Kidney function decline mediates the adverse effects of per- and poly-fluoroalkyl substances (PFAS) on uric acid levels and hyperuricemia risk.

Previous studies indicated per- and poly-fluoroalkyl substances (PFAS) were related to uric acid and hyperuricemia risk, but evidence for the exposure-response (E-R) curves and combined effect of PFAS mixture is limited. Moreover, the potential mediation effect of kidney function was not assessed. Hence, we conducted a national cross-sectional study involving 13,979 US adults in NHANES 2003-2018 to examine the associations of serum PFAS with uric acid and hyperuricemia risk, and the mediation effects of kidney function. Generalized linear models and E-R curves showed positive associations of individual PFAS with uric acid and hyperuricemia risk, and nearly linear E-R curves indicated no safe threshold for PFAS. Weighted quantile sum regression found positive associations of PFAS mixture with uric acid and hyperuricemia risk, and PFOA was the dominant contributor to the adverse effect of PFAS on uric acid and hyperuricemia risk. Causal mediation analysis indicated significant mediation effects of kidney function decline in the associations of PFAS with uric acid and hyperuricemia risk, with the mediated proportion ranging from 19 % to 57 %. Our findings suggested that PFAS, especially PFOA, may cause increased uric acid and hyperuricemia risk increase even at low levels, and kidney function decline plays a crucial mediation effect.

Prenatal organophosphate esters exposure and neurodevelopment trajectory in infancy: Evidence from the Shanghai Maternal-Child Pairs Cohort.

BACKGROUND: Concerns remain about the neurotoxic properties of the ubiquitous organophosphate esters (OPEs), the replacement of the toxicant polybrominated diphenyl ethers. OBJECTIVES: We examined the associations of prenatal exposure to OPEs and their mixtures with early-life neurodevelopment trajectories. METHODS: Totally 1276 mother-child pairs were recruited from the Shanghai Maternal-Child Pairs Cohort. A high-performance liquid chromatography-triple quadrupole mass spectrometer was used to measure the levels of 7 OPEs in cord serum. Ages and Stages Questionnaires was used to examine children's neuropsychological development at 2, 6, 12, and 24 months of age. Group-based trajectory models were applied to derive the neurodevelopmental trajectories. Multiple linear regression and logistic regression model were performed to assess the relationships between OPEs exposure and neurodevelopment and trajectories. Mixtures for widely detected OPEs (n = 4) were investigated using quantile-based g-computation. RESULTS: Tributyl phosphate (TBP), tris (2-butoxy ethyl) phosphate (TBEP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and 2-ethylhexyl diphenyl phosphate (EHDPP), had detection rates >50 %. TDCPP had the highest median concentration (1.02 µg/L) in cord serum. EHDPP concentrations were negatively associated with scores in most domains at 12 months of age, with effect values (ß) ranging from -1.89 to -0.57. EHDPP could negatively affect the total ASQ (OR = 1.07, 95 % CI: 1, 1.15) and gross-motor (OR = 1.09, 95 % CI: 1.02, 1.17) trajectory in infancy. Joint exposure to OPEs was associated with decreased scores in the total ASQ, gross-motor, fine-motor and problem-solving domain of 12-month-old infants, with ß ranging from -5.93 to -1.25. In addition, the qgcomp models indicated significant positive associations between the concentrations of OPEs mixtures and risks of the persistently low group of the total ASQ, gross-motor and fine-motor development in early childhood. The impact of OPEs was more pronounced in boys. DISCUSSION: Our findings suggested OPEs, especially EHDPP, had a persistently negative effect on neurodevelopment during the first 2 years.

Carrier rate of thalassemia among 25,910 high school students in Shaoguan area, China.

OBJECTIVES: As one of the most common hereditary diseases, thalassemia affects a large number of people in China. The aim of this study was to investigate the feasibility of a method based on next-generation sequencing (NGS) for screening of thalassemia carriers among high school students in the Shaoguan area. MATERIALS AND METHODS: The NGS-based method was performed using 25,910 high school students recruited from 38 schools. The screening yield was systematically analyzed. Before screening, a lecture on how the disease is inherited, the symptoms of thalassemia, and how to prevent it was given to 28,780 students. RESULTS: Implying successful delivery of information on the disease, 90.03% (25,910 of 28,780) of the students agreed to join this program for thalassemia screening. A thalassemia carrier rate of 15.99% (4144 of 25,910) was found. Also, 69 rare genotypes (28 of α-thalassemia and 41 of ß-thalassemia) and 9 novel variants were identified. CONCLUSIONS: This NGS-based method provided a feasible platform for high school population thalassemia screening. Combined with a clinical follow-up strategy, it could help eventually to prevent the births of affected children.

Prenatal exposure to multiple environmental chemicals and birth size.

BACKGROUND: Epidemiological studies addressing the combined effects of exposure to chemical mixtures at different stages of pregnancy on birth size are scarce. OBJECTIVE: To evaluate the association between prenatal exposure to chemical mixtures and birth size. METHODS: Our previous study repeatedly measured the urinary concentrations of 34 chemical substances among 743 pregnant women and identified three distinct clusters of exposed population and six dominant principal components of exposed chemicals in each trimester. In this study, we assessed the associations of these exposure profiles with birth weight, birth length, and ponderal index using multivariable linear regression. RESULTS: We found that compared with women in cluster 1 (lower urinary chemical concentrations), women in cluster 2 (higher urinary concentrations of metals, benzothiazole, benzotriazole, and some phenols), and women in cluster 3 (higher urinary concentrations of phthalates) were more likely to give birth to children with higher birth length [0.23 cm (95% CI: -0.03, 0.49); 0.29 cm (95%CI: 0.03, 0.54), respectively]. This association was observed only in 1st trimester. In addition, prenatal exposure to PC3 (higher benzophenones loading) was associated with reduced birth length across pregnancy [-0.07 cm (95% CI: -0.18, 0.03) in 1st and 2nd trimester; -0.13 cm (95% CI: -0.24, -0.03) in 3rd trimester]. Exposure to PC6 (higher thallium and BPA loading in 2nd trimester) was associated with increased birth length [0.15 cm (95% CI: 0.05, 0.26)]. Compared with other outcomes, associations of both clusters and PCs with birth length were stronger, and these associations were more pronounced in boys. IMPACT STATEMENT: Exposure to multiple chemicals simultaneously, the actual exposure situation of pregnant women, was associated with birth size, indicating that chemical mixtures should be taken more seriously when studying the health effects of pollutants.

Ozone Exposure During Pregnancy and Risk of Gestational Hypertension or Preeclampsia in China.

Importance: Although certain air pollutants have been associated with adverse obstetric outcomes, evidence regarding the association of ozone (O3) exposure with the risk of hypertensive disorders in pregnancy (HDP) is limited and inconsistent. Objectives: To evaluate the association between gestational O3 exposure and HDP (ie, gestational hypertension and preeclampsia) risk, and to explore the window of susceptibility for O3 exposure during pregnancy. Design, Setting, and Participants: This cohort study recruited pregnant patients from the Obstetrics and Gynecology Hospital of Fudan University in Shanghai, China, from March 2017 to December 2018. Participants were older than 18 years, had no infectious diseases or chronic noncommunicable diseases before pregnancy, were Shanghai residents with intent to participate in the study, and had plans to give birth in Shanghai. Gestational hypertension and preeclampsia were diagnosed according to the diagnostic criteria of the Chinese Society of Obstetrics and Gynecology during the study period. Data on residential addresses, demographic characteristics, and household living environments were collected from participants through a questionnaire survey. Data were analyzed from December 10, 2021, to May 10, 2022. Exposures: A high temporospatial resolution model was applied to predict individual levels of daily O3 exposure during pregnancy. Main Outcomes and Measures: The outcomes were gestational hypertension and preeclampsia, and data on these diagnoses were extracted from the hospital's information system. A logistic regression model was used to estimate the associations between O3 exposure and risk of gestational hypertension or preeclampsia. Exposure-response associations were confirmed by restricted cubic spline functions. Distributed lag models were used to identify the O3 exposure window of susceptibility. Results: Among the 7841 participants (all females; mean [SD] age, 30.4 [3.8] years), 255 (3.2%) had gestational hypertension and 406 (5.2%) had preeclampsia. Pregnant individuals with HDP had considerably higher prepregnancy body mass indexes and lower educational levels. The mean (SD) O3 exposure levels were 97.66 (25.71) µg/m3 in the first trimester and 106.13 (22.13) µg/m3 in the second trimester. Each 10-µg/m3 increment of O3 exposure during the first trimester was associated with higher gestational hypertension risk (relative risk, 1.28; 95% CI, 1.04-1.57). However, gestational O3 exposure was not associated with the risk of preeclampsia. The restricted cubic spline function analysis revealed an exposure-response association between O3 exposure and risk of gestational hypertension. Conclusions and Relevance: Results of this study showed an association between increased gestational hypertension risk and O3 exposure during the first trimester. Furthermore, gestational weeks 1 to 9 were identified as the window of susceptibility for O3 exposure and elevated gestational hypertension risk. Sustainable O3 control is needed to reduce the disease burden of gestational hypertension.

POLQ inhibition elicits an immune response in homologous recombination-deficient pancreatic adenocarcinoma via cGAS/STING signaling.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination-repair (HR-repair) proteins in 20%-25% of cases. Defects in HR impart a specific vulnerability to poly ADP ribose polymerase inhibitors and platinum-containing chemotherapy in tumor cells. However, not all patients who receive these therapies respond, and many who initially respond ultimately develop resistance. Inactivation of the HR pathway is associated with the overexpression of polymerase theta (Polθ, or POLQ). This key enzyme regulates the microhomology-mediated end-joining (MMEJ) pathway of double-strand break (DSB) repair. Using human and murine HR-deficient PDAC models, we found that POLQ knockdown is synthetically lethal in combination with mutations in HR genes such as BRCA1 and BRCA2 and the DNA damage repair gene ATM. Further, POLQ knockdown enhances cytosolic micronuclei formation and activates signaling of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), leading to enhanced infiltration of activated CD8+ T cells in BRCA2-deficient PDAC tumors in vivo. Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to blocking tumor growth while concurrently activating the cGAS-STING signaling pathway to enhance tumor immune infiltration, highlighting what we believe to be a new role for POLQ in the tumor immune environment.

Associations of prenatal PFAS exposure and early childhood neurodevelopment: Evidence from the Shanghai Maternal-Child Pairs Cohort.

Epidemiological data on the effects of perfluoroalkyl and polyfluoroalkyl substances (PFAS) on infant neurodevelopment trajectories are far from being sufficiently addressed. In this study, 1285 mother-child pairs were recruited during 2016-2017. A high-performance liquid chromatography-triple quadrupole mass spectrometer was used to measure 16 PFAS levels in cord serum. Ages and Stages Questionnaires were used to examine children's neurodevelopment at 2, 6, 12, and 24 months of age. Group-based trajectory models were applied to derive the neurodevelopmental trajectories. Children with relatively low scores from 2 to 24 months were classified into a low-score group and were used as a risk group in each domain. Multiple linear regression, logistic regression, and quantile-based g-computation were performed to assess associations of single or mixture PFAS exposures with neurodevelopment and trajectories. Perfluorooctane sulphonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), and 6:2 chlorinated polyfluorooctane ether sulfonate (6:2Cl-PFESA) were detected in over 90 % samples. PFOA had the highest concentration (median: 4.61 µg/L). Each ln-unit (µg/L) increase of PFAS (e.g., PFOA, PFOS, PFHxS, 6:2Cl-PFESA) was associated with poor scores of communication domain at 6 months, with the effect size ranging from -0.69 to -0.44. PFOS (OR: 1.14, (1.03, 1.26), PFDA (OR:1.08, (1.02, 1.15)), PFHxS (OR:1.31, (1.12, 1.56)), and 6:2Cl-PFESA (OR:1.08, (1.00, 1.16)) were associated with an increased risk of being in the low-score group in the early childhood communication domain's trajectory. Each mixture quartile increment was associated with a 1.60 (-2.76, -0.45) decrease in communication domain scores of 6-month-old infants, and the mixture effect was mainly attributed to PFOS. Each mixture quartile increase was associated with a 1.23-fold (1.03, 1.46) risk of being in the low-score group of the communication domain, and the mixture effect was mainly attributed to PFOS. In conclusion, PFAS and their mixtures might adversely affect childhood neurodevelopment. The gender-specific associations existed in the above associations.

Mixed exposure to phthalates and organic UV filters affects Children's pubertal development in a gender-specific manner.

BACKGROUND: Previous studies showed phthalates and UV filters are endocrine-disruptive and associated with puberty. However, few studies have examined effects of mixed exposure. METHODS: Six phthalate metabolites and 12 organic UV filters were detected among 223 school-age children. Puberty development was evaluated at baseline and after 18 months of follow-up. Ordered logistic regression models, least absolute shrinkage and selection operator (LASSO) regression and quantile-based g-computation (qgcomp) were used to evaluate relationships between phthalate metabolites or UV filters exposure and pubertal development. RESULTS: Six phthalate metabolites and 5 UV filters were detectable in urine samples. In boys, BP-3 and 4'-MAP were negatively associated with genital (ORBP-3 = 0.52, (0.27, 0.93), OR4'-MAP = 0.45, (0.25, 0.74)) and pubic hair development (ORBP-3:0.24, (0.05, 0.76), OR4'-MAP:0.24, (0.05, 0.77)). In girls, MEP levels were associated with advanced breast development (OR: 1.29, (1.04, 1.64)). LASSO regression identified BP-3, 4'-MAP, and OD-PABA for inverse associations with pubertal development in boys. MEP was related to an increase in girls' breast development (OR: 1.64, (1.08, 2.63)). Overall mixture was related to a 70% reduction in boys' genital development stage, with a larger effect size than a single chemical in qgcomp. Mixed exposure was associated with girls' earlier puberty onset (OR: 2.61, (1.06, 6.42)). CONCLUSIONS: Our results suggested higher levels of phthalate metabolites and UV filters were associated with delayed pubertal development in boys but with earlier puberty in girls. Higher effect size of joint exposure than single chemicals suggested phthalates and UV filters might have synergistic effects on puberty and distort adolescent endocrine function together.

Associations of ozone exposure with gestational diabetes mellitus and glucose homeostasis: Evidence from a birth cohort in Shanghai, China.

BACKGROUND: Associations between individual exposure to ozone (O3) and gestational diabetes mellitus (GDM) have rarely been investigated, and critical windows of O3 exposure for GDM have not been identified. OBJECTIVES: We aimed to explore the associations of gestational O3 exposure with GDM and glucose homeostasis as well as to identify the potential critical windows. METHODS: A total of 7834 pregnant women were included. Individual O3 exposure concentrations were evaluated using a high temporal-spatial resolution model. Each participant underwent an oral glucose tolerance test (OGTT) to screen for GDM between 24 and 28 gestational weeks. Multiple logistic and multiple linear regression models were used to estimate the associations of O3 with GDM risks and with blood glucose levels of OGTT, respectively. Distributed lag nonlinear models (DLNMs) were used to estimate the critical windows of O3 exposure for GDM. RESULTS: Nearly 13.29 % of participants developed GDM. After controlling for covariates, we observed increased GDM risks per IQR increment of O3 exposure in the first trimester (OR = 1.738, 95 % CI: 1.002-3.016) and the first two trimesters (OR = 1.576, 95 % CI: 1.005-2.473). Gestational O3 exposure was positively associated with increased fasting blood glucose (the first trimester: ß = 2.964, 95 % CI: 1.529-4.398; the first two trimesters: ß = 1.620, 95 % CI: 0.436-2.804) and 2 h blood glucose (the first trimester: ß = 6.569, 95 % CI: 1.775-11.363; the first two trimesters: ß = 6.839, 95 % CI: 2.896-10.782). We also observed a concentration-response relationship of gestational O3 exposure with GDM risk, as well as fasting and 2 h blood glucose levels. Additionally, 5-10 gestational weeks was identified as a critical window of O3 exposure for GDM development. CONCLUSION: In summary, we found that gestational O3 exposure disrupts glucose homeostasis and increases the risk of GDM in pregnant women. Furthermore, 5-10 gestational weeks could be a critical window for the effects of O3 exposure on GDM.

Indoor metabolites and chemicals outperform microbiome in classifying childhood asthma and allergic rhinitis.

Indoor microorganisms impact asthma and allergic rhinitis (AR), but the associated microbial taxa often vary extensively due to climate and geographical variations. To provide more consistent environmental assessments, new perspectives on microbial exposure for asthma and AR are needed. Home dust from 97 cases (32 asthma alone, 37 AR alone, 28 comorbidity) and 52 age- and gender-matched controls in Shanghai, China, were analyzed using high-throughput shotgun metagenomic sequencing and liquid chromatography-mass spectrometry. Homes of healthy children were enriched with environmental microbes, including Paracoccus, Pseudomonas, and Psychrobacter, and metabolites like keto acids, indoles, pyridines, and flavonoids (astragalin, hesperidin) (False Discovery Rate < 0.05). A neural network co-occurrence probability analysis revealed that environmental microorganisms were involved in producing these keto acids, indoles, and pyridines. Conversely, homes of diseased children were enriched with mycotoxins and synthetic chemicals, including herbicides, insecticides, and food/cosmetic additives. Using a random forest model, characteristic metabolites and microorganisms in Shanghai homes were used to classify high and low prevalence of asthma/AR in an independent dataset in Malaysian schools (N = 1290). Indoor metabolites achieved an average accuracy of 74.9% and 77.1% in differentiating schools with high and low prevalence of asthma and AR, respectively, whereas indoor microorganisms only achieved 51.0% and 59.5%, respectively. These results suggest that indoor metabolites and chemicals rather than indoor microbiome are potentially superior environmental indicators for childhood asthma and AR. This study extends the traditional risk assessment focusing on allergens or air pollutants in childhood asthma and AR, thereby revealing potential novel intervention strategies for these diseases.

PM2.5 exposure associated with prenatal anxiety and depression in pregnant women.

BACKGROUND: Associations of air pollution with anxiety and depression were found in previous studies. However, whether air pollution exposure during pregnancy contributes to prenatal anxiety and depression or not is under-investigated. In this study, we aimed to analyze associations between fine particulate matter (PM2.5) exposure with anxiety and depression during pregnancy and to explore the critical window of PM2.5 exposure. METHODS: This study was based on the Shanghai Maternal-Child Pairs Cohort (Shanghai MCPC). We used a gap-filling random forest model to estimate PM2.5 exposure concentration during pregnancy of each participant. The Self-Rating Anxiety Scale (SAS) and the Center for Epidemiological Survey-Depression Scale (CES-D) were used to quantify the anxiety and depression levels in late pregnancy. Covariate information was obtained from medical records and questionnaires. We performed generalized linear regression and logistic regression models to assess the association and the critical window. RESULTS: Totally 3731 pregnant women were included, with the age of 28.85 ± 3.97 years old. Anxiety and depression rates were 10.8 % and 11.5 % respectively, according to the cut-off value of SAS and CES-D. Generalized linear regression results showed that the increase of PM2.5 concentration in three stages (gestational 0-13 weeks, 0-26 weeks, 0-36 weeks) was related to the increase of scale score. The PM2.5 concentration in 0-13 weeks could increase the risk of anxiety and depression by approximately 23 % and 25 %, respectively. And the gestational weeks 4th-13th were the suspicious critical window of PM2.5 exposure. CONCLUSION: The increased risk of anxiety or depression was related to PM2.5 exposure during pregnancy, especially early pregnancy.

Prenatal Exposure of Organophosphate Esters and Its Trimester-Specific and Gender-Specific Effects on Fetal Growth.

The toxicity of organophosphate esters (OPEs) on embryonic development is well noted in animal experiments, but epidemiological studies are still lacking. This study evaluated the prenatal exposure of OPEs and its trimester-specific and gender-specific effects on fetal growth. The correlations between OPE exposure and fetal growth were investigated by linear mixed-effect models and multivariable linear regression analyses. Prenatal exposure to tributyl phosphate (TBP) was negatively associated with a z-score of fetal abdominal circumference (AC), biparietal diameter (BPD), femur length (FL), and head circumference (HC). In the second trimester, the serum concentration of TBP was inversely related to the z-score of AC, BPD, and HC. In the third trimester, serum concentration of TBP was inversely related to AC, BPD, and FL z-scores. Prenatal exposure to tri-m-cresyl phosphate (TMCP) was inversely related to the z-score of AC, BPD, and HC. In the second trimester, TMCP was negatively correlated with AC, BPD, FL, and HC z-scores. After stratification by gender, male fetuses were more sensitive to OPE exposure. The above results remained robust after excluding pregnant women who gave preterm birth or those with low or high pre-pregnancy BMI. Our findings suggested that health effects of typical OPEs, particularly TBP and TMCP, should be taken into consideration in future works.

Interleukin 4 Controls the Pro-Tumoral Role of Macrophages in Mammary Cancer Pulmonary Metastasis in Mice.

Metastasis is the systemic manifestation of cancer and the main cause of death from breast cancer. In mouse models of lung metastases, recruitment of classical monocytes from blood to the lung and their differentiation to metastasis-associated macrophages (MAMs) facilitate cancer cell extravasation, survival and growth. Ablation of MAMs or their monocytic progenitors inhibits metastasis. We hypothesized that factors controlling macrophage polarization modulate tumor cell extravasation in the lung. We evaluated whether signaling by Th1 or Th2 cytokines in macrophages affected transendothelial migration of tumor cells in vitro. Interferon gamma and LPS inhibited macrophage-dependent tumor cell extravasation while the Th2 cytokine interleukin-4 (IL4) enhanced this process. We demonstrated that IL4 receptor (IL4rα)-null mice developed fewer and smaller lung metastasis in E0771-LG mammary cancer models of this disease. Adoptive transfer of wild-type monocytes to IL4rα-deficient mice partially rescued this phenotype. IL4 signaling in macrophages controlled the expression of the chemokine receptor CXCR2, necessary for IL4-mediated tumor cell extravasation in vitro. Furthermore, IL4 signaling in macrophages regulated the transcript abundance of several other genes already causally associated with mammary cancer lung metastasis including Ccl2, Csf1, Ccr1, Hgf and Flt1. The central role of IL4 signaling in MAMs was confirmed by high-resolution intravital imaging of the lung in mice at the time of metastatic seeding, which showed reduced physical interaction between tumor cells and IL4rα-deficient macrophages. This interaction with wild-type MAMs enhanced tumor cell survival and seeding, which was lost in the IL4rα mice. These data indicate that IL4 signaling in monocytes and macrophages is key during seeding and growth of breast metastasis in the lung, as it regulates pro-tumoral paracrine signaling between cancer cells and macrophages.

[Oocyte maturation arrest due to compound heterozygous variants of the PATL2 gene in a case].

OBJECTIVE: To explore the genetic etiology of a patient with primary infertility and repeated failure of assisted reproductive technology. METHODS: Peripheral blood samples of the patient and her husband were collected for the extraction of genomic DNA and clinical exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: The patient was found to harbor compound heterozygous variants of the PATL2 gene, namely c.223-14_223-2del and c.1369G>T (p.G457*). Sanger sequencing has verified that they were respectively inherited from her father and mother. The patient was diagnosed with oocyte maturation defect type 4. CONCLUSION: Oocyte maturation arrest due to mutations of the PATL2 gene can result in primary female infertility. Discovery of the novel c.1369G>T (p.G457*) variant has expanded the spectrum of pathogenic variants of the PATL2 gene.

ß-Klotho promotes glycolysis and glucose-stimulated insulin secretion via GP130.

Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of type-2 diabetes. However, cellular signaling machineries that control GSIS remain incompletely understood. Here, we report that ß-klotho (KLB), a single-pass transmembrane protein known as a co-receptor for fibroblast growth factor 21 (FGF21), fine tunes GSIS via modulation of glycolysis in pancreatic ß-cells independent of the actions of FGF21. ß-cell-specific deletion of Klb but not Fgf21 deletion causes defective GSIS and glucose intolerance in mice and defective GSIS in islets of type-2 diabetic mice is mitigated by adenovirus-mediated restoration of KLB. Mechanistically, KLB interacts with and stabilizes the cytokine receptor subunit GP130 by blockage of ubiquitin-dependent lysosomal degradation, thereby facilitating interleukin-6-evoked STAT3-HIF1α signaling, which in turn transactivates a cluster of glycolytic genes for adenosine triphosphate production and GSIS. The defective glycolysis and GSIS in Klb-deficient islets are rescued by adenovirus-mediated replenishment of STAT3 or HIF1α. Thus, KLB functions as a key cell-surface regulator of GSIS by coupling the GP130 receptor signaling to glucose catabolism in ß-cells and represents a promising therapeutic target for diabetes.

Simultaneous determination of poly- and perfluoroalkyl substances and organophosphorus flame retardants in serum by ultra-performance liquid chromatography/tandem mass spectrometry.

RATIONALE: Poly- and perfluoroalkyl substances (PFASs) and organophosphorus flame retardants (OPFRs) are two types of emerging organic pollutants with potential human health hazards. Here, a rapid and sensitive method was developed for the determination of sixteen PFASs and seven OPFRs in human serum by ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS). METHODS: After optimizing the chromatographic and mass spectrometric conditions, respectively, 100 µL of serum sample was liquid-liquid extracted using 8 mL of methyl tert-butyl ether. The 23 targets were quantified within 8 min. All targets were quantified by the isotope-internal standard method in both negative- and positive-ion mode by UPLC/MS/MS. RESULTS: The method was validated in terms of sensitivity, linearity, precision, and accuracy. The limit of detection ranged between 0.004 and 0.650 ng/mL. Recoveries ranged from70.0% to 118.9% with a relative standard deviation lower than 20%. The developed method was successfully applied to analyze targeted analytes in human serum samples. A total of 13 of 23 analytes were detected in over 50% of samples. CONCLUSIONS: A sensitive and rapid method was developed to quantify sixteen PFASs and seven OPFRs in serum. Sensitivity, linearity, recovery, and precision were validated and found to be satisfactory. This method can be a valuable tool for evaluation of exposure to both PFASs and OPFRs with high separation efficiency and sensitivity.

Machine Learning for Investigation on Endocrine-Disrupting Chemicals with Gestational Age and Delivery Time in a Longitudinal Cohort.

Endocrine-disrupting chemicals (EDCs) are widespread environmental chemicals that are often considered as risk factors with weak activity on the hormone-dependent process of pregnancy. However, the adverse effects of EDCs in the body of pregnant women were underestimated. The interaction between dynamic concentration of EDCs and endogenous hormones (EHs) on gestational age and delivery time remains unclear. To define a temporal interaction between the EDCs and EHs during pregnancy, comprehensive, unbiased, and quantitative analyses of 33 EDCs and 14 EHs were performed for a longitudinal cohort with 2317 pregnant women. We developed a machine learning model with the dynamic concentration information of EDCs and EHs to predict gestational age with high accuracy in the longitudinal cohort of pregnant women. The optimal combination of EHs and EDCs can identify when labor occurs (time to delivery within two and four weeks, AUROC of 0.82). Our results revealed that the bisphenols and phthalates are more potent than partial EHs for gestational age or delivery time. This study represents the use of machine learning methods for quantitative analysis of pregnancy-related EDCs and EHs for understanding the EDCs' mixture effect on pregnancy with potential clinical utilities.

A Metabolite Array Technology for Precision Medicine.

The application of metabolomics in translational research suffers from several technological bottlenecks, such as data reproducibility issues and the lack of standardization of sample profiling procedures. Here, we report an automated high-throughput metabolite array technology that can rapidly and quantitatively determine 324 metabolites including fatty acids, amino acids, organic acids, carbohydrates, and bile acids. Metabolite identification and quantification is achieved using the Targeted Metabolome Batch Quantification (TMBQ) software, the first cross-vendor data processing pipeline. A test of this metabolite array was performed by analyzing serum samples from patients with chronic liver disease (N = 1234). With high detection efficiency and sensitivity in serum, urine, feces, cell lysates, and liver tissue samples and suitable for different mass spectrometry systems, this metabolite array technology holds great potential for biomarker discovery and high throughput clinical testing. Additionally, data generated from such standardized procedures can be used to generate a clinical metabolomics database suitable for precision medicine in next-generation healthcare.

An Optimized Weighted Naïve Bayes Method for Flood Risk Assessment.

Floods occur frequently and cause considerable damage to local environments. Effectively assessing the flood risk contributes to reducing loss caused by such disasters. In this study, the weighted naïve Bayes (WNB) method was selected to evaluate flood risk, and the entropy weight method was employed to compute the weights. A sampling and verifying model was employed to generate the most accurate conditional probability table (MACPT) to calculate the probability of flooding. When using the framework integrating WNB with the sampling and verifying model, previous studies could not obtain a WNB-based MACPT and the WNB classification accuracy, for lacking WNB functions that could be called directly. Facing this issue, in this study we developed WNB functions with the MATLAB platform to directly integrate with the sampling and verifying model to generate a WNB-based MACPT, contributing to the greater interpretability and extensibility of the model. Shantou and Jieyang cities in China were selected as the study area. The results demonstrate that: (1) a WNB-based MACPT can reflect the real spatial distribution of flood risk and (2) the WNB outperform the NB when integrated with the sampling and verifying model. The resulting gridded estimation reveal a detailed spatial pattern of flood risk, which can serve as a realistic reference for decision making related to floods. Furthermore, the proposed method uses less data, which would be helpful in developing countries where long-term intensive hydrologic monitoring is limited.