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Background: Previous studies have indicated a correlation between maternal imbalances in essential trace elements during pregnancy and the occurrence of spontaneous abortion (SA). Nonetheless, the impact of these elements from both partners and during the preconception period remains unexplored. Objective: This study sought to evaluate the relationship between preconception essential trace elements and spontaneous abortion (SA) based on husband–wife dyads. Methods: This study selected 390 couples with spontaneous abortion (SA) and 390 matched couples with live births from a preconception cohort of 33,687 couples. Urine samples collected prior to pregnancy were analyzed for ten essential trace elements (Se, Cr, Mo, Cu, Zn, Fe, Mn, V, Co, and Ni) using inductively coupled plasma mass spectrometry (ICP-MS). Results: Multivariate conditional logistic regression analysis identified that elevated concentrations of Zn (OR = 0.73) and Ni (OR = 0.69) in couples were associated with a reduced risk of SA, whereas elevated levels of Cr (OR = 1.30) and Mn (OR = 1.39) were linked to an increased risk. Restricted cubic spline models suggested a U-shaped association between couples’ Cu and Co concentrations and SA. Bayesian Kernel Machine Regression further supported a U-shaped relationship between the mixture of ten elements and SA, showing significant protection at the 50th and 55th percentiles compared to the 10th percentile. Additionally, the effects of Cr, Zn, Mn, and Ni on SA varied when the concentrations of the other nine elements were held constant at their 25th, 50th, and 75th percentiles. Stratified analysis revealed that maternal Cu (OR = 0.43) and Fe (OR = 0.63) reduced the risk of SA when paternal Cu and Fe were in the lower quartile. Conversely, maternal Cu (OR = 2.03) and Fe (OR = 1.77) increased the risk of SA when paternal concentrations were in the higher quartile. Similar patterns were observed for Cr, Mn, Co, and Zn. Conclusion: Elevated urinary concentrations of Zn and Ni in couples were associated with a reduced risk of SA, while higher levels of Cr and Mn were linked to an increased risk. Cu, Co, and a mixture of ten essential trace elements exhibited a U-shaped relationship with SA. The impact of certain essential trace elements (Cu, Fe, Cr, Mn, Co, and Zn) on SA in one partner was influenced by their concentrations in the other partner.

Alzheimer's disease, among the most common neurodegenerative disorders, is characterized by progressive cognitive impairment. At present, the Alzheimer's disease main risk remains genetic risks, but major environmental factors are increasingly shown to impact Alzheimer's disease development and progression. Microglia, the most important brain immune cells, play a central role in Alzheimer's disease pathogenesis and are considered environmental and lifestyle “sensors.” Factors like environmental pollution and modern lifestyles (e.g., chronic stress, poor dietary habits, sleep, and circadian rhythm disorders) can cause neuroinflammatory responses that lead to cognitive impairment via microglial functioning and phenotypic regulation. However, the specific mechanisms underlying interactions among these factors and microglia in Alzheimer's disease are unclear. Herein, we: discuss the biological effects of air pollution, chronic stress, gut microbiota, sleep patterns, physical exercise, cigarette smoking, and caffeine consumption on microglia; consider how unhealthy lifestyle factors influence individual susceptibility to Alzheimer's disease; and present the neuroprotective effects of a healthy lifestyle. Toward intervening and controlling these environmental risk factors at an early Alzheimer's disease stage, understanding the role of microglia in Alzheimer's disease development, and targeting strategies to target microglia, could be essential to future Alzheimer's disease treatments.

End-stage renal disease (ESRD) coexisted with cirrhosis, ascites, and primary liver cancer represents an extraordinarily rare clinical condition that typically occurs in very late-stage decompensated cirrhosis and is associated with an extremely poor prognosis. We present a case of a 68-year-old male patient with ESRD who experienced various decompensated complications of liver cirrhosis, particularly massive ascites and hepatic space-occupying lesions. Peritoneal dialysis (PD) catheter insertion and continuous ambulatory peritoneal dialysis (CAPD) treatment were successfully performed. During meticulous follow-up, the patient survived for one year but ultimately succumbed to complications related to liver cancer. PD can serve as an efficacious therapeutic approach for such late-stage patients afflicted together with severe cirrhosis, massive ascites and primary liver cancer.

Background: Endometriosis is a common gynecological disease that affects approximately 5 %∼10 % of reproductive-aged women. Zinc (Zn), selenium (Se), copper (Cu), cobalt (Co) and molybdenum (Mo) are essential trace elements and are very important for human health. However, studies on the relationship between mixtures of essential trace elements and the risk of endometriosis are limited and inconsistent. In particular, studies confirming the association via different sample types are limited. Objective: This study aimed to investigate the associations between Zn, Se, Cu, Co and Mo concentrations in blood and follicular fluid (FF) and endometriosis risk in a Chinese population. Methods: A total of 609 subjects undergoing in vitro fertilization (IVF) were recruited; 836 samples were analyzed, including 451 blood samples (234 controls and 217 cases) and 385 FF samples (203 controls and 182 cases). In addition, 227 subjects provided both blood and FF samples. Zn, Se, Cu, Co and Mo concentrations in blood and FF were quantified via inductively coupled plasma−mass spectrometry (ICP−MS). The associations between the levels of Zn, Se, Cu, Co and Mo and the risk of endometriosis were assessed using single-element models (logistic regression models), and the combined effect of the trace elements on endometriosis risk was assessed using multielement models (Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) regression). Results: Based on the single-element models, significant associations of Zn concentrations in blood (high-level vs. low-level group: aOR = 14.17, 95 % CI: 7.31, 27.50) and FF (first tertile vs. second tertile group: aOR = 0.34, 95 % CI: 0.16, 0.71; third tertile vs. second tertile group: aOR = 2.32, 95 % CI: 1.38, 3.91, respectively) and Co concentrations in blood (first tertile vs. second tertile group, aOR = 0.24, 95 % CI: 0.12, 0.48) and FF (third tertile vs. second tertile group: aOR = 3.87, 95 % CI: 2.19, 6.84) with endometriosis risk were found after adjustment for all confounders. In FF, Cu and Mo levels were significantly greater among the cases than among the controls, with a positive association with endometriosis risk (Cu (first tertile vs. second tertile group: aOR = 0.39, 95 % CI: 0.19, 0.81; third tertile vs. second tertile group: aOR = 2.73, 95 % CI: 1.61, 4.66, respectively) and Mo (high-level vs. low-level group: aOR = 14.93, 95 % CI: 7.16, 31.12)). However, similar associations between blood Cu and Mo levels and endometriosis risk were not found. In addition, the levels of these five essential trace element mixtures in blood and in FF were significantly and positively associated with endometriosis risk according to the BKMR analyses; the levels of Zn and Cu in blood and the levels of Mo in FF were significantly related to the risk of endometriosis, and the posterior inclusion probabilities (PIPs) were 1.00, 0.99 and 1.00 for Zn and Cu levels in blood and Mo levels in FF, respectively. Furthermore, Zn and Mo were the highest weighted elements in blood and FF, respectively, according to WQS analyses. Conclusion: The risk of endometriosis was associated with elevated levels of several essential trace elements (Zn, Cu and Co). Elevated levels of these elements may be involved in the pathomechanism of endometriosis. However, further studies with larger sample sizes will be necessary to confirm these associations.

Abstract Our previous study data suggested that the synapse-associated protein 97 (SAP97) rs3915512 polymorphism is significantly related to clinical performance in schizophrenia. The cerebellum exhibits abundant expression of SAP97, which is involved with negative symptoms, cognition and emotion in schizophrenia. As functional dysconnectivity with the cortical-subcortical-cerebellar circuitry has been widely shown in patients with schizophrenia, cortical-subcortical-cerebellar dysconnectivity can therefore be considered a possible intermediate phenotype that connects risk genes with schizophrenia. In this study, resting-state functional magnetic resonance imaging (fMRI) was applied to evaluate whether the SAP97 rs3915512 polymorphism changes cortical/subcortical-cerebellar resting-state functional connectivity (RSFC) in 104 Han Chinese subjects (52 first-episode schizophrenia (FES) patients and 52 matched healthy controls (HCs)). To examine RSFC between cortical/subcortical regions and the cerebellum, a ROI (region of interest)-wise functional connectivity analysis was conducted. The association between abnormal cortical/subcortical-cerebellar connectivity and clinical manifestation was further assessed in FES patients with different genotypes. The interactive effect of disease and genotype on RSFC was found between the frontal gyrus (rectus) and cerebellum. A positive correlation was suggested between RSFC in the cerebellum and the hostility scores in FES patients with the A allele, and no correlation was found in FES patients with the TT genotype. The current findings identified that SAP97 may be involved in the process of mental symptoms in FES patients via cerebellar connectivity depending on the rs3915512 polymorphism genotype.

There is limited evidence linking exposure to ambient particulate matter (PM) with internal doses of metals and metalloids (metal(loid)s). This study aimed to evaluate the effects of short-term exposure to ambient PM on urine metal(loid)s among Chinese older adults. Biological monitoring data of 15 urine metal(loid)s collected in 3, 970 community-dwelling older adults in Fuyang city, Anhui Province, China, from July to September 2018, were utilized. PMs with an aerodynamic diameter ≤ 1 µm (PM1), ≤ 2.5 µm (PM2.5), and ≤ 10 µm (PM10) up to eight days before urine collection were estimated by space–time extremely randomized trees (STET) model. Residential greenness was reflected by Normalized Difference Vegetation Index (NDVI). We used generalized additive model (GAM) combined with distributed lag linear/non-linear models (DLMs/DLNMs) to estimate the associations between short-term PM exposure and urine metal(loid)s. The results suggested that the cumulative exposures to PM1, PM2.5, or PM10 over two days (lag0-1 days) before urine collection were associated with elevated urine metal(loid)s in DLMs, while exhibited linear or “inverted U-shaped” relationships with seven urine metal(loid)s in DLNMs, including Gallium (Ga), Arsenic (As), Aluminum (Al), Magnesium (Mg), Calcium (Ca), Uranium (U), and Barium (Ba). Aforementioned results indicated robust rather than spurious associations between PMs and these seven metal(loid)s. After standardizations for three PMs, PM1 was the greatest contributor to U, PM2.5 made the greatest contributions to Ga, As, Al, and Ba, and PM10 contributed the most to Mg and Ca. Furthermore, the effects of three PMs on urine Ga, As, Al, Mg, Ca, and Ba were reduced when exposed to higher levels of NDVI. Overall, short-term exposures to ambient PMs contribute to elevated urinary metal(loid) levels in older adults, and three PMs exhibit various contributions to different urine metal(loid)s. Moreover, residential greenness may attenuate the effects of PMs on urine metal(loid)s.

Abstract Ovarian reserve (OR) and fertility are critical in women's healthcare. Clinical methods for encoding OR and fertility rely on the combination of tests, which cannot serve as a multi‐functional platform with limited information from specific biofluids. Herein, metabolic fingerprinting of follicular fluid (MFFF) from follicles is performed, using particle‐assisted laser desorption/ionization mass spectrometry (PALDI‐MS) to encode OR and fertility. PALDI‐MS allows efficient MFFF, showing fast speed (≈30 s), high sensitivity (≈60 fmol), and desirable reproducibility (coefficients of variation

Objective To explore the diagnostic value of different subtypes of Treponema pallidum (Tp) adhesin protein TP0136 in the blood of neurosyphilitic patients. Methods The general conditions were compared in syphilitic patients with vs. without neuroinvolvement. Molecular cloning technique was used to express and purify Nichols Seattle TP0136 (abbreviated as NST) and Nichols Houston TP0136 (abbreviated as NHT) recombinant proteins. ELISA assay was used to measure serum levels of NST and NHT antibodies in neurosyphilitic and non-neurosyphilitic patients. Results There were no significant differences in age, gender, geographic region and occupation between neurosyphilitic and non-neurosyphilitic patients (P>0.05), while marital status, neurological symptoms, serum or plasma TRUST and TPPA titer, serum or plasma TP-IgM positive rate, cerebrospinal fluid TRUST and TPPA titer differed significantly (P

BackgroundEarly embryonic arrest (EEA) leads to repeated cessation of fresh cycles among infertile women undergoing in vitro fertilization (IVF). Whether the levels of some essential trace elements [copper (Cu), zinc (Zn), selenium (Se) and cobalt (Co)] in the bodies of women are related to the risk of EEA warrants study.ObjectiveOur study aimed to investigate the associations of peripheral blood levels of Cu, Zn, Se, and Co and their mixtures with the risk of EEA.MethodsA total of 74 EEA cases (123 IVF cycles) and 157 controls (180 IVF cycles) from the reproductive center of the First Affiliated Hospital of Anhui Medical University in Hefei, China, between June 2017 and March 2020 were included in our study. Demographic and clinical data were collected from electronic medical records. Cu, Zn, Se, and Co levels were measured in blood samples collected on the day of oocyte retrieval when infertile women entered clinical treatment for the first time using an inductively coupled plasma mass spectrometer (ICP−MS). Generalized estimating equation (GEE) models were used to evaluate the associations of four essential trace element concentrations individually with the risk of EEA, and Bayesian kernel machine regression (BKMR) was used to explore the associations between four essential trace element mixtures and the risk of EEA.ResultsSe concentrations of infertile women were significantly lower in the case group compared with the control group. Co levels were significantly higher in the case group compared with the control group. The differences in Cu and Zn concentrations between the two groups were not significant. Based on single-metal models, Co was positively associated with the risk of EEA before and after adjustment for all confounders (odd ratio (OR) = 1.72, 95% confidence interval (CI): 1.18−2.52; OR = 2.27, 95% CI: 1.37−3.77, respectively), and Se was negatively associated with the risk of EEA before adjustment for all confounders (OR = 0.18, 95% CI: 0.07−0.51). BKMR analyses showed that Se was significantly and negatively associated with the risk of EEA when all the other three metals (Cu, Zn, and Co) were fixed at the 25th, 50th, or 75th percentiles, whereas Zn displayed a significant and positive association with the risk of EEA when all the other three metals (Cu, Se and Co) were fixed at the 25th, 50th, or 75th percentiles. Co did not show any effect on the risk of EEA when all the other metals (Cu, Zn, and Se) were fixed at the 25th, 50th, or 75th percentiles. In addition, an increasing trend of the joint effect of four essential trace elements on the risk of EEA was found, although it was not statistically significant.ConclusionThe levels of essential trace elements (Cu, Zn, Se, and Co) might correlate with the risk of EEA to some extent. The present study might provide a real-world perspective on the relationship between essential trace elements and the risk of EEA when considering them as a single element or as mixtures.

The mitochondrial DNA (mtDNA) m.3243A>G mutation is one of the most common pathogenic mtDNA variants, showing complex genetics, pathogenic molecular mechanisms, and phenotypes. In recent years, the prevention of mtDNA-related diseases has trended toward precision medicine strategies, such as preimplantation genetic diagnosis (PGD) and mitochondrial replacement therapy (MRT). These techniques are set to allow the birth of healthy children, but clinical implementation relies on thorough insights into mtDNA genetics. The genotype and phenotype of m.3243A>G vary greatly from mother to offspring, which compromises genetic counseling for the disease. This review is the first to systematically elaborate on the characteristics of the m.3243A>G mutation, from genetics to phenotype and the relationship between them, as well as the related influencing factors and potential strategies for preventing disease. These perceptions will provide clarity for clinicians providing genetic counseling to m.3243A>G patients.

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease that usually leads to selective degeneration of retinal ganglion cells (RGCs) and optic atrophy in young adults. One of three common mitochondrial DNA (mtDNA) mutations (m.11778G > A, m.3460G > A, m.14484 T > C) account for 90% of LHON cases. All three affect the function of respiration chain complex I. However, m.3635G > A, affecting the structure and function of MT-ND1 gene, is also associated with LHON. Here, we successfully generated a human induced pluripotent stem cell (hiPSC) line from an LHON patient carrying a homoplasmic m.3635G > A mutation in the MT-ND1 gene.

Objective: The objective of this retrospective study was to compare the efficacy of azithromycin versus doxycycline in the treatment of urogenital Chlamydia trachomatis infection. Methods: A retrospective study was conducted on all patients who tested positive for Chlamydia in our clinic from May 2017 to May 2019. Patients who did not follow the standard dose and course of treatment, did not receive the test-of-cure, or received other drugs that may affect the efficacy were excluded. Results: Of the 68 patients who initially received a 1 g single dose azithromycin, the total microbiological cure rate was 79.4% (54/68), while the microbiological cure rate in 19 patients who received doxycycline treatment was 100% (19/19). Use of drugs from different manufacturers and shorter time after completion of treatment to perform test-of-cure might lead to the possibility of underestimation of microbiological cure rate. Conclusions: These results suggest that 7-day doxycycline should be recommended as the 1st line treatment for urogenital Chlamydia infection. Considering the convenient dosage, ong-gram single dose of azithromycin could be recommended as an alternative treatment for urogenital Chlamydia infection.

This paper studies the privacy risk perception of online medical community users based on deep neural network. Firstly, this paper introduces privacy protection based on deep neural network and users’ privacy risk perception in online medical community. Then, using the fuzzy neural network to deal with highly complex and nonlinear data, we can better obtain the accurate evaluation value, and use the improved gravity search optimization algorithm to optimize the fuzzy neural network evaluation model and improve the convergence puzzle of the model. Finally, using the experimental method of questionnaire survey, and the questionnaire is composed of three parts. The first part investigates the basic personal information of the subjects, including gender, age, educational background, physical condition, physical examination frequency, Internet use experience, long-term residence, etc.; The second part is the measurement items of each variable in the theoretical model, including nine variables: service quality, personalized service, reciprocal norms, result expectation, material reward, perceived risk, trust in doctors, trust in websites, and willingness to disclose health privacy information. The experimental results show that the correlation coefficient between the interaction items of personalized service and reciprocal norms on material reward is positive (β = 0.072, P < 0.01), and the correlation coefficient between sexual service and material reward was positive (β = 0.202, P < 0.01), then reciprocal norms positively regulate the relationship between personalized service and material reward.

Abstract Background Antimicrobial resistance in M. genitalium is a growing clinical problem. We investigated the mutations associated with macrolide and fluoroquinolone resistance, two commonly used medical regimens for treatment in China. Our aim is to analyze the prevalence and diversity of mutations among M. genitalium-positive clinical specimens in Guangzhou, south China. Methods A total of 154 stored M. genitalium positive specimens from men and women attending a STI clinic were tested for macrolide and fluoroquinolone mutations. M. genitalium was detected via TaqMan MGB real-time PCR. Mutations associated with macrolide resistance were detected using primers targeting region V of the 23S rRNA gene. Fluoroquinolone resistant mutations were screened via primers targeting topoisomerase IV (parC) and DNA gyrase (gyrA). Results 98.7% (152/154), 95.5% (147/154) and 90.3% (139/154) of M. genitalium positive samples produced sufficient amplicon for detecting resistance mutations in 23S rRNA, gyrA and parC genes, respectively. 66.4% (101/152), 0.7% (1/147) and 77.7% (108/139) samples manifested mutations in 23S rRNA, gyrA and parC genes, respectively. A2072G (59/101, 58.4%) and S83I (79/108, 73.1%) were highly predominating in 23S rRNA and parC genes, respectively. Two samples had amino acid substitutions in gyrA (M95I and A96T, respectively). Two samples had two amino acid substitutions in parC (S83I + D87Y). 48.6% (67/138) of samples harbored both macrolide and fluoroquinolone resistance-associated mutations. The most common combination of mutations was A2072G (23S rRNA) and S83I (parC) (40/67, 59.7%). One sample had three amino acid changes in 23S rRNA, gyrA and parC genes (A2072G + A96T + S83I). Conclusions The high antimicrobial resistance rate of M. genitalium in Guangzhou is a very worrying problem and suggests that antimicrobial resistance testing and the development of new antibiotic regimens are crucially needed.

Background: Toxic and essential trace elements are reported to have impact on female fertility. However, studies on the potential synergistic or antagonistic effects of metal mixtures on IVF outcomes remain limited. Objective: To evaluate whether serum concentrations of metals, individually and as mixtures, are associated with pregnancy outcomes in women undergoing IVF. Methods: In a prospective birth cohort study about IVF from the First Affiliated Hospital of Anhui Medical University (n = 1184), we measured the concentrations of serum metals by ICP-MS according to a previously established method. Oocyte/embryo development indicators and follow-up results were also collected. The individual and joint effects of metals were estimated using logistic regressions and Bayesian kernel machine regressions (BKMR). Results: At embryonic stage, we found negative associations between the serum lead (Pb) (β = −0.14, 95%CI: −0.32, −0.04) and cadmium (Cd) (β = −0.24, 95%CI: −0.39, −0.09) concentrations and the high-quality embryos rate; and positive associations between the serum cobalt (Co) (β = 0.18, 95%CI: 0.05, 0.31) and selenium (Se) (β = 0.17, 95%CI: 0.06, 0.41) concentrations and the MII rate. Regarding to the pregnancy outcomes, the serum Pb was negatively related with successful implantation (OR=0.85, 95%CI: 0.77, 0.94) and clinical pregnancy (OR=0.95, 95%CI: 0.91, 0.99); and positively associated with spontaneous abortion (OR=1.39, 95% CI: 1.02, 1.91). The BKMR analysis showed linear or parabolic associations between the metal mixtures and pregnancy outcomes, with Pb showing the highest posterior inclusion probabilities. Conclusions: The toxic (Pb, Cd) and essential (Co, Se) metals could be incorporated as simultaneous predictors of IVF outcomes including potential antagonistic effects, in which Pb exhibits major contributions.

This research aimed to investigate the role of glyoxalase 1 (Glo-1) polymorphisms in the susceptibility of schizophrenia. Using the real-time polymerase chain reaction (PCR) and spectrophotometric assays technology, significant differences in Glo-1 messenger ribonucleic acid (mRNA) expression (P = 3.98 × 10−5) and enzymatic activity (P = 1.40 × 10−6) were found in peripheral blood of first-onset antipsychotic-naïve patients with schizophrenia and controls. The following receiver operating characteristic (ROC) curves analysis showed that Glo-1 could predict the schizophrenia risk (P = 4.75 × 10−6 in mRNA, P = 1.43 × 10−7 in enzymatic activity, respectively). To identify the genetic source of Glo-1 risk in schizophrenia, Glo-1 polymorphisms (rs1781735, rs1130534, rs4746, and rs9470916) were genotyped with SNaPshot technology in 1,069 patients with schizophrenia and 1,023 healthy individuals. Then, the impact of risk polymorphism on the promoter activity, mRNA expression, and enzymatic activity was analyzed. The results revealed significant differences in the distributions of genotype (P = 0.020, false discovery rate (FDR) correction) and allele (P = 0.020, FDR correction) in rs1781735, in which G > T mutation significantly showed reduction in the promoter activity (P = 0.016), mRNA expression, and enzymatic activity (P = 0.001 and P = 0.015, respectively, GG vs. TT, in peripheral blood of patients with schizophrenia) of Glo-1. The expression quantitative trait locus (eQTL) findings were followed up with the resting-state functional magnetic resonance imaging (fMRI) analysis. The TT genotype of rs1781735, associated with lower RNA expression in the brain (P < 0.05), showed decreased neuronal activation in the left middle frontal gyrus in schizophrenia (P < 0.001). In aggregate, this study for the first time demonstrates how the genetic and biochemical basis of Glo-1 polymorphism culminates in the brain function changes associated with increased schizophrenia risk. Thus, establishing a combination of multiple levels of changes ranging from genetic variants, transcription, protein function, and brain function changes is a better predictor of schizophrenia risk.

The development and application of high-throughput omics technologies have enabled a more in-depth understanding of mitochondrial biosynthesis metabolism and the pathogenesis of mitochondrial diseases. In accordance with this, a host of new treatments for mitochondrial disease are emerging. As an essential pathway in maintaining mitochondrial proteostasis, the mitochondrial unfolded protein response (UPRmt) is not only of considerable significance for mitochondrial substance metabolism but also plays a fundamental role in the development of mitochondrial diseases. Furthermore, in mammals, the integrated stress response (ISR) and UPRmt are strongly coupled, functioning together to maintain mitochondrial function. Therefore, ISR and UPRmt show great application prospects in the treatment of mitochondrial diseases. In this review, we provide an overview of the molecular mechanisms of ISR and UPRmt and focus on them as potential targets for mitochondrial disease therapy.

Functional and structural disturbances in the orbitofrontal–striatal–thalamic circuitry are thought to be associated with mental symptoms and neurocognitive impairments in schizophrenia. This study tested whether synapse-associated protein 97 (SAP97), a reasonable candidate gene for schizophrenia, is related to orbitofrontal–striatal–thalamic connection changes in first-episode schizophrenia (FES) patients and the clinical performance of schizophrenic patients by affecting this integrity. Fifty-two FES patients and 52 matched healthy controls were recruited. All subjects underwent genotyping via the improved multiplex ligation detection reaction technique and scanning with magnetic resonance imaging (MRI) to provide orbitofrontal–striatal–thalamic functional and structural imaging data. A two-way analysis of covariance model was employed to examine abnormal brain connectivities, and Spearman correlations were applied to estimate the relationships between brain connectivity and clinical manifestations. In the FES group, those with the SAP97 rs3915512 TT genotype showed lower structural and functional connectivity than A allele carriers between the orbitofrontal gyrus and striatum/thalamus. In the FES group, negative correlations were found between resting-state functional connectivity (RSFC) in the orbitofrontal gyrus and thalamus, and positive symptoms between structural connections in the orbitofrontal gyrus and striatum and cognitive functions, and positive correlations were suggested between RSFC in the orbitofrontal gyrus and thalamus and negative symptoms. Our findings suggested that the SAP97 rs3915512 polymorphism may be involved in mental symptoms and cognitive dysfunction in FES patients by influencing structural and functional connectivity of the orbitofrontal–striatal and orbitofrontal–thalamic regions.

Formononetin is one of the main active components of traditional Chinese medicine red clover (Trifolium pratense L). Prior studies have demonstrated that formononetin is a typical phytoestrogen and exhibits an estrogen-like effect that protects the cardiovascular system with minimal side effects. In this study, we further investigated the role of formononetin in human umbilical vein endothelial cells (HUVECs) and its potential molecular mechanisms. We founded that formononetin promotes proliferation and migration of HUVECs as assessed by the MTT and wound healing assays. Meanwhile, insulin-like growth factor 1 (IGF-1) and intercellular adhesion molecule 1 (ICAM-1) protein levels were increased in a dose-dependent manner. Our findings illustrated that formononetin exhibits a protective effect on HUVECs, and the molecular mechanisms may correlate with IGF-1R and ICAM-1, as well as upregulation of vascular endothelial growth factor (VEGF) and activation of extracellular signal-regulated kinase (ERK).

Background: Thallium (Tl) exposure remains a public health problem with potential impacts on humans. Studies have suggested that prenatal exposure to thallium may be associated with fetal growth, but no studies are known have explored its association with early childhood anthropometry. Objective: To investigate the effects of prenatal Tl exposures on early child growth and development aged 0–2 years in a prospective birth cohort study. Methods: 3080 pregnant women and their children participated in the study, which were recruited from a birth cohort in China. Serum samples collected in the first and second trimester of pregnant subjects and umbilical cord blood of infants were analyzed for Tl exposure assessment. Infant length or standing height and weight were obtained from medical records and 2 years planned visits. We used length/height and weight to calculate z-scores for weight-for-age (WAZ), height-for-age (HAZ), weight-for-height (WHZ), and body mass index-for-age (zBMI) based on World Health Organization standards. Linear mixed model was used to investigate the association between serum concentrations of Tl and the children's anthropometric characteristics (WAZ, HAZ, WHZ, and zBMI), and stratification analysis by sex was also examined. Results: The median (P25-P75) of Tl levels in the first trimester, second trimester and umbilical cord serum were 61.7 (50.7–77.0), 60.1 (50.9–74.8) and 38.4 (33.6–43.9) ng/L, respectively. Paired Mann-Whitney tests found Tl concentrations in umbilical cord serum were significantly less than that in maternal serum during the first and second trimesters (all p

Objective: To investigate the effects of microRNA-137 (MIR137) polymorphisms (rs1198588 and rs2660304) on the risk of schizophrenia in a Han Chinese population.Methods: Schizophrenia was diagnosed according to the DSM-5. Clinical symptoms and cognitive functions were assessed with the Positive and Negative Symptom Scale (PANSS) and Brief Assessment of Cognition in Schizophrenia (BACS), respectively. The polymorphisms were genotyped by improved multiplex ligation detection reaction (iMLDR) technology in 1,116 patients with schizophrenia and 1,039 healthy controls.Results: Significant associations were found between schizophrenia and MIR137 in the distributions of genotypes (p = 0.037 for rs1198588; p = 0.037 for rs2660304, FDR corrected) and alleles (p = 0.043 for rs1198588; p = 0.043 for rs2660304, FDR corrected) of two SNPs. When the population was stratified by sex, we found female-specific associations between MIR137 and schizophrenia in terms of genotype and allele distributions of rs1198588 (χ2 = 4.41, p = 0.036 and χ2 = 4.86, p = 0.029, respectively, FDR corrected) and rs2660304 (χ2 = 4.74, p=0.036 and χ2 = 4.80, p = 0.029, respectively, FDR corrected). Analysis of the MIR137 haplotype rs1198588-rs2660304 showed a significant association with schizophrenia in haplotype T-T [χ2 = 4.60, p = 0.032, OR = 1.32, 95% CI (1.02–1.70)]. Then, significant female-specific associations were found with the haplotypes T-T and G-A [χ2 = 4.92, p = 0.027, OR = 1.62, 95% CI (1.05–2.50); χ2 = 4.42, p = 0.035, OR = 0.62, 95% CI (0.39–0.97), respectively]. When the TT genotype of rs1198588 was compared to the GT+GG genotype, a clinical characteristics analysis also showed a female-specific association in category instances (t = 2.76, p = 0.042, FDR corrected).Conclusion: The polymorphisms within the MIR137 gene are associated with susceptibility to schizophrenia, and a female-specific association of MIR137 with schizophrenia was reported in a Han Chinese population.

Background: The potential maternal and neonatal thyrotoxicity associated with exposure to arsenic during pregnancy is very limited and unclear. Objectives: This study aimed to examine the associations between arsenic exposure levels in maternal and cord serum and maternal and neonatal thyroid hormone parameters in a prospective birth cohort study. Methods: The study including 2089 mother-neonate pairs was based upon Ma’an Shan birth cohort study in China. The exposure variables including maternal serum arsenic levels in the first, second and third trimester and average arsenic exposure level during pregnancy and cord serum arsenic level. Maternal serum TSH and FT4 levels in the first, second and third trimester and cord serum TSH and FT4 levels were determined using the electrochemiluminescence immunoassay with Cobas Elecsys 411. Linear mixed models were used to examine associations between arsenic exposure variables during pregnancy and maternal thyroid hormone parameters, and multiple linear regression analyses were used to examine associations between arsenic exposure during pregnancy and neonatal thyroid hormone parameters. Bayesian kernal machine regression (BKMR) analyses based on a kernel function were also used to examine the effects of exposure to metal mixtures (arsenic, mercury, cadmium and selenium). Results: The geometric means of arsenic exposure levels across 3 trimesters were 1.74 μg/L, 1.81 μg/L and 1.99 μg/L, respectively, and 1.90 μg/L in cord serum; the geometric means of maternal FT4 levels across 3 trimesters were 16.91 pmol/L, 11.91 pmol/L and 13.16 pmol/L, respectively, and 16.10 pmol/L in cord serum; the geometric means of maternal TSH levels across 3 trimesters were 1.27 μIU/mL, 2.32 μIU/mL and 2.08 μIU/mL, respectively, and 8.47 μIU/mL in cord serum. Maternal serum arsenic levels in the first, seond, third trimester and average arsenic exposure level during pregnancy were all not associated with maternal thyroid hormone parameters after adjustment for all the covariates, the adjusted β (95% CI) were −0.002 (−0.10 to 0.09), 0.05 (−0.05 to 0.16), −0.09 (−0.17 to 0.003) and −0.05 (−0.22 to 0.11) for maternal FT4, respectively; and −0.005 (−0.04 to 0.03), −0.003 (−0.04 to 0.03), −0.004 (−0.03 to 0.02) and −0.01 (−0.06 to 0.04) for maternal lnTSH, respectively. Maternal serum arsenic levels in the first, second trimester and average arsenic exposure level during pregnancy were all inversely associated with neonatal FT4 level after adjustment for all the confounders, the adjusted β (95% CI) were −0.19 (−0.31 to −0.07), −0.14 (−0.26 to −0.01), −0.22 (−0.42 to −0.02), respectively; and cord serum arsenic level was positively related with neonatal TSH level, the adjusted β (95% CI) were 0.04 (0.001 to 0.08). The adverse joint toxic effect of the four metals in maternal serum in the first trimester and in cord serum on neonatal thyroid hormone parameters were also found. Conclusions: In this study, exposure to low levels of arsenic during pregnancy could directly affect neonatal thyroid hormone parameters without being mediated by maternal effect of exposure, and maternal serum arsenic levels in the first, second trimester and average arsenic exposure level during pregnancy and cord serum arsenic level may be risk factors affecting neonatal thyroid hormones. These findings indicate that neonates are more sensitive to the thyrotoxicity of arsenic exposure even at low levels. In addition, the adverse joint toxic effect of metal mixtures is also worthy of attention.

Our previous study suggested that the synapse-associated protein 97 (SAP97) gene rs3915512 polymorphism may influence neurocognition in schizophrenia patients. Neuroimaging studies have shown a possible association between cognitive function and brain activity/connectivity. Considering the poor understanding of whether the disease state and SAP97 rs3915512 polymorphism have interactive effects on brain activity/connectivity, 52 first-episode schizophrenia (FES) patients and 52 healthy controls were genotyped using blood DNA samples and underwent magnetic resonance imaging scanning. A two-way ANCOVA model was performed with rs3915512 genotypes and disease state as the between-subject factors. A significant disease × SAP97 interactive effect was found for the amplitude of low-frequency fluctuation (ALFF) in the right supplementary motor area, left rolandic opercularis area (ROC-L), and bilateral middle occipital gyrus (MOG). In addition, among auditory/visual-related brain areas, a significant interactive effect was found for resting-state functional connectivity (RSFC) between the MOG-L and bilateral superior temporal gyrus (STG) in the STG-L with ROC-R, right cuneus (Cu-R), left fusiform (Fu-L), and left lingual gyrus (LG-L). Positive correlations were found between ALFF in the ROC-L and motor speed scores, between RSFC in the STG-L and LG-L and between Brief Assessment of Cognition in Schizophrenia verbal memory scores in FES. The SAP97 rs3915512 polymorphism may affect neurocognitive function in patients with schizophrenia by changing the brain activity and connectivity of auditory/visual-related brain areas.

Progressive functional deterioration and loss of neurons underlies neurological diseases and constitutes an important cause of disability and death worldwide. The causes of various types of neurological diseases often share several critical nerve-related cellular mechanisms and pathological features, particularly the neuroinflammatory response in the nervous system. A rapidly growing body of evidence indicates that various microRNAs play pivotal roles in these processes in neurological diseases and might be viable therapeutic targets. Among these microRNAs, microRNA-146a (miR-146a) stands out due to the rapid increase in recent literature on its mechanistic involvement in neurological diseases. In this review, we summarize and highlight the critical role of miR-146a in neurological diseases. MiR-146a polymorphisms are associated with the risk of neurological disease. Alterations in miR-146a expression levels are crucial events in the pathogenesis of numerous neurological diseases that are spatially and temporally diverse. Additionally, the target genes of miR-146a are involved in the regulation of pathophysiological processes in neurological diseases, particularly the neuroinflammatory response. In summary, miR-146a mainly plays a critical role in neuroinflammation during the progression of neurological diseases and might be a prospective biomarker and therapeutic target. Understanding the mechanisms by which miR-146a affects the neuroinflammatory response in different neurological injuries, different cell types, and even different stages of certain neurological diseases will pave the way for its use as a therapeutic target in neurodegenerative diseases.

The relationship between prenatal arsenic exposure at low levels and poor development in children, especially in regard to neurodevelopment, has aroused several concerns, but the conclusions have been inconsistent. It still remains unclear whether such adverse effect is associated with a specific profile of the developing brain in early life. To investigate the association between arsenic exposure in utero and children’s development and behaviour, we performed a large prospective birth cohort study including 2315 mother-infant pairs in Anhui Province, China. The Ages and Stages Questionnaire of China (ASQ-C) was used to assess the status of children’s development and behaviour at 6 months postpartum, and the levels of arsenic were determined in umbilical cord serum samples. Odds ratios for suspected developmental delay (SDD) in each domain of the ASQ-C clusters were estimated using logistic regression models. Compared with low arsenic levels group, medium and high arsenic levels were significantly associated with the increased risks of SDD in the personal-social domain among infants aged 6 months after adjustment for all potential confounders (OR = 1.33, 95% CI (1.01, 1.75) and OR = 1.47, 95% CI (1.08, 2.00), respectively). Sex stratification analysis demonstrated that this association was stronger in females. The sensitivity analyses also showed that high cord serum arsenic levels were associated with a 1.80-fold (95% CIs (1.12, 2.90)) higher risk of a more severe developmental delay in the personal-social domain among six-month-old females. Our results suggest that low-level arsenic exposure in utero could have an adverse domain-specific effect on children’s development at 6 months of age, particularly among females. Further studies are warranted to support the findings and explore the mechanism of these domain-and sex-specific associations. Keywords: Arsenic, Umbilical cord serum, Development, Prenatal exposure, Infants, China

Autism spectrum disorder (ASD) and dyslexia are both neurodevelopmental disorders with high prevalence in children. Both disorders have strong genetic basis, and share similar social communication deficits co-occurring with impairments of reading or language. However, whether these two disorders share common genetic risks remain elusive. DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia. Dock4 is important for neuronal development and social behaviors. Two DOCK4 variations, Exon27-52 deletion (protein product: Dock4-945VS) and a missense mutation at rs2074130 (protein product: Dock4-R853H), are associated with dyslexia and/or ASD with reading difficulties. The present study explores the molecular and cellular functions of these two DOCK4 variants on neuronal development, by comparing them with the wild-type Dock4 protein. Notably, it is revealed that both mutants of Dock4 showed decreased ability to activate not only Rac1, but also another small GTPase Rap1. Consistently, both mutants were dysfunctional for regulation of cell morphology and cytoskeleton. Using Neuro-2a cells and hippocampus neurons as models, we found that both mutants had compromised function in promoting neurite outgrowth and dendritic spine formation. Electrophysiological recordings further showed that R853H partially lost the ability to promote excitatory synaptic transmission, whereas 945VS totally lost the ability. Together, we identified R853 as a previously uncharacterized site for the regulation of the integrity of Dock4 function, and provides insights in understanding the common molecular pathophysiology of ASD and dyslexia.

Abstract Introduction Schizophrenia is a serious mental illness with a genetic predisposition. Genome‐wide association studies (GWAS) have identified the α‐1C subunit of the L‐type voltage‐gated calcium channel (CACNA1C) gene as a significant risk gene for schizophrenia. However, there are inconsistent conclusions in case–control studies. Methods We performed a comprehensive meta‐analysis of all available samples from existing studies under four different genetic models (recessive model, dominant model, additive model and allele model) to further confirm whether CACNA1C rs1006737 is an authentic risk single nucleotide polymorphism (SNP) for schizophrenia. Results A statistically significant difference under the four models (all p

Objective: Schizophrenia is thought to be a neurodevelopmental disorder. As a key regulator in the development of the central nervous system, transcription factor 4 (TCF4) has been shown to be involved in the pathogenesis of schizophrenia. The aim of our study was to assay the association of TCF4 single nucleotide polymorphisms (SNPs) with schizophrenia and the effect of these SNPs on phenotypic variability in schizophrenia in Southern Chinese Han Population.Methods: Four SNPs (rs9960767, rs2958182, rs4309482, and rs12966547) of TCF4 were genotyped in 1137 schizophrenic patients and 1035 controls in a Southern Chinese Han population using the improved multiplex ligation detection reaction (iMLDR) technique. For patients with schizophrenia, the severity of symptom phenotypes was analyzed by the five-factor model of the Positive and Negative Symptom Scale (PANSS). Cognitive function was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) scale.Results: The results showed that the genotypes and alleles of the three SNPs (rs2958182, rs4309482, and rs12966547) were not significantly different between the control group and the case group (all P > 0.05). rs9960767 could not be included in the statistics for the extremely low minor allele frequency. However, the genotypes of rs4309482 shown a potential risk in the positive symptoms (P = 0.04) and excitement symptoms (P = 0.04) of the five-factor model of PANSS, but not survived in multiple test correction. The same potential risk was shown in the rs12966547 in positive symptoms of the PANSS (P = 0.03).Conclusion: Our results failed to find the associations of SNPs (rs2958182, rs4309482, and rs12966547) in TCF4 with schizophrenia in Southern Chinese Han Population.

The SAP97 gene is located in the schizophrenia susceptibility locus 3q29, and it encodes the synaptic scaffolding protein that interacts with the N-methyl-D-aspartate (NMDA) receptor, which is presumed to be dysregulated in schizophrenia. In this study, we genotyped a single-nucleotide polymorphism (SNP) (rs3915512) in the SAP97 gene in 1114 patients with schizophrenia and 1036 healthy-matched controls in a Han Chinese population through the improved multiplex ligation detection reaction (imLDR) technique. Then, we analyzed the association between this SNP and the patients' clinical symptoms and neurocognitive function. Our results showed that there were no significant differences in the genotype and allele frequencies between the patients and the controls for the rs3915512 polymorphism. However, patients with the rs3915512 polymorphism TT genotype had higher neurocognitive function scores (list learning scores, symbol coding scores, category instances scores and controlled oral word association test scores) than the subjects with the A allele (P = 4.72 × 10−5, 0.027, 0.027, 0.013, respectively). Our data are the first to suggest that the SAP97 rs3915512 polymorphism may affect neurocognitive function in patients with schizophrenia.