardised β=0.358, 0.230, 0.055, and 0.250, P<0.01). These results highlighted the importance of trust in government in the control of COVID-19

Luxury brands consumption: The segment of “Chandlers”

The purpose of this paper is to introduce the segment of “chandlers” to the Russian academic society and to describe the specifics of their contemporary consumer behavior. The term “chandler” for this study was borrowed from American classical literature and applied to marketing. The study was conducted in April 2016 and comprised of two stages. The first stage was a series of in-depth interviews with seven representatives of the target audience from Moscow. It allowed to formulate the hypotheses which were proved/disproved by these hypotheses during the online survey. 117 relevant respondents were chosen for the study (72 — from Moscow, 45 — from regional city Ufa). The results allowed to formulate a preliminary conclusion there are no сhandlers in Ufa now. The most popular luxury brands for the Moscow сhandlers and specifics of their consumption were determined. This research is the first descriptive step to understanding the specifics of contemporary сhandlers — how they manage to consume luxury in the form of material artefacts and services, while being kept on a shoestring budget. The research entails a few limitations. The investigation comprised only a limited numbers of the respondents from Russian cities as Moscow and Ufa. In future, more consumers will be involved in the sample to cover more cities in Russia and respondents from other countries will be included. Upon the research completion a range of the recommendations has been provided to the luxury producers whose brands are already presented in Moscow and also for those who are planning to open their stores there. The results may serve as a guide for marketing tools development in the luxury industry. The originality of the paper lies in the term “chandlers’ segment” which is introduced in marketing theory for the first time

Lives versus Livelihoods? Perceived economic risk has a stronger association with support for COVID-19 preventive measures than perceived health risk

This paper examines whether compliance with COVID-19 mitigation measures is motivated by wanting to save lives or save the economy (or both), and which implications this carries to fight the pandemic. National representative samples were collected from 24 countries (N = 25,435). The main predictors were (1) perceived risk to contract coronavirus, (2) perceived risk to suffer economic losses due to coronavirus, and (3) their interaction effect. Individual and country-level variables were added as covariates in multilevel regression models. We examined compliance with various preventive health behaviors and support for strict containment policies. Results show that perceived economic risk consistently predicted mitigation behavior and policy support—and its effects were positive. Perceived health risk had mixed effects. Only two significant interactions between health and economic risk were identified—both positive

Polo kinase recruitment via the constitutive centromere-associated network at the kinetochore elevates centromeric RNA

The kinetochore, a multi-protein complex assembled on centromeres, is essential to segregate chromosomes during cell division. Deficiencies in kinetochore function can lead to chromosomal instability and aneuploidy-a hallmark of cancer cells. Kinetochore function is controlled by recruitment of regulatory proteins, many of which have been documented, however their function often remains uncharacterized and many are yet to be identified. To identify candidates of kinetochore regulation we used a proteome-wide protein association strategy in budding yeast and detected many proteins that are involved in post-translational modifications such as kinases, phosphatases and histone modifiers. We focused on the Polo-like kinase, Cdc5, and interrogated which cellular components were sensitive to constitutive Cdc5 localization. The kinetochore is particularly sensitive to constitutive Cdc5 kinase activity. Targeting Cdc5 to different kinetochore subcomplexes produced diverse phenotypes, consistent with multiple distinct functions at the kinetochore. We show that targeting Cdc5 to the inner kinetochore, the constitutive centromere-associated network (CCAN), increases the levels of centromeric RNA via an SPT4 dependent mechanism