Assessing the causal role of immune traits in rheumatoid arthritis by bidirectional Mendelian randomization analysis.

Rheumatoid arthritis (RA) is one of the most common autoimmune joint disorders that leads to cartilage degradation. However, its specific correlation with immune cells has not been thoroughly clarified. Based on the two-sample Mendelian randomization (MR) analysis, the association between RA and 731 immune phenotypes which include morphological parameters (MP), relative cell (RC), median fluorescence intensities (MFI), and absolute cells (AC) was comprehensively determined. After false discovery rate correction, RA and immunophenotypes were statistically associated with each other. It was observed that four immune phenotypes, including 1 MPs, 8 RCs, 15 MFIs, and 10 ACs were causally associated with the risk of RA. Meanwhile, several identified immune traits could serve as independent factors for RA and be robust against pleiotropy. While considering the role of RA in immune traits, the involvement of RA in multiple immunophenotypes including CD62L- myeloid DC AC, CD3 on secreting Treg, CD3 on activated and secreting Treg, and CD3 on CD4 Treg was revealed. This study is the first comprehensive evaluation of the interaction between immune response and RA risk, thus providing therapeutic strategies for RA from an immunological perspective.

Social trust and the location choices of foreign firms in China-The moderating role of formal institution and cultural distance.

The institutional environment has a significant impact on the location of overseas investments by multinational enterprises (MNEs). However, there remain two research gaps. First, fewer studies focused on the impact of subnational regional institutions on the location choices of MNEs. Second, study on informal institutions has been more limited. This study investigates the effect of the informal institution (social trust) in the Chinese subnational region on the location choices of foreign firms and the mechanism of its role. Using the sample of foreign firms' location choices in China from 2008 to 2020 in Orbis Global Enterprise Database, this study finds that social trust positively related to the location choices of foreign firms in subnational regions. Our results also show that this positive effect is contingent on the formal institution and the cultural distance between home and host country. When the formal institution is strong and the cultural distance between home and host country is high, social trust has a more significant positive impact on the location choices of foreign firms in subnational regions. Besides, the results show that cost advantage, information advantage and innovation advantage are important mechanisms for social trust to influence foreign firms' location choices in subnational regions. This study is important for understanding the role of subnational regional informal institutions in influencing strategic decisions of MNEs. At the same time, it has certain guiding significance for governments in attracting foreign direct investment and for multinational enterprises in selecting suitable overseas investment locations.

Sirtuin-3 mediates sex differences in kidney ischemia-reperfusion injury.

Studies suggest that biological sex influences susceptibility to kidney diseases with males demonstrating greater risk for developing ischemic acute kidney injury (AKI). Sex-related differences in mitochondrial function and homeostasis exist, likely contributing to sexual dimorphism in kidney injury, but the mechanisms are not well characterized. Our observations reveal lower baseline expression of Sirtuin-3 (Sirt3, a major mitochondrial acetyltransferase) in the kidneys of male mice versus females. We tested the hypothesis that differential expression of kidney Sirt3 may mediate sexual dimorphism in AKI using a bilateral kidney ischemia-reperfusion injury (IRI) model and three transgenic mouse models: (1) mice with global transgenic overexpression of Sirt3; (2) mice with inducible, kidney tubule-specific Sirt3 knockdown (iKD); and (3) mice with global Sirt3 knockout. Low mitochondrial Sirt3 (mtSirt3) in males versus females is associated with development of kidney tubular epithelium vacuoles, increased mitochondrial ROS and susceptibility to IRI. Transgenic overexpression of Sirt3 in males protects against kidney IRI and development of tubular epithelium vacuoles. In both sexes, mice with partial kidney tubular epithelium-specific Sirt3 knockdown display intermediate - while global Sirt3 knockout mice display the highest susceptibility to IRI. Female Sirt3 iKD mice demonstrate decreased survival and kidney function after IRI indistinguishable from control males, abolishing the protective effects observed in females. Mechanistically, observed differences in kidney mtSirt3 are sex hormone-dependent; estradiol increases - while testosterone decreases mtSirt3 protein. Our results demonstrate that Sirt3 is an important contributor to the observed sex-related differences in IRI susceptibility, and a potential therapeutic target in the clinical management of AKI.

How Does Social Support Affect the Retention Willingness of Cross-Border E-Commerce Sellers?

E-commerce research usually focuses more on how to protect consumers' rights and increase their purchase intention from the perspective of consumers. However, we still lack understanding of e-commerce sellers, especially cross-border e-commerce sellers. Based on the stimulus-body-response theory, this paper built a moderated mediation model to test the relationships among social support, perceived benefits, perceived usefulness and sellers' willingness to retain. The results show that social support has a positive impact on perceived benefits and sellers' willingness to retain; perceived benefits play a partial intermediary role between social support and sellers' willingness to retain; and perceived usefulness moderates these mediating effects. The research results further expand the perspective of e-commerce research and reveal the mechanism and boundary conditions of the influence of social support on the retention willingness of cross-border e-commerce sellers.

A Comparison of Hydroxyl Radical and Hydrogen Peroxide Generation in Ambient Particle Extracts and Laboratory Metal Solutions.

Generation of reactive oxygen species (ROS) - including superoxide ((•)O(2) (-)), hydrogen peroxide (HOOH), and hydroxyl radical ((•)OH) - has been suggested as one mechanism underlying the adverse health effects caused by ambient particulate matter (PM). In this study we compare HOOH and (•)OH production from fine and coarse PM collected at an urban (Fresno) and rural (Westside) site in the San Joaquin Valley (SJV) of California, as well as from laboratory solutions containing dissolved copper or iron. Samples were extracted in a cell-free, phosphate-buffered saline (PBS) solution containing 50 µM ascorbate (Asc). In our laboratory solutions we find that Cu is a potent source of both HOOH and (•)OH, with approximately 90% of the electrons that can be donated from Asc ending up in HOOH and (•)OH after 4 h. In contrast, in Fe solutions there is no measurable HOOH and only a modest production of (•)OH. Soluble Cu in the SJV PM samples is also a dominant source of HOOH and (•)OH. In both laboratory copper solutions and extracts of ambient particles we find much more production of HOOH compared to (•)OH: e.g., HOOH generation is approximately 30 - 60 times faster than (•)OH generation. The formation of HOOH and (•)OH are positively correlated, with roughly 3 % and 8 % of HOOH converted to (•)OH after 4 and 24 hr of extraction, respectively. Although the SJV PM produce much more HOOH than (•)OH, since (•)OH is a much stronger oxidant it is unclear which species might be more important for oxidant-mediated toxicity from PM inhalation.

Zinc deficiency induces vascular pro-inflammatory parameters associated with NF-kappaB and PPAR signaling.

OBJECTIVES: Marginal intake of dietary zinc can be associated with increased risk of cardiovascular diseases. In the current study we hypothesized that vascular dysfunction and associated inflammatory events are activated during a zinc deficient state. DESIGN: We tested this hypothesis using both vascular endothelial cells and mice lacking the functional LDL-receptor gene. RESULTS: Zinc deficiency increased oxidative stress and NF-kappaB DNA binding activity, and induced COX-2 and E-selectin gene expression, as well as monocyte adhesion in cultured endothelial cells. The NF-kappaB inhibitor CAPE significantly reduced the zinc deficiency-induced COX-2 expression, suggesting regulation through NF-kappaB signaling. PPAR can inhibit NF-kappaB signaling, and our previous data have shown that PPAR transactivation activity requires adequate zinc. Zinc deficiency down-regulated PPARalpha expression in cultured endothelial cells. Furthermore, the PPARgamma agonist rosiglitazone was unable to inhibit the adhesion of monocytes to endothelial cells during zinc deficiency, an event which could be reversed by zinc supplementation. Our in vivo data support the importance of PPAR dysregulation during zinc deficiency. For example, rosiglitazone induced inflammatory genes (e.g., MCP-1) only during zinc deficiency, and adequate zinc was required for rosiglitazone to down-regulate pro-inflammatory markers such as iNOS. In addition, rosiglitazone increased IkappaBalpha protein expression only in zinc adequate mice. Finally, plasma data from LDL-R-deficient mice suggest an overall pro-inflammatory environment during zinc deficiency and support the concept that zinc is required for proper anti-inflammatory or protective functions of PPAR. CONCLUSIONS: These studies suggest that zinc nutrition can markedly modulate mechanisms of the pathology of inflammatory diseases such as atherosclerosis.

Zinc nutritional status modulates expression of ahr-responsive p450 enzymes in vascular endothelial cells.

Zinc has anti-inflammatory properties and is crucial for the integrity of vascular endothelial cells, and the development and homeostasis of the cardiovascular system. The aryl hydrocarbon receptor (AhR) which is expressed in the vascular endothelium also plays an important role in responses to xenobiotic exposure and cardiovascular development. We hypothesize that cellular zinc can modulate induction of AhR responsive genes in endothelial cells. To determine if zinc deficiency can alter responses to AhR ligands, aortic endothelial cells were exposed to the AhR ligands 3,3',4,4'-tetrachlorobiphenyl (PCB77) or beta-naphthoflavone (beta-NF) alone or in combination with the membrane permeable zinc chelator TPEN, followed by measurements of the AhR responsive cytochrome P450 enzymes CYP1A1 and 1B1. Compared to vehicle treated cells, both PCB77-induced CYP1A1 activity (EROD) and mRNA expression were significantly reduced during zinc deficiency. In addition, PCB77 and beta-NF-mediated upregulation of CYP1A1 and CYP1B1 protein expression was significantly reduced in zinc-deficient endothelial cells. The inhibition of CYP1A1 and CYP1B1 protein expression caused by zinc deficiency was reversible by cellular zinc supplementation. Overall, our results strongly suggest that nutrition can modulate an environmental toxicant-induced biological outcome and that adequate levels of individual nutrients such as zinc are necessary for induction of AhR responsive genes in vascular endothelial cells.

Zinc deficiency alters lipid metabolism in LDL receptor deficient mice treated with rosiglitazone.

Zinc is a structural and functional component of PPAR and zinc deficiency may be associated with an increased risk for cardiovascular diseases. We tested the hypothesis that zinc deficiency compromises lipid metabolism in rosiglitazone (RSG)-treated mice lacking the LDL-receptor (LDL-R) gene. LDL-R-deficient mice were maintained for 3 wk on low-fat (7 g/100 g) diets that were either zinc deficient or zinc adequate. Subsequently, diets were adjusted to a high-fat (HF) (15 g/100 g) regimen for 1 wk to produce a biological environment of mild oxidative and inflammatory stress. One-half of the mice within each zinc group was gavaged daily with the PPARgamma agonist RSG starting 2 d prior to the HF feeding. Selected lipid parameters were studied. Zinc deficiency increased plasma total cholesterol, which was also elevated by RSG. Zinc deficiency also caused an increased lipoprotein-cholesterol distribution toward the non-HDL fraction (VLDL, intermediate density lipoprotein, LDL). Plasma total fatty acids tended to increase during zinc deficiency and RSG treatment resulted in similar changes in the fatty acid profile in zinc-deficient mice. Fatty acid translocase (FAT/CD36) expression in abdominal aorta was upregulated by RSG only in zinc-deficient mice. In contrast, RSG treatment markedly increased lipoprotein lipase (LPL) expression only in zinc-adequate mice. In vitro studies confirmed that adequate zinc is required for RSG-induced PPARgamma activity to transactivate target genes. These data suggest that in this atherogenic mouse model treated with RSG, lipid metabolism can be compromised during zinc deficiency and that adequate dietary zinc may be considered during therapy with the antidiabetic medicine RSG.

The p-benzoquinone DNA adducts derived from benzene are highly mutagenic.

Benzene is a human leukemia carcinogen, resulting from its cellular metabolism. A major benzene metabolite is p-benzoquinone (pBQ), which can damage DNA by forming the exocyclic base adducts pBQ-dC, pBQ-dA, and pBQ-dG in vitro. To gain insights into the role of pBQ in benzene genotoxicity, we examined in vitro translesion synthesis and in vivo mutagenesis of these pBQ adducts. Purified REV1 and Polkappa were essentially incapable of translesion synthesis in response to the pBQ adducts. Opposite pBQ-dA and pBQ-dC, purified human Poliota was capable of error-prone nucleotide insertion, but was unable to perform extension synthesis. Error-prone translesion synthesis was observed with Poleta. However, DNA synthesis largely stopped opposite the lesion. Consistent with in vitro results, replication of site-specifically damaged plasmids was strongly inhibited by pBQ adducts in yeast cells, which depended on both Polzeta and Poleta. In wild-type cells, the majority of translesion products were deletions at the site of damage, accounting for 91%, 90%, and 76% for pBQ-dA, pBQ-dG, and pBQ-dC, respectively. These results show that the pBQ-dC, pBQ-dA, and pBQ-dG adducts are strong blocking lesions, and are highly mutagenic by predominantly inducing deletion mutations. These results are consistent with the lesion structures predicted by molecular dynamics simulation. Our results led to the following model. Translesion synthesis normally occurs by directly copying the lesion site through base insertion and extension synthesis. When the lesion becomes incompatible in accommodating a base opposite the lesion in DNA, translesion synthesis occurs by a less efficient lesion loop-out mechanism, resulting in avoiding copying the damaged base and leading to deletion.

Role of DNA polymerase eta in the bypass of abasic sites in yeast cells.

Abasic (AP) sites are major DNA lesions and are highly mutagenic. AP site-induced mutagenesis largely depends on translesion synthesis. We have examined the role of DNA polymerase eta (Poleta) in translesion synthesis of AP sites by replicating a plasmid containing a site-specific AP site in yeast cells. In wild-type cells, AP site bypass resulted in preferred C insertion (62%) over A insertion (21%), as well as -1 deletion (3%), and complex event (14%) containing multiple mutations. In cells lacking Poleta (rad30), Rev1, Polzeta (rev3), and both Poleta and Polzeta, translesion synthesis was reduced to 30%, 30%, 15% and 3% of the wild-type level, respectively. C insertion opposite the AP site was reduced in rad30 mutant cells and was abolished in cells lacking Rev1 or Polzeta, but significant A insertion was still detected in these mutant cells. While purified yeast Polalpha effectively inserted an A opposite the AP site in vitro, purified yeast Poldelta was much less effective in A insertion opposite the lesion due to its 3'-->5' proofreading exonuclease activity. Purified yeast Poleta performed extension synthesis from the primer 3' A opposite the lesion. These results show that Poleta is involved in translesion synthesis of AP sites in yeast cells, and suggest that an important role of Poleta is to catalyze extension following A insertion opposite the lesion. Consistent with these conclusions, rad30 mutant cells were sensitive to methyl methanesulfonate (MMS), and rev1 rad30 or rev3 rad30 double mutant cells were synergistically more sensitive to MMS than the respective single mutant strains.

Translesion synthesis of acetylaminofluorene-dG adducts by DNA polymerase zeta is stimulated by yeast Rev1 protein.

Translesion synthesis is an important mechanism in response to unrepaired DNA lesions during replication. The DNA polymerase zeta (Polzeta) mutagenesis pathway is a major error-prone translesion synthesis mechanism requiring Polzeta and Rev1. In addition to its dCMP transferase, a non-catalytic function of Rev1 is suspected in cellular response to certain types of DNA lesions. However, it is not well understood about the non-catalytic function of Rev1 in translesion synthesis. We have analyzed the role of Rev1 in translesion synthesis of an acetylaminofluorene (AAF)-dG DNA adduct. Purified yeast Rev1 was essentially unresponsive to a template AAF-dG DNA adduct, in contrast to its efficient C insertion opposite a template 1,N6-ethenoadenine adduct. Purified yeast Polzeta was very inefficient in the bypass of the AAF-dG adduct. Combining Rev1 and Polzeta, however, led to a synergistic effect on translesion synthesis. Rev1 protein enhanced Polzeta-catalyzed nucleotide insertion opposite the AAF-dG adduct and strongly stimulated Polzeta-catalyzed extension from opposite the lesion. Rev1 also stimulated the deficient synthesis by Polzeta at the very end of undamaged DNA templates. Deleting the C-terminal 205 aa of Rev1 did not affect its dCMP transferase activity, but abolished its stimulatory activity on Polzeta-catalyzed extension from opposite the AAF-dG adduct. These results suggest that translesion synthesis of AAF-dG adducts by Polzeta is stimulated by Rev1 protein in yeast. Consistent with the in vitro results, both Polzeta and Rev1 were found to be equally important for error-prone translesion synthesis across from AAF-dG DNA adducts in yeast cells.

[Effects of p-nonylphenol on expression of ER protein and ER alpha mRNA of MCF-7 cells].

OBJECTIVE: To investigate the estrogenicity of p-nonylphenol (p-NP) through observation of its effects on expression of estrogen receptor (ER) and ER alpha mRNA of MCF-7 human breast cancer cells. METHODS: MCF-7 cells were maintained in RPMI-1640 medium containing 10% bovine serum. Before addition of p-NP, the cells were washed by phenol red-free DMEM medium and then maintained in phenol red-free DMEM medium containing 3% charcoal/dextran treated fetal bovine serum for 3 days. The effects of five concentrations of p-NP on expression of ER protein and ER alpha mRNA were assayed using semi-quantitative immunohistochemical method and quantitative RT-PCR respectively, vehicle control and positive control were used. RESULTS: Expression of ER protein in MCF-7 cells was down regulated by 1 x 10(-5) mol/L p-NP when cells were treated for 24 h. Expression of ER alpha mRNA in MCF-7 cells was down regulated by 1 x 10(-6) mol/L-1 x 10(-5) mol/L p-NP when cells were treated for 2 h and 24 h. Expression of both ER protein and ER alpha mRNA in MCF-7 cells showed a tendency of decline when the time of exposure to different concentrations of p-NP was elongated. CONCLUSION: p-NP could down regulate the expression of both ER protein and ER alpha mRNA in MCF-7 cells, which mimicked the effects of estradiol and thus revealed the estrogenicity of p-NP.