Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.

Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.

SLC25A39 links mitochondrial GSH sensing with iron metabolism.

Two recent studies by Liu et al.1 in Science and Shi et al.2 in this issue of Molecular Cell identify a mitochondrial GSH-sensing mechanism that couples SLC25A39-mediated GSH import to iron metabolism, advancing our understanding of nutrient sensing within organelles.

Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

Porcine Enteric Alphacoronavirus Entry through Multiple Pathways (Caveolae, Clathrin, and Macropinocytosis) Requires Rab GTPases for Endosomal Transport.

Porcine enteric alphacoronavirus (PEAV) is a new bat HKU2-like porcine coronavirus, and its endemic outbreak has caused severe economic losses to the pig industry. Its broad cellular tropism suggests a potential risk of cross-species transmission. A limited understanding of PEAV entry mechanisms may hinder a rapid response to potential outbreaks. This study analyzed PEAV entry events using chemical inhibitors, RNA interference, and dominant-negative mutants. PEAV entry into Vero cells depended on three endocytic pathways: caveolae, clathrin, and macropinocytosis. Endocytosis requires dynamin, cholesterol, and a low pH. Rab5, Rab7, and Rab9 GTPases (but not Rab11) regulate PEAV endocytosis. PEAV particles colocalize with EEA1, Rab5, Rab7, Rab9, and Lamp-1, suggesting that PEAV translocates into early endosomes after internalization, and Rab5, Rab7, and Rab9 regulate trafficking to lysosomes before viral genome release. PEAV enters porcine intestinal cells (IPI-2I) through the same endocytic pathway, suggesting that PEAV may enter various cells through multiple endocytic pathways. This study provides new insights into the PEAV life cycle. IMPORTANCE Emerging and reemerging coronaviruses cause severe human and animal epidemics worldwide. PEAV is the first bat-like coronavirus to cause infection in domestic animals. However, the PEAV entry mechanism into host cells remains unknown. This study demonstrates that PEAV enters into Vero or IPI-2I cells through caveola/clathrin-mediated endocytosis and macropinocytosis, which does not require a specific receptor. Subsequently, Rab5, Rab7, and Rab9 regulate PEAV trafficking from early endosomes to lysosomes, which is pH dependent. The results advance our understanding of the disease and help to develop potential new drug targets against PEAV.

UV-A radiation increases biomass yield by enhancing energy flow and carbon assimilation in the edible cyanobacterium Nostoc sphaeroides.

Ultraviolet (UV) A radiation (315-400 nm) is the predominant component of solar UV radiation that reaches the Earth's surface. However, the underlying mechanisms of the positive effects of UV-A on photosynthetic organisms have not yet been elucidated. In this study, we investigated the effects of UV-A radiation on the growth, photosynthetic ability, and metabolome of the edible cyanobacterium Nostoc sphaeroides. Exposures to 5-15 W m-2 (15-46 µmol photons m-2 s-1) UV-A and 4.35 W m-2 (20 µmol photons m-2 s-1) visible light for 16 days significantly increased the growth rate and biomass production of N. sphaeroides cells by 18%-30% and 15%-56%, respectively, compared to the non-UV-A-acclimated cells. Additionally, the UV-A-acclimated cells exhibited a 1.8-fold increase in the cellular nicotinamide adenine dinucleotide phosphate (NADP) pool with an increase in photosynthetic capacity (58%), photosynthetic efficiency (24%), QA re-oxidation, photosystem I abundance, and cyclic electron flow (87%), which further led to an increase in light-induced NADPH generation (31%) and ATP content (83%). Moreover, the UV-A-acclimated cells showed a 2.3-fold increase in ribulose-1,5-bisphosphate carboxylase/oxygenase activity, indicating an increase in their carbon-fixing capacity. Gas chromatography-mass spectrometry-based metabolomics further revealed that UV-A radiation upregulated the energy-storing carbon metabolism, as evidenced by the enhanced accumulation of sugars, fatty acids, and citrate in the UV-A-acclimated cells. Therefore, our results demonstrate that UV-A radiation enhances energy flow and carbon assimilation in the cyanobacterium N. sphaeroides.IMPORTANCEUltraviolet (UV) radiation exerts harmful effects on photo-autotrophs; however, several studies demonstrated the positive effects of UV radiation, especially UV-A radiation (315-400 nm), on primary productivity. Therefore, understanding the underlying mechanisms associated with the promotive effects of UV-A radiation on primary productivity can facilitate the application of UV-A for CO2 sequestration and lead to the advancement of photobiological sciences. In this study, we used the cyanobacterium Nostoc sphaeroides, which has an over 1,700-year history of human use as food and medicine, to explore its photosynthetic acclimation response to UV-A radiation. As per our knowledge, this is the first study to demonstrate that UV-A radiation increases the biomass yield of N. sphaeroides by enhancing energy flow and carbon assimilation. Our findings provide novel insights into UV-A-mediated photosynthetic acclimation and provide a scientific basis for the application of UV-A radiation for optimizing light absorption capacity and enhancing CO2 sequestration in the frame of a future CO2 neutral, circular, and sustainable bioeconomy.

WTAP promotes the progression of ulcerative colitis by silencing the expression of CES2 through m6A modification.

OBJECTIVE: This study will explore the function of WTAP, the critical segment of m6A methyltransferase complex, in UC and its regulation on immune response. METHODS: The expression levels of key proteins were detected in colon tissues which were derived from UC patients and mice. Macrophage polarization and CD4+ T cell infiltration were detected by flow cytometry and IF staining. ELISA assay was utilized to analyze the level of the inflammatory cytokines. m6A-RIP-PCR, actinomycin D test, and RIP assays were utilized to detect the m6A level, stability, and bound proteins of CES2 mRNA. A dual luciferase reporter assay was conducted to confirm the transcriptional interactions between genes. A co-culture system of intestinal epithelium-like organs was constructed to detect the primary mouse intestinal epithelial cells (PMIEC) differentiation. The interaction between proteins was detected via Co-IP assay. RESULTS: The expression of WTAP and CES2 in UC tissues was increased and decreased, respectively. Knockdown of WTAP inhibited the progression of UC in mice by inhibiting M1 macrophage polarization and CD4+ T cell infiltration. WTAP combined YTHDF2 to promote the m6A modification of CES2 mRNA and inhibited its expression. CES2 co-expressed with EPHX2 and overexpression of CES2 promoted the differentiation of PMIEC. The inhibitory effect of WTAP knockdown on the progress of UC was partially abrogated by CES2 knockdown. CONCLUSION: WTAP/YTHDF2 silences CES2 by promoting its m6A modification and then promotes the progression of UC. WTAP could be a promoting therapy target of UC.

Changes in the nasopharyngeal and oropharyngeal microbiota in pediatric obstructive sleep apnea before and after surgery: a prospective study.

OBJECTIVE: To explore the changes and potential mechanisms of microbiome in different parts of the upper airway in the development of pediatric OSA and observe the impact of surgical intervention on oral microbiome for pediatric OSA. METHODS: Before adeno-tonsillectomy, we collected throat swab samples from different parts of the oropharynx and nasopharynx of 30 OSA patients and 10 non-OSA patients and collected throat swab samples from the oropharynx of the above patients one month after the adeno-tonsillectomy. The 16 S rRNA V3-V4 region was sequenced to identify the microbial communities. The correlation analysis was conducted based on clinical characteristics. RESULTS: There was a significant difference of alpha diversity in different parts of the upper airway of pediatric OSA, but this difference was not found in children with non-OSA. Beta diversity was significantly different between non-OSA and pediatric OSA. At the genus level, the composition of flora in different parts is different between non-OSA and pediatric OSA. The correlation analysis revealed that the relative abundance of Neisseria was significantly correlated with obstructive apnea hypopnea index. Furthermore, the functional prediction revealed that pathways related to cell proliferation and material metabolism were significantly different between non-OSA and pediatric OSA. Besides, the adeno-tonsillectomy has minimal impact on oral microbiota composition in short term. CONCLUSION: The changes in upper airway microbiome are highly associated with pediatric OSA. The relative abundance of some bacteria was significantly different between OSA and non-OSA. These bacteria have the potential to become new diagnostic and early warning biomarkers.

Assisted reproductive technology treatment failure and the detection of intrauterine HPV through spent embryo transfer media sample.

Cervical human papillomavirus (HPV) infection is believed to increase the risks of pregnancy failure and abortion, however, whether the uterine cavity HPV infection reduces pregnancy rate or increases miscarriage rate remains unclarified in infertile women undergoing assisted reproductive technology (ART) treatment. Therefore, we aimed to assess ART outcomes in the presence of intrauterine HPV. This was a hospital-based multicenter (five reproductive medicine centers) matched cohort study. This study involved 4153 infertile women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection treatment in five reproductive medicine centers between October 2018 and 2020. The spent embryo transfer media sample with endometrium tissue were collected and performed with flow-through hybridization and gene chips to detect HPV DNA. According to basic characteristics, HPV-positive and negative patients were matched in a ratio of 1:4 by age, body mass index transfer timing, transfer type, and number of embryos transferred. The primary outcome was pregnancy and clinical miscarriage rates in the transfer cycle underwent HPV detection. 92 HPV-positive and 368 HPV-negative patients were screened and analyzed statistically. Univariate analysis showed uterine cavity HPV infection resulted in lower rates of ongoing pregnancy (31.5% vs. 44.6%; p = 0.023), implantation (32.3% vs. 43.1%; p = 0.026), biochemical pregnancy (47.8% vs. 62.5%; p = 0.010), and clinical pregnancy (40.2% vs. 54.3%; p = 0.015) compared with HPV negative group. The infertile female with positive HPV also had a slightly higher frequency of biochemical miscarriage (15.9% vs. 13.0%; p = 0.610) and clinical miscarriage (24.3% vs. 15.5%; p = 0.188). These findings suggest that HPV infection in the uterine cavity is a high risk for ART failure. HPV screening is recommended before ART treatment, which may be benefit to improving pregnancy outcome.

Hypoxia-induced BAP1 enhances erastin-induced ferroptosis in nasopharyngeal carcinoma by stabilizing H2A.

BACKGROUND: Hypoxia plays an important role in the chemotherapy resistance of nasopharyngeal carcinoma (NPC). Ferroptosis is a newly discovered form of programmed cell death and ferroptosis inducers showed promising therapeutic effects in some cancers. However, the sensibility of NPC cells to ferroptosis under the hypoxic microenvironment is still unclear, and this study was designed to clarify it. METHODS: NPC cells, treated with erastin, were placed in a normoxia or hypoxic environment (5% CO2, 94% N2 and 1% O2) at 37℃for 24 h. After exposed to hypoxia, ferroptosis-associated phenotypes were detected by CCK8, MDA, GSH, lipid ROS and Fe. The gene expression profiles of head and neck squamous cell carcinoma (HNSCC) tissues were downloaded from the TCGA database to screen construction molecule. BAP1 was screened out and its functions on erastin-induced ferroptosis in NPC cells were detected by knockdown of BAP1. Luciferase reporter assay and co-IP experiment were performed to explore the molecular mechanism. Finally, the tumour xenograft model was applied to further verify these results in vivo. RESULTS: CCK8 assay showed that IC50 of NPC cells treated with erastin under hypoxia was significantly lower than that under normoxia. Hypoxia significantly increased the levels of lipid ROS and MDA, and decreased GSH content induced by erastin. A prognostic risk model for HNSCC with six ferroptosis-related genes was constructed and validated based on TCGA database. BAP1 was significantly up-regulated under hypoxia, and luciferase reporter assay showed that HIF-1α was an upstream transcription regulator of BAP1. Knockdown of BAP1 in NPC cells significantly increased the IC50 value of erastin under hypoxia and significantly ameliorated erastin-induced ferroptosis under hypoxia in aspect of lipid ROS, MDA content and GSH. Co-IP results showed that BAP1 mediated deubiquitination of H2A and decreased SLC7A11 expression. Finally, knockdown of BAP1 reduced sensitivity to erastin-induced ferroptosis in a tumour xenograft model. And the level of H2A was significantly decreased in xenograft tumors of BAP1 knockdown cells. CONCLUSION: Hypoxia-induced BAP1 enhances erastin-induced ferroptosis in NPC by stabilizing H2A. Ferroptosis inducers targeting BAP1 may be an effective way to improve chemotherapy resistance in NPC, especially in the hypoxic microenvironment.

Development and validation of a prognostic model for assessing long COVID risk following Omicron wave-a large population-based cohort study.

BACKGROUND: Long coronavirus disease (COVID) after COVID-19 infection is continuously threatening the health of people all over the world. Early prediction of the risk of Long COVID in hospitalized patients will help clinical management of COVID-19, but there is still no reliable and effective prediction model. METHODS: A total of 1905 hospitalized patients with COVID-19 infection were included in this study, and their Long COVID status was followed up 4-8 weeks after discharge. Univariable and multivariable logistic regression analysis were used to determine the risk factors for Long COVID. Patients were randomly divided into a training cohort (70%) and a validation cohort (30%), and factors for constructing the model were screened using Lasso regression in the training cohort. Visualize the Long COVID risk prediction model using nomogram. Evaluate the performance of the model in the training and validation cohort using the area under the curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: A total of 657 patients (34.5%) reported that they had symptoms of long COVID. The most common symptoms were fatigue or muscle weakness (16.8%), followed by sleep difficulties (11.1%) and cough (9.5%). The risk prediction nomogram of age, diabetes, chronic kidney disease, vaccination status, procalcitonin, leukocytes, lymphocytes, interleukin-6 and D-dimer were included for early identification of high-risk patients with Long COVID. AUCs of the model in the training cohort and validation cohort are 0.762 and 0.713, respectively, demonstrating relatively high discrimination of the model. The calibration curve further substantiated the proximity of the nomogram's predicted outcomes to the ideal curve, the consistency between the predicted outcomes and the actual outcomes, and the potential benefits for all patients as indicated by DCA. This observation was further validated in the validation cohort. CONCLUSIONS: We established a nomogram model to predict the long COVID risk of hospitalized patients with COVID-19, and proved its relatively good predictive performance. This model is helpful for the clinical management of long COVID.

Implementation of Thermal-Triggered Binary-Ternary Switchable Memory Performance in Zn/polysulfide/organic Complex-Based Memorizers by Finely Modulating the S62- Relaxation.

Polysulfide-based multilevel memorizers are promising as novel memorizers, in which the occurrence of Sn2- relaxation is key for their multilevel memory. However, the effects of crystal packing and the side group of organic ligands on Sn2- relaxation are still ambiguous. In this work, ionic [Zn(S6)2·Zn2(Bipy)2SO4 (1), Zn(S6)2·Zn(Pmbipy)3 (2)] and neutral [ZnS6(Ombipy) (3), ZnS6(Phen)2 (4)] Zn/polysulfide/organic complexes with different packing modes and structures of organic ligands have been synthesized and were fabricated as memory devices. In both ionic and neutral Zn complexes, the S62- relaxation will be blocked by steric hindrances due to the packing of counter-cations and hydrogen-bond restrictions. Consequently, only the binary memory performances can be seen in FTO/1/Ag, FTO/2/Ag, and FTO/4/Ag, which originate from the more condensed packing of conjugated ligands upon electrical stimulus. Interestingly, FTO/3/Ag illustrates the unique thermally triggered reversible binary-ternary switchable memory performance. In detail, after introducing a methyl group on the 6'-position of bipyridine in ZnS6(Ombipy) (3), the ring-to-chain relaxation of S62- anions at room temperature will be inhibited, but it can happen at a higher temperature of 120 °C, which has been verified by elongated S-S lengths and the strengthened C-H···S hydrogen bond upon heating. The rules drawn in this work will provide a useful guide for the design of stimulus-responsive memorizers that can be applied in special industries such as automobile, oil, and gas industries.

Can depression lead to chronic constipation, or does chronic constipation worsen depression? NHANES 2005-2010 and bidirectional mendelian randomization analyses.

BACKGROUND: Depression and chronic constipation often co-occur, but the reciprocal influence between the two remains unclear. The purpose of this study is to explore the potential association between depression and chronic constipation. METHODS: This study initially utilized data from National Health and Nutrition Examination Survey (NHANES) 2005-2010 to explore the correlation between depression scores and chronic constipation, assessing the non-linear relationship between the two. Subsequently, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal relationship between depression and major depression with chronic constipation. The Inverse Variance Weighting (IVW) method served as the primary reference, supplemented by sensitivity tests. Finally, a reverse MR analysis was performed to assess the presence of any reverse causation. The STROBE-MR checklist for the reporting of MR studies was used in this study. RESULTS: In the NHANES analysis, survey-weighted logistic regression revealed a significantly positive correlation between depression scores and chronic constipation (OR = 1.04, 95% CI = 1.02-1.07, p = 0.002), even after adjusting for the included covariates. The nonlinear analysis using Restricted Cubic Splines (RCS) enhanced the robustness of the association (P-non-liner = 0.01). The MR analysis also confirmed the causal relationship between depression (OR = 11.43, 95% CI = 1.85-70.67, p = 0.008) and major depression (OR = 1.12, 95% CI = 1.03-1.22, p = 0.007) with chronic constipation, passing rigorous sensitivity tests. No evidence of reverse causation was observed in the reverse MR analysis (P > 0.05). CONCLUSIONS: Depression is positively correlated with the risk of chronic constipation. Therefore, enhancing attention to chronic constipation in patients with depression may be effective in clinical practice.

Neurotransmitter Metabolism in Arsenic Exposure-Induced Cognitive Impairment: Emerging Insights and Predictive Implications.

Scholars have long been interested in the association between arsenic (As) exposure and neurological disorders; however, existing systematic epidemiological investigations are insufficient and lack the inclusion of diagnostic or predictive biological markers. This study sought to evaluate the association between As exposure and cognitive impairment and identify potential biomarkers by developing predictive models. Here, we found that logarithm (Ln)-transformed urinary As concentrations were negatively linearly related to the mini-mental state examination (MMSE) score exposure-response curves. Subsequently, we identified a unique plasma neurometabolite profile in subjects exposed to As compared with the reference group. Further analyses showed that tryptophan, tyrosine, dopamine, epinephrine, and homovanillic acid were all significantly associated with both urinary As concentrations and MMSE scores. Notably, the association between As exposure and MMSE scores was partly mediated by tryptophan, tyrosine, dopamine, and epinephrine. Importantly, an unprecedented prediction model utilizing neurotransmitters was established to assess the risk of cognitive impairment due to As exposure. A 91.1% consistency rate was found between the predicted and the actual probabilities. Additionally, machine learning models also produced highly accurate predictions. Overall, this study revealed a dose-dependent cognitive decline in As-exposed adults accompanied by a disturbance in the signature of neurotransmitter metabolites, offering new predictive insights.

Neuroimaging studies of resting-state functional magnetic resonance imaging in eating disorders.

Eating disorders (EDs), including anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), and pica, are psychobehavioral conditions characterized by abnormal eating behaviors and an excessive preoccupation with weight and body shape. This review examines changes in brain regions and functional connectivity in ED patients over the past decade (2013-2023) using resting-state functional magnetic resonance imaging (rs-fMRI). Key findings highlight alterations in brain networks such as the default mode network (DMN), central executive network (CEN), and emotion regulation network (ERN). In individuals with AN, there is reduced functional connectivity in areas associated with facial information processing and social cognition, alongside increased connectivity in regions linked to sensory stimulation, aesthetic judgment, and social anxiety. Conversely, BED patients show diminished connectivity in the dorsal anterior cingulate cortex within the salience network and increased connectivity in the posterior cingulate cortex and medial prefrontal cortex within the DMN. These findings suggest that rs-fMRI could serve as a valuable biomarker for assessing brain function and predicting treatment outcomes in EDs, paving the way for personalized therapeutic strategies.

Exposure to four typical heavy metals induced telomere shortening of peripheral blood mononuclear cells in relevant with declined urinary aMT6s in rats.

Environmental heavy metals pollution have seriously threatened the health of human beings. An increasing number of researches have demonstrated that environmental heavy metals can influence the telomere length of Peripheral Blood Mononuclear Cells (PBMCs), which implicate biological aging as well as predicts diseases. Our previous study has shown that methylmercury (MeHg)-induced telomere shortening in rat brain tissue was associated with urinary melatonin metabolite 6-sulfatoxymelatonin (aMT6s) levels. Here, we aimed to further elucidate the impact of 4 typical heavy metals (As, Hg, Cd and Pb) on telomere length of PBMCs and their association with urinary aMT6s in rats. In this study, eighty-eight male Sprague-Dawley rats were randomized grouped into eleven groups. Among them, forty 3-month-old (young) and forty 12-month-old (middle-aged) rats were divided into young or middle-aged control groups as well as typical heavy metals exposed groups, respectively. Eight 24-month-old rats (old) was divided into aging control group. The results showed that MeHg exposure in young rats while sodium arsenite (iAs), MeHg, cadmium chloride (CdCl2), lead acetate (PbAc) exposure in middle-aged rats for 3 months significantly reduced the levels of and urinary aMT6s, as well as telomere length of PBMCs. In addition, they also induced abnormalities in serum oxidative stress (SOD, MDA and GPx) and inflammatory (IL-1ß, IL-6 and TNF-α) indicators. Notably, there was a significant positive correlation between declined level of urinary aMT6s and the shortening of telomere length in PBMCs in rats exposed to 4 typical heavy metals. These results suggested that 4 typical heavy metals exposure could accelerate the reduction of telomere length of PBMCs partially by inducing oxidative stress and inflammatory in rats, while ageing may be an important synergistic factor. Urinary aMT6s detection may be a alternative method to reflect telomere toxic effects induced by heavy metal exposure.

Post-fertilization 2-ethylhexyl-4-methoxycinnamate (EHMC) exposure affects axonal growth, muscle fiber length, and motor behavior in zebrafish embryos.

Organic UV filters, which are often found in the environment, have been the focus of much public health concern. 2-ethylhexyl-4-methoxycinnamate (EHMC) is one of the most common organic UV filters present in the environment. However, few studies have investigated its developmental neurotoxic (DNT) effects and the underlying molecular mechanisms. In the present study, zebrafish embryos were exposed to low concentration of EHMC (0, 0.01, 0.1, 1 mg/L) in static water starting from 6 h post-fertilization (hpf). Results showed that EHMC exposure caused a reduction in somite count at 13 hpf, a diminishment in head-trunk angle at 30 hpf, a delay in hatching at 48 hpf, and a decrease in head depth and head length at both 30 and 48 hpf. Additionally, EHMC led to abnormal motor behaviors at various developmental stages including altered spontaneous movement at both 23 and 24 hpf, and decreased touch response at 30 hpf. Consistent with these morphological changes and motor behavior deficits, EHMC inhibited axonal growth of primary motor neurons at 30 and 48 hpf, and yielded subtle changes in muscle fiber length at 48 hpf, suggesting the functional relevance of structural changes. Moreover, EHMC exposure induced excessive cell apoptosis in the head and spinal cord regions, increased the production of reactive oxygen species (ROS) and malondialdehyde (MDA), and reduced the level of glutathione (GSH). Defects of lateral line system neuromasts were also observed, but no structural deformity of blood vessels was seen in developing zebrafish. Abnormal expression of axonal growth-related genes (gap43, mbp, shha, and α1-tubulin) and apoptosis-related genes (bax/bcl-2 and caspase-3) revealed potential molecular mechanisms regarding the defective motor behaviors and aberrant phenotype. In summary, our findings indicate that EHMC induced developmental neurotoxicity in zebrafish, making it essential to assess its risks and provide warnings regarding EHMC exposure.

LC-MS based untargeted metabolomics studies of the metabolic response of Ginkgo biloba extract on arsenism patients.

Arsenic is an environmentally ubiquitous toxic metalloid. Chronic exposure to arsenic may lead to arsenicosis, while no specific therapeutic strategies are available for the arsenism patients. And Ginkgo biloba extract (GBE) exhibited protective effect in our previous study. However, the mechanisms by which GBE protects the arsenism patients remain poorly understood. A liquid chromatography-mass spectrometry (LC-MS) based untargeted metabolomics analysis was used to study metabolic response in arsenism patients upon GBE intervention. In total, 39 coal-burning type of arsenism patients and 50 healthy residents were enrolled from Guizhou province of China. The intervention group (n = 39) were arsenism patients orally administered with GBE (three times per day) for continuous 90 days. Plasma samples from 50 healthy controls (HC) and 39 arsenism patients before and after GBE intervention were collected and analyzed by established LC-MS method. Statistical analysis was performed by MetaboAnalyst 5.0 to identify differential metabolites. Multivariate analysis revealed a separation in arsenism patients between before (BG) and after GBE intervention (AG) group. It was observed that 35 differential metabolites were identified between BG and AG group, and 30 of them were completely or partially reversed by GBE intervention, with 14 differential metabolites significantly up-regulated and 16 differential metabolites considerably down-regulated. These metabolites were involved in promoting immune response and anti-inflammatory functions, and alleviating oxidative stress. Taken together, these findings indicate that the GBE intervention could probably exert its protective effects by reversing disordered metabolites modulating these functions in arsenism patients, and provide insights into further exploration of mechanistic studies.

Effect of brominated flame retardants exposure on liver function and the risk of non-alcoholic fatty liver disease in the US population.

BACKGROUND: The relationship between brominated flame retardants (BFRs) exposure and the human liver was still not well understood. METHODS: A total of 3108 participants (age > 12) from the National Health and Nutrition Examination Survey (NHANES) database spanning from 2005 to 2016 were included as the study population, with nine BFRs exhibiting a detection rate of over 70% serving as the exposure factor. The singular effects and combined effects of BFRs exposure on liver injury, non-alcoholic fatty liver disease (NAFLD), and advanced hepatic fibrosis (AHF) were evaluated separately. Finally, COX regression was employed to explore the hazard ratios associated with individual BFRs. RESULTS: In our analysis of individual exposures, we found significant positive association of PBB153 with alanine aminotransferase (ALT), PBB153 with aspartate aminotransferase (AST), PBDE47, PBDE85, PBDE99, PBDE100, and PBDE154 with alkaline phosphatase (ALP), PBDE28 and PBB153 with gamma-glutamyl transaminase (GGT), PBB153 with the risk of NAFLD and AHF; and significant negative association of PBB153 with ALP, PBDE28, PBDE47, PBDE99, PBDE100, PBDE85, PBDE209, and PBDE154 with albumin (ALB), PBB153 with AST/ALT. The nonlinear analysis results from Restricted Cubic Spline (RCS) further validated these associations (all P<0.05). In the mixed analysis combining Weighted Quantile Sum (WQS) regression and Quantile G-computation (QGC) analysis, BFRs were positively associated with ALT (ß>0, P<0.001), GGT (ß>0, P<0.001), and the risk of NAFLD (OR>1, P=0.007). Conversely, BFRs exhibited significant negative correlations with ALP (ß<0, P<0.001), ALB (ß<0, P<0.001), and AST/ALT (ß<0, P<0.001). Furthermore, the COX regression analysis revealed that PBB153 had the highest hazard ratio among the BFRs. CONCLUSIONS: BFR exposure may increase the risk of liver injury and NAFLD, with no significant association with AHF risk. The impact of BFR exposure on liver health should not be overlooked, especially in individuals residing in impoverished areas.

The effect of torus tubarius size on upper airway aerodynamics in children: a computational fluid dynamics study.

PURPOSE: Some children with sleep-disordered breathing (SDB) continue to experience symptoms after adenotonsillectomy. One possible cause is the excessive size of the torus tubarius. METHODS: In this study, the relationship between torus tubarius size and surgical outcome in 24 children with SDB who underwent adenotonsillectomy was retrospectively analyzed based on cone beam computed tomography (CBCT) imaging measurements and medical records. A computational fluid dynamics (CFD) approach was used to quantitatively compare the effects of different torus tubarius sizes on upper airway (UA) aerodynamics in children. RESULTS: The percentage of UA area occupied by the torus tubarius (TTA%) was significantly different between the excellent and poor groups (10.4 ± 3.58% vs. 17.71 ± 4.7%, p < 0.001). The results of CFD simulation showed that the mean airflow velocity, wall shear stress (WSS) and pressure drop (ΔP) in the nasopharynx significantly increased when the TTA% was > 15%. CONCLUSION: Our study confirmed the effect of round pillow size on the aerodynamics of the UA in children. When the TTA% exceeds 15%, it causes change in aerodynamics, which may affect the outcome of children with SDB.

Chronic arsenite exposure induced skeletal muscle atrophy by disrupting angiotensin II-melatonin axis in rats.

Arsenic is a well-known environmental toxicant and emerging evidence suggests that arsenic exposure has potential skeletal muscle toxicity; however, the underlying mechanism has not yet been clarified. The aim of this study was to investigate the correlation among adverse effects of subchronic and chronic environmental arsenic exposure on skeletal muscle as well as specific myokines secretion and angiotensin II (AngII)-melatonin (MT) axis in rats. Four-week-old rats were exposed to arsenite (iAs) in drinking water at environmental relevant concentration of 10 ppm for 3 or 9 months. Results indicated that the gastrocnemius muscle had atrophied and its mass was decreased in rats exposed to arsenite for 9 months, whereas, they had no significant changes in rats exposed to arsenite for 3 months. The levels of serum-specific myokine irisin and gastrocnemius muscle insulin-like growth factor-1 (IGF-1) were increased in 3-month exposure group and decreased in 9-month exposure group, while serum myostatin (MSTN) was increased significantly in 9-month exposure group. In addition, serum AngII level increased both in 3- and 9-month exposure groups, while serum MT level increased in 3-month exposure group and decreased in 9-month exposure group. Importantly, the ratio of AngII to MT level in serum increased gradually with the prolongation of arsenite exposure. It showed a certain correlation between AngII-MT axis and gastrocnemius muscle mass, gastrocnemius muscle level of IGF-1 or serum levels of irisin and MSTN. In conclusion, the disruption of AngII-MT axis balance may be a significant factor for skeletal muscle atrophy induced by chronic environmental arsenic exposure.