Results from the long-term extension of PRIME: A randomized Phase 1b trial of aducanumab.

INTRODUCTION: Aducanumab selectively targets aggregated forms of amyloid beta (Aß), a neuropathological hallmark of Alzheimer's disease (AD). METHODS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. During the 12-month placebo-controlled period, participants with prodromal AD or mild AD dementia were randomized to receive aducanumab or placebo. At week 56, participants could enroll in a long-term extension (LTE), in which all participants received aducanumab. The primary endpoint was safety and tolerability. RESULTS: Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event. Dose titration was associated with a decrease in the incidence of ARIA-E. Over 48 months, aducanumab decreased brain amyloid levels in a dose- and time-dependent manner. Exploratory endpoints suggested a continued benefit in the reduction of clinical decline over 48 months. DISCUSSION: The safety profile of aducanumab remained unchanged in the LTE of PRIME. Amyloid plaque levels continued to decrease in participants treated with aducanumab. HIGHLIGHTS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. We report cumulative safety and 48-month efficacy results from PRIME. Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event (AE); 61% of participants with ARIA-E were asymptomatic. Dose titration was associated with a decrease in the incidence of ARIA-E. Aducanumab decreased levels of amyloid beta (Aß) in a dose- and time-dependent manner.

Development and external validation of a nomogram for predicting overall survival of patients with non-endometrioid endometrial cancer: A population-based analysis.

Objectives: The main objective of this study was to identify the key predictors and construct a nomogram that can be used to predict the overall survival of individuals with non-endometrioid endometrial cancer. Methods: A total of 2686 non-endometrioid endometrial cancer patients confirmed between 1988 and 2018 were selected from the Surveillance, Epidemiology, and End Results database. They were divided into a training cohort and an internal validation cohort. Independent risk factors were chosen by Cox regression analyses. A predictive nomogram model for overall survival was constructed based on above factors. A Chinese cohort of 41 patients was collected to be an external validation cohort. Results: Eight variables were estimated as independent predictors for overall survival. A nomogram was established using these factors. The C-index for predicting the overall survival of patients with non-endometrioid endometrial cancer from the nomogram was 0.734, 0.700, and 0.767 in training, internal, and external validation cohort, respectively. Calibration plots and decision curve analysis showed that the nomogram was valuable for further clinical application. Conclusion: We constructed a nomogram which can be used as an effective tool to predict the 3- and 5-year overall survival of Non-endometrioid endometrial cancer patients.

[Research on mechanism of hypolipidemic effect of Massa Medicata Fermentata based on metabolomics].

This paper aims to study the therapeutic effect of Massa Medicata Fermentata on hyperlipidemia model rats and investigate its mechanism of hypolipidemic effect with the help of non-targeted metabolomics. The mixed hyperlipidemia model rats were constructed by giving high-fat chow. After successful modeling, the rats were divided into the model group, pravastatin sodium group(4.4 mg·kg~(-1)), lipotropic group(0.1 g·kg~(-1)), high-dose group(2.4 g·kg~(-1)), medium-dose group(1.2 g·kg~(-1)), and low-dose group(0.6 g·kg~(-1)) of Massa Medicata Fermentata, and they were administered for four weeks once daily. An equal volume of ultrapure water was given to the blank group and model group. Serum lipid level and liver hematoxylin-eosin(HE) staining were used as indicators to estimate the intervention effect of Massa Medicata Fermentata on mixed hyperlipidemia, and the changes in metabolites in plasma of mixed hyperlipidemia model rats were analyzed by non-targeted metabolomics. The mechanism of the hypolipidemic effect of Massa Medicata Fermentata was analyzed through metabolite pathway enrichment. The results showed that compared with the model group, the Massa Medicata Fermentata administration group, especially the high-dose group, could significantly reduce the content of total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c)(P<0.05 or P<0.01), and liver HE staining revealed that the number of adipocytes in the high-dose group was reduced to some extent. The potential biomarkers obtained by non-targeted metabolomics screening included glycerol 3-phosphate, sphingomyelin, sphingosine 1-phosphate, and deoxyuridine, which were mainly involved in the sphingolipid metabolism process, glycerophospholipid metabolism process, glycerol ester metabolism pathway, and pyrimidine metabolism pathway, totaling four possible metabolic pathways related to lipid metabolism. This study provides a reference for an in-depth investigation of the hypolipidemic mechanism of Massa Medicata Fermentata, which is of great significance for further promoting the clinical application of Massa Medicata Fermentata and increasing the indications.

Mitochondrial carrier homolog 2 increases malignant phenotype of human gastric epithelial cells and promotes proliferation, invasion, and migration of gastric cancer cells.

BACKGROUND: The precise role of mitochondrial carrier homolog 2 (MTCH2) in promoting malignancy in gastric mucosal cells and its involvement in gastric cancer cell metastasis have not been fully elucidated. AIM: To determine the role of MTCH2 in gastric cancer. METHODS: We collected 65 samples of poorly differentiated gastric cancer tissue and adjacent tissues, constructed MTCH2-overexpressing and MTCH2-knockdown cell models, and evaluated the proliferation, migration, and invasion of human gastric epithelial cells (GES-1) and human gastric cancer cells (AGS) cells. The mitochondrial membrane potential (MMP), mitochondrial permeability transformation pore (mPTP) and ATP fluorescence probe were used to detect mitochondrial function. Mitochondrial function and ATP synthase protein levels were detected via Western blotting. RESULTS: The expression of MTCH2 and ATP2A2 in gastric cancer tissues was significantly greater than that in adjacent tissues. Overexpression of MTCH2 promoted colony formation, invasion, migration, MMP expression and ATP production in GES-1 and AGS cells while upregulating ATP2A2 expression and inhibiting cell apoptosis; knockdown of MTCH2 had the opposite effect, promoting overactivation of the mPTP and promoting apoptosis. CONCLUSION: MTCH2 can increase the malignant phenotype of GES-1 cells and promote the proliferation, invasion, and migration of gastric cancer cells by regulating mitochondrial function, providing a basis for targeted therapy for gastric cancer cells.

17ß-Estradiol protects female rats from bilateral oophorectomy-induced nonalcoholic fatty liver disease induced by improving linoleic acid metabolism alteration and gut microbiota disturbance.

After surgical or natural menopause, women face a high risk of nonalcoholic fatty liver disease (NAFLD), which can be diminished by hormone replacement therapy (HRT). The gut microbiota is subject to modulation by various physiological changes and the progression of diseases. This microbial ecosystem coexists symbiotically with the host, playing pivotal roles in immune maturation, microbial defense mechanisms, and metabolic functions essential for nutritional and hormone homeostasis. E2 supplementation effectively prevented the development of NAFLD after bilateral oophorectomy (OVX) in female rats. The changes in the gut microbiota such as abnormal biosynthetic metabolism of fatty acids caused by OVX were partially restored by E2 supplementation. The combination of liver transcriptomics and metabolomics analysis revealed that linoleic acid (LA) metabolism, a pivotal pathway in fatty acids metabolism was mainly manipulated during the induction and treatment of NAFLD. Further correlation analysis indicated that the gut microbes were associated with abnormal serum indicators and different LA metabolites. These metabolites are also closely related to serum indicators of NAFLD. An in vitro study verified that LA is an inducer of hepatic steatosis. The changes in transcription in the LA metabolism pathway could be normalized by E2 treatment. The metabolic perturbations of LA may directly and secondhand impact the development of NAFLD in postmenopausal individuals. This research focused on the sex-specific pathophysiology and treatment of NAFLD, providing more evidence for HRT and calling for the multitiered management of NAFLD.

Surface-Phosphided Metal Oxide Microspheres as Catalytic Host of Sulfur to Enhance the Performance of Lithium-Sulfur Batteries.

Lithium-sulfur (Li-S) batteries are one of the most promising high-energy density secondary batteries due to their high theoretical energy density of 2600 Wh kg-1. However, the sluggish kinetics and severe "shuttle effect" of polysulfides are the well-known barriers that hinder their practical applications. A carefully designed catalytic host of sulfur may be an effective strategy that not only accelerates the conversion of polysulfides but also limit their dissolution to mitigate the "shuttle effect." Herein, in situ surface-phosphided Ni0.96Co0.03Mn0.01O (p-NCMO) oxide microspheres are prepared via gas-phase phosphidation as a catalytic host of sulfur. The as-prepared unique heterostructured microspheres, with enriched surface-coated metal phosphide, exhibit superior synergistic effect of catalytic conversion and absorption of the otherwise soluble intermediate polysulfides. Correspondingly, the sulfur cathode exhibits excellent electrochemical performance, including a high initial discharge capacity (1162 mAh gs-1 at 0.1C), long cycling stability (491 mAh gs-1 after 1000 cycles at 1C), and excellent rate performance (565 mAh gs-1 at 5C). Importantly, the newly prepared sulfur cathode shows a high areal capacity of 4.0 mAh cm-2 and long cycle stability under harsh conditions (high sulfur loading of 5.3 mg cm-2 and lean electrolyte/sulfur ratio of 5.8 µL mg-1). This work proposes an effective strategy to develop the catalytic hosts of sulfur for achieving high-performance Li-S batteries via surface phosphidation.

Computed tomography-based radiomics diagnostic approach for differential diagnosis between early- and late-stage pancreatic ductal adenocarcinoma.

BACKGROUND: One of the primary reasons for the dismal survival rates in pancreatic ductal adenocarcinoma (PDAC) is that most patients are usually diagnosed at late stages. There is an urgent unmet clinical need to identify and develop diagnostic methods that could precisely detect PDAC at its earliest stages. AIM: To evaluate the potential value of radiomics analysis in the differentiation of early-stage PDAC from late-stage PDAC. METHODS: A total of 71 patients with pathologically proved PDAC based on surgical resection who underwent contrast-enhanced computed tomography (CT) within 30 d prior to surgery were included in the study. Tumor staging was performed in accordance with the 8th edition of the American Joint Committee on Cancer staging system. Radiomics features were extracted from the region of interest (ROI) for each patient using Analysis Kit software. The most important and predictive radiomics features were selected using Mann-Whitney U test, univariate logistic regression analysis, and minimum redundancy maximum relevance (MRMR) method. Random forest (RF) method was used to construct the radiomics model, and 10-times leave group out cross-validation (LGOCV) method was used to validate the robustness and reproducibility of the model. RESULTS: A total of 792 radiomics features (396 from late arterial phase and 396 from portal venous phase) were extracted from the ROI for each patient using Analysis Kit software. Nine most important and predictive features were selected using Mann-Whitney U test, univariate logistic regression analysis, and MRMR method. RF method was used to construct the radiomics model with the nine most predictive radiomics features, which showed a high discriminative ability with 97.7% accuracy, 97.6% sensitivity, 97.8% specificity, 98.4% positive predictive value, and 96.8% negative predictive value. The radiomics model was proved to be robust and reproducible using 10-times LGOCV method with an average area under the curve of 0.75 by the average performance of the 10 newly built models. CONCLUSION: The radiomics model based on CT could serve as a promising non-invasive method in differential diagnosis between early and late stage PDAC.

Validation of the PL-C Quest in China: understanding the pictorial physical literacy self-report scale.

Introduction: The notion of physical literacy is gaining interest from several countries as a potential mechanism for understanding the development of the physical self. This research endeavor represents an inaugural attempt to translate the Australian Physical Literacy Questionnaire for Children (PL-C Quest) into Chinese to evaluate the reliability and validity of the Chinese version of the PL-C Quest to assess physical literacy among children in mainland China. Methods: The Beaton translation paradigm was used to carry out language translation, back-translation, cultural adaptation, and presurveys. Data were collected from 642 children aged 6-12 years, with a mean age of 9.71 years (SD 1.816), to test the reliability of the Chinese version of the PL-C Quest. Results: The PL-C Quest items translated well (6.187 ~ 15.499) and correlated well (0.441 ~ 0.622). The Chinese version of the PL-C Quest had good reliability, with retest reliability values ranging from 0.91 to 0.74, Cronbach's alpha from 0.65 to 0.894, and McDonald's ω from the Spearman-Brown Coefficient was 0.84. The validity results are acceptable because the CFI, IFI, and TLI values are above 0.8 and close to 0.9, but the model fit's chi-square degrees-of-freedom ratio of 2.299, the RMSEA of 0.05, which was less than 0.08. Discussion: After translation and cultural adaptation, the Chinese version of the PL-C Quest is a reliable measurement tool and can be used in the Chinese region.

Differential genetic mutations and immune cell infiltration in high- and low-risk STAD: Implications for prognosis and immunotherapy efficacy.

This study investigates genetic mutations and immune cell dynamics in stomach adenocarcinoma (STAD), focusing on identifying prognostic markers and therapeutic targets. Analysis of TCGA-STAD samples revealed C > A as the most common single nucleotide variant (SNV) in both high and low-risk groups. Key mutated driver genes included TTN, TP53 and MUC16, with frame-shift mutations more prevalent in the low-risk group and missense mutations in the high-risk group. Interaction analysis of hub genes such as C1QA and CD68 showed significant correlations, impacting immune cell infiltration patterns. Using ssGSEA, we found higher immune cell infiltration (B cells, CD4+ T cells, CD8+ T cells, DC cells, NK cells) in the high-risk group, correlated with increased risk scores. xCell algorithm results indicated distinct immune infiltration levels between the groups. The study's risk scoring model proved effective in prognosis prediction and immunotherapy efficacy assessment. Key molecules like CD28, CD27 and SLAMF7 correlated significantly with risk scores, suggesting potential targets for high-risk STAD patients. Drug sensitivity analysis showed a negative correlation between risk scores and sensitivity to certain treatments, indicating potential therapeutic options for high-risk STAD patients. We also validated the carcinogenic role of RPL14 in gastric cancer through phenotypic experiments, demonstrating its influence on cancer cell proliferation, invasion and migration. Overall, this research provides crucial insights into the genetic and immune aspects of STAD, highlighting the importance of a risk scoring model for personalized treatment strategies and clinical decision-making in gastric cancer management.

Aspongopus chinensis Dallas induces pro-apoptotic and cell cycle arresting effects in hepatocellular carcinoma cells by modulating miRNA and mRNA expression.

Aspongopus chinensis Dallas is a traditional Chinese medicinal insect with several anticancer properties can inhibit cancer cell growth, by inhibiting cell division, autophagy and cell cycle. However, the precise therapeutics effects and mechanisms of this insect on liver cancer are still unknown. This study examined the inhibitory influence of A. chinensis on the proliferation of hepatocellular carcinoma (HCC) cells and explore the underlying mechanism using high-throughput sequencing. The results showed that A. chinensis substantially reduced the viability of Hep G2 cells. A total of 33 miRNAs were found to be upregulated, while 43 miRNAs were downregulated. Additionally, 754 mRNAs were upregulated and 863 mRNAs were downregulated. Significant enrichment of differentially expressed genes was observed in signaling pathways related to tumor cell growth, cell cycle regulation, and apoptosis. Differentially expressed miRNAs exhibited a targeting relationship with various target genes, including ARC, HSPA6, C11orf86, and others. Hence, cell cycle and apoptosis were identified by flow cytometry. These findings indicate that A. chinensis impeded cell cycle advancement, halted the cell cycle in the G0/G1 and S stages, and stimulated apoptosis. Finally, mouse experiments confirmed that A. chinensis significantly inhibits tumor growth in vivo. Therefore, our findings indicate that A. chinensis has a notable suppressive impact on the proliferation of HCC cells. The potential mechanism of action could involve the regulation of mRNA expression via miRNA, ultimately leading to cell cycle arrest and apoptosis. The results offer a scientific foundation for the advancement and application of A. chinensis in the management of HCC.

Development and validation of a novel prognostic nomogram for advanced diffuse large B cell lymphoma.

Advanced diffuse large B cell lymphoma (DLBCL) is a common malignant tumor with aggressive clinical features and poor prognosis. At present, there is lack of effective prognostic tool for patients with advanced (stage III/IV) DLBCL. The aim of this study is to identify prognostic indicators that affect survival and response and establish the first survival prediction nomogram for advanced DLBCL. A total of 402 patients with advanced DLBCL were enrolled in this study. COX multivariate analysis was used to obtain independent prognostic factors. The independent prognostic factors were included in the nomogram, and the nomogram to predict the performance of the model was established by R rms package, C-index (consistency index), AUC curve and calibration curve. The training and validation cohorts included 281 and 121 patients. In the training cohort, multivariate analysis showed that Ki-67 (70% (high expression) vs ≤ 70% (low expression), p < 0.001), LDH (lactate dehydrogenase) (elevated vs normal, p = 0.05), FER (ferritin) (elevated vs normal, p < 0.001), and ß2-microglobulin (elevated vs normal, p < 0.001) were independent predictors and the nomogram was constructed. The nomogram showed that there was a significant difference in OS among the low-risk, intermediate-risk and high-risk groups, with 5-year survival rates of 81.6%, 44% and 6%, respectively. The C-index of the nomogram in the training group was 0.76. The internal validation of the training group showed good consistency. In the internal validation cohort of the training group, the AUC was 0.828, and similar results were obtained in the validation group, with a C-index of 0.74 and an AUC of 0.803. The proposed nomogram provided a valuable individualized risk assessment of OS in advanced DLBCL patients.

DIAGNOSTIC PERFORMANCE OF CENTRAL NERVOUS SYSTEM INFECTIONS IN PATIENTS WITH NEUROSURGICAL INTENSIVE CARE USING METAGENOMIC NEXT-GENERATION SEQUENCING: A PROSPECTIVE OBSERVATIONAL STUDY.

ABSTRACT: Background. Identifying the causative pathogens of central nervous system infections (CNSIs) is crucial, but the low detection rate of traditional culture methods in cerebrospinal fluid (CSF) has made the pathogenic diagnosis of CNSIs a longstanding challenge. Patients with CNSIs after neurosurgery often overlap with inflammatory and bleeding. Metagenomic next-generation sequencing (mNGS) has shown some benefits in pathogen detection. This study aimed to investigate the diagnostic performance of mNGS in the etiological diagnosis of CNSIs in patients after neurosurgery. Methods. In this prospective observational study, we enrolled patients with suspected CNSIs after neurosurgical operations who were admitted to the intensive care unit of Beijing Tiantan Hospital. All enrolled patients' CSF was tested using mNGS and pathogen culture. According to comprehensive clinical diagnosis, the enrolled patients were divided into CNSIs group and non-CNSIs group to compare the diagnostic efficiency of mNGS and pathogen culture. Results. From December 2021 to March 2023, 139 patients were enrolled while 66 in CNSIs group and 73 in non-CNSIs. The mNGS exceeded culture in the variety and quantity of pathogens detected. The mNGS outperformed traditional pathogen culture in terms of positive percent agreement (63.63%), accuracy (82.01%), and negative predictive value (75.00%), with statistically significant differences ( P < 0.05) for traditional pathogen culture. The mNGS also detected bacterial spectrum and antimicrobial resistance genes. Conclusions. Metagenomics has the potential to assist in the diagnosis of patients with CNSIs who have a negative culture.

Decay pattern of SARS-CoV-2 RNA surface contamination in real residences.

The COVID-19 pandemic has provided valuable lessons that deserve deep thought to prepare for the future. The decay pattern of surface contamination by SARS-CoV-2 RNA in the residences of COVID-19 patients is important but still unknown. We collected 2,233 surface samples from 21 categories of objects in 141 residences of COVID-19 patients in Shanghai when attacked by the omicron variant in spring 2022. Several characteristics of the patients and their residences were investigated to identify relevant associations. The decay of contamination was explored to determine the persistence. Approximately 8.7% of the surface samples were tested positive for SARS-CoV-2 RNA. The basin, water tap, and sewer inlet had the highest positive rates, all exceeding 20%. Only time was significantly associated with the level of surface contamination with SARS-CoV-2, showing a negative association. The decrease fit a first-order decay model with a decay rate of 0.77 ± 0.07 day-1, suggesting a 90% reduction in three days. Positive associations between the cumulative number of newly diagnosed patients in the same building and the positive rate of SARS-CoV-2 RNA in the public corridor were significant during the three days. Our results, in conjunction with the likely lower infectivity or viability, demonstrate that fomite transmission played a limited role in COVID-19 spread. The time determined SARS-CoV-2 RNA contamination, which was reduced by three days. This study is the first to show the decay patterns of SARS-CoV-2 contamination in real residential environments, providing insight into the patterns of transmission, as well as community-based prevention and control of similar threats.

Effect modification by maternal vitamin D status in the association between prenatal exposure to per- and polyfluoroalkyl substances and neurodevelopment in 2-year-old children.

BACKGROUND: Pregnant women in the Shanghai Birth Cohort (SBC) of China faced dual threats of per- and polyfluoroalkyl substances (PFAS) exposure and vitamin D (VD) insufficiency, potentially impacting offspring neurodevelopment. However, little is known about whether maternal VD status modifies PFAS-related neurodevelopment effect. OBJECTIVES: To explore the modifying role of maternal VD status in the effect of prenatal PFAS exposure on childhood neurodevelopment. METHODS: We included 746 mother-child pairs from the SBC. Ten PFAS congeners and VD levels were measured in maternal blood samples collected during the first and second trimester respectively. At 2 years of age, toddlers underwent neurodevelopment assessments using Bayley-III Scales. Multivariate linear, logistic regression, and weighted quantile sum approach were used to estimate associations of Bayley-III scores with individual and mixture PFAS. We stratified participants into VD sufficient and insufficient groups and further balanced PFAS differences between these groups by matching all PFAS levels. We fitted the same statistical models in each VD group before and after matching. RESULTS: Nearly half (46.5 %) of pregnant women were VD insufficient (<30 ng/mL). In the overall population, PFAS exposure was associated with lower language scores and an increased risk for neurodevelopmental delay, but higher cognitive scores. However, adverse associations with PFAS were mainly observed in the VD sufficient group, while the VD insufficient group showed positive cognitive score associations. Higher PFAS concentrations were found in the VD sufficient group compared to the VD insufficient group. Post-matching, adverse associations in the VD sufficient group were nullified, whereas in the VD insufficient group, positive associations disappeared and adverse associations becoming more pronounced. CONCLUSION: In this Chinese birth cohort, high prenatal PFAS exposure and low maternal VD levels collectively heighten the risk of adverse childhood neurodevelopment. However, disentangling PFAS and VD interrelationships is crucial to avoid paradoxical findings.

PLD1 promotes spindle assembly and migration through regulating autophagy in mouse oocyte meiosis.

PLD1 has been implicated in cytoskeletal reorganization and vesicle trafficking in somatic cells; however, its function remains unclear in oocyte meiosis. Herein, we found PLD1 stably expresses in mouse oocytes meiosis, with direct interaction with spindle, RAB11A+ vesicles and macroautophagic/autophagic vacuoles. The genetic or chemical inhibition of PLD1 disturbed MTOC clustering, spindle assembly and its cortical migration, also decreased PtdIns(4,5)P2, phosphorylated CFL1 (p-CFL1 [Ser3]) and ACTR2, and their local distribution on MTOC, spindle and vesicles. Furthermore in PLD1-suppressed oocytes, vesicle size was significantly reduced while F-actin density was dramatically increased in the cytoplasm, the asymmetric distribution of autophagic vacuoles was broken and the whole autophagic process was substantially enhanced, as illustrated with characteristic changes in autophagosomes, autolysosome formation and levels of ATG5, BECN1, LC3-II, SQSTM1 and UB. Exogenous administration of PtdIns(4,5)P2 or overexpression of CFL1 hyperphosphorylation mutant (CFL1S3E) could significantly improve polar MTOC focusing and spindle structure in PLD1-depleted oocytes, whereas overexpression of ACTR2 could rescue not only MTOC clustering, and spindle assembly but also its asymmetric positioning. Interestingly, autophagy activation induced similar defects in spindle structure and positioning; instead, its inhibition alleviated the alterations in PLD1-depleted oocytes, and this was highly attributed to the restored levels of PtdIns(4,5)P2, ACTR2 and p-CFL1 (Ser3). Together, PLD1 promotes spindle assembly and migration in oocyte meiosis, by maintaining rational levels of ACTR2, PtdIns(4,5)P2 and p-CFL1 (Ser3) in a manner of modulating autophagy flux. This study for the first time introduces a unique perspective on autophagic activity and function in oocyte meiotic development.Abbreviations: ACTR2/ARP2: actin related protein 2; ACTR3/ARP3: actin related protein 3; ATG5: autophagy related 5; Baf-A1: bafilomycin A1; BFA: brefeldin A; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GOLGA2/GM130: golgin A2; GV: germinal vesicle; GVBD: germinal vesicle breakdown; IVM: in vitro maturation; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MI: metaphase of meiosis I; MII: metaphase of meiosis II; MO: morpholino; MTOC: microtubule-organizing center; MTOR: mechanistic target of rapamycin kinase; PB1: first polar body; PLA: proximity ligation assay; PLD1: phospholipase D1; PtdIns(4,5)P2/PIP2: phosphatidylinositol 4,5-bisphosphate; RAB11A: RAB11A, member RAS oncogene family; RPS6KB1/S6K1: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TUBA/α-tubulin: tubulin alpha; TUBG/γ-tubulin: tubulin gamma; UB: ubiquitin; WASL/N-WASP: WASP like actin nucleation promoting factor.

Prenatal exposure to a mixture of organophosphate flame retardants and infant neurodevelopment: A prospective cohort study in Shandong, China.

BACKGROUND: Previous studies have suggested that prenatal exposure to organophosphate flame retardants (OPFRs) may have adverse effect on early neurodevelopment, but limited data are available in China, and the overall effects of OPFRs mixture are still unclear. OBJECTIVE: This study aimed to investigate the association between prenatal exposure to OPFR metabolites mixture and the neurodevelopment of 1-year-old infants. METHODS: A total of 270 mother-infant pairs were recruited from the Laizhou Wan (Bay) Birth Cohort in China. Ten OPFR metabolites were measured in maternal urine. Neurodevelopment of 1-year-old infants was assessed using the Gesell Developmental Schedules (GDS) and presented by the developmental quotient (DQ) score. Multivariate linear regression and weighted quantile sum (WQS) regression models were conducted to estimate the association of prenatal exposure to seven individual OPFR metabolites and their mixture with infant neurodevelopment. RESULTS: The positive rates of seven OPFR metabolites in the urine of pregnant women were greater than 70% with the median concentration ranged within 0.13-3.53 µg/g creatinine. The multivariate linear regression model showed significant negative associations between bis (1-chloro-2-propyl) phosphate (BCIPP), din-butyl phosphate (DnBP), and total OPFR metabolites exposure and neurodevelopment in all infants. Results from the WQS model consistently revealed that the OPFR metabolites mixture was inversely associated with infant neurodevelopment. Each quartile increased in the seven OPFR metabolites mixture was associated with a 1.59 decrease (95% CI: 2.96, -0.21) in gross motor DQ scores, a 1.41 decrease (95% CI: 2.38, -0.43) in adaptive DQ scores, and a 1.08 decrease (95% CI: 2.15, -0.02) in social DQ scores, among which BCIPP, bis (1, 3-dichloro-2-propyl) phosphate (BDCIPP) and DnBP were the main contributors. CONCLUSION: Prenatal exposure to a mixture of OPFRs was negatively associated with early infant neurodevelopment, particularly in gross motor, adaptive, and social domains.

Aspongopus chinensis ach-miR-276a-3p induces breast cancer cell cycle arrest by targeting APPL2 to regulate the CDK2-Rb-E2F1 signaling pathway.

Breast cancer, the most common cancer, presents a significant challenge to the health and longevity of women. Aspongopus chinensis Dallas is an insect with known anti-breast cancer properties. However, the anti-breast cancer effects and underlying mechanisms have not been elucidated. Exogenous microRNAs (miRNAs), which are derived from plants and animals, have been revealed to have notable capacities for controlling the proliferation of cancerous cells. To elucidate the inhibitory effects of miRNAs derived from A. chinensis and the regulatory mechanism involved in the growth of breast cancer cells, miRNA sequencing was initially employed to screen for miRNAs both in A. chinensis hemolymph and decoction and in mouse serum and tumor tissue after decoction gavage. Subsequently, the experiments were performed to assess the suppressive effect of ach-miR-276a-3p, the miRNA screened out from a previous study, on the proliferation of MDA-MB-231 and MDA-MB-468 breast cancer cell lines in vitro and in vivo. Finally, the regulatory mechanism of ach-miR-276a-3p in MDA-MB-231 and MDA-MB-468 breast cancer cells was elucidated. The results demonstrated that ach-miR-276a-3p notably inhibited breast cancer cell proliferation, migration, colony formation, and invasion and induced cell cycle arrest at the G0/G1 phase. Moreover, the ach-miR-276a-3p mimics significantly reduced the tumor volume and weight in xenograft tumor mice. Furthermore, ach-miR-276a-3p could induce cell cycle arrest by targeting APPL2 and regulating the CDK2-Rb-E2F1 signaling pathway. In summary, ach-miR-276a-3p, derived from A. chinensis, has anti-breast cancer activity by targeting APPL2 and regulating the CDK2-Rb-E2F1 signaling pathway and can serve as a promising candidate anticancer agent.

Patterns of atrial fibrillation, relevant cardiac structural and functional changes predict functional and cognitive outcomes in patients with ischemic stroke and atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) pattern, relevant cardiac changes are important predictors of outcomes in AF, but their impact on patients with ischemic stroke and AF remained unclear. We aimed to explore the impact of AF patterns, cardiac structural and functional markers on long-term functional and cognitive outcomes in ischemic stroke patients with AF. METHODS: Ischemic stroke patients diagnosed with AF were enrolled in this retrospective cohort study. AF pattern was defined by both traditional and novel classification, in which patients were divided into AF diagnosed after stroke (AFDAS) and known before stroke (KAF). Left atrial (LA) diameter, left ventricular ejection fraction (LVEF), natriuretic peptide (BNP) and cardiac troponin (cTnI) were dichotomized according to the median value. Outcomes include poor functional outcome and cognitive impairment at the 1-year follow-up. Multivariable logistic regression was performed to validate the association between AF pattern, parameters of cardiac change and functional and cognitive outcome. RESULTS: A total of 377 patients were included. Non-paroxysmal AF patients had a higher risk of poor functional outcome (OR = 3.59, P < 0.0001) and cognitive impairment (OR = 2.38, P = 0.019) than paroxysmal AF patients, while there were no differences between AFDAS and KAF. Lower LVEF (OR = 1.83, P = 0.045) and higher BNP (OR = 2.66, P = 0.001) were associated with poor functional outcome. Lower LVEF (OR = 2.86, P = 0.004), higher LA diameter (OR = 2.72, P = 0.008) and BNP (OR = 2.31, P = 0.023) were associated with cognitive impairment. CONCLUSIONS: AF type and related cardiac markers can serve as predictors for poor functional and cognitive outcomes. Comprehensive cardiac assessment and monitoring should be strengthened after stroke.

Enhanced photocatalytic ammonia oxidation over WO3@TiO2 heterostructures by constructing an interfacial electric field.

WO3 nanorods and xWO3@TiO2 (WO3/TiO2 mass ratio (x) = 1-5) photocatalysts were synthesized using the hydrothermal and sol-gel methods, respectively. The photocatalytic activities of xWO3@TiO2 for NH3 oxidation first increased and then decreased with a rise in TiO2 content. Among them, the heterostructured 3WO3@TiO2 photocatalyst showed the highest NH3 conversion (58 %) under the simulated sunlight irradiation, which was about two times higher than those of WO3 and TiO2. Furthermore, the smallest amounts of by-products (i.e., NO and NO2) were produced over 3WO3@TiO2. The enhancement in photocatalytic performance (i.e., NH3 conversion and N2 selectivity) of 3WO3@TiO2 was mainly attributed to the formed interfacial electric field between WO3 and TiO2, which promoted efficient separation and transfer of photogenerated charge carriers. Based on the results of reactive species trapping and active radical detection, photocatalytic oxidation of NH3 over 3WO3@TiO2 was governed by the photogenerated holes and superoxide radicals. This work combines two strategies of morphological regulation and interfacial electric field construction to simultaneously improve light utilization and photogenerated charge separation efficiency, which promotes the development of full-spectrum photocatalysts for the removal of ammonia.