The distinct spatiotemporal evolutionary landscape of HBV and HDV largely determines the unique epidemic features of HDV globally.

Chronic infection of hepatitis B virus (HBV) and hepatitis D virus (HDV) causes the most severe form of viral hepatitis. Due to the dependence on HBV, HDV was deemed to co-evolve and co-migrate with HBV. However, we previously found that the naturally occurred HDV/HBV combinations do not always reflect the most efficient virological adaptation (Wang et al., 2021). Moreover, regions with heavy HBV burden do not always correlate with high HDV prevalence (e.g., East Asia), and vice versa (e.g., Central Asia). Herein, we systematically elucidated the spatiotemporal evolutionary landscape of HDV to understand the unique epidemic features of HDV. We found that the MRCA of HDV was from South America around the late 13th century, was globally dispersed mainly via Central Asia, and evolved into eight genotypes from the 19th to 20th century. In contrast, the MRCA of HBV was from Europe ∼23.7 thousand years ago (Kya), globally dispersed mainly via Africa and East Asia, and evolved into eight genotypes ∼1100 years ago. When HDV stepped in, all present-day HBV genotypes had already formed and its global genotypic distribution had stayed stable geographically. Nevertheless, regionalized HDV adapted to local HBV genotypes and human lineages, contributing to the global geographical separation of HDV genotypes. Additionally, a sharp increase in HDV infections was observed after the 20th century. In conclusion, HDV exhibited a distinct spatiotemporal distribution path compared with HBV. This unique evolutionary relationship largely fostered the unique epidemic features we observe nowadays. Moreover, HDV infections may continue to ramp up globally, thus more efforts are urgently needed to combat this disease.

Effect of carboxyl group on photoelectrochemical performance of TiO2nanowire arrays for water splitting.

TiO2is one of the most studied semiconductor materials for the photoelectrochemical water splitting to hydrogen production, but it only responds to ultraviolet light. The introduction of organic compound is one of the common means to expand the visible light response of TiO2. In this work, rutile TiO2nanowire arrays (NWs) were grown on conductive glass by a modified solvothermal method using oleic acid as the key additive. The obtained TiO2NWs are characterized using x-ray diffraction, x-ray photoelectron spectroscopy, infrared spectroscopy and electrochemical characterization. The results show that the carboxyl groups arising from oleic acid are chemically bonded with the TiO2NWs in the form of chelating bidentate, which increases the visible light absorption range and active sites of TiO2, and reduces the transfer resistance between the photoelectrode and the electrolyte. The photocurrent density is doubled to 0.17 mA cm-2at 1.23 V vs. RHE. This work provides a novel idea for the design of metal oxide semiconductor photoanodes by adsorbing organic compounds.

Association of ESR1 gene polymorphisms with the susceptibility to Hepatitis B virus infection and the clinical outcomes.

Estrogen receptor alpha (ESR1) has been implicated in the pathological process of Hepatitis B virus (HBV) infection and is probably an important determinant for gender differences. In this study, a total of 975 subjects including 368 healthy controls, 323 hepatocellular carcinoma (HCC) patients with HBsAg positive, and 284 HBV-infected subjects without HCC were included. Three single nucleotide polymorphisms of ESR1 (rs2234693, rs2077647, rs2228480) were detected to investigate the correlation between ESR1 polymorphisms and the susceptibility to HBV persistence and the clinical outcomes. The association of ESR1 polymorphisms with HCC prognosis was investigated in our cohort enrolling 376 HBV-HCC patients. The frequency of rs2234693 C allele was lower in chronic Hepatitis B (CHB) and liver cirrhosis (LC) than that in HCC patients in the males (adjusted odds ratio [AOR] = 0.63, 95% confidence interval [CI] = 0.41-0.96). rs2228480 A allele was associated with increased risk of LC (AOR = 2.20, 95% CI = 1.06-4.56) in HBV genotype C, and significantly decreased the risk of HCC recurrence (p = 0.010) and ESR1 mRNA level in tumor tissues (p = 0.032). Haplotype C-G-G was associated with significantly increased risk of HBV persistence (OR = 1.37, 95% CI = 1.08-1.73), while it was opposite for C-A-G and T-G-G (OR = 0.41, 95% CI = 0.27-0.62; OR = 0.53, 95% CI = 0.32-0.85, respectively). These results imply that combinations of these ESR1 polymorphisms may be valuable for the prediction of HBV persistence.

Transcriptional repression and apoptosis influence the effect of APOBEC3A/3B functional polymorphisms on biliary tract cancer risk.

APOBEC3-related somatic mutations are predominant in biliary tract cancers (BTCs). We aimed to elucidate the roles of APOBEC3A/3B functional polymorphisms and their influencing factors on the development of cholangiocarcinoma (CCA) and gallbladder cancer (GBC). Polymorphisms at the promoter regions of APOBEC3A and APOBEC3B were genotyped in 3231 participants using quantitative PCR. Dual-luciferase reporter assay was applied to investigate the promoter activity. The difference in gene accessibility between CCA cells and GBC cells was analyzed through single-cell transposase accessible chromatin sequencing. The effect of APOBEC3A on apoptosis was examined by cytometry. It is found that rs2267401-G at the APOBEC3B promoter decreases CCA risk (age-, gender-adjusted odds ratio [AOR], 0.69; 95% confidence interval [CI], 0.51-0.94) but increases GBC risk (AOR, 2.04; 95% CI, 1.35-3.10). rs2267401-G confers a decreased APOBEC3B promoter activity in CCA cells but an increased activity in GBC cells, possibly because the transcriptional repressor TFAP2A is over-expressed in CCA. Tumor necrosis factor-α (TNF-α) increases the level of APOBEC3B via inhibiting TFAP2A expression rather than directly increasing the accessibility of APOBEC3B promoter. APOBEC3A promoter rs12157810-C decreased the risks of CCA and GBC, with an AOR (95% CI) of 0.80 (0.66-0.97) and 0.75 (0.59-0.95), respectively. rs12157810-C upregulated the promoter activity in both CCA and GBC cells. TNF-α upregulated the activity of the APOBEC3A promoter with rs12157810-C via increasing the accessibility of Ets-1 p68. APOBEC3A overexpression attenuates cancer evolution by causing apoptosis, in contrast to APOBEC3B. The heterogeneity in the transcriptional regulation of APOBEC3B affects the evolutionary potential of cancer cells in the inflammatory microenvironment.

Assessing the responses of vegetation to meteorological drought and its influencing factors with partial wavelet coherence analysis.

The increase in drought frequency in recent years is considered as an important factor affecting vegetation diversity. Understanding the responses of vegetation dynamics to drought is helpful to reveal the behavioral mechanisms of terrestrial ecosystems and propose effective drought control measures. In this study, long time series of Normalized Difference Vegetation Index (NDVI) and Solar-induced chlorophyll fluorescence (SIF) were used to analyze the vegetation dynamics in the Pearl River Basin (PRB). The relationship between vegetation and meteorological drought was evaluated, and the corresponding differences among different vegetation types were revealed. Based on an improved partial wavelet coherence (PWC) analysis, the influences of teleconnection factors (i.e., large-scale climate patterns and solar activity) on the response relationship between meteorological drought and vegetation were quantitatively analyzed to determine the roles of factors. The results indicate that (a) vegetation in the PRB showed an increasing trend from 2001 to 2019, and the SIF increased more than that of NDVI; (b) the vegetation response time (VRT) based on NDVI (VRTN) was typically 4-6 months, while the VRT based on SIF (VRTS) was typically 2-4 months. The VRT was shortest in the woody savannas and longest in the evergreen broadleaf forests. (c) The relationship between the SIF and meteorological drought was more significant than that between the NDVI and meteorological drought. (d) There was a significant positive correlation between meteorological drought and vegetation in the period of 8-20 years. The El Niño Southern Oscillation (ENSO), Pacific Decadal Oscillation (PDO) and sunspots were important driving factors affecting the response relationship between drought and vegetation. Specifically, the PDO had the greatest impacts among these factors.

Photosynthesis of winter wheat effectively reflected multiple physiological responses under short-term drought-rewatering conditions.

BACKGROUND: Based on the interrelationship among photosynthesis (Pn), water consumption and drought resistance physiology under water changes, this study aimed to explore whether easily measured Pn could be used to reflect the physiological state of winter wheat and soil moisture. The study was a greenhouse pot experiment, with three growth periods and four gradients of moisture. RESULTS: The instantaneous water use efficiency of wheat improved significantly under short-term regulated deficit irrigation conditions. The photosynthetic parameters could effectively reflect the level of soil moisture (receiver operating characteristic curve analysis, area under the curve = 0.683-0.988). There was a significant correlation between Pn and yield under drought and rewatering (P < 0.05). The water consumption of winter wheat was significantly reduced by 15.5% to 47.6% (P < 0.05) during drought owing to the reduction of stomatal conductance and transpiration rate (Tr). There was a significant linear relationship between Tr and daily water consumption (R2 > 0.745, P< 0.05). There was a significant quadratic linear relationship (R2 > 0.600, P < 0.05) between Pn and the drought resistance indicators. The protective effect of drought resistance physiology on Pn was more significant during drought than during rewatering. Among the four physiological indicators of drought resistance, the relationship between peroxidase activity and Pn was relatively close (grey relational analysis, GRO = 1). CONCLUSIONS: The photosynthetic parameters during conditions of short-term water changes could effectively reflect the status of soil moisture, water consumption, yield and drought resistance. A focus on Pn and the rational use of related relationships are conducive to the selection of drought-resistant varieties and developing refined agricultural management. © 2021 Society of Chemical Industry.

Compartmentalized evolution of hepatitis B virus contributes differently to the prognosis of hepatocellular carcinoma.

Serum hepatitis B virus (HBV) mutations can predict hepatocellular carcinoma (HCC) occurrence. We aimed to clarify if HBV evolves synchronously in the sera, adjacent liver and tumors and predict HCC prognosis equally. A total of 203 HBV-positive HCC patients with radical hepatectomy in Shanghai, China, during 2011-15 were enrolled in this prospective study. Quasispecies complexity (QC) in HBV core promoter region was assessed using clone-based sequencing. We performed RNA sequencing on tumors and paired adjacent tissues of another 15 HCC patients and analyzed it with three public data sets containing 127 samples. HBV QC was positively correlated to APOBEC3s' expression level (r = 0.28, P < 0.001), higher in the adjacent tissues than in the tumors (P = 6.50e-3), and higher in early tumors than in advanced tumors (P = 0.039). The evolutionary distance between the sera-derived HBV strains and the tumor-derived ones was significantly longer than that between the sera-derived ones and the adjacent tissue-derived ones (P < 0.001). Multivariate Cox regression analyses indicated that high HBV QC in the sera predicted an unfavorable overall survival (P = 0.002) and recurrence-free survival (RFS; P = 0.004) in HCC, whereas, in the tumors, it predicted a favorable RFS (P < 0.001). APOBECs-related HBV mutations, including G1764A, were more frequent in the sera than in the adjacent tissues. High-frequent A1762T/G1764A in the sera predicted an unfavorable RFS (P < 0.001), whereas, in the tumors, it predicted a favorable RFS (P = 0.035). In conclusion, HBV evolves more advanced in the sera than in the tumors. HBV QC and A1762T/G1764A in the sera and tumors have contrary prognostic effects in HCC.

Polyethylene Glycol 40-Modified Peptide with High Therapeutic Efficacy in Simian-Human Immunodeficiency Virus-Acutely Infected Rhesus Monkeys.

Anti-human immunodeficiency virus type 1 (anti-HIV-1) fusion peptides have been studied for nearly 2 decades, but few candidates have found useful clinical applications. One factor underlying the failure of such agents to reach the clinic is their poor pharmacokinetic properties, and many efforts have been made to overcome this problem. In this study, we modified C34, a peptide inhibitor of HIV-1 fusion, at its conserved glycosylation site using polyethylene glycols (PEGs) of different molecular weights. PEG40-NC, a conjugate of C34 and branched PEG 40 kDa (PEG40), which has been previously shown to improve the pharmacokinetic profiles of proteins, showed a significantly extended half-life (t1/2; 10.39 h in rats), which compensated for decreased in vitro activity (50% effective concentration [EC50] of 18.51 nM). PEG40-NC also showed a mechanism of action similar to that of C34. PEG40-NC monotherapy in acutely simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys significantly suppressed viral load compared with a control treatment. Efficacy was linked to the extended half-life and lymphatic exposure conferred by attached PEG40. These results highlight the potential of further clinical investigations of PEG40-NC in combination with antiretroviral therapy or other anti-HIV agents.IMPORTANCE Poor pharmacokinetics have severely hindered the clinical use of anti-HIV peptides. Different small molecules, such as lipid, cholesterol, and small PEG, were designed to modify peptides to improve their pharmacokinetics. In this study, we incorporated large branched PEG to anti-HIV peptide and obtained a conjugate with extended half-life and improved in vivo efficacy. The strategy we developed in this study can also be applicable for the development of other peptide candidates.

Increase in HIV-1-transmitted drug resistance among ART-naïve youths at the China-Myanmar border during 2009 ~ 2017.

BACKGROUND: HIV-transmitted drug resistance (TDR) is found in antiretroviral therapy (ART)-naïve populations infected with HIV-1 with TDR mutations and is important for guiding future first- and second-line ART regimens. We investigated TDR and its effect on CD4 count in ART-naïve youths from the China-Myanmar border near the Golden Triangle to better understand TDR and effectively guide ART. METHODS: From 2009 to 2017, 10,832 HIV-1 infected individuals were newly reported along the Dehong border of China, 573 ART-naïve youths (16 ~ 25 y) were enrolled. CD4 counts were obtained from whole blood samples. HIV pol gene sequences were amplified from RNA extracted from plasma. The Stanford REGA program and jpHMM recombination prediction tool were used to determine genotypes. TDR mutations (TDRMs) were analyzed using the Stanford Calibrated Population Resistance tool. RESULTS: The most common infection route was heterosexuals (70.51%), followed by people who inject drugs (PWID, 19.20%) and men who have sex with men (MSM) (8.90%). The distribution of HIV genotypes mainly included the unique recombinant form (URF) (44.08%), 38.68% were CRFs, 13.24% were subtype C and 4.04% were subtype B. The prevalence of TDR increased significantly from 2009 to 2017 (3.48 to 9.48%) in ART-naïve youths (4.00 to 13.16% in Burmese subjects, 3.33 to 5.93% in Chinese subjects), and the resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) were 3.49, 2.62, and 0.52%, respectively. Most (94.40%, n = 34) of HIV-1-infected patients with TDRM had mutation that conferred resistance to a single drug class. The most common mutations Y181I/C and K103N, were found in 7 and 9 youths, respectively. The mean CD4 count was significantly lower among individuals with TDRMs (373/mm3 vs. 496/mm3, p = 0.013). CONCLUSIONS: The increase in the prevalence of HIV-1 TDR increase and a low CD4 count of patients with TDRMs in the China-Myanmar border suggests the need for considering drug resistance before initiating ART in HIV recombination hotspots.

Propagation of meteorological to hydrological drought for different climate regions in China.

Drought can lead to considerable agricultural, ecological, and societal damage. Improving our understanding of the propagation relationship between meteorological and hydrological drought is necessary to lessen drought impacts. The different drought responses and underlying mechanisms among different climate types are not yet sufficiently understood. By applying the standardized precipitation index and standardized runoff index, we investigated the propagation relationship between meteorological and hydrological drought. Because of short-term response between meteorological and hydrological droughts, the propagation time was considered among time scales of 1-12 months. Wavelet analysis was employed to examine the two types of drought from 1902 to 2014. Our results showed that arid environments had a weaker propagation relationship than moist environments. There was a stronger relationship between the two types of drought in summer and autumn than in spring and winter. The climate was not the only factor impacting drought propagation; land (cover and topographic feature) may also impact propagation time and intensity from meteorological to hydrological drought. This study analyzed and highlighted that the most susceptible regions in China and global scale, respectively. The most susceptible regions were tropical and subtropical Chinese southern zones in China and equatorial and warm temperate climate zones in global; however, arid climate zones showed little interaction between the two kinds of drought. Other factors that impact drought propagation, such as land cover, landforms, and human activity, should be considered in future research.

Associations of socioeconomic factors with cause-specific Mortality and burden of cardiovascular diseases: findings from the vital registration in urban Shanghai, China, during 1974-2015.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality worldwide. The effect of socioeconomic factors on cause-specific mortality and burden of CVD is rarely evaluated in low- and middle-income countries, especially in a rapidly changing society. METHODS: Original data were derived from the vital registration system in Yangpu, a representative, population-stable district of urban Shanghai, China, during 1974-2015. Temporal trends for the mortality rates and burden of CVD during 1974-2015 were evaluated using Joinpoint Regression Software. The burden was evaluated using age-standardized person years of life loss per 100,000 persons (SPYLLs). Age-sex-specific CVD mortality rates were predicted by using age-period-cohort Poisson regression model. RESULTS: A total of 101,822 CVD death occurred during 1974-2015, accounting for 36.95% of total death. Hemorrhagic stroke, ischemic heart disease, and ischemic stroke were the 3 leading causes of CVD death. The age-standardized CVD mortality decreased from 144.5/100,000 to 100.7/100,000 in the residents (average annual percentage change [AAPC] -1.0, 95% confidence interval [CI] -1.7 to - 0.2), which was mainly contributed by women (AAPC -1.3, 95% CI - 2.0 to - 0.7), not by men. Hemorrhagic stroke, the major CVD death in the mid-aged population, decreased dramatically after 1991. The crude mortality of ischemic heart disease kept increasing but its age-adjusted mortality decreased continually after 1997. SPYLLs of CVD death increased from 1974 to 1986 (AAPC 2.1, 95% CI 0.4 to 3.8) and decreased after 1986 (AAPC 1.8, 95% CI - 2.3 to - 1.3). These changes were in concert with the implementation of policies including extended medical insurance coverage, pollution control, active prophylaxis of CVD including lifestyle promotion, and national health programs. The mortality of CVD increased in those born during 1937-1945, a period of the Japanese military occupation, and during 1958-1965, a period including the Chinese Famine. Sequelae of CVD and ischemic heart disease are predicted to be the leading causes of CVD death in 2029. CONCLUSIONS: Exposure to serious malnutrition in early life might increase CVD mortality in later life. Improvements in medical services, pollution control, and lifestyle could decrease CVD death. New strategy is needed to prevent the aging-related CVD death and burden in the future.

Discrepancies in precipitation changes over the Southwest River Basin of China based on ISIMIP3b.

Selecting appropriate global climate models (GCMs) is crucial for minimizing uncertainty in regional climate projections under future scenarios. Previous studies have predominantly assessed the modeling capability of GCMs for regional precipitation climatology and its long-term patterns based on annual and seasonal precipitation data. Building upon these, we primally evaluated the performance of five GCMs from phase 3b of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP3b) in simulating precipitation concentration and its variations in the Southwest River Basin (SWRB) of China using the precipitation concentration index (PCI). The results indicate that: (1) The 5 GCMs generally capture the spatial distribution of annual average precipitation in the SWRB but significantly overestimate its magnitude, with a maximum regional average deviation of 207.80 mm. Furthermore, all models tend to overestimate the overall drying trend in the SWRB and show limited capability in simulating interdecadal variations of annual precipitation. (2) While the 5 GCMs reasonably simulate the spatial distribution of annual average PCI in the SWRB, they tend to overestimate its values, with a maximum regional average deviation of 1.54. Additionally, their simulation performance in capturing PCI trends and interdecadal variations is also limited. (3) The 5 GCMs tend to overestimate seasonal precipitation in the SWRB, with the best simulation performance for the distribution of autumn precipitation, followed by spring and summer, and the poorest for winter. Significant differences exist in the simulation performance of the models for seasonal precipitation proportions, which result in discrepancies in the models' representation of PCI. Moreover, the models' poor simulation performance of PCI trends is partly due to their inadequate modeling of trends in seasonal precipitation proportions. The findings will contribute to laying the foundation for meteorological hydrological research and water resource management in the SWRB.

Trends in disease burden and risk factors of asthma from 1990 to 2019 in Belt and Road Initiative countries: evidence from the Global Burden of Disease Study 2019.

This study outlines asthma burden trends across age, sex, regions and risk factors in 'Belt and Road' (B&R) countries from 1990 to 2019 using the Global Burden of Disease Study 2019 data. Incidence, mortality, prevalence, years lived with disability (YLDs), disability-adjusted life years (DALYs) and risk factors for asthma were measured. India, China and Indonesia bore the heaviest burden in 2019. Despite the significant decline in the average annual percent change for age-standardized mortality and years of life lost from 1990 to 2019, increases were observed in several East Asian, Central Asian, North African and Middle Eastern countries between 2010 and 2019. For both sexes, YLDs decreased in most B&R countries but increased in Montenegro, Saudi Arabia, Armenia, Vietnam and Oman. YLDs in Georgia, the United Arab Emirates and Albania increased in males but decreased in females. YLDs increased for those aged <15 years in Central Asia and Europe, while China's 50-74-year age group showed the lowest YLD change. High body mass index (BMI) led to increased YLDs in East, Central and Southeast Asia; North Africa; and the Middle East. Conclusively, asthma burden varies significantly by country. Tailoring control efforts to specific regions, sex and high BMI could enhance asthma management.

Assessments of various precipitation product performances and disaster monitoring utilities over the Tibetan Plateau.

The Tibetan Plateau, often referred to as Asia's water tower, is a focal point for studying spatiotemporal changes in water resources amidst global warming. Precipitation is a crucial water resource for the Tibetan Plateau. Precipitation information holds significant importance in supporting research on the Tibetan Plateau. In this study, we estimate the performance and applicability of Climate Prediction Center Merged Analysis of Precipitation (CMAP), Integrated Multi-Satellite Retrievals for Global Precipitation Measurement (IMERG), Global Land Data Assimilation System (GLDAS), and Global Precipitation Climatology Project (GPCP) precipitation products for estimating precipitation and different disaster scenarios (including extreme precipitation, drought, and snow) across the Tibetan Plateau. Extreme precipitation and drought indexes are employed to describe extreme precipitation and drought conditions. We evaluated the performance of various precipitation products using daily precipitation time series from 2000 to 2014. Statistical metrics were used to estimate and compare the performances of different precipitation products. The results indicate that (1) Both CMAP and IMERG showed higher fitting degrees with gauge precipitation observations in daily precipitation. Probability of detection, False Alarm Ratio, and Critical Success Index values of CMAP and IMERG were approximately 0.42 to 0.72, 0.38 to 0.56, and 0.30 to 0.42, respectively. Different precipitation products presented higher daily average precipitation amount and frequency in southeastern Tibetan Plateau. (2) CMAP and GPCP precipitation products showed relatively great and poor performance, respectively, in predicting daily and monthly precipitation on the plateau. False alarms might have a notable impact on the accuracy of precipitation products. (3) Extreme precipitation amount could be better predicted by precipitation products. Extreme precipitation day could be badly predicted by precipitation products. Different precipitation products showed that the bias of drought estimation increased as the time scale increased. (4) GLDAS series products might have relatively better performance in simulating (main range of RMSE: 2.0-4.5) snowfall than rainfall and sleet in plateau. G-Noah demonstrated slightly better performance in simulating snowfall (main range of RMSE: 1.0-2.1) than rainfall (main range of RMSE: 2.0-3.8) and sleet (main range of RMSE: 1.5-3.8). This study's findings contribute to understanding the performance variations among different precipitation products and identifying potential factors contributing to biases within these products. Additionally, the study sheds light on disaster characteristics and warning systems specific to the Tibetan Plateau.

Prospective cohort studies underscore the association of abnormal glycemic measures with all-cause and cause-specific mortalities.

The role of fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and triglyceride-glucose index (TyG index) in predicting all-cause and cause-specific mortalities remains elusive. This study included 384,420 adults from the Shanghai cohort and the UK Biobank (UKB) cohort. After multivariable adjustment in the Cox models, FPG ≥7.0 mmol/L or HbA1c ≥ 6.5% increased the risk of all-cause mortality, FPG ≥5.6 mmol/L or HbA1c ≥ 6.5% increased CVD-related mortality, and higher or lower TyG index increased all-cause and CVD-related mortalities in the Shanghai cohort; FPG ≥5.6 mmol/L, HbA1c ≥ 5.7%, TyG index <8.31 or ≥9.08 increased the risks of all-cause, CVD-related, and cancer-related mortalities in the UKB cohort. FPG or HbA1c increased the discrimination of the conventional risk model in predicting all-cause and CVD-related mortalities in both cohorts. Thus, increased levels of FPG and HbA1c and U-shaped TyG index increase the risks of all-cause especially CVD-related mortalities.

Molecular determinants within the C-termini of L-HDAg that regulate hepatitis D virus replication and assembly.

Background & Aims: Hepatitis D virus (HDV) is the causative agent of chronic hepatitis delta, the most severe form of viral hepatitis. HDV encodes one protein, hepatitis delta antigen (HDAg), in two isoforms: S- and L-HDAg. They are identical in sequence except that L-HDAg contains an additional 19-20 amino acids at its C-terminus, which confer regulatory roles that are distinct from those of S-HDAg. Notably, these residues are divergent between different genotypes. We aimed to elucidate the molecular determinants within the C-termini that are essential for the regulatory role of L-HDAg in HDV replication and assembly. Methods: Northern blot, reverse-transcription quantitative PCR, and a newly established HDV trans-complementary system were used in this study. Results: C-termini of L-HDAg, albeit with high sequence variation among different genotypes, are interchangeable with respect to the trans-inhibitory function of L-HDAg and HDV assembly. The C-terminus of L-HDAg features a conserved prenylation CXXQ motif and is enriched with proline and hydrophobic residues. Abolishment of the CXXQ motif attenuated the inhibitory effect of L-HDAg on HDV replication. In contrast, the enrichment of proline and hydrophobic residues per se does not modify the trans-inhibitory function of L-HDAg. Nevertheless, these residues are essential for HDV assembly. Mechanistically, prolines and hydrophobic residues contribute to HDV assembly via a mode of action independent of the prenylated CXXQ motif. Conclusions: Within the C-terminus of L-HDAg, the CXXQ motif and the enrichment of proline and hydrophobic residues are all essential determinants of L-HDAg's regulatory roles in HDV replication and assembly. This intrinsic viral regulatory mechanism we elucidated deepens our understanding of the unique life cycle of HDV. Impact and implications: Hepatitis D virus (HDV) encodes one protein, hepatitis delta antigen (HDAg), in two isoforms: S- and L-HDAg. They are identical in sequence except that L-HDAg contains an additional 19-20 amino acids at its C-terminus. This C-terminal extension in L-HDAg confers regulatory roles in the HDV life cycle that are distinct from those of S-HDAg. Herein, we found that C-termini of L-HDAg, although with high sequence variation, are interchangeable among different HDV genotypes. Within the C-terminus of L-HDAg, the prenylation motif, and the enrichment of proline and hydrophobic residues are all essential determinants of L-HDAg's regulatory roles in HDV replication and assembly.

Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions.

Hepatitis E virus (HEV) infection can cause severe complications and high mortality, particularly in pregnant women, organ transplant recipients, individuals with pre-existing liver disease and immunosuppressed patients. However, there are still unmet needs for treating chronic HEV infections. Herein, we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds. Upon screening, we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities. Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase (DHODH) inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection. Pyrazofurin selectively targets uridine monophosphate synthetase (UMPS). Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains. Encouragingly, both drugs exhibited a sizeable therapeutic window against HEV. For instance, the IC50 value of vidofludimus calcium is 4.6-7.6-fold lower than the current therapeutic doses in patients. Mechanistically, their anti-HEV mode of action depends on the blockage of pyrimidine synthesis. Notably, two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants (Y1320H, G1634R). Their combination with IFN-α resulted in synergistic antiviral activity. In conclusion, we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections. Based on their antiviral potency, and also the favorable safety profile identified in clinical studies, our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.

Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy.

BACKGROUND: NR4A2, an orphan nuclear receptor essential in the generation of dopaminergic neurons, has been recently linked to inflammation and cancer. This study sought to identify the role of NR4A2 on chemoresistance and postoperative prognosis of gastric cancer (GC). METHODS: NR4A2 was transfected into GC cells to investigate its effects on chemoresistance to 5-fluorouracil and the tumorigenicity in nude mice. This study also investigated prostaglandin E2 (PGE2 )-induced NR4A2 expression and its effect on chemoresistance. Surgical specimens from patients with stage I through III GC were examined immunohistochemically for NR4A2 expression. Median follow-up time was 76 months for 245 patients. RESULTS: Ectopic expression of NR4A2 significantly increased the chemoresistance and attenuated 5-fluorouracil-induced apoptosis. Transient treatment of GC cells with PGE2 significantly upregulated NR4A2 expression via the protein kinase A pathway and increased the chemoresistance. Ectopic expression of NR4A2 significantly increased the tumorigenicity. In clinical samples, NR4A2 was preferentially expressed in lymphocytes and epithelial cytoplasm in adjacent mucosa. High expression of NR4A2 (immunoreactive score ≥ 3) in cancer cells significantly predicted an unfavorable postoperative disease-specific survival of patients with stage I to III GC (P = .011), especially for those who received 5-fluorouracil-based chemotherapy (P = .016). This effect was not found in those without the chemotherapy. In multivariate Cox analyses, age, TNM (tumor/node/metastasis) stage, and high NR4A2 expression significantly predicted an unfavorable postoperative survival. CONCLUSIONS: High NR4A2 expression in GC cells confers chemoresistance, attenuates 5-fluorouracil-induced apoptosis, and predicts an unfavorable survival, especially for those who received chemotherapy. NR4A2 might serve as a prognostic and predictive factor and therapeutic target for patients with GC. Cancer 2013;119:3436-3445.. © 2013 American Cancer Society.

Stress measurement of aero-engine thin-walled catheter based on ultrasonic guided wave.

A pipeline system made of catheters is used for liquid-gas transportation in aero-engines. It is important to measure the residual stresses, such as the assembly stress in this system, as they influence performance and lifetime. Compared to other testing techniques, ultrasonic measurement methods based on acoustic-elastic effects can better solve problems. For the above requirements, this paper researches an aero-engine thin-wall catheter's assembly stress measurement method based on ultrasonic guided waves's acoustic, elastic effect. The propagation and dispersion characteristics of guided ultrasonic waves in the catheter were studied. Then, the excitation frequency, guided wave mode, and single-mode excitation mode of the simulation model were determined. Next, a finite element simulation model was established for simulation experiments. In order to reduce the influence of sampling rate and working environment noise on the measurement accuracy of assembly stress, the ultrasonic guided wave signal was processed by the wavelet threshold method. A good noise reduction effect was obtained by determining the wavelet base and the number of decomposition layers. Finally, an experimental platform was built to measure the assembly stress of thin-walled catheters. The maximum measurement error of the assembly stress of a thin-walled catheter was 21.1 MPa, which verified the feasibility of the measurement method. This study provides a promising method for accurately measuring the assembly stress of thin-walled catheters in aero-engines.

Premature death patterns and trends in diseases of the musculoskeletal system and connective tissue in Shanghai China from 1973 to 2019.

OBJECTIVES: The long-term trends in crude mortality rates (CMRs) and age-standardized mortality rates characterized by Segi's world standard population (ASMRWs) of DMSCT in Pudong New Area (PNA), Shanghai, were evaluated from 1973 to 2019, and the role of demographic and non-demographic factors in the mortality of diseases of the musculoskeletal system and connective tissue (DMSCT) was explored. METHODS: The PNA district has the largest population and area in Shanghai. Therefore, the mortality registration system of the PNA district was used to calculate and verify the number of deaths. Then, the Joinpoint Regression Program was used to analyze the time trend of mortality. The difference decomposition method was used to visualize the mortality of population and non-population factors, and GraphPad Prism was used for image visualization. RESULTS: A total of 2260 deaths from DMSCT occurred from 1973 to 2019. The CMR and ASMRW of DMSCT were 2.56/105 person-years and 1.57/105 person-years, respectively. The number of people aged ≥80 (696 deaths) who died of DMSCT was the highest among total deaths, the highest number of years of life lost (YLL) was observed in the 45-59 age group, and the YLL rate in the ≥80 age group was the highest. The CMR and YLL rates of DMSCT showed upward trends in the total population from 1973 to 2019. CONCLUSION: The CMR and YLL rates of DMSCT showed upward trends in the total population from 1973 to 2019 in PNA, Shanghai, and age was closely related to the occurrence of DMSCT. Similarly, demographic factors played a role in this process.