Targeting RNA G-quadruplex with repurposed drugs blocks SARS-CoV-2 entry.

The rapid emergence of SARS-CoV-2 variants of concern, the complexity of infection, and the functional redundancy of host factors, underscore an urgent need for broad-spectrum antivirals against the continuous COVID-19 pandemic, with drug repurposing as a viable therapeutic strategy. Here we report the potential of RNA G-quadruplex (RG4)-targeting therapeutic strategy for SARS-CoV-2 entry. Combining bioinformatics, biochemical and biophysical approaches, we characterize the existence of RG4s in several SARS-CoV-2 host factors. In silico screening followed by experimental validation identify Topotecan (TPT) and Berbamine (BBM), two clinical approved drugs, as RG4-stabilizing agents with repurposing potential for COVID-19. Both TPT and BBM can reduce the protein level of RG4-containing host factors, including ACE2, AXL, FURIN, and TMPRSS2. Intriguingly, TPT and BBM block SARS-CoV-2 pseudovirus entry into target cells in vitro and murine tissues in vivo. These findings emphasize the significance of RG4 in SARS-CoV-2 pathogenesis and provide a potential broad-spectrum antiviral strategy for COVID-19 prevention and treatment.

Microbial Necromass, Lignin, and Glycoproteins for Determining and Optimizing Blue Carbon Formation.

Coastal wetlands contribute to the mitigation of climate change through the sequestration of "blue carbon". Microbial necromass, lignin, and glycoproteins (i.e., glomalin-related soil proteins (GRSP)), as important components of soil organic carbon (SOC), are sensitive to environmental change. However, their contributions to blue carbon formation and the underlying factors remain largely unresolved. To address this paucity of knowledge, we investigated their contributions to blue carbon formation along a salinity gradient in coastal marshes. Our results revealed decreasing contributions of microbial necromass and lignin to blue carbon as the salinity increased, while GRSP showed an opposite trend. Using random forest models, we showed that their contributions to SOC were dependent on microbial biomass and resource stoichiometry. In N-limited saline soils, contributions of microbial necromass to SOC decreased due to increased N-acquisition enzyme activity. Decreases in lignin contributions were linked to reduced mineral protection offered by short-range-ordered Fe (FeSRO). Partial least-squares path modeling (PLS-PM) further indicated that GRSP could increase microbial necromass and lignin formation by enhancing mineral protection. Our findings have implications for improving the accumulation of refractory and mineral-bound organic matter in coastal wetlands, considering the current scenario of heightened nutrient discharge and sea-level rise.

Risk of heavy metal(loid) compositions in fine particulate matter on acute cardiovascular mortality: a poisson analysis in Anyang, China.

Fine particulate matter (PM2.5) is a risk factor of cardiovascular disease. Associations between PM2.5 compositions and cardiovascular disease are a point of special interest but inconsistent. This study aimed to explore the cardiovascular effects of heavy metal(loid) compositions in PM2.5. Data for mortality, air pollutants and meteorological factors in Anyang, China from 2017 to 2021 were collected. Heavy metal(loid) in PM2.5 were monitored and examined monthly. A Case-crossover design was applied to the estimated data set. The interquartile range increase in cadmium (Cd), antimony (Sb) and arsenic (As) at lag 1 was associated with increment of 8.1% (95% CI: 3.3, 13.2), 4.8% (95% CI: 0.2, 9.5) and 3.5% (95% CI: 1.1, 6.0) cardiovascular mortality. Selenium in lag 2 was inversely associated with cerebrovascular mortality (RR = 0.920 95% CI: 0.862, 0.983). Current-day exposure of aluminum was positively associated with mortality from ischemic heart disease (RR = 1.083 95% CI: 1.001, 1.172). Stratified analysis indicated sex, age and season modified the cardiovascular effects of As (P < 0.05). Our study reveals that heavy metal(loid) play key roles in adverse effects of PM2.5. Cd, Sb and As were significant risk factors of cardiovascular mortality. These findings have potential implications for accurate air pollutants control and management to improve public health benefits.

Mediation of mitochondrial DNA copy number and oxidative stress in fluoride-related bone mineral density alteration in Chinese farmers.

Excessive fluoride can adversely affect bone mineral density (BMD). Oxidative stress and mitochondrial dysfunction are crucial mechanisms of health damage induced by fluoride. Here, a cross-sectional survey involving 907 Chinese farmers (aged 18-60) was carried out in Tongxu County in 2017, aiming to investigate the significance of mitochondrial DNA copy number (mtDNAcn) and oxidative stress in fluoride-related BMD change. Concentrations of urinary fluoride (UF), serum oxidative stress biomarkers, including total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA), as well as relative mtDNAcn in peripheral blood were determined. The multivariable linear model and mediation analysis were performed to assess associations between UF, oxidative stress, and relative mtDNAcn with BMD. Results showed that GSH-Px levels increased by 6.98 U/mL [95% confidence interval (CI) 3.41-10.56)] with each 1.0 mg/L increment of UF. After stratification, the T-AOC, relative mtDNAcn, and BMD decreased by 0.04 mmol/L (-0.08 ~ -0.01), 0.29-unit (-0.55 ~ -0.04), and 0.18-unit (-0.33 ~ -0.03) with every 1.0 mg/L elevation of UF in the excessive fluoride group (EFG, adults with UF > 1.6 mg/L), respectively. Furthermore, T-AOC and relative mtDNAcn were favorably related to the BMD in the EFG (ß = 0.82, 95%CI 0.16-1.48 for T-AOC; ß = 0.11, 95%CI 0.02-0.19 for relative mtDNAcn). Mediation analysis showed that relative mtDNAcn and T-AOC mediated 15.4% and 17.1% of the connection between excessive fluoride and reduced BMD, respectively. Findings suggested that excessive fluoride was related to lower BMD in adults, and the decrement of T-AOC and relative mtDNAcn partially mediate this relationship.

Pan-cancer analysis of G6PD carcinogenesis in human tumors.

Glucose-6-phosphate dehydrogenase (G6PD) is involved in the catalytic pentose phosphate pathway (PPP), which is closely related to energy metabolism. G6PD plays a crucial role in many types of cancer, but the specific molecular mechanisms of G6PD in cancer remain unclear. Therefore, we investigated the potential oncogenic role of G6PD in various tumors based on The Cancer Genome Atlas (TCGA), the cBioPortal datasets, the University of California Santa Cruz (UCSC) Xena browser, and the UALCAN-based online tool. G6PD was highly expressed in several cancer tissues (hepatocellular carcinoma, glioma, and breast cancer) compared with normal tissues and was significantly associated with poor prognosis of hepatocellular carcinoma, clear cell renal cell carcinoma, and breast cancer. Promoter methylation levels of G6PD were lower in Bladder Urothelial Carcinoma (BLCA) (P = 2.77e-02), breast invasive carcinoma (BRCA) (P = 1.62e-12), kidney renal clear cell carcinoma (KIRC) (P = 4.23e-02), kidney renal papillary cell carcinoma (KIRP) (P = 2.64e-03), liver hepatocellular carcinoma (LIHC) (P = 1.76e-02), stomach adenocarcinoma (STAD) (P = 3.50e-02), testicular germ cell tumors (TGCT) (P = 1.62e-12), higher in prostate adenocarcinoma (PRAD) (P = 1.81e-09), and uterine corpus endometrial carcinoma (UCEC) (P = 2.96e-04) compared with corresponding normal tissue samples. G6PD expression was positively correlated with the infiltration level of immune cells in most tumors, suggesting that G6PD may be involved in tumor immune infiltration. In addition, the functional mechanism of G6PD also involves 'Carbon metabolism', 'Glycolysis/Gluconeogenesis', 'Pentose phosphate pathway', and 'Central carbon pathway metabolism in cancer signaling pathway'. This pan-cancer study provides a relatively broad understanding of the oncogenic role of G6PD in various tumors and presents a theoretical basis for the development of G6PD inhibitors as therapeutic drugs for multiple cancers.

Complementary belowground strategies underlie species coexistence in an early successional forest.

Unravelling belowground strategies is critical for understanding species coexistence and successional dynamics; yet, our knowledge of nutrient acquisition strategies of forest species at different successional stages remains limited. We measured morphological (diameter, specific root length, and root tissue density), architectural (branching ratio), physiological (ammonium, nitrate, and glycine uptake rates) root traits, and mycorrhizal colonisation rates of eight coexisting woody species in an early successional plantation forest in subtropical China. By incorporating physiological uptake efficiency, we revealed a bi-dimensional root economics space comprising of an 'amount-efficiency' dimension represented by morphological and physiological traits, and a 'self-symbiosis' dimension dominated by architectural and mycorrhizal traits. The early pioneer species relied on root-fungal symbiosis, developing densely branched roots with high mycorrhizal colonisation rates for foraging mobile soil nitrate. The late pioneer species invested in roots themselves and allocated effort towards improving uptake efficiency of less-mobile ammonium. Within the root economics space, the covariation of axes with soil phosphorus availability also distinguished the strategy preference of the two successional groups. These results demonstrate the importance of incorporating physiological uptake efficiency into root economics space, and reveal a trade-off between expanding soil physical space exploration and improving physiological uptake efficiency for successional species coexistence in forests.

Molecular epidemiology analysis of symptomatic and asymptomatic norovirus infections in Chinese infants.

BACKGROUND: Norovirus is a leading cause of acute gastroenteritis among children. Previous studies based on symptomatic infections indicated that mutations, rather than recombination drove the evolution of the norovirus ORF2. These characteristics were found in hospital-based symptomatic infections, whereas, asymptomatic infections are frequent and contribute significantly to transmission. METHODS: We conducted the first norovirus molecular epidemiology analysis covering both symptomatic and asymptomatic infections derived from a birth cohort study in the northern China. RESULTS: During the study, 14 symptomatic and 20 asymptomatic norovirus infections were detected in 32 infants. Out of the 14 strains that caused symptomatic infections, 12 strains were identified as GII.3[P12], and others were GII.4[P31]. Conversely, 17 asymptomatic infections were caused by GII.4[P31], two by GII.2[P16], and one by GII.4[P16]. Regardless of symptomatic and asymptomatic infections, the mutations were detected frequently in the ORF2 region, and almost all recombination were identified in the RdRp-ORF2 region. The majority of the mutations were located around the predefined epitope regions of P2 subdomain indicating a potential for immune evasion. CONCLUSION: The role of symptomatic as well as asymptomatic infections in the evolution of norovirus needs to be evaluated continuously.

An advanced LC-MS/MS protocol for simultaneous detection of pharmaceuticals and personal care products in the environment.

RATIONALE: The development of appropriate analytical screening techniques for pharmaceuticals and personal care products (PPCPs) is the basis for studying the distribution and environmental impact of emerging contaminants (ECs). Mass spectrometry-based screening methods vary with the complexity of the target compounds. It is challenging to balance both positive and negative ion quantification with a low detection limit. To establish a set of experimental methods including extraction, chromatography-separation and mass spectrometry screening is one of the most important topics in PPCP research. This paper describes a universal and efficient qualification and quantification protocol for the simultaneous detection of 34 PPCPs in different environmental samples in a single analytical data acquisition run. METHODS: Thirty-four representative PPCPs, which are widely distributed in the environment with high ecological toxicity and complex chemical structures, were selected as representative target ECs. The extraction of the target PPCPs was achieved using only one solid-phase extraction cartridge without the need to adjust the pH of samples. The enriched samples were detected by LC-MS/MS in both positive and negative ion modes simultaneously. The protocol was evaluated based on the accuracy, precision, detection limits and matrix effects. RESULTS: This method achieved simultaneous detection of PPCPs in both positive and negative ion modes, with a single analytical cycle of 12 min. The observed SPE recoveries were between 40% and 115%. The instrumental detection limits (IDL) varied from 0.01 to 1 pg, and the method detection limits (MDL) were between 0.002 and 3.323 ng/l in different matrices. Most of the PPCPs were subjected to matrix suppression below 30%. The method was successfully applied for quantitative analysis of the PPCPs in different environmental samples, including river samples, wastewater treatment plant (WWTP) samples and soil samples. CONCLUSIONS: This protocol developed a rapid and efficient detection method to simultaneous qualitative and quantitative 34 representative PPCPs in the environment. The IDL ranged from 0.01 to 1 pg and the MDL ranged from 0.002 to 3.323 ng/l in different matrices. The detection limit was one order of magnitude lower compared to previous studies. The protocol also provided a wide application range for different environmental matrices, which permitted the migration and transformation of PPCPs to be explored.

Mortality trend analysis of ischemic heart disease in China between 2010 and 2019: a joinpoint analysis.

BACKGROUND: This study presented the mortality trend of ischemic heart disease (IHD) in Chinese residents from 2010 to 2019 and provided a basis for further establishment of relevant interventions. METHODS: Data, such as sex, age, urban and rural areas, and death status, were extracted from the China Death Surveillance Dataset from 2010 to 2019, with mortality and age-adjusted death rates (AADRs) as the main indicators. The joinpoint regression model was used to analyze mortality and AADRs trends in IHD. A semi-structured expert interview was conducted to propose targeted intervention measures and countermeasures. RESULTS: We observed an overall upward trend in IHD mortality rates and AADRs in China from 2010 to 2019 (average annual percentage change [AAPC] = 5.14%, AAPCAADRs = 1.60%, P < 0.001). Mortality rates and AADRs increased for both males (AAPC = 4.91%, AAPCAADRs = 1.09%, P < 0.05) and females (AAPC = 5.57%, AAPCAADRs = 1.84%, P < 0.001), with higher mortality rate for males than females but higher variation for females than males. Urban (AAPC = 4.80%, AAPCAADRs = 1.76%, P < 0.05) and rural (AAPC = 5.31%, P < 0.001; AAPCAADRs = 0.99%, P > 0.05) mortality rates increased, with the mortality rate higher in rural areas than in urban areas. In the age analysis, mortality rate was higher in middle-aged and older adults than in other age groups. The age-sex cross-analysis found the highest trend in mortality rates among females aged ≥ 75 years (annual percentage change [APC] = 2.43%, P < 0.05). CONCLUSIONS: The upward trend in IHD mortality in China from 2010 to 2019, especially among female residents aged ≥ 75 years, poses continuing challenges to public health policies and actions.

Microcystin-LR accelerates follicular atresia in mice via JNK-mediated adherent junction damage of ovarian granulosa cells.

Microcystin-LR (MC-LR), one of aquatic environmental contaminants with reproductive toxicity produced by cyanobacterial blooms, but its toxic effects and mechanisms on the ovary are not fully understood. Here, proteomic techniques and molecular biology experiments were performed to study the potential mechanism of MC-LR-caused ovarian toxicity. Results showed that protein expression profile of ovarian granulosa cells (KK-1) was changed by 17 µg/mL MC-LR exposure. Comparing with the control group, 118 upregulated proteins as well as 97 downregulated proteins were identified in MC-LR group. Function of differentially expressed proteins was found to be enriched in pathways related to adherent junction, such as cadherin binding, cell-cell junction, cell adhesion and focal adherens. Furthermore, in vitro experiments, MC-LR significantly downregulated the expression levels of proteins associated with adherent junction (ß-catenin, N-cadherin, and α-catenin) as well as caused cytoskeletal disruption in KK-1 cells (P < 0.05), indicating that the adherent junction was damaged. Results of in vivo experiments have shown that after 14 days of acute MC-LR exposure (40 µg/kg), damaged adherent junction and an increased number of atretic follicles were observed in mouse ovaries. Moreover, MC-LR activated JNK, an upstream regulator of adherent junction proteins, in KK-1 cells and mouse ovarian tissues. In contrast, JNK inhibition alleviated MC-LR-induced adherent junction damage in vivo and in vitro, as well as the number of atretic follicles. Taken together, findings from the present study indicated that JNK is involved in MC-LR-induced granulosa cell adherent junction damage, which accelerated follicular atresia. Our study clarified a novel mechanism of MC-LR-caused ovarian toxicity, providing a theoretical foundation for protecting female reproductive health from environmental pollutants.

Integrated 16S rDNA sequencing and metabolomics to explore the intestinal changes in children and rats with dental fluorosis.

Dental fluorosis (DF) is a widely prevalent disease caused by excessive fluoride with limited awareness of its underlying pathogenesis. Here, a pilot population study was conducted to explore the pathogenesis of DF from the perspective of intestinal microbiome changes, and verified it in animal experiments combining intestinal microbiome and metabolomics. A total of 23 children were recruited in 2017 in China and divided into DF (n = 9) and control (n = 14) groups (DFG and CG, respectively). The SD rat model was established by drinking water containing sodium fluoride (NaF). Gut microbiome profiles of children and rats were analyzed by16S rDNA V3-V4 sequencing, and the intestinal metabolomics analysis of rats was performed by LC-MS methods. The 16 S rDNA sequencing revealed that the gut microbiome composition was significantly perturbed in children in DFG compared to that in CG. Acidobacteria and Thermi were specifically observed in DFG and CG, respectively. Besides, 15 fecal microbiotas were significantly altered at the genus level in DFG. Furthermore, only the expression of annotated genes for pentose and glucuronate interconversion pathway was significant lower in DFG than that in CG (P = 0.04). Notably, in NaF-treated rats, we also observed the changes of some key components of pentose and glucuronate interconversion pathway at the level of microorganisms and metabolites. Our findings suggested that the occurrence of DF is closely related to the alteration of intestinal microorganisms and metabolites annotated in the pentose and glucuronate interconversion pathway.

In Silico Analysis of Ferroptosis-Related Genes and Its Implication in Drug Prediction against Fluorosis.

Fluorosis is a serious global public health problem. Interestingly, so far, there is no specific drug treatment for the treatment of fluorosis. In this paper, the potential mechanisms of 35 ferroptosis-related genes in U87 glial cells exposed to fluoride were explored by bioinformatics methods. Significantly, these genes are involved in oxidative stress, ferroptosis, and decanoate CoA ligase activity. Ten pivotal genes were found by the Maximal Clique Centrality (MCC) algorithm. Furthermore, according to the Connectivity Map (CMap) and the Comparative Toxicogenomics Database (CTD), 10 possible drugs for fluorosis were predicted and screened, and a drug target ferroptosis-related gene network was constructed. Molecular docking was used to study the interaction between small molecule compounds and target proteins. Molecular dynamics (MD) simulation results show that the structure of the Celestrol-HMOX1 composite is stable and the docking effect is the best. In general, Celastrol and LDN-193189 may target ferroptosis-related genes to alleviate the symptoms of fluorosis, which may be effective candidate drugs for the treatment of fluorosis.

Association between fluoride exposure and blood pressure in children and adolescents aged 6 to19 years in the United States: NHANES, 2013-2016.

To examine the association between fluoride exposure and childhood blood pressure (BP), we used data involving 3260 subjects participating in the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016. Both plasma and water fluoride concentrations were measured using the ion-specific electrode. Outcome variables were systolic blood pressure (SBP) and diastolic blood pressure (DBP). For a 1-mg/L increase in water fluoride concentration, the participants' SBP decreased by 0.473 mm Hg (95% CI: -0.860, -0.087). Specifically, inverse associations were found between water fluoride and SBP in girls (ß= -0.423, 95% CI: -0.886, -0.021), adolescents (ß= -0.623, 95% CI: -0.975, -0.272), and non-Hispanic whites (ß= -0.694, 95% CI: -1.237, -0.151). Also, every 1-µmol/L increase in plasma fluoride concentration was associated with a 1.183 mm Hg decrease in SBP among other races (95% CI: -2.258, -0.108). This study suggested that fluoride exposure may affect childhood blood pressure.

Mycorrhizal symbiosis pathway and edaphic fertility frame root economics space among tree species.

The root economics space (RES) is multidimensional and largely shaped by belowground biotic and abiotic influences. However, how root-fungal symbioses and edaphic fertility drive this complexity remains unclear. Here, we measured absorptive root traits of 112 tree species in temperate and subtropical forests of China, including traits linked to functional differences between arbuscular mycorrhizal (AM) and ectomycorrhizal (ECM) hosts. Our data, from known mycorrhizal tree species, revealed a 'fungal-symbiosis' dimension distinguishing AM from ECM species. This divergence likely resulted from the contrasting mycorrhizal evolutionary development of AM vs ECM associations. Increased root tissue cortical space facilitates AM symbiosis, whereas increased root branching favours ECM symbiosis. Irrespective of mycorrhizal type, a 'root-lifespan' dimension reflecting aspects of root construction cost and defence was controlled by variation in specific root length and root tissue density, which was fully independent of root nitrogen content. Within this function-based RES, we observed a substantial covariation of axes with soil phosphorus and nitrate levels, highlighting the role played by these two axes in nutrient acquisition and conservation. Overall, our findings demonstrate the importance of evolved mycorrhizal symbiosis pathway and edaphic fertility in framing the RES, and provide theoretical and mechanistic insights into the complexity of root economics.

The type of previous abortion modifies the association between air pollution and the risk of preterm birth.

BACKGROUND: Air pollution and previous abortion have been reported to be related to preterm birth (PTB). But rare study examined the effect of air pollution on PTB risk among mothers with previous abortion. OBJECTIVE: To estimate the effect of air pollution on PTB and the potential effect modification of previous abortion on such an association in rural part of Henan province (China). METHOD: Based on National Free Preconception Health Examination Project (NFPHEP), information from the medical records of 57,337 mothers with previous abortion were obtained. An inverse distance-weighted model was used to estimate exposure levels of air pollutants. The effect of air pollution on the risk of PTB was estimated with a multiple logistic regression model. Stratified and interaction analyses were undertaken to explore the potential effect modification of previous abortion on this association. RESULTS: The risk of PTB was positively associated with exposure to levels of nitrogen dioxide (NO2; OR: 1.03; 95%CI: 1.02-1.04)], and sulfur dioxide (SO2; 1.04; 1.02-1.07), and negatively associated with ozone (O3) exposure (0.97; 0.97-0.98) during the entire pregnancy. Besides, we observed a positive effect of carbon monoxide (CO) exposure during the third trimester of pregnancy on PTB (1.14; 1.01-1.29). The type of previous abortion could modify the effect of air pollution on the PTB risk (P-interaction < 0.05). Compared with mothers with previous induced abortion, mothers with previous spontaneous abortion carried a higher risk of PTB induced by NO2, CO, and O3. CONCLUSIONS: The risk of PTB was positively associated with levels of NO2, SO2 and CO, and negatively associated with the O3 level. The types of previous abortion could modify the effect of air pollution on PTB. Mothers who had an abortion previously, especially spontaneous abortion, should avoid exposure to air pollution to improve their pregnancy outcome.

Effect of prenatal and postnatal exposure to home renovation on the risk of common cold in preschool children.

Common cold is usually considered to be associated with outdoor climate, but the evidence linking with indoor environmental factors is lacking. The role of indoor renovations during which critical timing window on childhood common cold remains unclear. Therefore, we investigated the effect of exposure to new furniture and/or redecoration during prenatal and postnatal periods on the occurrence and duration of common cold in preschool children. We conducted a retrospective cohort study of 39 782 children aged 3-6 years in seven cities of China. The occurrence and duration of common cold in children, and their lifetime exposures to indoor new furniture and redecoration (including pregnancy, the first year of life, and after one year old) were assessed using a questionnaire administered by the parents. Associations between high frequency (>5 colds) and long duration (≥2 weeks per cold) of common cold during past 12 months and exposure to indoor new furniture/redecoration were examined by logistic regression models in terms of odds ratio (OR) and 95% confidence interval (CI). We found that the prevalence of high frequency and long duration of common cold in preschool children in China were, respectively, 9.2% and 11.9%. Frequent common cold was significantly associated with exposure to indoor new furniture/redecoration during pregnancy, first year, and after 1 year old, respectively, with the ORs (95% CI) = 1.25 (1.12-1.39), 1.11 (1.00-1.25), and 1.09 (1.01-1.18). Furthermore, childhood long duration per cold was associated with exposure to indoor new furniture/redecoration during pregnancy with OR (95% CI) of 1.14 (1.03-1.25) but not with postnatal exposure. We identified that prenatal exposure to home renovation was more critical than postnatal exposure for an increased risk of high frequency and long duration of common cold. Sensitivity analysis showed that the association between prenatal exposure to indoor renovations and the risk of childhood common cold was consistent and robust, and the associations were modified by some personal and indoor environmental factors. Our findings indicated that prenatal and postnatal exposure to home renovation played an important role in the risk of childhood common cold, supporting the hypothesis of "fetal origin of childhood infection."

Role of Glycolysis/Gluconeogenesis and HIF-1 Signaling Pathways in Rats with Dental Fluorosis Integrated Proteomics and Metabolomics Analysis.

Fluoride is widely distributed, and excessive intake will lead to dental fluorosis. In this study, six offspring rats administrated 100 mg/L sodium fluoride were defined as the dental fluorosis group, and eight offspring rats who received pure water were defined as the control group. Differentially expressed proteins and metabolites extracted from peripheral blood were identified using the liquid chromatography tandem mass spectrometry and gas chromatography mass spectrometry, with the judgment criteria of fold change >1.2 or <0.83 and p < 0.05. A coexpression enrichment analysis using OmicsBean was conducted on the identified proteins and metabolites, and a false discovery rate (FDR) < 0.05 was considered significant. Human Protein Atlas was used to determine the subcellular distribution of hub proteins. The Gene Cards was used to verify results. A total of 123 up-regulated and 46 down-regulated proteins, and 12 up-regulated and 2 down-regulated metabolites were identified. The significant coexpression pathways were the HIF-1 (FDR = 1.86 × 10−3) and glycolysis/gluconeogenesis (FDR = 1.14 × 10−10). The results of validation analysis showed the proteins related to fluorine were mainly enriched in the cytoplasm and extrinsic component of the cytoplasmic side of the plasma membrane. The HIF-1 pathway (FDR = 1.01 × 10−7) was also identified. Therefore, the HIF-1 and glycolysis/gluconeogenesis pathways were significantly correlated with dental fluorosis.

The association between polymorphisms in miRNA and the cholinesterase activity of workers in an omethoate-exposed environment.

To explore the association between polymorphisms in microRNAs (miRNAs) and the cholinesterase (ChE) activity in omethoate-exposed workers, we recruited 180 omethoate-exposed workers and 115 controls to measure their ChE activity using acetylcholine and dithio-bis-(nitrobenzoic acid) and genotype susceptible SNPs in their miRNA by time-of-flight mass spectrometry. ChE activity in the exposure group was lower than that in the control group (P < 0.001). The analysis of covariance result showed that ChE activity was lower in the (- -/- T) genotype in miR-30a rs111456995 (1.97 ± 0.47) than in the TT genotype (2.23 ± 0.59) of the exposure group (P = 0.004). Multivariate linear regression was performed to find influencing factors on ChE activity, and variables kept in the model included omethoate exposure (b = -1.094, P < 0.001), gender (b = -0.381, P < 0.001), miR-30a rs111456995 (- -/- T)(b = -0.248, P < 0.001), and drinking (b = 0.258, P =0.019). The results suggest that individuals carrying a (- -/- T) genotype in miR-30a rs111456995 were more susceptible to damage in their cholinesterase induced by omethoate exposure.

[Analysis of a child with Johanson-Blizzard syndrome due to novel compound heterozygous variants of UBR1 gene].

OBJECTIVE: To analyze the clinical and genetic characteristics of a boy featuring unexplained developmental delay, malnutrition and distinct facial appearance. METHODS: Physical examination was carried out for the child. Peripheral blood samples were collected from the child and his parents for the extraction of genomic DNA and trio-whole exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: The patient had facial dysmorphism including nasal alae aplasia, scalp defect and teeth deformities, in addition with recurrent diarrhea due to pancreatic exocrine insufficiency. DNA sequencing revealed that he has harbored compound heterozygous variants of the UBR1 gene, namely c.3167C>G (p.S1056X) and c.1911+14C>G, which were inherited from his father and mother, respectively. Database search has suggested the c.3167C>G to be a novel nonsense variant and c.1911+14C>G a known splicing variant. Based on the guidelines of the American College of Medical Genetics and Genomics, the two variants were predicted to be pathogenic and likely pathogenic, respectively. CONCLUSION: The child was diagnosed with Johanson-Blizzard syndrome due to the compound heterozygous variants of the UBR1 gene. Above finding has enriched the mutational spectrum of the UBR1 gene and provided a basis for genetic counseling for this family.

[Clinical characteristics and identification of a novel IL10RA variant in association with very early-onset inflammatory bowel disease].

OBJECTIVE: To carry out clinical and genetic analysis for an infant manifesting perianal lesions, diarrhea and multiple intestinal perforations. METHODS: Genomic DNA of the infant was extracted and subjected to targeted capture exome sequencing. Candidate variants were verified by Sanger sequencing of his family members. RESULTS: The patient was found to harbor c.301C>T and c.188+1G>A compound heterozygous variants of the IL10RA gene, which has suggested the diagnosis of IL10RA-related very early-onset inflammatory bowel disease (VEOIBD). CONCLUSION: The patient was diagnosed with IL10RA-related VEOIBD. The newly discovered c.188+1G>A variant has enriched the spectrum of IL10RA gene variations.