A C-terminal glutamine recognition mechanism revealed by E3 ligase TRIM7 structures.

The E3 ligase TRIM7 has emerged as a critical player in viral infection and pathogenesis. However, the mechanism governing the TRIM7-substrate association remains to be defined. Here we report the crystal structures of TRIM7 in complex with 2C peptides of human enterovirus. Structure-guided studies reveal the C-terminal glutamine residue of 2C as the primary determinant for TRIM7 binding. Leveraged by this finding, we identify norovirus and SARS-CoV-2 proteins, and physiological proteins, as new TRIM7 substrates. Crystal structures of TRIM7 in complex with multiple peptides derived from SARS-CoV-2 proteins display the same glutamine-end recognition mode. Furthermore, TRIM7 could trigger the ubiquitination and degradation of these substrates, possibly representing a new Gln/C-degron pathway. Together, these findings unveil a common recognition mode by TRIM7, providing the foundation for further mechanistic characterization of antiviral and cellular functions of TRIM7.

Heritability of tea drinking and its relationship with cigarette smoking in the Chinese male adult twins.

The aims of this study are to estimate the contributions of genetic factors to the variation of tea drinking and cigarette smoking, to examine the roles of genetic factors in their correlation and further to investigate underlying causation between them. We included 11 625 male twin pairs from the Chinese National Twin Registry (CNTR). Bivariate genetic modelling was fitted to explore the genetic influences on tea drinking, cigarette smoking and their correlation. Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) was further used to explore the causal relationship between them. We found that genetic factors explained 17% and 23% of the variation in tea drinking and cigarette smoking, respectively. A low phenotypic association between them was reported (rph = 0.21, 95% confidence interval [CI]: [0.19, 0.24]), which was partly attributed to common genetic factors (rA = 0.45, 95% CI [0.19, 1.00]). In the ICE FALCON analysis with current smoking as the exposure, tea drinking was associated with his own (ßself = 0.39, 95% CI [0.23, 0.55]) and his co-twin's smoking status (ßco-twin = 0.25, 95% CI [0.10, 0.41]). Their association attenuated with borderline significance conditioning on his own smoking status (p = 0.045), indicating a suggestive causal effect of smoking status on tea drinking. On the contrary, when we used tea drinking as the predictor, we found familial confounding between them only. In conclusion, both tea drinking and cigarette smoking were influenced by genetic factors, and their correlation was partly explained by common genetic factors. In addition, our finding suggests that familial confounders account for the relationship between tea drinking and cigarette smoking. And current smoking might have a causal effect on weekly tea drinking, but not vice versa.

Visfatin Promotes Monocyte Adhesion by Upregulating ICAM-1 and VCAM-1 Expression in Endothelial Cells via Activation of p38-PI3K-Akt Signaling and Subsequent ROS Production and IKK/NF-κB Activation.

BACKGROUND/AIMS: Visfatin is known to act as a mediator in several metabolic disorders, such as obesity, diabetes, and cardiovascular diseases. This study aimed to investigate the effect of visfatin on the adhesion of THP-1 monocytes to human vascular endothelial cells and the underlying mechanism. METHODS: Monocytes adhesion to endothelial cells was determined by using fluorescence-labeled monocytes. ICAM-1 and VCAM-1 expression in endothelial cells were measured by western blotting. Production of reactive oxygen species (ROS) was measured by using a fluorescent dye. The amounts of nuclear factor-kappa B (NF-κB) and phosphorylation of inhibitory factor of NF-κB (IκB) were determined by using western blot analysis. The translocation of NF-κB from the cytoplasm to the nucleus was determined by using immunofluorescence. RESULTS: Here we showed that visfatin significantly caused the upregulation of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells, as well as enhanced monocyte adhesion to endothelial cells. Moreover, we found that inhibition of PI3K, Akt, and p38 MAPK activation significantly prevented visfatin-enhanced expression of ICAM-1 and VCAM-1 and monocyte adhesion to endothelial cells. Visfatin enhanced ROS production and IKK/NF-кB activation and then led to upregulation of ICAM-1 and VCAM-1 and enhanced monocyte adhesion to endothelial cells. These effects were also p38/PI3K/Akt-dependent. CONCLUSION: These results demonstrated that visfatin promoted monocyte-endothelial cell adhesion by increasing ICAM-1 and VCAM-1 expression via the activation of p38/PI3K/Akt signaling and downstream ROS production and IKK/NF-кB activation.

Does the calcification of adamantinomatous craniopharyngioma resemble the calcium deposition of osteogenesis/odontogenesis?

AIMS: Calcification in adamantinomatous craniopharyngioma (ACP) is troublesome for surgical intervention. The aim of this study was to examine the osteogenic proteins that play important roles in the calcium deposition of the odontogenic/osteogenic tissues in craniopharyngioma. METHODS AND RESULTS: Craniopharyngiomas (n = 89) were investigated for the presence and expression pattern of the osteoinductive/odontoinductive factor bone morphogenetic protein-2 (Bmp2) and two osteoblastic differentiation makers, Runt-related transcription factor-2 (Runx2) and Osterix, using immunohistochemistry and Western blotting. Our results showed that Bmp2, Runx2 and Osterix levels increased in cases with high calcification and correlated positively with the degree of calcification in ACP, whereas they showed little or no expression in squamous papillary craniopharyngioma. In ACP, Bmp2 was expressed primarily in the stellate reticulum and whorl-like array cells; Runx2 and Osterix tended to be expressed in calcification-related epithelia, including whorl-like array cells and epithelia in/around wet keratin and calcification lesions. CONCLUSIONS: Our study indicated, for the first time, that osteogenic factor Bmp2 may play an important role in the calcification of ACP via autocrine or paracrine mechanisms. Given the presence of osteogenic markers (Runx2 and Osterix), craniopharyngioma cells could differentiate into an osteoblast-like lineage, and the process of craniopharyngioma calcification resembles that which occurs in osteogenesis/odontogenesis.

Impact of the COVID-19 pandemic on rural communities: a cross-sectional study in the Sichuan Province of China.

OBJECTIVE: Recently, China has experienced a considerable influence of the COVID-19 pandemic on the local people's health and economy. Hence, the current research aims to investigate the psychological and socioeconomic impact of COVID-19 on rural communities in the Sichuan Province of China. METHODS: A total of 499 participants (village representatives of Sichuan Province) were approached to partake in a cross-sectional online survey and share their experience regarding the ongoing pandemic. The descriptive statistics and ordinary least squares (OLS) regression were used to analyse the data. RESULTS: Our analysis revealed that the pandemic has significantly affected local people psychologically, leading to socioeconomic vulnerability. Notably, we find that local households are worried about their income losses regardless of their socioeconomic status (40%-43%), level of income (37%-43%) and industry involvement (38%-43%). However, as income increases, the level of stress decreases. The results further show that government transfer payment is a significant factor in reducing stress due to its reliable and uninterrupted income flow. Contrary to our proposition, the pandemic stress was less observed, which might be because of people's trust in government and effective antiepidemic countermeasures to contain the disease. CONCLUSION: This study finds that COVID-19 has a significant impact on local people's health, psychology and income. This study is one of the first to provide empirical evidence regarding the early health and socioeconomic effects of COVID-19 at the household level in rural communities, which are very important to devise policies to ease the outbreak and prevent further losses at the local community level.

Socio-economic status, resilience, and vulnerability of households under COVID-19: Case of village-level data in Sichuan province.

This paper investigates economic impacts of COVID-19 on households based on differences in the socio-economic status (SES). We determine the household-level effects of the COVID-19 shock using income sources, types of industries, communities' resilience, household susceptibility, and relevant policy measures. For this purpose, we used primary data of 555 households collected through snowball sampling technique using an online survey questionnaire from different villages mostly located in Sichuan Province, China. Using step-wise binary logistic regression analysis, we estimated and validated the model. Results suggest the use of SES as a better measure for understanding the impacts of COVID-19 on different households. We find that households with low SES tend to depend more on farmland income and transfer payments from the government. Contrarily, high SES households focus more on business and local employment as sources of income generation. Poor households were less resilient and more likely to fall back into poverty due to COVID-19, while the opposite stands true for non-poor households with high SES. Based on the estimations, policies encouraging employment and businesses complemented with loans on lower interest rates are recommended, which may increase the SES, thus minimizing vulnerability and enhancing the households' resilience towards poverty alleviation and economic shocks.

VISFATIN PROMOTES FOAM CELL FORMATION BY DYSREGULATING CD36, SRA, ABCA1, AND ABCG1 EXPRESSION IN RAW264.7 MACROPHAGES.

BACKGROUND: Visfatin is produced in and secreted from adipocytes. Increased circulating visfatin level is observed in obese subjects. Previous studies demonstrated that visfatin was involved in obesity-related cardiovascular diseases. AIMS: This study aims to explore the regulatory effects of adipokine visfatin on foam cell formation, a key step in the development of atherosclerosis. METHODS: Effect of visfatin on protein and mRNA expression of scavenger receptor and ATP binding cassette transporter in RAW264.7 macrophages were measured by western blotting and real-time RT-PCR. To confirm the influence of visfatin-regulated scavenger receptor and ATP binding cassette transporter to foam cell formation, the visfatin-caused changes of ox-LDL uptake, cholesterol efflux, and foam cell formation were determined. RESULTS: Visfatin significantly increased the expression of CD36 and scavenger receptor A (SRA), decreased the expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1), and had no effect on the expression of SR-B1. Visfatin increased oxidized-LDL (ox-LDL) uptake and decreased cholesterol efflux, which increased foam cell formation. The PI3K inhibitor LY294002 blocked the effect of visfatin on the protein and mRNA expression levels of CD36, SRA, and ABCG1 and ox-LDL uptake and cholesterol efflux. The ERK inhibitor PD98059 also prevented visfatin-induced ABCA1 instability and subsequently decreased cholesterol efflux. CONCLUSIONS: Visfatin upregulated CD36 and SRA expression and downregulated ABCA1 and ABCG1 expression, subsequently increased ox-LDL uptake and decreased cholesterol efflux, and finally promoted foam cell formation via the PI3K- and ERK-dependent pathways.

Chronic endothelin-1 infusion causes adipocyte hyperplasia in rats.

OBJECTIVE: The aim of this study was to investigate the regulatory mechanism of endothelin-1 (ET-1), an endothelium-derived vasoconstrictor, on adipogenesis in vitro and in vivo. METHODS: 3T3-L1 preadipocytes were used to explore the mechanisms mediating ET-1 actions on preadipocyte proliferation and adipocyte differentiation. To investigate the in vivo effect of ET-1, male Sprague-Dawley rats were infused with ET-1 or saline for 4 weeks via intraperitoneally implanted osmotic pumps, and the fat pad weight and adipocyte size of adipose tissues were measured. RESULTS: ET-1 stimulated preadipocyte proliferation and increased the cell number at the mitotic clonal expansion stage of adipocyte differentiation via the endothelin A receptor (ETAR) and activation of the protein kinase C (PKC) pathway. ET-1, via ETAR, inhibited adipocyte differentiation partially through an ERK-dependent pathway. Furthermore, no significant difference in the body weight and fat pad weight was observed in either ET-1- or saline-infused rats. Compared with saline-infused rats, the adipocyte cell number was significantly increased but the adipocyte size was significantly decreased in ET-1-infused rats. CONCLUSIONS: Chronic ET-1 infusion increased the number of small adipocytes without the change of white adipose tissue mass in rats, which were associated with ET-1-stimulated preadipocyte proliferation, but not ET-1-suppressed adipocyte differentiation.

Adipocytes play an etiological role in the podocytopathy of high-fat diet-fed rats.

Obesity is a risk factor that promotes progressive kidney disease. Studies have shown that an adipocytokine imbalance contributes to impaired renal function in humans and animals, but the underlying interplay between adipocytokines and renal injury remains to be elucidated. We aimed to investigate the mechanisms linking obesity to chronic kidney disease. We assessed renal function in high-fat (HF) diet-fed and normal diet-fed rats, and the effects of preadipocyte- and adipocyte-conditioned medium on cultured podocytes. HF diet-fed and normal diet-fed Sprague Dawley rats were used to analyze the changes in plasma BUN, creatinine, urine protein and renal histology. Additionally, podocytes were incubated with preadipocyte- or adipocyte-conditioned medium to investigate the effects on podocyte morphology and protein expression. In the HF diet group, 24 h urinary protein excretion (357.5 ± 64.2 mg/day vs 115.9 ± 12.4 mg/day, P < 0.05) and the urine protein/creatinine ratio were significantly higher (1.76 ± 0.22 vs 1.09 ± 0.15, P < 0.05), increased kidney weight (3.54 ± 0.04 g vs 3.38 ± 0.04 g, P < 0.05) and the glomerular volume and podocyte effacement increased by electron microscopy. Increased renal expression of desmin and decreased renal expression of CD2AP and nephrin were also seen in the HF diet group (P < 0.05). Furthermore, we found that adipocyte-conditioned medium-treated podocytes showed increased desmin expression and decreased CD2AP and nephrin expression compared with that in preadipocyte-conditioned medium-treated controls (P < 0.05). These findings show that adipocyte-derived factor(s) can modulate renal function. Adipocyte-derived factors play an important role in obesity-related podocytopathy.

Evidence in obese children: contribution of hyperlipidemia, obesity-inflammation, and insulin sensitivity.

BACKGROUND: Evidence shows a high incidence of insulin resistance, inflammation and dyslipidemia in adult obesity. The aim of this study was to assess the relevance of inflammatory markers, circulating lipids, and insulin sensitivity in overweight/obese children. METHODS: We enrolled 45 male children (aged 6 to 13 years, lean control = 16, obese = 19, overweight = 10) in this study. The plasma total cholesterol, HDL cholesterol, triglyceride, glucose and insulin levels, the circulating levels of inflammatory factors, such as TNF-α, IL-6, and MCP-1, and the high-sensitive CRP level were determined using quantitative colorimetric sandwich ELISA kits. RESULTS: Compared with the lean control subjects, the obese subjects had obvious insulin resistance, abnormal lipid profiles, and low-grade inflammation. The overweight subjects only exhibited significant insulin resistance and low-grade inflammation. Both TNF-α and leptin levels were higher in the overweight/obese subjects. A concurrent correlation analysis showed that body mass index (BMI) percentile and fasting insulin were positively correlated with insulin resistance, lipid profiles, and inflammatory markers but negatively correlated with adiponectin. A factor analysis identified three domains that explained 74.08% of the total variance among the obese children (factor 1: lipid, 46.05%; factor 2: obesity-inflammation, 15.38%; factor 3: insulin sensitivity domains, 12.65%). CONCLUSIONS: Our findings suggest that lipid, obesity-inflammation, and insulin sensitivity domains predominantly exist among obese children. These factors might be applied to predict the outcomes of cardiovascular diseases in the future.

Land use change influences soil C, N, and P stoichiometry under 'Grain-to-Green Program' in China.

Changes in land use might affect the combined C, N and P stoichiometry in soil. The Grain-to-Green Program (GTGP), which converts low-yield croplands or abandoned lands into forest, shrub, and/or grassland, was the largest land reforestation project in China. This study collected the reported C, N and P contents of soil in GTGP zones to achieve the factors driving the changes in the C:N, C:P, and N:P values. The results showed that the annual average precipitation exerted significant effects on the C:P value, and on the N:P value became significant 20 years after the change in land use. The annual average temperature was the main factor affecting the C:N value during the first 10 years, while the annual average precipitation strongly affected this value afterwards. In addition, "Redfield-like" interactions between C, N, and P in the soil may exist. A linear regression revealed significant positive correlations between the C:N, C:P, and N:P values and the restoration age, temperature, and precipitation after a change in land use. Therefore large-scale changes in land use under the 'GTGP' program might significantly affect the C:N, C:P and N:P ratios in soil.

Neck muscle stiffness quantified by sonoelastography is correlated with body mass index and chronic neck pain symptoms.

This study aimed to quantify neck muscle stiffness in the normal population with ultrasound elastography. We applied the acoustic radiation force impulse technique and measured shear wave velocities (SWVs) as representative values. The mean ± standard deviation values of SWV in 20 healthy volunteers were 2.09 ± 0.45, 1.21 ± 0.30, 1.12 ± 0.17 and 0.97 ± 0.10 m/s for the trapezius, levator scapulae, scalene anterior and sternocleidomastoid muscles, respectively. The SWV values of the four muscles significantly differed (Kruskal-Wallis test, p < 0.001). The SWV values for the trapezius muscle correlated with body mass indexes (Pearson's correlation, p = 0.034). Subjects with chronic neck pain symptoms had significantly stiffer trapezius muscle (Mann-Whitney U test, p = 0.008). This study demonstrated the technique and feasibility of quantifying neck muscle stiffness using acoustic radiation force impulse elastography and shear wave velocity detection. Further study is necessary to evaluate its diagnostic power in assessing various neck muscle diseases.

Losartan ameliorates renal injury, hypertension, and adipocytokine imbalance in 5/6 nephrectomized rats.

The mechanisms underlying insulin sensitivity and fat tissue distribution in chronic renal insufficiency remain unclear. Previous studies have shown the benefits of angiotensin II receptor blockers on moderately nourished to well-nourished patients with the metabolic syndrome. The current study explored the effect of losartan, the first selective angiotensin II receptor blocker, on insulin sensitivity and visceral fat tissue distribution in a 5/6 nephrectomized (N) rat model and investigated the expression of adipose tissue adipocytokines. Male Sprague-Dawley rats (200 g to 250 g) were subjected to 5/6 nephrectomy, and the adipocytes isolated from the visceral fat tissues were then studied. Results showed that desmin expression was significantly suppressed and systolic blood pressure was successfully normalized in the losartan-administered (NA) group. The weight of the visceral fat pad remarkably decreased in the N and NA groups (100 mg/500 ml drinking water) compared with the control group. The weight did not decrease further in the NA group compared with the N group. Insulin resistance was more remarkable in the N group compared with the control and NA groups. Moreover, the adipose tissue expression of adiponectin and leptin was downregulated whereas that of resistin was upregulated in the N group compared with the control group. However, the adiponectin, leptin, and resistin adipose tissue expression returned to their basal values in the NA group. These findings indicated that losartan administration ameliorated renal injury, systolic blood pressure, and adipocytokine imbalance of the adipose tissue in chronic renal insufficiency. Insulin sensitivity was not improved.

Increased depression and readmission risk in patients with new-onset angina after the Sichuan earthquake.

INTRODUCTION: Earthquake exposure has been associated with adverse consequences for coronary heart disease. However, the natural history and prognostic significance of earthquake-related, new-onset angina have not been characterized. OBJECTIVE: The objective of this study was to evaluate the association between episodes of depressive symptoms and one-year prognosis after the first admission to the hospital among adults with new-onset angina before and after the Sichuan earthquake. METHODS: One hundred forty-one first hospitalized patients with new-onset angina before and after the Sichuan earthquake underwent psychological assessments during their first admission to the hospital following the earthquake. Patients were followed for 12 months to determine survival status. The independent relationships between baseline variables and readmission risk after the earthquake were examined. Baseline somatic and psychosocial variables were collected with the aid of standard, validated questionnaires. RESULTS: The proportion of patients with moderate/severe depression symptom in the earthquake-related group is higher than among their counterparts (23.7% vs. 8.9%, p = 0.026). Patients with new-onset angina after the Sichuan earthquake had a higher risk of readmission (22.4% vs. 8.9%, p = 0.041) and longer total hospitalization (average of 13.4 ±6.8 vs. 10.7 ±5.5 days, p = 0.015). The risks for readmission was associated with moderate/severe depression (adjusted hazard ratio, 9.18 [95% confidence interval (CI) = 3.09-27.23, p = 0.0000]) and low ejection fraction (adjusted hazard ratio, 6.66 [95%CI = 2.131-20.781, p = 0.001]). CONCLUSIONS: Among patients diagnosed with new-onset angina, those with first episode after the Sichuan earthquake generated more moderate/severe depressive symptoms and had a higher risk for readmission and longer hospital stay. Depressive symptoms upon admission and low ejection fractions were significant predictors of 12-month risk for readmission, which indicates that antidepressants should be prescribed.