Cost-effectiveness of varicella vaccination for 1-4-year-olds in Shanghai, China.

INTRODUCTION: Varicella has not yet been included in the National Immunization Program (NIP) in China, and varicella vaccination strategies vary by region. To determine the optimal varicella vaccination strategy in Shanghai, China, the cost-effectiveness and five-year costs of five immunization scenarios were analyzed. METHODS: A static decision tree-Markov model was developed in 2022 to assess the cost-effectiveness and five-year costs of voluntary and routine varicella vaccination programs in the 2019 birth cohort in Shanghai from a societal perspective. Parameters were collected in 2022 from the varicella surveillance system, a questionnaire survey of 414 guardians of patients with childhood varicella, and semi-structured interviews with 20 experts on varicella outbreaks from different institutions in Shanghai. The outcomes included varicella cases avoided, quality-adjusted life year (QALY) loss, and incremental costs per QALY (ICER). The five-year costs were compared with local medical expenditures. RESULTS: Among the five scenarios, one dose of routine varicella vaccination was the most cost-saving (USD 70.2) and cost-effective (Dominant) with a five-year immunization expenditure of USD 9.9 million. Two doses of routine varicella vaccination had the highest QALY (29.9), and its ICER (USD 791.9/QALY) was below the willingness-to-pay threshold (USD 5,203-23,767/QALY). The five-year immunization expenditure was USD 19.8 million. The effectiveness and price of vaccines, vaccination coverage, and per capita income are the four main factors that affect ICERs. CONCLUSIONS: In Shanghai, the two doses of routine varicella vaccination strategy for 1- and 4-year-olds with a 95% coverage rate was found to be the optimal varicella immunization strategy.

Accurate Prediction of Rat Acute Oral Toxicity and Reference Dose for Thousands of Polycyclic Aromatic Hydrocarbon Derivatives Based on Chemometric QSAR and Machine Learning.

Acute oral toxicity is currently not available for most polycyclic aromatic hydrocarbons (PAHs), especially their derivatives, because it is cost-prohibitive to experimentally determine all of them. Here, quantitative structure-activity relationship (QSAR) models using machine learning (ML) for predicting the toxicity of PAH derivatives were developed, based on oral toxicity data points of 788 individual substances of rats. Both the individual ML algorithm gradient boosting regression trees (GBRT) and the stacking ML algorithm (extreme gradient boosting + GBRT + random forest regression) provided the best prediction results with satisfactory determination coefficients for both cross-validation and the test set. It was found that those PAH derivatives with fewer polar hydrogens, more large-sized atoms, more branches, and lower polarizability have higher toxicity. Software based on the optimal ML-QSAR model was successfully developed to expand the application potential of the developed model, obtaining reliable prediction of pLD50 values and reference doses for 6893 external PAH derivatives. Among these chemicals, 472 were identified as moderately or highly toxic; 10 out of them had clear environment detection or use records. The findings provide valuable insights into the toxicity of PAHs and their derivatives, offering a standard platform for effectively evaluating chemical toxicity using ML-QSAR models.

A nationwide characterization of organochlorine pesticides (OCPs) in livestock and poultry food products across China: Residual levels, origin and the associated health risks.

Organochlorine pesticides (OCPs) are still occurring in various foodstuffs after the ban on their use. However, it remains unclear concerning the contamination source of OCPs in livestock and poultry food products and associated health risks. To fill this gap, we characterized the residual levels of 19 OCPs in multiple types of meats and eggs, which were sampled across China within the same period. Dichlorodiphenyltrichloroethanes (DDTs) were dominant in eggs, with the mean levels being 0.76 and 2.03 µg/kg for chicken eggs and duck eggs, respectively. By contrast, hexachlorocyclohexanes (HCHs) were the top one OCP in beef and lamb, with its mean levels being 0.51 and 0.65 µg/kg, respectively. Hexachlorobenzene (HCB) was rather detected in the poultry products. The componential ratio analysis implicated recent inputs of several banned OCPs including technical HCH and DDT, HCB and aldrin in multiple regions, which may origin from local industrial activities or possible illegal use. Risk assessment based on the risk quotient method suggested that daily consumption of cooked meats and eggs contaminated by dieldrin may pose a carcinogenic risk in adult residents of Jiangsu province. We concluded that OCPs remain present in meats and eggs at levels of health concern regionally in China.

OsG6PGH1 affects various grain quality traits and participates in the salt stress response of rice.

Cytoplasmic 6-phosphogluconate dehydrogenase (G6PGH) is a key enzyme in the pentose phosphate pathway that is involved in regulating various biological processes such as material metabolism, and growth and development in plants. However, it was unclear if OsG6PGH1 affected rice grain quality traits. We perform yeast one-hybrid experiments and reveal that OsG6PGH1 may interact with OsAAP6. Subsequently, yeast in vivo point-to-point experiments and local surface plasmon resonance experiments verified that OsG6PGH1 can bind to OsAAP6. OsG6PGH1 in rice is a constitutive expressed gene that may be localized in the cytoplasm. OsAAP6 and protein-synthesis metabolism-related genes are significantly upregulated in OsG6PGH1 overexpressing transgenic positive endosperm, corresponding to a significant increase in the number of protein bodies II, promoting accumulation of related storage proteins, a significant increase in grain protein content (GPC), and improved rice nutritional quality. OsG6PGH1 positively regulates amylose content, negatively regulates chalkiness rate and taste value, significantly affects grain quality traits such as appearance, cooking, and eating qualities of rice, and is involved in regulating the expression of salt stress related genes, thereby enhancing the salt-stress tolerance of rice. Therefore, OsG6PGH1 represents an important genetic resource to assist in the design of high-quality and multi-resistant rice varieties.

Effects of Planarization of the Triphenylamine Unit on the Electronic and Transport Properties of Triarylamine-Fluorene Copolymers in Both Doped and Undoped Forms.

Triarylamine-alt-fluorene (TAF) copolymers are widely used for hole injection and transport in organic electronics. Despite suggestions to planarize the triphenylamine moiety, little research has been conducted. Here, we report a comprehensive investigation of the effects of planarization on the electronic and transport properties of a model TAF polymer semiconductor core. We compared the conventional twisted-propeller N-4-methoxyphenyl-N,N-diphenylamine-4',4″-diyl (TA) unit and its planarized bridged analogue (bTA) where adjacent o,o'-positions are linked by 1,1-dimethylmethylene. We studied both polyelectrolyte and non-polyelectrolyte forms of this core in both doped and undoped states. We found that planarization leads to an unprecedented trap-free transport of holes, and a pronounced enhancement of their mobility in the undoped state though less so in the doped state. Planarization also induces a slight reduction in the ionization energy of the undoped polymer, consequently lowering the work function of the doped polymer. This is accompanied by small spectral shifts: a red shift in the first absorption band of the undoped polymer and a blue shift in the first absorption band of the polaron. Furthermore, this study unveils new fundamental features of TAF polymers: (i) Doping induces the formation of three polaron bands within the subgap. (ii) Absorption of both neutral and polaron segments exhibit a linear intensity relationship with doping level. (iii) Electrical conductivity reaches a maximum at the half-doped state, varying as σ ∼ (x (1 - x))3 for 0.1 ≲ x ≲ 0.9, where x is the doping level. Finally, we demonstrate the successful integration of these self-compensated hole-doped TAF polymers as efficient hole injection layers in organic semiconductor diodes.

Proteomic profiling of laser capture microdissection kidneys from diabetic nephropathy patients.

Diabetic nephropathy (DN) remains the primary cause of end-stage renal disease (ESRD), warranting equal attention and separate analysis of glomerular, tubular, and interstitial lesions in its diagnosis and intervention. This study aims to identify the specific proteomics characteristics of DN, and assess changes in the biological processes associated with DN. 5 patients with DN and 5 healthy kidney transplant donor control individuals were selected for analysis. The proteomic characteristics of glomeruli, renal tubules, and renal interstitial tissue obtained through laser capture microscopy (LCM) were studied using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Significantly, the expression of multiple heat shock proteins (HSPs), tubulins, and heterogeneous nuclear ribonucleoproteins (hnRNPs) in glomeruli and tubules was significantly reduced. Differentially expressed proteins (DEPs) in the glomerulus showed significant enrichment in pathways related to cell junctions and cell movement, including the regulation of actin cytoskeleton and tight junction. DEPs in renal tubules were significantly enriched in glucose metabolism-related pathways, such as glucose metabolism, glycolysis/gluconeogenesis, and the citric acid cycle. Moreover, the glycolysis/gluconeogenesis pathway was a co-enrichment pathway in both DN glomeruli and tubules. Notably, ACTB emerged as the most crucial protein in the protein-protein interaction (PPI) analysis of DEPs in both glomeruli and renal tubules. In this study, we delve into the unique proteomic characteristics of each sub-region of renal tissue. This enhances our understanding of the potential pathophysiological changes in DN, particularly the potential involvement of glycolysis metabolic disorder, glomerular cytoskeleton and cell junctions. These insights are crucial for further research into the identification of disease biomarkers and the pathogenesis of DN.

Research on image recognition of tomato leaf diseases based on improved AlexNet model.

Aiming at the problems that the traditional image recognition technology is challenging to extract useful features and the recognition time is extended; the AlexNet model is improved to improve the effect of image classification and recognition. This study focuses on 8 types of tomato leaf diseases and healthy leaves. By using HOG and LBP weighted fusion to extract image features, a tomato leaf disease recognition model based on the AlexNet model is proposed, and transfer learning is used to train the AlexNet model. Transfer the knowledge learned by the AlexNet model on the PlantVillage image dataset to this model while reducing the number of fully connected layers. Keras deep learning framework and programming language Python were used. The model was implemented, and the classification and identification of tomato leaf diseases were carried out. The recognition rate of feature-weighted fusion classification is higher than that of serial and parallel methods, and the recognition time is the shortest. When the weight coefficient ratio of HOG and LBP is 3:7, the image recognition rate is the highest, and its value is 97.2 %. From the model performance curve See, when the number of iterations is more than 150 times, the training set and test accuracy rate both exceed 97 %, the loss rate shows a gradient decline, and the change is relatively stable; compared with the traditional AlexNet model, HOG + LBP + SVM model, and VGG model, improved AlexNet model has the highest recognition rate, and it has high recall value, accuracy, and F1 value; Compared with the latest convolutional neural network disease recognition models, improved AlexNet model recognition accuracy was 98.83 %, and the F1 value was 0.994. It shows that the model has good convergence performance, fast prediction speed, and low loss rate and can effectively identify 8 types of tomato leaf images, which provides a reference for the research on crop disease identification.

Comparative analysis of the fatty acid profiles in goat milk during different lactation periods and their interactions with volatile compounds and metabolites.

This study aimed to compare the composition of fatty acids in goat milk during lactation with human milk, as well as analyze the differences in their interaction with odor and metabolites. Polyunsaturated fatty acids content was higher in human milk, while odd-chain, branched-chain, and monounsaturated fatty acids content were higher in goat milk with a decreasing trend during lactation. PUFAs in human milk undergo auto-oxidation to produce aldehydes (hexanal), giving it a mild aroma. Butyric acid in goat colostrum mediates the synthesis and auto-oxidation of PUFA, while taurine mediated the hydrolysis of amino acids. They produce a furanone compound (2(5H)-furanone) with a buttery flavor. The presence of butyric acid in goat transitional milk had an impact on flavor and metabolites. The medium chain fatty acid composition of the goat mature milk was affected by nucleic acid compounds, which then oxidized to produce methyl ketone (2-nonanone), giving it an unpleasant flavor.

Dysregulation of the Suprachiasmatic Nucleus Disturbs the Circadian Rhythm and Aggravates Epileptic Seizures by Inducing Hippocampal GABAergic Dysfunction in C57BL/6 Mice.

The interplay between circadian rhythms and epilepsy has gained increasing attention. The suprachiasmatic nucleus (SCN), which acts as the master circadian pacemaker, regulates physiological and behavioral rhythms through its complex neural networks. However, the exact role of the SCN and its Bmal1 gene in the development of epilepsy remains unclear. In this study, we utilized a lithium-pilocarpine model to induce epilepsy in mice and simulated circadian disturbances by creating lesions in the SCN and specifically knocking out the Bmal1 gene in the SCN neurons. We observed that the pilocarpine-induced epileptic mice experienced increased daytime seizure frequency, irregular oscillations in core body temperature, and circadian gene alterations in both the SCN and the hippocampus. Additionally, there was enhanced activation of GABAergic projections from the SCN to the hippocampus. Notably, SCN lesions intensified seizure activity, concomitant with hippocampal neuronal damage and GABAergic signaling impairment. Further analyses using the Gene Expression Omnibus database and gene set enrichment analysis indicated reduced Bmal1 expression in patients with medial temporal lobe epilepsy, potentially affecting GABA receptor pathways. Targeted deletion of Bmal1 in SCN neurons exacerbated seizures and pathology in epilepsy, as well as diminished hippocampal GABAergic efficacy. These results underscore the crucial role of the SCN in modulating circadian rhythms and GABAergic function in the hippocampus, aggravating the severity of seizures. This study provides significant insights into how circadian rhythm disturbances can influence neuronal dysfunction and epilepsy, highlighting the therapeutic potential of targeting SCN and the Bmal1 gene within it in epilepsy management.

Multidimensional occurrence and diet risk of emerging contaminants in freshwater with urban agglomerations.

Freshwater systems near highly urbanized areas are extremely susceptible to emerging contaminants (ECs), yet their stereoscopic persistence in aquatic ecosystems and related risks remain largely unknown. Herein, we characterized the multi-mediums distribution of 63 ECs in Baiyangdian Lake, the biggest urban lake in the North of China. We identified variations in the seasonal patterns of aquatic EC levels, which decreased in water and increased in sediment from wet to dry seasons. Surprisingly, higher concentrations and a greater variety of ECs were detected in reeds than in aquatic animals, indicating that plants may contribute to the transferring of ECs. Source analysis indicated that human activity considerably affected the distribution and risk of ECs. The dietary risk of ECs is most pronounced among children following the intake of aquatic products, especially with a relatively higher risk associated with fish consumption. Besides, a comprehensive scoring ranking method was proposed, and 9 ECs, including BPS and macrolide antibiotics, are identified as prioritized control pollutants. These findings highlight the risks associated with aquatic ECs and can facilitate the development of effective management strategies.

Balloon angiopLasty for intracranial Atherosclerotic minor Stroke/TIA (BLAST): study protocol for a multicenter prospective cohort study.

Rationale/Aim: Intracranial atherosclerotic stenosis (ICAS) is a common cause of stroke in Asia and is significantly associated with stroke recurrence. The Balloon angiopLasty for intracranial Atherosclerotic minor Stroke/TIA (BLAST) study aims to evaluate the safety and effectiveness of early submaximal balloon angioplasty (SBA) combined with standard medical therapy vs. standard medical therapy alone in patients with minor stroke or transient ischemic attack (TIA) due to ICAS. Methods: The BLAST study is a multicenter prospective cohort study which will enroll patients with minor stroke or TIA due to symptomatic ICAS within 1 week of symptom onset from 20 centers in China. Eligible patients will receive either SBA with standard medical therapy or standard medical therapy alone based on the decision of the patient or legal representative. Participants will be followed up for 1 year. Study outcomes: The primary outcome is a composite of stroke or death within 30 days or ischemic stroke in the culprit artery territory from 30 days to 1 year. Secondary outcomes include stroke or death within 30 days, ischemic stroke in the culprit artery territory from 30 days to 1 year, restenosis rate of the culprit artery at 1 year, and neurological improvement at 90 days (assessed by mRS score). Safety outcomes include intracranial hemorrhage within 30 days and endovascular complications. Sample size estimate: According to previous studies, the incidence of the composite clinical outcomes is 15% in the group receiving medical therapy alone. We assumed the incidence would decrease to 5% in the SBA combined with the medical therapy group. The target sample size is 416 patients (208 per group), with 90% power and 5% type I error, allowing for a 10% loss to follow-up. Implications: The BLAST study will provide evidence regarding whether early SBA can reduce stroke recurrence and mortality in patients with minor stroke/TIA due to ICAS compared with medical therapy alone.Clinical trial registration:Clinicaltrials.gov, NCT06014723.

Joint effects about antibiotics combined using with antibiotics or phytochemicals on Aeromonas hydrophila.

Aeromonas hydrophila is highly prevalent in aquaculture animals and aquaculture environment. Due to the abuse of antibiotics, A. hydrophila can change the antibiotic resistance spectrum directly and affect human health indirectly. The use of combined drugs replacement therapy and the long-term coexistence with drug-resistant bacteria are the reality that human beings have to face in dealing with the problem of antibiotic resistance in the future. This study showed the characteristics and trends through abundant results of combined effects related with the combinations of antibiotic and the combinations of antibiotic and phytochemical on A. hydrophila, and revealed the antagonism probability of combinations of antibiotic and phytochemical is significantly higher than that of the combinations of antibiotic. Meanwhile, the combinations of antibiotic and phytochemical could protect the host cells which also achieved the same effectiveness as combination of antibiotics, and the enrichment pathway was proved to be relatively discrete. In addition, the possible mechanism about the reverse "U" shape of the combined effect curve on wild/antibiotic-resistant bacteria was clarified, and it was confirmed that the antagonism for the combinations of antibiotic and phytochemical might has the significance in inhibiting the evolution of bacterial resistance mutations. This study was aims to provide theoretical basis and some clues for the antibiotic resistance control associated with A. hydrophila.

Visible-light-driven photoelectrochemical sensor based on conjugated microporous polymer-grafted graphene for o-aminophenol detection.

The pollutant o-aminophenol (o-AP) presents considerable risk to environmental safety, and its detection is therefore critical. Although various optical and electrochemical methods have been proposed for the detection of o-AP, there are a limited number of detection methods based on photoelectrochemical (PEC) sensors. In this study, a sensitive visible-light-driven PEC sensor was developed for o-AP detection in water. A conjugated microporous polymer (CMP)-coated graphene heterostructure (CMP-rGO) was synthesized and used to develop a PEC sensor. Under optimal conditions, the proposed sensor exhibited a high sensitivity of 0.03 µM with a wide linear range of 0.0034-37.6 µM. The PEC sensor also displayed acceptable repeatability and reproducibility, good long-term stability, and excellent recovery (98-102%). In addition, the binding patterns of CMP to o-AP and o-AP analog molecules were analyzed by molecular docking. Therefore, this study provides a new and feasible PEC sensor-based detection scheme for o-AP detection.

Comparison of the Lipid Composition of Milk Fat Globules in Goat (Capra hircus) Milk during Different Lactations and Human Milk.

Goat milk is considered the optimal substitute for human milk and is characterized by variations in the lipid composition of its fat globules across lactation phases. Therefore, the objective of this study was to thoroughly analyze the differences between goat milk during different lactations and human milk, aiming to offer scientific guidance for the production of functional dairy products. Compared with transitional and mature milk, the findings indicated that the total membrane protein content in goat colostrum exhibited greater similarity to that found in human milk. Additionally, goat milk exhibited higher milk fat globule size, as well as a higher total lipid and protein content than human milk. A total of 1461 lipid molecules across 61 subclasses were identified in goat milk and human milk. The contents of glycerides and glycerophospholipids were higher in goat colostrum, whereas sphingolipids and fatty acids were more abundant in human milk. Meanwhile, the compositions of lipid subclasses were inconsistent. There were 584 differentially expressed lipids identified between human and goat milk, including 47 subclasses that were primarily involved in the metabolism of glycerophospholipids, sphingolipids, and triglycerides. In summary, for both the membrane protein and the lipid composition, there were differences between the milk of different goat lactations and human milk.

Intraplatelet miRNA-126 regulates thrombosis and its reduction contributes to platelet inhibition.

AIMS: MicroRNA-126 (miR-126), one of the most abundant microRNAs in platelets, is involved in the regulation of platelet activity and the circulating miR-126 is reduced during antiplatelet therapy. However, whether intraplatelet miR-126 plays a role in thrombosis and platelet inhibition remains unclear. METHODS AND RESULTS: Here, using tissue-specific knockout mice, we reported that the deficiency of miR-126 in platelets and vascular endothelial cells significantly prevented thrombosis and prolonged bleeding time. Using chimeric mice, we identified that the lack of intraplatelet miR-126 significantly prevented thrombosis. Ex vivo experiments further demonstrated that miR-126-deficient platelets displayed impaired platelet aggregation, spreading and secretory functions. Next, miR-126 was confirmed to target phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) in platelet, which encodes a negative regulator of the PI3 K/AKT pathway, enhancing platelet activation through activating the integrin αIIbß3-mediated outside-in signaling. After undergoing myocardial infarction (MI), chimeric mice lacking intraplatelet miR-126 displayed reduced microvascular obstruction and prevented MI expansion in vivo. In contrast, overexpression of miR-126 by the administration of miR-126 agonist (agomiR-126) in wild-type mice aggravated microvascular obstruction and promoted MI expansion, which can be almost abolished by aspirin administration. In patients with cardiovascular diseases, antiplatelet therapies, either aspirin alone or combined with clopidogrel, decreased the level of intraplatelet miR-126. The reduction of intraplatelet miR-126 level was associated with the decrease of platelet activity. CONCLUSIONS: Our murine and human data reveal that (i) intraplatelet miR-126 contributes to platelet activity and promotes thrombus formation, and (ii) the reduction of intraplatelet miR-126 contributes to platelet inhibition during antiplatelet therapy.

Developmental effects and lipid disturbances of zebrafish embryos exposed to three newly recognized bisphenol A analogues.

Bisphenol G (BPG), bisphenol M (BPM) and bisphenol TMC (BPTMC), are newly recognized analogues of bisphenol A (BPA), which have been detected in multiple environmental media. However, the understanding of their negative impacts on environmental health is limited. In this study, zebrafish embryos were exposed to BPA and the three analogues (0.1, 10, and 1000 µg/L) to identify their developmental toxic effects. According to our results, all of the three analogues induced significant developmental disorders on zebrafish embryos including inhibited yolk sac absorption, altered heart rate, and teratogenic effects. Oil Red O staining indicated lipid accumulation in the yolk sac region of zebrafish after bisphenol analogues exposure, which was consistent with the delayed yolk uptake. Untargeted lipidomic analysis indicated the abundance of triacylglycerols, ceramides and fatty acids was significantly altered by the three analogues. The combined analysis of lipidomics and transcriptomics results indicated BPG and BPM affected lipid metabolism by disrupting peroxisome proliferator-activated receptor pathway and interfering with lipid homeostasis and transport. This partly explained the morphological changes of embryos after bisphenol exposure. In conclusion, our study reveals that BPG, BPM and BPTMC possess acute and developmental toxicity toward zebrafish, and the developmental abnormalities are associated with the disturbances in lipid metabolism.

Dynamic performance of combined biochar from co-pyrolysis of pig manure with invasive weed: Effect of natural aging on Pb and As mobilization in polluted mining soil.

Due to the natural biochar aging, the improvement of soil quality and immobilization of soil pollutants achieved by biochar may change; understanding the dynamic evolution of the in situ performance of biochar in these roles is essential to discuss the long-term sustainability of biochar remediation. Therefore, in this study, combined biochar from co-pyrolysis of pig manure and invasive Japanese knotweed - P1J1, as well as pure pig manure - PM - and pure Japanese knotweed - JK - derived biochar were applied to investigate their remediation performance in a high As- and Pb-polluted soil with prolonged incubation periods (up to 360 days). Biochar application, especially P1J1 and PM, initially promoted soil pH, dissolved organic carbon, and EC, but the improvements were not constant through time. The JK-treated soil exhibited the highest increase of soil organic matter (OM), followed by P1J1 and then PM, and OM did not change with aging. Biochar, especially P1J1, was a comprehensive nutrient source of Ca, K, Mg, and P to improve soil fertility. However, while soluble cationic Ca, K, and Mg increased with time, anionic P decreased over time, indicating that continuous P availability might not be guaranteed with the aging process. The total microorganism content declined with time; adding biochars slowed down this tendency, which was more remarkable at the later incubation stage. Biochar significantly impeded soil Pb mobility but mobilized soil As, especially in PM- and P1J1-treated soils. However, mobilized As gradually re-fixed in the long run; meanwhile, the excellent Pb immobilization achieved by biochars was slightly reduced with time. The findings of this study offer fresh insights into the alterations in metal(loid)s mobility over an extended duration, suggesting that the potential mobilization risk of As is reduced while Pb mobility slightly increases over time.

Multi-omics reveals the molecular mechanism of the combined toxic effects of PFOA and 4-HBP exposure in MCF-7 cells and the key player: mTORC1.

With the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10-8 M to 4 × 10-7 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity.

Sex difference in nocturnal blood pressure dipping in adolescents with varying degrees of adiposity.

BACKGROUND: For adolescents, abnormal dipping patterns in blood pressure (BP) are associated with early-onset organ damage and a higher risk of cardiovascular disorders in adulthood. Obesity is one of the most common reasons for abnormal BP dipping in young people. However, it is unknown whether the severity of obesity is associated with BP dipping status and whether this association is sex-dependent. METHODS: 499 participants between 12 and 17 years old with overweight or obesity underwent ambulatory blood pressure monitoring (ABPM) between April 2018 and January 2019 in Beijing and Baoding. Participants were grouped by body mass index (BMI) into overweight (BMI 85th-95th percentile), obese (BMI ≥ 95th percentile) and severely obese (BMI ≥ 120% of 95th percentile or ≥ 35 kg/m2) groups. Non-dipping was defined as a < 10% reduction in BP from day to night. The interaction effect between sex and obesity degree was also analyzed. RESULTS: 326 boys and 173 girls were included, of whom 130 were overweight, 189 were obese, and 180 were severely obese. Girls with severe obesity had a higher prevalence of non-dipping, but boys showed no significant differences in BP dipping status between obesity categories. In addition, as obesity severity went up, a more evident increase in night-time SBP was observed in girls than in boys. CONCLUSIONS: Severely obese is associated with a higher prevalence of non-BP dipping patterns in girls than in boys, which suggests that the relationship between the severity of obesity and BP dipping status might be sex-specific.

Layer-by-layer self-assembly of PLL/CPP-ACP multilayer on SLA titanium surface: Enhancing osseointegration and antibacterial activity in vitro and in vivo.

Dental Implants are expected to possess both excellent osteointegration and antibacterial activity because poor osseointegration and infection are two major causes of titanium implant failure. In this study, we constructed layer-by-layer self-assembly films consisting of anionic casein phosphopeptides-amorphous calcium phosphate (CPP-ACP) and cationic poly (L-lysine) (PLL) on sandblasted and acid etched (SLA) titanium surfaces and evaluated their osseointegration and antibacterial performance in vitro and in vivo. The surface properties were examined, including microstructure, elemental composition, wettability, and Ca2+ ion release. The impact the surfaces had on the adhesion, proliferation and differentiation abilities of MC3T3-E1 cells were investigated, as well as the material's antibacterial performance after exposure to the oral microorganisms such as Porphyromonas gingivalis (P. g) and Actinobacillus actinomycetemcomitans (A. a). For the in vivo studies, SLA and Ti (PLL/CA-3.0)10 implants were inserted into the extraction socket immediately after extracting the rabbit mandibular anterior teeth with or without exposure to mixed bacteria solution (P. g & A. a). Three rabbits in each group were sacrificed to collect samples at 2, 4, and 6 weeks of post-implantation, respectively. Radiographic and histomorphometry examinations were performed to evaluate the implant osseointegration. The modified titanium surfaces were successfully prepared and appeared as a compact nano-structure with high hydrophilicity. In particular, the Ti (PLL/CA-3.0)10 surface was able to continuously release Ca2+ ions. From the in vitro and in vivo studies, the modified titanium surfaces expressed enhanced osteogenic and antibacterial properties. Hence, the PLL/CPP-ACP multilayer coating on titanium surfaces was constructed via a layer-by-layer self-assembly technology, possibly improving the biofunctionalization of Ti-based dental implants.