Host genetic variants, Epstein-Barr virus subtypes, and the risk of nasopharyngeal carcinoma: Assessment of interaction and mediation.

Epstein-Barr virus (EBV) and human leukocyte antigen (HLA) polymorphisms are well-known risk factors for nasopharyngeal carcinoma (NPC). However, the combined effects between HLA and EBV on the risk of NPC are unknown. We applied a causal inference framework to disentangle interaction and mediation effects between two host HLA SNPs, rs2860580 and rs2894207, and EBV variant 163364 with a population-based case-control study in NPC-endemic southern China. We discovered the strong interaction effects between the high-risk EBV subtype and both HLA SNPs on NPC risk (rs2860580, relative excess risk due to interaction [RERI] = 4.08, 95% confidence interval [CI] = 2.03-6.14; rs2894207, RERI = 3.37, 95% CI = 1.59-5.15), accounting for the majority of genetic risk effects. These results indicate that HLA genes and the high-risk EBV have joint effects on NPC risk. Prevention strategies targeting the high-risk EBV subtype would largely reduce NPC risk associated with EBV and host genetic susceptibility.

Fixed-Time Coverage Control of Mobile Robot Networks Considering the Time Cost Metric.

In this work, we studied the area coverage control problem (ACCP) based on the time cost metric of a robot network with an input disturbance in a dynamic environment, which was modeled by a time-varying risk density function. A coverage control method based on the time cost metric was proposed. The area coverage task that considers the time cost consists of two phases: the robot network is driven to cover the task area with a time-optimal effect in the first phase; the second phase is when the accident occurs and the robot is driven to the accident site at maximum speed. Considering that there were movable objects in the task area, a time-varying risk density function was used to describe the risk degree at different locations in the task area. In the presence of the input disturbance, a robust controller was designed to drive each robot, with different maximum control input values, to the position that locally minimized the time cost metric function in a fixed time, and the conditions for maximum control input were obtained. Finally, simulation results and comparison result are presented in this paper.

Regional Social Development Gap and Regional Coordinated Development Based on Mixed-Methods Research: Evidence From China.

Due to the continuous acceleration of the global urbanization process, the unbalanced development of regional cities has become an unavoidable reality under the rapid economic and social development of China. Unbalanced social development will affect coordinated and sustainable economic development, regional ethnic unity, and political and social stability. This research uses data from the 2011-2015 period, 2016-2020 period, and various special development plans of 35 large and medium cities, combines qualitative analysis and quantitative analysis, establishes a comprehensive evaluation model, and conducts cluster analysis, using standard deviation. The coefficient of variation aims to measure and study whether the gap in China's regional social development has continued to widen over the past decade. This study found that: (1) From the overall national perspective, there are obvious differences in the level of social development in the development plans of 35 large and medium-sized cities. The social development level of each large and medium-sized city has been improved to a certain extent, and the social development gap between cities has also been reduced to a certain extent. (2) From the 2011-2015 period to the 2016-2020 period, the social development gap between the three regions of my country's eastern, central, and western regions has declined. (3) The trend of social development disparity within the three major regions of the eastern, central, and western regions is not the same. The internal social development gap in the eastern region shows a downward trend, while the internal social development gap in the central and western regions shows an upward trend. This study provides a valuable reference for rapidly urbanizing developing countries in the process of globalization.

Prenatal inflammation causes obesity and abnormal lipid metabolism via impaired energy expenditure in male offspring.

INTRODUCTION: Obesity has becoming a global health issue. Fetus exposed to adversity in the uterine are susceptible to unhealth stimulus in adulthood. Prenatal inflammation is related to poor neonatal outcomes like neurodevelopmental impairments and respiratory complications. Recent studies suggested prenatal lipopolysaccharide (LPS) exposure could result in metabolic disorders. Thus, we hypothesized that offspring exposed to prenatal inflammation could develop into metabolic disorder. METHODS: The pregnant C57BL/6J mice were intraperitoneally injected with 50 µg/kg LPS or saline only once at GD15. The male offspring were weighted weekly until sacrificed. Indirect calorimetry and body composition were both performed at 9 and 18 weeks old. At 20 weeks old, mice were fasted overnight before collecting blood samples and liver for metabolomics analysis and RNA sequencing, respectively. Differentially expressed genes were further verified by RT-qPCR and western blotting. RESULTS: Prenatal inflammation resulted in obesity with increased fat percentage and decreased energy expenditure in middle-age male offspring. Abnormal lipid accumulation, changes of gene expression profile and upregulation of multi-component mechanistic target of rapamycin complex 1 (mTOR)/Peroxisome proliferator-activated receptor-γ pathway was observed in liver, accompanied with decreased bile acids level, unsaturated fatty acids androgens and prostaglandins in serum. Indirect calorimetry showed increased respiratory exchange rate and deceased spontaneous activity at 9 weeks in LPS group. Impaired energy expenditure was also observed at 18 weeks in LPS group. CONCLUSION: Prenatal LPS exposure led to obesity and abnormal lipid metabolism through impaired energy expenditure.

Quantitative assessment of the effects of biochar amendment on photosynthetic carbon assimilation and dynamics in a rice-soil system.

Biochar amendment has been proposed as a promising means to increase carbon (C) sequestration and simultaneously benefit plant productivity. However, quantifying the assimilation and dynamics of photosynthetic C in plant-soil systems under biochar addition remains elusive. This study established two experimental factors involving biochar addition and nitrogen (N) fertilization to quantitatively assess the effect of biochar on photosynthetic C fate in a rice plant-soil system. The rice plants and soil samples were collected and analyzed after 6-h pulse labeling with 13 CO2 at the tillering, jointing, heading and ripening stages. Biochar did not affect the proportions of photoassimilated carbon-13 (13 C) allocations in plant-soil systems. Nevertheless, biochar enhanced the 13 C contents in the shoot, root, and soil pools, especially when combined with N fertilization, and biochar increased the cumulative assimilated 13 C contents in the shoot, root, and soil pools by 23%, 14% and 20%, respectively, throughout the whole growth stage. Moreover, biochar addition significantly enhanced the N use efficiency (NUE) by c. 23% at the heading and ripening stages. In summary, biochar increases the content of photoassimilated C in plant-soil systems by improving plant productivity via enhancing NUE, thus resulting in a higher soil C sequestration potential.

Does functional specialization affect collaborative development? Evidence from four Chinese metropolitan areas.

The layout of urban spatial functions may play an important role in sustainable regional development. Given the rapid development of urbanization in China, this study attempts to analyze how functional specialization affects coordinated regional development. To quantitatively measure the degree of coordinated development within different regions, the coordinated degree index is used to calculate the degree of coordinated development of four Chinese metropolitan areas from 2008 to 2019. The panel vector autoregressive (PVAR) model is employed to empirically test the impact of urban functional specialization on coordinated regional development. The results indicate that high market activity is conducive to the formation of functional specialization synergy in space, and the level of social productivity directly affects the functional specialization and the level of synergy within a region. With the continuous strengthening of the implementation of local government policies, the functional specialization and synergy in metropolitan areas have gradually strengthened. However, the promotion effects and the expression of functional specialization, the coordinated development of government actions, and spatial functions differ across metropolitan areas in China.

Prospective assessment of a nasopharyngeal carcinoma risk score in a population undergoing screening.

Despite evidence suggesting the utility of Epstein-Barr virus (EBV) markers to stratify individuals with respect to nasopharyngeal carcinoma (NPC) risk in NPC high-risk regions, no validated NPC risk prediction model exists. We aimed to validate an EBV-based NPC risk score in an endemic population undergoing screening for NPC. This prospective study was embedded within an ongoing NPC screening trial in southern China initiated in 2008, with 51 235 adult participants. We assessed the score's discriminatory ability (area under the receiver-operator-characteristics curve, AUC). A new model incorporating the EBV score, sex and family history was developed using logistic regression and internally validated using cross-validation. AUCs were compared. We also calculated absolute NPC risk combining the risk score with population incidence and competing mortality data. A total of 151 NPC cases were detected in 2008 to 2016. The EBV-based score was highly discriminating, with AUC = 0.95 (95% CI = 0.93-0.97). For 90% specificity, the score had 87.4% sensitivity (95% CI = 81.0-92.3%). As specificity increased from 90% to 99%, the positive predictive value increased from 2.4% (95% CI = 1.9-3.0%) to 12.5% (9.9-15.5%). Correspondingly, the number of positive tests per detected NPC case decreased from 272 (95% CI = 255-290) to 50 (41-59). Combining the score with other risk factors (sex, first-degree family history of NPC) did not improve AUC. Men aged 55 to 59 years with the highest risk profile had the highest 5-year absolute NPC risk of 6.5%. We externally validated the discriminatory accuracy of a previously developed EBV score in a high-risk population. Adding nonviral risk factors did not improve NPC prediction.

Toxicokinetic testing strategies to demonstrate bone marrow exposure in in vivo micronucleus study for genotoxicity assessment of agrochemicals.

Following adoption of the new OECD test guideline (TG) 474 for the in vivo mammalian erythrocyte micronucleus (MN) test (29 July 2016), demonstration of exposure of target tissue (bone marrow) is required, if the test result is negative i.e. no cytogenetic damage. It implies that for many active ingredients, relevant metabolites or significant impurities with existing in vivo MN tests resulting in negative genotoxicity findings, evidence of target tissue exposure may be lacking and is considered a data gap in regulatory reviews. We present here toxicokinetic (TK) testing strategies for the design and conduct of studies that would demonstrate evidence of delivery of the test substance to the bone marrow. To illustrate this, three examples are presented with methods utilized under each scenario. We also propose a decision tree that may help design suitable TK studies to establish evidence of bone marrow exposure.

Multilaboratory Assessment of Epstein-Barr Virus Serologic Assays: the Case for Standardization.

IgA antibodies targeting Epstein-Barr virus (EBV) have been proposed for screening for nasopharyngeal carcinoma (NPC). However, methods differ, and the antigens used in these assays differ considerably between laboratories. To enable formal comparisons across a range of established EBV serology assays, we created a panel of 66 pooled serum samples and 66 pooled plasma samples generated from individuals with a broad range of IgA antibody levels. Aliquots from these panels were distributed to six laboratories and were tested by 26 assays measuring antibodies against VCA, EBNA1, EA-EBNA1, Zta, or EAd antigens. We estimated the correlation between assay pairs using Spearman coefficients (continuous measures) and percentages of agreement (positive versus negative, using predefined positivity cutoffs by each assay developer/manufacturer). While strong correlations were observed between some assays, considerable differences were also noted, even for assays that targeted the same protein. For VCA-IgA assays in serum, two distinct clusters were identified, with a median Spearman coefficient of 0.41 (range, 0.20 to 0.66) across these two clusters. EBNA1-IgA assays in serum grouped into a single cluster with a median Spearman coefficient of 0.79 (range, 0.71 to 0.89). Percentages of agreement differed broadly for both VCA-IgA (12% to 98%) and EBNA1-IgA (29% to 95%) assays in serum. Moderate-to-strong correlations were observed across assays in serum that targeted other proteins (correlations ranged from 0.44 to 0.76). Similar results were noted for plasma. We conclude that standardization of EBV serology assays is needed to allow for comparability of results obtained in different translational research studies across laboratories and populations.

Reproductive history and risk of nasopharyngeal carcinoma: A population-based case-control study in southern China.

OBJECTS: Nasopharyngeal carcinoma (NPC) incidence exhibits a remarkable sex disparity, with higher risk among males. Whether this pattern can be partly explained by female reproductive history is unclear. METHODS: A population-based case-control study of NPC was conducted in southern China between 2010 and 2014, including 674 histopathologically verified female NPC cases and 690 female controls randomly selected from population-based registries. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression after adjusting for potential confounders. RESULTS: Women who had 3, 4, or ≥5 pregnancies compared with 2 pregnancies were at significantly increased risk for NPC (ORs 1.56, 1.45 and 1.88, respectively). History of deliveries was similarly associated with a greater risk of NPC. These positive associations were more prominent in women who were younger than 50 years, had less than 10 years of education, or were white-collar workers. Increasing time since menopause was associated with a diminished NPC risk (Ptrend = 0.010). Women more than 15 years after menopause had a 0.35-fold (95% CI: 0.16-0.75) NPC risk compared with those 0-3 years after menopause. CONCLUSION: Contrary to our hypothesis, a history of pregnancy or delivery increased the risk of NPC and the risk decreased with increasing time since menopause. However, the non-linear relationship and no consistent risk patterns across strata indicate that the observed associations are unlikely to be causal, and may at least partially be ascribed to residual confounding by socioeconomic factors.

Quantitative Ultrasound Assessment of Cartilage Degeneration in Ovariectomized Rats with Low Estrogen Levels.

The aim of this study was to assess quantitatively the site-specific degeneration of articular cartilage in ovariectomized rats with low estrogen levels using a high-frequency ultrasound system. Fourteen female Sprague-Dawley rats were randomly divided into two groups (n = 7 per group): a sham group in which only the peri-ovarian fatty tissue was exteriorized and an ovariectomized group that underwent bilateral ovariectomy to create a menopause model with low estrogen levels. All animals were sacrificed at the end of the third week after ovariectomy. Hindlimbs were harvested. The articular cartilage from five anatomic sites (i.e., femoral caput [FC], medial femoral condyle [MFC], lateral femoral condyle [LFC], medial tibial plateau [MTP] and lateral tibial plateau [LTP]) was examined with ultrasound. Four parameters were extracted from the ultrasound radiofrequency data: reflection coefficient of the cartilage surface (RC1), reflection coefficient of the cartilage-bone interface (RC2), ultrasound roughness index (URI) and thickness of the cartilage tissue. The results indicated significant (p < 0.05) site dependence for cartilage thickness, URI and RC1 in the sham group. The 3-wk post-menopause ovariectomized rats exhibited significant increases (p < 0.05) in the URI at the LFC, MTP and LTP; significant decreases (p < 0.05) in RC1 at the FC, LFC and MTP; and significant decreases (p < 0.05) in cartilage thickness at the MFC, LFC, MTP and LTP. These results of this study suggest that post-menopausal estrogen reduction induces morphologic and acoustic alterations in the articular cartilage of the hip and knee joints in ovariectomized rats.

[Assessment of hepatic reserve function of cirrhosis liver using dynamic SPECT (99m)Tc-galactosyl human serum albumin scintigraphy].

OBJECTIVE: To evaluate the effectiveness of dynamic SPECT (99m)Tc-galactosyl human serum albumin (GSA) scintigraphy on the assessment of reserve function of cirrhosis liver. METHODS: From January 2010 to December 2011, 55 patients with cirrhosis liver were enrolled in this study. The case numbers of male and female were 43 and 12 respectively and the age was (51 ± 9) years (ranging from 35 to 69 years). After routine biochemistry test, CT scan and (99m)Tc-GSA dynamic SPECT scan were performed in turn using a juxtaposed SPECT/CT system. Then the morphologic volume of liver parenchyma (MLV), functional liver volume (FLV) and the hepatic cell absorption rate constant (GSA-K) were calculated. The correlations between GSA-K and routine biochemistry test, Child-Pugh score, indocyanine green clearance rate (ICG-K) were analyzed. The patients were further divided into 3 groups according to whether there was occlusion or stenosis in the main branch of left portal vein (group 1, n = 5), right portal vein (group 2, n = 13) or not (group 3, n = 37) and the regional hepatic functions index of the 3 groups were compared. RESULTS: The value of FLV of the whole, left and right liver was (594 ± 152) ml, (244 ± 119) ml and (356 ± 171) ml, respectively. There were correlations between GSA-K and total bilirubin, prothrombintime, Child-Pugh score and ICG-K (r = -0.730--0.298, P < 0.05). The FLV and MLV ratios of involved hemiliver to uninvolved hemiliver were 0.09 ± 0.06 and 0.30 ± 0.14 in group 1, 0.57 ± 0.43 and 1.08 ± 0.63 in group 2, 0.71 ± 0.30 and 0.71 ± 0.48 in group 3. The difference in MLV-FLV ratio was signifcant between group 1 and group 3, between group 2 and group 3 (P = 0.000). CONCLUSIONS: The dynamic SPCECT (99m)Tc-GSA scintigraphy can not only assess the whole liver function of cirrhosis liver effectively, but also evaluate the variation of regional liver function accurately.

Carbofuran occupational dermal toxicity, exposure and risk assessment.

BACKGROUND: Carbofuran is a carbamate insecticide that inhibits AChE. Although toxic by ingestion in mammals, it has low dermal toxicity, with relatively few confirmed worker illnesses. This risk assessment describes its time of onset, time to peak effect and time to recovery in rats using brain AChE inhibition in acute and 21 day dermal studies; in vitro rat/human relative dermal absorption for granular (5G) and liquid (4F) formulations; occupational exposure estimates using the Pesticide Handlers' Exposure Database and Agricultural Handlers' Exposure Database (PHED/AHED). RESULTS: The point of departure for acute risk calculation (BMDL(10)) was 6.7 mg kg(-1) day(-1) for brain AChE inhibition after 6 h exposure. In a 21 day study, the BMDL(10) was 6.8 mg kg(-1) day(-1), indicating reversibility. At 75 mg kg(-1) day(-1), time of onset was ≤ 30 min and time to peak effect was 6-12 h. Rat skin had ca tenfold greater dermal absorption of carbofuran (Furadan(®) 5G or 4F) than human skin. Exposure estimates for 5G in rice and 4F in ten crops had adequate margins of exposure (>100). CONCLUSION: Rat dermal carbofuran toxicity was assessed in terms of dose and time-related inhibition of AChE. Comparative dermal absorption in rats was greater than in humans. Worker exposure estimates indicated acceptable risk for granular and liquid formulations of carbofuran.

Quantitative Assessment of Force Fields on Both Low-Energy Conformational Basins and Transition-State Regions of the (ϕ-ψ) Space.

The free energy surfaces (FESs) of alanine dipeptide are studied to illustrate a new strategy to assess the performance of classical molecular mechanics force field on the full range of the (ϕ-ψ) conformational space. The FES is obtained from metadynamics simulations with five commonly used force fields and from ab initio density functional theory calculations in both gas phase and aqueous solution. The FESs obtained at the B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d,p) level of theory are validated by comparison with previously reported MP2 and LMP2 results as well as with experimentally obtained probability distribution between the C5-ß (or ß-PPII) and αR states. A quantitative assessment is made for each force field in three conformational basins, LeRI (C5-ß-C7eq), LeRII (ß2-αR), and LeRIII(αL-C7ax-αD) as well as three transition-state regions linking the above conformational basins. The performance of each force field is evaluated in terms of the average free energy of each region in comparison with that of the ab initio results. We quantify how well a force field FES matches the ab initio FES through the calculation of the standard deviation of a free energy difference map between the two FESs. The results indicate that the performance varies largely from region to region or from force field to force field. Although not one force field is able to outperform all others in all conformational areas, the OPLSAA/L force field gives the best performance overall, followed by OPLSAA and AMBER03. For the three top performers, the average free energies differ from the corresponding ab initio values from within the error range (<0.4 kcal/mol) to ∼1.5 kcal/mol for the low-energy regions and up to ∼2.0 kcal/mol for the transition-state regions. The strategy presented and the results obtained here should be useful for improving the parametrization of force fields targeting both accuracy in the energies of conformers and the transition-state barriers.