OBJECTIVE— The implication of innate immunity in type 1 diabetes development has long been proposed. High-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, was recently recognized to be a potent innate inflammatory mediator when released extracellularly. We sought to test the hypothesis that HMGB1 acts as an innate immune mediator implicated in type 1 diabetes pathogenesis. RESEARCH DESIGN AND METHODS— Eight- and 12-week-old NOD mice were treated with an HMGB1 neutralizing antibody once a week until 25 weeks of age and monitored for insulitis progression and diabetes onset. The underlying mechanisms of HMGB1 regulation of autoimmune response were further explored. RESULTS— During autoimmunity, HMGB1 can be passively released from damaged pancreatic β-cells and actively secreted by islet infiltrated immune cells. Extracellular HMGB1 is potent in inducing NOD dendritic cell maturation and stimulating macrophage activation. Blockade of HMGB1 significantly inhibited insulitis progression and diabetes development in both 8- and 12-week-old NOD mice. HMGB1 antibody treatment decreased the number and maturation of pancreatic lymph node (PLN) CD11c ++ CD11b + dendritic cells, a subset of dendritic cells probably associated with autoantigen presentation to naïve T-cells, but increased the number for PLN CD4 + Foxp3 + regulatory T-cells. Blockade of HMGB1 also decreased splenic dendritic cell allo-stimulatory capability associated with increased tolergenic CD11c + CD8a + dendritic cells. Interestingly, the number of CD8 + interferon-γ + (Tc1) T-cells was increased in the PLNs and spleen after blockade of HMGB1, which could be associated with retarded migration of activated autoreactive T-cells into the pancreatic islets. CONCLUSIONS— Extracellular HMGB1 functions as a potent innate immune mediator contributing to insulitis progression and diabetes onset.

Cadmium is a highly toxic environmental contaminant that has been implicated in various disorders. A major mechanism for cadmium detoxification in the yeast Saccharomyces cerevisiae relies on extrusion via Pca1, a P-type ATPase. While an N-terminal degron targets Pca1 for degradation before its secretion to the plasma membrane, cadmium in the growth media rapidly upregulates Pca1 by preventing its turnover. Here we show that the endoplasmic reticulum-associated degradation (ERAD) system, known for its role in quality control of secretory proteins, is unexpectedly responsible for the regulation of Pca1 expression by cadmium. Direct cadmium sensing at the ER by a degron in Pca1 leads to an escape of Pca1 from ERAD. This regulated conversion of an ERAD substrate to a secretory competent state in response to a cellular need illustrates a mechanism for expressional control of a plasma membrane protein. Yeast has likely evolved this mode of regulation for a rapid response against cadmium toxicity at the expense of constant synthesis and degradation of Pca1. ERAD of a portion of secretory proteins might occur via signal-dependent regulatory mechanisms as demonstrated for Pca1.etal ions are highly toxic, although several metals such as iron, copper, and zinc are essential micronutrients. Organisms possess delicate systems for detoxification and excretion of nonphysiological metals and homeostatic metabolism of nutritional yet toxic metals (1, 2). Pca1 in S. cerevisiae is a multi-spanning transmembrane protein that belongs to the family of P 1B -type ATPase heavy-metal transporters widely distributed from bacteria to humans (3). Pca1 functions in the efflux of cadmium across the plasma membrane (4), an extremely toxic environmental pollutant that causes various human diseases, such as cancer, kidney disease, and endocrine disruption (5).We have previously demonstrated that Pca1 is a short-lived protein that is targeted for ubiquitination and proteasomal degradation via its cytosolic N-terminal domain (amino acids 1-392) before reaching the cell surface (6). However, in the presence of cadmium, Pca1 is rapidly up-regulated due to the prevention of its degradation (6). An autonomous degron encompassing amino acid residues 250-350 within the N-terminal cytosolic domain is necessary and sufficient for both degradation and metal sensing (6). Given that the cell surface expression of several plasma membrane proteins is regulated by ubiquitinmediated endocytosis followed by vacuolar degradation, Pca1 turnover and cadmium-responsive degradation represents an interesting mode of expressional control in which subcellular trafficking and stability are determined by its substrate during secretion.To uncover molecular factors involved in the expressional control of Pca1, we have devised a genetic screen to identify mutants that are defective in Pca1 degradation in the absence of cadmium. Unexpectedly, our data presented herein demonstrate that components of the ER-associated degradation (ERAD) system target Pca1 for proteasomal degra...

No abstract

On the basis of Dunning's Investment Development Path (IDP) hypothesis, this paper tests the macroeconomic determinants of Chinese Offshore Direct Investment (ODI) from a home-country perspective. We review the recent firm-and country-level studies on determinants of Chinese ODI. We propose a model and test seven home-country macroeconomic variables as determinants of Chinese ODI. Our results reveal that the macroeconomic variables such as interest rate, exchange rate, import and foreign reserve are important determinants of Chinese outward Foreign Direct Investment (FDI).

PurposeThis study aims to build a research model from the perspectives of knowledge hiding and idea implementation to examine what factors influence idea implementation and the cross-level moderating role of team territory climate.Design/methodology/approachData were collected from universities, 52 (R&D) teams in China via a two-wave survey. The final sample contained 209 team members and their immediate supervisors. Hierarchical linear modeling was used to test hypotheses.FindingsThe results indicated that individuals’ knowledge-hiding behavior had a significantly negative impact on idea implementation and creative process engagement, which played a mediating role. Team territorial climate played a cross-level moderating role between knowledge hiding and idea implementation. If team territorial climate was at a high level, then the negative connection between knowledge hiding and idea implementation would be weaker.Research limitations/implicationsUnder the perspective of territorial behavior in Chinese cultural, it can help to distinguish territorial behavior and be preventive at individual and team levels. This study not only enables managers to clearly understand the precipitating factors of idea implementation but also provides constructive strategies for alleviating the negative effects of knowledge territoriality on creative process engagement and idea implementation.Originality/valueThis study constructs a cross-level model to explore the relationship among knowledge hiding, creative process engagement and idea implementation at individual and team levels in the context of Chinese R&D enterprises. Additionally, the study analyzes the influence of territoriality on idea implementation under boundary conditions.