Integrative metagenomic and lipidomic analyses reveal alterations in children with obesity and after lifestyle intervention.

Background: Despite emerging evidence linking alterations in gut microbiota to childhood obesity, the metabolic mechanisms linking gut microbiota to the lipid profile during childhood obesity and weight loss remain poorly understood. Methodology: In this study, children with obesity were treated with lifestyle weight loss therapy. Metagenomics association studies and serum untargeted lipidomics analyses were performed in children with obesity and healthy controls before and after weight loss. Main findings: We identified alterations in gut microbiota associated with childhood obesity, as well as variations in circulating metabolite concentrations. Children with obesity showed significant decreases in the levels of s-Rothia_kristinae and s-Enterobacter_roggenkampii, alongsige elevated levels of s-Clostridiales_bacterium_Marseille-P5551. Following weight loss, the levels of s-Streptococcus_infantarius and s-Leuconostoc_citreum increased by factors of 3.354 and 1.505, respectively, in comparison to their pre-weight loss levels. Correlation analyses indicated a significant positive relationship between ChE(2:0) levels and both with s-Lachnospiraceae_bacterium_TF09-5 and fasting glucose levels. CoQ8 levels were significantly negatively correlated with s-Rothia_kristinae and HOMA-IR. Conclusion: We linked altered gut microbiota and serum lipid levels in children with obesity to clinical indicators, indicating a potential impact on glucose metabolism via lipids. This study contributes to understanding the mechanistic relationship between altered gut microbiota and childhood obesity and weight loss, suggesting gut microbiome as a promising target for intervention. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=178971, ChiCTR2300072179.

Radical Replacement Process for Ligated Boryl Radical-Mediated Activation of Unactivated Alkyl Chlorides for C(sp3)-C(sp3) Bond Formation.

The ligated boryl radical (LBR) has emerged as a potent tool for activating alkyl halides in radical transformations through halogen-atom transfer (XAT). However, unactivated alkyl chlorides still present an open challenge for this strategy. We herein describe a new activation mode of the LBR for the activation of unactivated alkyl chlorides to construct a C(sp3)-C(sp3) bond. Mechanistic studies reveal that the success of the protocol relies on a radical replacement process between the LBR and unactivated alkyl chloride, forming an alkyl borane intermediate as the alkyl radical precursor. Aided with the additive K3PO4, the alkyl borane then undergoes one-electron oxidation, generating an alkyl radical. The incorporation of the radical replacement activation model to activate unactivated alkyl chlorides significantly enriches LBR chemistry, which has been applied to activate alkyl iodides, alkyl bromides, and activated alkyl chlorides via XAT.

[Differential effects of Qingqiao and Laoqiao on bleomycin-induced pulmonary fibrosis in mice by principal component analysis].

The mechanism of alleviating bleomycin-induced pulmonary fibrosis in mice was compared between Qingqiao(Forsythiae Fructus produced with immature fruits) and Laoqiao(Forsythiae Fructus produced with mature fruits) from the pharmacodynamic correlation and composition differences. Mice were randomized into normal, model, pirfenidone(50 mg·kg~(-1)), low-and high-dose(1.3, 2.6 g·kg~(-1), respectively) Qingqiao, and low-and high-dose(1.3, 2.6 g·kg~(-1), respectively) Laoqiao groups. The mouse model of pulmonary fibrosis was established by intratracheal instillation of bleomycin, during which the survival rate and body weight changes of the mice were measured. After modeling, the lung index was calculated, and the pathological changes in the lung tissue were evaluated by hematoxylin-eosin(HE), Masson, and Sirius red staining. Transmission electron microscopy was employed to observe the ultrastructure of the lung tissue. The biochemical assay was employed to measure the levels of transforming growth factor-ß1(TGF-ß1), α-smooth muscle actin(α-SMA), E-cadherin, and hydroxyproline(HYP) in the lung tissue and interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) in the bronchoalveolar lavage fluid(BALF). The mRNA and protein levels of matrix metalloproteinase 7(MMP7), collagen Ⅰ, E-cadherin, TNF-α, vimentin, TGF-ß1, and α-SMA in the lung tissue were determined by RT-qPCR and Western blot, respectively. The expression of α-SMA in the lung tissue was detected by the immunofluorescence assay. Principal component analysis was performed to compare the effects of Qingqiao and Laoqiao in ameliorating pulmonary fibrosis. Molecular docking was employed to analyze the binding between the compounds with high content in Laoqiao and TGF-ß1. The cell-counting kit(CCK-8) assay was used to examine the effects of the active compounds on TGF-ß1-induced BEAS-2B and HFL1 cell models. The results showed that Qingqiao and Laoqiao increased the survival rate, reduced the lung index, alleviated the pathological damage and collagen deposition in the lung tissue, ameliorated the damage of lamellar bodies in alveolar epithelial type Ⅱ cells, lowered the level of IL-6 and TNF-α in the BALF, down-regulated the expression of HYP, MMP7, vimentin, collagen Ⅰ, TGF-ß1, and α-SMA, and up-regulated the expression of E-cadherin in the lung tissue of the mouse model of pulmonary fibrosis. The collagen deposition in the mouse model of pulmonary fibrosis was comprehensively evaluated by principal component analysis, and the effects of different treatments followed the trend of high-dose Laoqiao>low-dose Laoqiao>high-dose Qingqiao>low-dose Qingqiao. Molecular docking showed that hydroxytyrosol, caffeic acid, phillygenin, and(-)-lariciresinol had strong binding affinity with TGF-ß1 receptor. The results of cell experiments showed that these compounds significantly attenuated the TGF-ß1-induced damage in BEAS-2B cells and inhibited the TGF-ß1-induced proliferation of HFL1 cells. In conclusion, both Qingqiao and Laoqiao were effective in ameliorating bleomycin-induced pulmonary fibrosis in mice. Laoqiao was superior to Qingqiao in reducing collagen deposition, which might be attributed to the higher content of hydroxytyrosol, caffeic acid, phillygenin, and(-)-lariciresinol in Laoqiao than in Qingqiao.

Mammary hydroxylated oestrogen activates the NLRP3 inflammasome in tumor-associated macrophages to promote breast cancer progression and metastasis.

Breast cancer remains one of the primary causes of cancer-related death. An imbalance of oestrogen homeostasis and an inflammatory tumor microenvironment (TME) are vital risk factors for the progression and metastasis of breast cancer. Here, we showed that oestrogen homeostasis was disrupted both in breast cancer patients and in a transgenic MMTV-PyMT mouse model of breast cancer, and significant levels of hydroxylated oestrogen accumulated in the mammary tissues of these patients and mice. We also observed that tumor-associated macrophages (TAMs) were the main population of immune cells present in the breast TME. TAM-dependent tumor metastasis could be triggered by hydroxylated oestrogen via NLRP3 inflammasome activation and IL-1ß production. Mechanistically, TAM-derived inflammatory cytokines induced the expression of matrix metalloproteinases (MMPs) in breast tumor cells, leading to breast tumor invasion and metastasis. Conceptually, our study reveals a previously unknown role of hydroxylated oestrogen in the reprogramming of the TME via NLRP3 inflammasome activation in TAMs, which ultimately facilitates breast cancer cells proliferation, migration, and invasion.

Genomic profiling of colorectal cancer in large-scale Chinese patients: amplification and somatic mutations in ERBB2.

Objectives: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have demonstrated potential benefits for metastatic colorectal cancer (mCRC) patients with HER2 amplification, but are not satisfactory in cases of HER2 mutant CRCs. Methods: Consequently, further elucidation of amplifications and somatic mutations in erythroblastic oncogene B-2 (ERBB2) is imperative. Comprehensive genomic profiling was conducted on 2454 Chinese CRC cases to evaluate genomic alterations in 733 cancer-related genes, tumor mutational burden, microsatellite instability, and programmed death ligand 1 (PD-L1) expression. Results: Among 2454 CRC patients, 85 cases (3.46%) exhibited ERBB2 amplification, and 55 cases (2.24%) carried ERBB2 mutation. p.R678Q (28%), p.V8421 (24%), and p.S310F/Y (12%) were the most prevalent of the 16 detected mutation sites. In comparison to the ERBB2 altered (alt) group, KRAS/BRAF mutations were more prevalent in ERBB2 wild-type (wt) samples (ERBB2wt vs. ERBB2alt, KRAS: 50.9% vs. 25.6%, p < 0.05; BRAF: 8.5% vs. 2.3%, p < 0.05). 32.7% (18/55) of CRCs with ERBB2 mutation exhibited microsatellite instability high (MSI-H), while no cases with HER2 amplification displayed MSI-H. Mutant genes varied between ERBB2 copy number variation (CNV) and ERBB2 single nucleotide variant (SNV); TP53 alterations tended to co-occur with ERBB2 amplification (92.3%) as opposed to ERBB2 mutation (58.3%). KRAS and PIK3CA alterations were more prevalent in ERBB2 SNV cases (KRAS/PIK3CA: 45.8%/31.2%) compared to ERBB2 amplification cases (KRAS/PIK3CA: 14.1%/7.7%). Conclusion: Our study delineates the landscape of HER2 alterations in a large-scale cohort of CRC patients from China. These findings enhance our understanding of the molecular features of Chinese CRC patients and offer valuable implications for further investigation.

Effect of Psychological Intervention on Quality of Life Among Patients with Psoriasis: A Meta-analysis.

BACKGROUND: Psychological distress can significantly obstruct the treatment outcomes of patients with psoriasis. This meta-analysis aimed to examine the effects of psychological intervention on the mental health and functional capabilities in patients with psoriasis. METHOD: PubMed, EMBASE, and Cochrane Library were searched for relevant studies published up to May 1, 2023. The primary outcome was a change in anxiety, depression, and quality of life (QoL). Standardized mean difference (SMD) was calculated, and 95% confidence interval (CI) was determined for the estimation. RESULTS: This meta-analysis involved 1048 subjects, including 515 patients who received psychological interventions and 533 patients in control groups who did not receive psychological interventions. The results showed that psychological intervention significantly improved anxiety symptoms (SMD - 0.41; 95%CI - 0.77, - 0.05; I2 = 71.5%; PHeterogeneity = 0 .001). There was no significant improvement in the symptoms of depression (SMD - 0.52; 95%CI - 1.13, 0.10; I2 = 86%; PHeterogeneity < 0 .001) and QoL (SMD - 0.05; 95%CI - 0.22, 0.11; I2 = 39%; PHeterogeneity = 0 .108) in patients who received psychological intervention compared with controls. CONCLUSION: Psychological intervention ameliorated anxiety symptoms in patients with psoriasis but had no significant impact on depression or QoL.

Evaluation and integration of cell-free DNA signatures for detection of lung cancer.

Cell-free DNA (cfDNA) analysis has shown potential in detecting early-stage lung cancer based on non-genetic features. To distinguish patients with lung cancer from healthy individuals, peripheral blood were collected from 926 lung cancer patients and 611 healthy individuals followed by cfDNA extraction. Low-pass whole genome sequencing and targeted methylation sequencing were conducted and various features of cfDNA were evaluated. With our customized algorithm using the most optimal features, the ensemble stacked model was constructed, called ESim-seq (Early Screening tech with Integrated Model). In the independent validation cohort, the ESim-seq model achieved an area under the curve (AUC) of 0.948 (95 % CI: 0.915-0.981), with a sensitivity of 79.3 % (95 % CI: 71.5-87.0 %) across all stages at a specificity of 96.0 % (95 % CI: 90.6-100.0 %). Specifically, the sensitivity of the ESim-seq model was 76.5 % (95 % CI: 67.3-85.8 %) in stage I patients, 100 % (95 % CI: 100.0-100.0 %) in stage II patients, 100 % (95 % CI: 100.0-100.0 %) in stage III patients and 87.5 % (95 % CI: 64.6%-100.0 %) in stage IV patients in the independent validation cohort. Besides, we constructed LCSC model (Lung Cancer Subtype multiple Classification), which was able to accurately distinguish patients with small cell lung cancer from those with non-small cell lung cancer, achieving an AUC of 0.961 (95 % CI: 0.949-0.957). The present study has established a framework for assessing cfDNA features and demonstrated the benefits of integrating multiple features for early detection of lung cancer.

Risk factors investigation for different outcomes between unilateral and bilateral chronic rhinosinusitis with nasal polyps patients.

BACKGROUND: Studies involving chronic rhinosinusitis with nasal polyps (CRSwNP) have mostly focused on bilateral cases, making unilateral CRSwNP inadequately recognized. This study examined the differences in clinical characteristics, outcomes, and risk factors for poor outcomes between unilateral and bilateral CRSwNP to facilitate a better assessment in the two groups. METHODS: Demographic information, tissue and blood cells, endoscopic scores, Lund-Mackay scores, recurrence rates, and disease control conditions were compared between 310 unilateral and 596 bilateral CRSwNP patients. Furthermore, the stepwise regression multivariate Cox proportional hazard models were performed to generate risk factors for poor outcomes in the two groups. RESULTS: Bilateral cases exhibited higher rates of smoking, AR, and asthma comorbidities, along with higher numbers of tissue eosinophils and blood inflammatory cells when compared to unilateral patients. Endoscopic nasal polyp score, total computed tomography (CT) score (with scores for each sinus cavity), and adjusted CT scores were significantly higher in the bilateral group, except for a markedly higher adjusted maxillary score in the unilateral group. Furthermore, significantly higher proportions of bilateral patients experienced nasal polyp recurrence, uncontrolled status, and most disease control-related symptoms at follow-up. The primary risk factors for poor outcomes were asthma, tissue eosinophils, and total CT score in the bilateral group and blood basophils in the unilateral group. CONCLUSIONS: Bilateral CRSwNP patients experience worse disease severity and outcomes than their unilateral counterparts. Primarily, asthma, tissue eosinophils, and total CT score were risk factors for poor outcomes in bilateral CRSwNP patients, with blood basophils in unilateral cases.

Delivery of PARP inhibitors through 2HG-incorporated liposomes for synergistically targeting DNA repair in cancer.

PARP inhibitors (PARPi) benefit only a small subset of patients with DNA homologous recombination (HR) defects. In addition, long-term administration of a PARPi can lead to the development of drug resistance. 2-Hydroxyglutarate (2HG) has long been known as an oncometabolite but is capable of inducing an HR defect, which makes tumor cells exquisitely sensitive to PARPi. To facilitate the translation of this discovery to the treatment of both HR-deficient and HR-proficient tumors, a liposomal formulation was developed for codelivery of 2HG and veliparib, a PARPi. A sequential loading protocol was developed such that the initial loading of 2HG into liposomes greatly facilitated the subsequent, pH gradient-driven remote loading of veliparib. The liposomes co-loaded with veliparib and 2HG exhibited favorable stability, slow kinetics of drug release, and targeted delivery to the tumor. Furthermore, the veliparib/2HG liposomes demonstrated enhanced anti-tumor activity in both PARPi-resistant BRCA mutant cancer and BRCA wildtype cancer by synergistically enhancing the defect in DNA repair. Moreover, combination of veliparib and 2HG via liposomal co-delivery also augmented the function of cytotoxic T cells by activating the STING pathway and downregulating PD-L1 expression via 2HG-induced hypermethylation.

Development of machine learning-based personalized predictive models for risk evaluation of hepatocellular carcinoma in hepatitis B virus-related cirrhosis patients with low levels of serum alpha-fetoprotein.

INTRODUCTION AND OBJECTIVES: The increasing incidence of hepatocellular carcinoma (HCC) in China is an urgent issue, necessitating early diagnosis and treatment. This study aimed to develop personalized predictive models by combining machine learning (ML) technology with a demographic, medical history, and noninvasive biomarker data. These models can enhance the decision-making capabilities of physicians for HCC in hepatitis B virus (HBV)-related cirrhosis patients with low serum alpha-fetoprotein (AFP) levels. PATIENTS AND METHODS: A total of 6,980 patients treated between January 2012 and December 2018 were included. Pre-treatment laboratory tests and clinical data were obtained. The significant risk factors for HCC were identified, and the relative risk of each variable affecting its diagnosis was calculated using ML and univariate regression analysis. The data set was then randomly partitioned into validation (20 %) and training sets (80 %) to develop the ML models. RESULTS: Twelve independent risk factors for HCC were identified using Gaussian naïve Bayes, extreme gradient boosting (XGBoost), random forest, and least absolute shrinkage and selection operation regression models. Multivariate analysis revealed that male sex, age >60 years, alkaline phosphate >150 U/L, AFP >25 ng/mL, carcinoembryonic antigen >5 ng/mL, and fibrinogen >4 g/L were the risk factors, whereas hypertension, calcium <2.25 mmol/L, potassium ≤3.5 mmol/L, direct bilirubin >6.8 µmol/L, hemoglobin <110 g/L, and glutamic-pyruvic transaminase >40 U/L were the protective factors in HCC patients. Based on these factors, a nomogram was constructed, showing an area under the curve (AUC) of 0.746 (sensitivity = 0.710, specificity=0.646), which was significantly higher than AFP AUC of 0.658 (sensitivity = 0.462, specificity=0.766). Compared with several ML algorithms, the XGBoost model had an AUC of 0.832 (sensitivity = 0.745, specificity=0.766) and an independent validation AUC of 0.829 (sensitivity = 0.766, specificity = 0.737), making it the top-performing model in both sets. The external validation results have proven the accuracy of the XGBoost model. CONCLUSIONS: The proposed XGBoost demonstrated a promising ability for individualized prediction of HCC in HBV-related cirrhosis patients with low-level AFP.

Dynamically Precise Constructing Dual-Atom Pd2 Catalyst:A Monodisperse Catalyst With High Stability for Semi-Hydrogenation of Alkyne.

Dual-atom catalysts (DACs) originate unprecedented reactivity and maximize resource efficiency. The fundamental difficulty lies in the high complexity and instability of DACs, making the rational design and targeted performance optimization a grand challenge. Here, an atomically dispersed Pd2 DAC with an in situ generated Pd─Pd bond is constructed by a dynamic strategy, which achieves high activity and selectivity for semi-hydrogenation of alkynes and functional internal acetylene, twice higher than commercial Lindlar catalyst. Density functional theory calculations and systematic experiments confirms the ultrahigh properties of Pd2 DAC originates from the synergistic effect of the dynamically generated Pd─Pd bonds. This discovery highlights the potential for dynamic strategies and opens unprecedented possibilities for the preparation of robust DACs on an industrial scale.

Photoinduced Single Electron Reduction of the 4-O-5 Linkage in Lignin Models for C-P Coupling Catalyzed by Bifunctional N-Heterocyclic Carbenes.

Catalytic activation of Caryl-O bonds is considered as a powerful strategy for the production of aromatics from lignin. However, due to the high reduction potentials of diaryl ether 4-O-5 linkage models, their single electron reduction remains a daunting challenge. This study presents the blue light-induced bifunctional N-heterocyclic carbene (NHC)-catalyzed one-electron reduction of diaryl ether 4-O-5 linkage models for the synthesis of trivalent phosphines. The H-bond between the newly devised bifunctional NHC and diaryl ethers is responsible for the success of the single electron transfer. Furthermore, this approach demonstrates selective one-electron reduction of unsymmetric diaryl ethers, oligomeric phenylene oxide, and lignin model.

Effects of Lime Powder on the Properties of Portland Cement-Sulphoaluminate Cement Composite System at Low Temperature.

In order to reduce the risk of early freezing damage to cement-based materials in winter construction, lime powder was used to improve the properties of the Portland cement-sulphoaluminate cement (PC-CSA) composite system at low temperatures. In this study, the effects of lime powder dosage on the properties of a PC-CSA blended system with two proportions (PC:CSA = 9:1 and 7:3) at -10 °C were investigated, and the mechanisms of improvement were revealed. The results showed that the compressive strength of the PC-CSA composite system was effectively improved, and the setting time was shortened by the addition of lime powder. Lime powder could effectively act as an early heating source in the PC-CSA composite system, as the maximum temperature of samples exposed to sub-zero temperatures was increased and the time before dropping to 0 °C was prolonged by the addition of lime powder. The extra CH generated by the hydration of lime powder provided an added hydration path for C4A3S¯, which accelerated the formation of AFt at each stage. Frozen water as well as the early frost damage were effectively decreased by lime powder because of the faster consumption of free water at an early stage. The modification of the hydration products also contributed to the denseness of the microstructure.

Pathogenic R163W Variant of the Copper Chaperone for Sod1 (Ccs) Functions as an Anti-chaperone.

The copper chaperone for Sod1 (Ccs) is a metallochaperone that plays a multifaceted role in the maturation of Cu,Zn superoxide dismutase (Sod1). The Ccs mutation R163W was identified in an infant with fatal neurological abnormalities. Based on a comprehensive structural and functional analysis, we developed the first data-driven model for R163W-related pathogenic phenotypes. The work here confirms previous findings that the substitution of arginine with tryptophan at this site, which is located adjacent to a conserved Zn binding site, creates an unstable Zn-deficient protein that loses its ability to efficiently activate Sod1. Intriguingly, R163W Ccs can reduce copper (i.e., Cu(II) → Cu(I)) bound in its Sod1-like domain (D2), and this novel redox event is accompanied by disulfide bond formation. The loss of Zn binding, along with the unusual ability to bind copper in D2, diverts R163W Ccs toward aggregation. The remarkably high affinity of D2 Cu(I) binding converts R163W from a Cu chaperone to a Cu scavenger that accelerates Sod1 deactivation (i.e., an Anti-chaperone). Overall, these findings present a first-of-its-kind molecular mechanism for Ccs dysfunction that leads to pathogenesis in humans.

Highly sensitive and selective detection of DCP vapors using pyridine-based fluorescent nanofilms.

A novel fluorescent nanofilm DBAP-ETTA has been developed for diethyl chlorophosphate (DCP) vapor detection with high sensitivity and selectivity. Its smooth, homogeneous structure and large Stokes shift enable significant fluorescence quenching upon DCP exposure. The protonation-based sensing mechanism makes it ideal for real-time, portable DCP vapor sensing.

Frailty and its Associated Factors Among Rural Community-Dwelling Older Adults: A Cross-Sectional Study.

To investigate the status quo and influencing factors of overall frailty and its 3 domains among rural community-dwelling older adults. This is a cross-sectional study. A convenience sample of 195 older adults from 6 villages in Bashang Area of Zhangjiakou City, Hebei Province, China, were recruited from August to September, 2022. The demographic characteristics, the Chinese version of Tilburg Frailty Indicator, Charlson Comorbidity Scale and Hospital Anxiety and Depression Scale were used to investigate frailty and its influencing factors. Univariate analysis and multiple linear regression analysis were employed. The prevalence of overall frailty among the older adults in Bashang Area was 85.13%. Multiple linear regression analysis showed that age, gender, marital status, regular exercise, comorbidity, and anxiety were the influencing factors of overall frailty. While anxiety was the only shared influencing factor for physical frailty, psychological frailty, and social frailty, age, gender, marital status, financial burden, the comorbidity, and regular exercise were factors which influenced 1 or 2 domains of frailty. The prevalence of overall frailty among the older adults in rural areas, Zhangjiakou City is high. It is influenced by many factors. Medical staff and policy makers should work hand in hand to improve frailty among rural community-dwelling older adults in China.

Spatiotemporal alterations in the brain oscillations of Arctic explorers.

BACKGROUND: The limited understanding of the physiology and psychology of polar expedition explorers has prompted concern over the potential cognitive impairments caused by exposure to extreme environmental conditions. Prior research has demonstrated that such stressors can negatively impact cognitive function, sleep quality, and behavioral outcomes. Nevertheless, the impact of the polar environment on neuronal activity remains largely unknown. METHODS: In this study, we aimed to investigate spatiotemporal alterations in brain oscillations of 13 individuals (age range: 22-48 years) who participated in an Arctic expedition. We utilized electroencephalography (EEG) to record cortical activity before and during the Arctic journey, and employed standardized low resolution brain electromagnetic tomography to localize changes in alpha, beta, theta, and gamma activity. RESULTS: Our results reveal a significant increase in the power of theta oscillations in specific regions of the Arctic, which differed significantly from pre-expedition measurements. Furthermore, microstate analysis demonstrated a significant reduction in the duration of microstates (MS) D and alterations in the local synchrony of the frontoparietal network. CONCLUSION: Overall, these findings provide novel insights into the neural mechanisms underlying adaptation to extreme environments. These findings have implications for understanding the cognitive consequences of polar exploration and may inform strategies to mitigate potential neurological risks associated with such endeavors. Further research is warranted to elucidate the long-term effects of Arctic exposure on brain function.

Impact of Bisphenol A exposure on maternal gut microbial homeostasis, placental function, and fetal development during pregnancy.

Pregnancy is extremely vulnerable to external environmental influences. Bisphenol A, an endocrine-disrupting chemical, poses a significant environmental hazard to individuals of all ages and stages, particularly during pregnancy. The placenta is a temporary organ facilitating the connection between the mother and fetus. While it can detoxify certain exogenous substances, it is also vulnerable to the impacts of endocrine disruptors. Likewise, the intestinal flora is highly sensitive to exogenous stresses and environmental pollutants. The regulation of gut microbiota plays a crucial role in ensuring the health of both the mother and the fetus. The gut-placental axis connects the gut, gut microbes, placenta, and fetus. Exploring possible effects on placental function and fetal development involves analyzing changes in gut microbiota composition. Given that bisphenol A may cross the intestine and affect intestinal function, gut microorganisms, and their metabolites, as well as its potential impact on the placenta, resulting in impaired placental function and fetal development, this study aims to establish a link between bisphenol A exposure, intestinal microorganisms, placental function, and fetal development. This paper seeks to analyze the effects of maternal exposure to bisphenol A during pregnancy on the balance of the maternal gut microbiota, placental function, and fetal development, considering the key role of the gut-placental axis. Additionally, this paper proposes potential directions for future research emphasizing the importance of mitigating the adverse outcomes of bisphenol A exposure during pregnancy in both human and animal studies.

Suppression of excitatory synaptic transmission in the centrolateral amygdala via presynaptic histamine H3 heteroreceptors.

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

Association between machine learning-assisted heavy metal exposures and diabetic kidney disease: a cross-sectional survey and Mendelian randomization analysis.

Background and objective: Heavy metals, ubiquitous in the environment, pose a global public health concern. The correlation between these and diabetic kidney disease (DKD) remains unclear. Our objective was to explore the correlation between heavy metal exposures and the incidence of DKD. Methods: We analyzed data from the NHANES (2005-2020), using machine learning, and cross-sectional survey. Our study also involved a bidirectional two-sample Mendelian randomization (MR) analysis. Results: Machine learning reveals correlation coefficients of -0.5059 and - 0.6510 for urinary Ba and urinary Tl with DKD, respectively. Multifactorial logistic regression implicates urinary Ba, urinary Pb, blood Cd, and blood Pb as potential associates of DKD. When adjusted for all covariates, the odds ratios and 95% confidence intervals are 0.87 (0.78, 0.98) (p = 0.023), 0.70 (0.53, 0.92) (p = 0.012), 0.53 (0.34, 0.82) (p = 0.005), and 0.76 (0.64, 0.90) (p = 0.002) in order. Furthermore, multiplicative interactions between urinary Ba and urinary Sb, urinary Cd and urinary Co, urinary Cd and urinary Pb, and blood Cd and blood Hg might be present. Among the diabetic population, the OR of urinary Tl with DKD is a mere 0.10, with a 95%CI of (0.01, 0.74), urinary Co 0.73 (0.54, 0.98) in Model 3, and urinary Pb 0.72 (0.55, 0.95) in Model 2. Restricted Cubic Splines (RCS) indicate a linear linkage between blood Cd in the general population and urinary Co, urinary Pb, and urinary Tl with DKD among diabetics. An observable trend effect is present between urinary Pb and urinary Tl with DKD. MR analysis reveals odds ratios and 95% confidence intervals of 1.16 (1.03, 1.32) (p = 0.018) and 1.17 (1.00, 1.36) (p = 0.044) for blood Cd and blood Mn, respectively. Conclusion: In the general population, urinary Ba demonstrates a nonlinear inverse association with DKD, whereas in the diabetic population, urinary Tl displays a linear inverse relationship with DKD.