Development of a highly reproducible GC-HRMS method for determination of Skatole in pig tissues.

This study presents a sensitive and reproducible mass spectrometry method for quantifying skatole in porcine adipose tissue, muscle, and serum samples applicable for abattoirs and laboratories. Leveraging gas chromatography-high-resolution Orbitrap microscopy and microwave-assisted liquefication of the adipose tissue, the method demonstrates robust performance across key parameters. Impressive linearity (R2) values of 0.9999 and 0.9996 for adipose tissue and serum, respectively. Notably, the method exhibits a low Limit of Detection (LoD) of 0.5 ppb for adipose tissue and 0.9 ppb for serum, with corresponding Limits of Quantification (LoQ) at 1.65 ppb and 3.04 ppb, respectively. The method showed significant reproducibility of 5.9% and repeatability (RSD%) of 8.78% for adipose tissue and 4.08% for serum, with recovery rates of 90% and 87%, respectively. This streamlined method offers promising, effective quantification of boar taint compounds, emphasizing its sensitivity and reproducibility.

Exosomes derived from mucoperiosteum Krt14+Ctsk+ cells promote bone regeneration by coupling enhanced osteogenesis and angiogenesis.

Repair of large bone defects is a sophisticated physiological process involving the meticulous orchestration of cell activation, proliferation, and differentiation. Cellular interactions between different cell types are paramount for successful bone regeneration, making it a challenging yet fascinating area of research and clinical practice. With increasing evidence underscoring the essential role of exosomes in facilitating intercellular and cell-microenvironment communication, they have emerged as an encouraging therapeutic strategy to promote bone repair due to their non-immunogenicity, diverse sources, and potent bioactivity. In this study, we characterized a distinctive population of Krt14+Ctsk+ cells from the orbital mucoperiosteum. In vitro experiments confirmed that exosomes from Krt14+Ctsk+ cells dramatically boosted the capacities of human umbilical vein endothelial cells (HUVECs) to proliferate, migrate, and induce angiogenesis. Additionally, the exosomes notably elevated the expression of osteogenic markers, thereby indicating their potential to augment osteogenic capabilities. Furthermore, in vivo experiments utilizing a rat calvarial defect model verified that exosome-loaded sodium alginate (SA) hydrogels accelerated local vascularized bone regeneration within the defective regions. Collectively, these findings suggest that exosomes secreted by Krt14+Ctsk+ cells offer an innovative method to accelerate bone repair via coupling enhanced osteogenesis and angiogenesis, highlighting the therapeutic potential in bone repair.

Identification of the BZR Family in Garlic (Allium sativum L.) and Verification of the AsBZR11 under Salt Stress.

Brassinazole-Resistant (BZR) is an important transcription factor (TF) in the brassinosteroid (BR) signaling pathway, which plays a crucial role in plant growth, development and stress resistance. In this study, we performed a genome-wide analysis of BZRs in garlic (Allium sativum L.) and identified a total of 11 members of the AsBZR gene family. By comparing the expression patterns of AsBZR genes under salt stress, the candidate gene AsBZR11 with salt tolerance function was identified. Subcellular localization results showed that AsBZR11 was localized in the nucleus. The salt tolerance of overexpression lines improved, and the germination rate and root length of overexpression lines increased as compared with wild type. The content of reactive oxygen species (ROS) decreased, and the activity of antioxidant enzymes increased in AsBZR11-OE, suggesting that AsBZR11 has the function of improving plant salt tolerance. Our results enriched the knowledge of plant BZR family and laid a foundation for the molecular mechanism of salt tolerance of garlic, which will provide a theoretical basis for the subsequent creation of salt-tolerant germplasm resources.

Visual Detection of Dopamine with CdS/ZnS Quantum Dots Bearing by ZIF-8 and Nanofiber Membranes.

Dopamine (DA) is a widely present, calcium cholinergic neurotransmitter in the body, playing important roles in the central nervous system and cardiovascular system. Developing fast and sensitive DA detection methods is of great significance. Fluorescence-based methods have attracted much attention due to their advantages of easy operation, a fast response speed, and high sensitivity. This study prepared hydrophilic and high-performance CdS/ZnS quantum dots (QDs) for DA detection. The waterborne CdS/ZnS QDs were synthesized in one step using the amphiphilic polymer PEI-g-C14, obtained by grafting tetradecane (C14) to polyethyleneimine (PEI), as a template. The polyacrylonitrile nanofiber membrane (PAN-NFM) was prepared by electrospinning (e-spinning), and a metal organic frame (ZIF-8) was deposited in situ on the surface of the PAN-NFM. The CdS/ZnS QDs were loaded onto this substrate (ZIF-8@PAN-NFM). The results showed that after the deposition of ZIF-8, the water contact angle of the hydrophobic PAN-NFM decreased to within 40°. The nanofiber membrane loaded with QDs also exhibited significant changes in fluorescence in the presence of DA at different concentrations, which could be applied as a fast detection method of DA with high sensitivity. Meanwhile, the fluorescence on this PAN-NFM could be visually observed as it transitioned from a blue-green color to colorless, making it suitable for the real-time detection of DA.

Smooth post-labial chaetae in Homidia (Collembola, Entomobryidae) and the description of four new species from China with the aid of DNA barcoding.

Four new species of Homidia are described from the Guangxi Zhuang Autonomous Region, China. Homidialongiantenna sp. nov. is characterised by its long antenna and slightly expanded post-labial chaetae; H.guangxiensis sp. nov. by the presence of smooth chaetae on the post-labium and posterior face of the ventral tube; H.huapingensis sp. nov. by the presence of smooth post-labial chaetae and pointed tenent hairs; and H.oligoseta sp. nov. by the pointed tenent hairs and fewer macrochaetae on Abdomen IV. Additions to the original description of Homidiaacutus Jing & Ma, 2022 are also provided.

CREBRF regulates apoptosis and estradiol via ISG15/ISGylation in pig granulosa cells.

Granulosa cells play a crucial role in the reproductive processes of female animals, as their proliferation, apoptosis, and hormonal secretion are vital for follicular development and ovulation. Although the role and mechanisms of CREBRF in the reproductive system have been partly reported, its functions in ovarian granulosa cells have not been fully explored. In this study, the results indicated that the expression of CREBRF in the ovaries at 30 days after birth was significantly higher than that during puberty and sexual maturity. Studies on the function of CREBRF found that CREBRF could enhance the synthesis of estradiol and had no effect on progesterone synthesis in pig granulosa cells. At the same time, CREBRF could suppress apoptosis through the Bax/caspase3/caspase9 pathway and modulation of ISG15/ISGylation in pig granulosa cells. During this process, the expression of many genes changed in granulosa cells. Several genes (CMPK2, MX1, MX2, ZBP1, PML, CHAC1, and BAX) which were promoted apoptosis, were upregulated after CREBRF knockdown with siRNA. ISG15-protein conjugation genes (HERC5, UBA7, UBE2L6, ISG15) were also were upregulated. On the contrary, the expression of anti-apoptotic (RFK, SNAP23) genes decreased. In conclusion, CREBRF could enhance the synthesis of estradiol and acted as anti-apoptosis role in pig granulosa cells. This discovery can provide novel insights for further elucidating the molecular mechanisms of granulosa cells in the ovary and potentially identifies CREBRF as a molecular target for improving fertility.

Sevoflurane Activates PI3K/AKT Signaling Pathway by Upregulating GDF11 Expression to Attenuate Ischemia/Reperfusion Injury in Cardiomyocytes.

BACKGROUND: Myocardial ischemia/reperfusion (I/R) injury stands as a primary contributor to ischemic heart disease. Sevoflurane (SEVO), a commonly used inhalation anesthetic, has been shown to exert a direct protective effect on ischemic heart injury. However, the specific mechanism by which it exerts the protective effect remains unclear. This study was designed to investigate the role of SEVO in myocardial I/R injury and its potential molecular mechanisms. METHODS: Blood samples were collected from patients with acute myocardial infarction (AMI) (n = 20) and healthy volunteers (n = 20). The human cardiomyocytes AC16 models of I/R injury were induced by hypoxia/reoxygenation. The mRNA expression levels of growth differentiation factor 11 (GDF11) in the cells and blood were determined by reverse transcription quantitative real-time PCR (RT-qPCR). The cell proliferation was detected by Cell Counting Kit-8 (CCK-8). Enzyme-Linked Immunosorbent Assay (ELISA) was utilized to detect the levels of inflammatory factors interleukin (IL)-8, IL-1ß and IL-6 in the cells. And biochemical assay kits were applied for the measurement of the activity of lactate dehydrogenase (LDH) and superoxide dismutase (SOD) as well as the malondialdehyde (MDA) level in the cells. Moreover, western blot was employed to evaluate the levels of the p-serine-threonine protein kinase (AKT), AKT, and phosphatidylinositol 3-kinase (PI3K), protein expression in the cells. RESULTS: The GDF11 expression was decreased in the blood of AMI patients and cardiomyocytes induced by I/R (p < 0.01). Besides, 1% SEVO was presented to promote cardiomyocyte proliferation, inhibit apoptosis, oxidative stress and inflammation, and activate the PI3K/AKT signaling pathway through up-regulation of GDF11 expression (p < 0.01). CONCLUSION: SEVO promotes proliferation and inhibits inflammatory response, apoptosis, and oxidative stress of I/R-treated cardiomyocytes by elevating GDF11 expression, thereby reducing myocardial I/R injury. Notably, the mechanism underlying the alleviation of the I/R injury may involve the activation of PI3K/AKT signaling pathway.

Genetic insights into the causal linkage between systemic inflammatory regulators and frailty.

OBJECTIVES: Previous studies have suggested the associations between systemic inflammation and the risk of frailty, but causal relationships between them remain not well established. We conducted a bi-directional Mendelian randomization (MR) analysis to investigate the causal links between systemic inflammatory regulators and frailty. METHODS: Genetic variants associated with systemic inflammatory regulators were obtained from a comprehensive genetic study on 41 circulating cytokines, such as interleukin-4 (IL-4), eotaxin, and macrophage inflammatory protein-1ß (MIP1ß). We integrated summary-level data on frailty from two independent genetic studies on frailty index (FI) and Fried frailty score (FFS). The inverse-variance weighted method was used to assess the causal estimate. Sensitivity and heterogeneity analysis was performed to evaluate the stability of the estimates. The false discovery rate (FDR) method was used for P value adjustment of multiple comparisons. RESULTS: Genetically elevated levels of MIP1ß and decreased levels of eotaxin were suggestively associated with increased FI (MIP1ß: ß = 0.016, Praw = 0.006, PFDR = 0.083; eotaxin: ß = -0.030, Praw = 0.007, PFDR = 0.083) and FFS (MIP1ß: ß = 0.008, Praw = 0.027, PFDR = 0.247; eotaxin: ß = -0.015, Praw = 0.014, PFDR = 0.247). In contrast, genetically predicted FI was suggestively associated with decreased levels of IL-4 (ß = -0.395, Praw = 0.040, PFDR = 0.638) and platelet-derived growth factor BB (PDGF-BB, ß = -0.385, Praw = 0.047, PFDR = 0.638) and increased levels of stem cell factor (SCF, ß = 0.527, Praw = 0.005, PFDR = 0.204). Similar results were obtained from different sensitivity analysis. CONCLUSIONS: The present study demonstrates that increased MIP-1ß levels and decreased eotaxin levels might lead to a higher risk of frailty, whereas frailty might reduce the levels of IL-4 and PDGF-BB and increase the levels of SCF.

Kinetic Analysis and Metabolism of Poly(Adenosine Diphosphate-Ribose) Polymerase-1-Targeted 18F-Fluorthanatrace PET in Breast Cancer.

The poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have demonstrated efficacy in ovarian, breast, and prostate cancers, but current biomarkers do not consistently predict clinical benefit. 18F-fluorthanatrace (18F-FTT) is an analog to rucaparib, a clinically approved PARPi, and is a candidate biomarker for PARPi response. This study intends to characterize 18F-FTT pharmacokinetics in breast cancer and optimize image timing for clinical trials. A secondary aim is to determine whether 18F-FTT uptake in breast cancer correlates with matched frozen surgical specimens as a reference standard for PARP-1 protein. Methods: Thirty prospectively enrolled women with a new diagnosis of breast cancer were injected with 18F-FTT and imaged dynamically 0-60 min after injection over the chest, with an optional static scan over multiple bed positions starting around 70 min. Kinetic analysis of lesion uptake was performed using blood-pool activity with population radiometabolite corrections. Normal breast and normal muscle reference tissue models were compared with PARP-1 protein expression in 10 patients with available tissue. Plasma radiometabolite concentrations and uptake in tumor and normal muscle were investigated in mouse xenografts. Results: Pharmacokinetics of 18F-FTT were well fit by Logan plot reference region models of reversible binding. However, fits of 2-tissue compartment models assuming negligible metabolite uptake were unstable. Rapid metabolism of 18F-FTT was demonstrated in mice, and similar uptake of radiometabolites was found in tumor xenografts and normal muscle. Tumor 18F-FTT distribution volume ratios relative to normal muscle reference tissue correlated with tissue PARP-1 expression (P < 0.02, n = 10). The tumor-to-normal muscle ratio from a 5-min frame between 50 and 60 min after injection, a potential static scan protocol, closely corresponded to the distribution volume ratio relative to normal muscle and correlated to PARP-1 expression (P < 0.02, n = 10). Conclusion: This study of PARPi analog 18F-FTT showed that uptake kinetics in vivo corresponded to expression of PARP-1 and that 18F-FTT quantitation is influenced by radiometabolites that are increasingly present late after injection. Radiometabolites can be controlled by using optimal image acquisition timing or normal muscle reference tissue modeling in dynamic imaging or a tumor-to-normal muscle ratio. Optimal image timing for tumor-to-normal muscle quantification in humans appears to be between 50 and 60 min after injection. Therefore, a clinically practical static imaging protocol commencing 45-55 min after injection may sufficiently balance 18F-FTT uptake with background clearance and radiometabolite interference for quantitative interpretation of PARP-1 expression in vivo.

The Synergistic Effect of Calcained Coal-Series Kaolinite and Limestone on the Hydration of Portland Cement.

Limestone calcined clay cement (LC3) presents a promising alternative material due to its reduced CO2 emissions and superior mechanical properties compared to traditional Portland cement (PC). This study investigates the synergistic effect of calcined coal-series kaolinite (CCK) and limestone (LS) on the hydration behavior of cement, specifically focusing on varying mass ratios. The combination of CCK and LS promotes the formation of strätlingite and carboaluminates, which enhances early-age strength development. Additionally, the inclusion of CCK facilitates the formation of carboaluminates during later stages of hydration. After 56 days of hydration, the content of carboaluminates is over 10%wt. This stimulation of secondary hydration products significantly refines the evolution of pore structure, with the harmful large pores gradually transformed into harmless medium pores and gel pores, leading to marked improvements in compressive strength from 7 to 28 days. Replacing 45% PC with CCK and LS at mass ratio of 7 to 2, the compressive strength of blends reaches 47.2 MPa at 28 days. Overall, the synergistic interaction between CCK and LS presents unique opportunities to minimize the CO2 footprint of the cement industry without compromising early and long-term performance.

Rapid and sensitive detection of methicillin-resistant Staphylococcus aureus through the RPA-PfAgo system.

Introduction: Both the incidence and mortality rates associated with methicillin-resistant Staphylococcus aureus (MRSA) have progressively increased worldwide. A nucleic acid testing system was developed in response, enabling swift and precise detection of Staphylococcus aureus (S. aureus) and its MRSA infection status. This facilitates improved prevention and control of MRSA infections. Methods: In this work, we introduce a novel assay platform developed by integrating Pyrococcus furiosus Argonaute (PfAgo) with recombinase polymerase amplification (RPA), which was designed for the simultaneous detection of the nuc and mecA genes in MRSA. Results: This innovative approach enables visual MRSA detection within 55 mins, boasting a detection limit of 102 copies/µL. Characterized by its high specificity, the platform accurately identifies MRSA infections without cross-reactivity to other clinical pathogens, highlighting its unique capability for S. aureus infection diagnostics amidst bacterial diversity. Validation of this method was performed on 40 clinical isolates, demonstrating a 95.0% accuracy rate in comparison to the established Vitek2-COMPACT system. Discussion: The RPA-PfAgo platform has emerged as a superior diagnostic tool, offering enhanced sensitivity, specificity, and identification efficacy for MRSA detection. Our findings underscore the potential of this platform to significantly improve the diagnosis and management of MRSA infection.

Phosphine-Mediated Reductive Insertion of α-Keto Esters and Isatins into Phthalic Anhydride Derivatives.

Herein, we report an unprecedented P(NMe2)3-mediated reductive insertion of 1,2-dicarbonyl compounds including α-keto esters and isatins into phthalic anhydride-derived alkenes and phthalic anhydrides, which furnishes the corresponding isochroman-1-ones and isochroman-1,4-diones, respectively, in moderate to excellent yields with high chemo- and regioselectivity. Furthermore, the asymmetric version of the ring expansion reaction could be realized by using a chiral auxiliary strategy. Mechanistically, the nucleophilic attack of the Kukhtin-Ramirez adduct, generated from P(NMe2)3 and 1,2-dicarbonyl compound, to the anhydride derivative, followed by a cascade ring-opening and ring-closure process, affords the ring expansion product. The reaction represents a novel metal-free carbon insertion ring expansion of aliphatic rings and also the first [1 + 5] annulation involving the Kukhtin-Ramirez adducts.

A nomogram predicting venous thromboembolism risk in primary liver cancer patients.

Cancer frequently causes venous thromboembolism (VTE), a leading cause of cancer-related mortality. Primary liver cancer (PLC) is prevalent and highly fatal, with an increased risk of venous thrombotic complications. Thus, we aimed to develop a nomogram model for predicting VTE in patients with PLC. We retrospectively analyzed 1,565 patients diagnosed with PLC between January 2018 and December 2022 at Chongqing University Cancer Hospital. Univariate logistic analysis and multivariate logistic regression identified eight significant risk factors: activated partial thromboplastin time (APTT) ≤ 32.20 s, D-dimer > 1.44 mg/L, lymphocyte count (LYM) ≤ 1.18 × 109/L, monocyte count (MONO) > 0.42 × 109/L, transarterial chemoembolization (TACE), surgical intervention, immunotherapy, and ß2-microglobulin. The nomogram model exhibited strong discriminatory power, with C indices of 0.753 and 0.710 for the training and validation cohorts, respectively. The calibration curve showed a strong correlation between predicted and actual probabilities. Additionally, decision curve analysis (DCA) and clinical impact curves (CIC) confirmed the model's clinical utility. This nomogram facilitates the identification of high-risk PLC patients, allowing for timely preventive and therapeutic interventions to reduce the risk of thrombosis.

Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk.

BACKGROUND: Persistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides. METHODS: In a phase 3 trial, we randomly assigned 75 patients with persistent chylomicronemia (with or without a genetic diagnosis) to receive subcutaneous plozasiran (25 mg or 50 mg) or placebo every 3 months for 12 months. The primary end point was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary end points were the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, and the incidence of acute pancreatitis. RESULTS: At baseline, the median triglyceride level was 2044 mg per deciliter. At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03). The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline. CONCLUSIONS: Patients with persistent chylomicronemia who received plozasiran had significantly lower triglyceride levels and a lower incidence of pancreatitis than those who received placebo. (Funded by Arrowhead Pharmaceuticals; PALISADE ClinicalTrials.gov number, NCT05089084.).

Effects of Compound Probiotics on Pharmacokinetics of Cytochrome 450 Probe Drugs in Rats.

Compound probiotics have been widely used and commonly coadministered with other drugs for treating various chronic illnesses, yet their effects on drug pharmacokinetics remain underexplored. This study elucidated the impact of VSL#3 on the metabolism of probe drugs for cytochrome P450 enzymes (P450s), specifically omeprazole, tolbutamide, midazolam, metoprolol, phenacetin, and chlorzoxazone. Male Wistar rats were administered drinking water containing VSL#3 or not for 14 days and then intragastrically administered a P450 probe cocktail; this was done to investigate the host P450's metabolic phenotype. Stool, liver/jejunum, and serum samples were collected for 16S ribosomal RNA sequencing, RNA sequencing, and bile acid profiling. The results indicated significant differences in both α and ß diversity of intestinal microbial composition between the probiotic and vehicle groups in rats. In the probiotic group, the bioavailability of omeprazole increased by 269.9%, whereas those of tolbutamide and chlorpropamide decreased by 28.1% and 27.4%, respectively. The liver and jejunum exhibited 1417 and 4004 differentially expressed genes, respectively, between the two groups. In the probiotic group, most of P450 genes were upregulated in the liver but downregulated in the jejunum. The expression of genes encoding metabolic enzymes and drug transporters also changed. The serum-conjugated bile acids in the probiotic group were significantly reduced. Shorter duodenal villi and longer ileal villi were found in the probiotic group. In summary, VSL#3 administration altered the gut microbiota, host drug-processing gene expression, and intestinal structure in rats, which could be reasons for pharmacokinetic changes. SIGNIFICANCE STATEMENT: This study focused on the effects of the probiotic VSL#3 on the pharmacokinetic profile of cytochrome P450 probe drugs and the expression of host drug metabolism genes. Compared with previous studies, the present study provides a comprehensive explanation for the host drug metabolism profile modified by probiotics, combined here with the bile acid profile and histopathological analysis.

Composted maize straw under fungi inoculation reduces soil N2O emissions and mitigates the microbial N limitation in a wheat upland.

Enhancement of microbial assimilation of inorganic nitrogen (N) by straw addition is believed to be an effective pathway to improve farmland N cycling. However, the effectiveness of differently pretreated straws on soil N2O emissions and soil N-acquiring enzyme activities remains unclear. In this study, a pot experiment with four treatments (I, no addition, CK; II, respective addition of maize straw, S; III, composted maize straw under no fungi inoculation, SC; and IV, composted maize straw under fungi inoculation, SCPA) at the same quantity of carbon (C) input was conducted under the same amount of inorganic N fertilization. Results showed that the seasonal cumulative N2O emissions following the SCPA treatment were the lowest at 4.03 kg N ha-1, representing a significant reduction of 19 % compared with the CK treatment. The S and SC treatments had no significant effects on N2O emissions. The decrease of soil N2O emissions following the SCPA treatment was mainly attributed to the increase of microbial N assimilation and the increased abundance of functional genes related to N2O reductase. The SCPA treatment significantly decreased soil alkaline phosphatase (ALP) activity and increased leucine aminopeptidase (LAP) activity at the basal fertilization, while increased soil ALP and LAP activity, decreased soil N-Acetyl-ß-D-Glucosidase (NAG) activity at harvest. Compared with the CK treatment, the S, SC, and SCPA treatment significantly increased soil ß-glucosidase (ß-GC) activity at harvest. The decrease in the (NAG+LAP)/ALP ratio following the SCPA treatment indicated that the composted maize straw under fungi inoculation alleviated microbial N limitation at harvest. Moreover, PICRUSt analysis also suggested that the SCPA treatment increased the abundance of bacterial genes associated with N assimilation and N2O reduction, whereas the S and SC treatment did not significantly affect the abundance of N2O reduction genes compared with the CK treatment. Our results suggest that the composted maize straw under fungi inoculation would reduce the risk of N2O emissions and effectively mitigate the microbial N limitation in dryland wheat system.

Overexpression of long noncoding RNA DUXAP8 inhibits ER-phagy through activating AKT/mTOR signaling and contributes to preeclampsia.

Preeclampsia (PE) is a life-threatening pregnancy-specific complication with controversial mechanisms and no effective treatment except delivery is available. Currently, increasing researchers suggested that PE shares pathophysiologic features with protein misfolding/aggregation disorders, such as Alzheimer disease (AD). Evidences have proposed defective autophagy as a potential source of protein aggregation in PE. Endoplasmic reticulum-selective autophagy (ER-phagy) plays a critical role in clearing misfolded proteins and maintaining ER homeostasis. However, its roles in the molecular pathology of PE remain unclear. We found that lncRNA DUXAP8 was upregulated in preeclamptic placentae and significantly correlated with clinical indicators. DUXAP8 specifically binds to PCBP2 and inhibits its ubiquitination-mediated degradation, and decreased levels of PCBP2 reversed the activation effect of DUXAP8 overexpression on AKT/mTOR signaling pathway. Function experiments showed that DUXAP8 overexpression inhibited trophoblastic proliferation, migration, and invasion of HTR-8/SVneo and JAR cells. Moreover, pathological accumulation of swollen and lytic ER (endoplasmic reticulum) was observed in DUXAP8-overexpressed HTR8/SVneo cells and PE placental villus trophoblast cells, which suggesting that ER clearance ability is impaired. Further studies found that DUXAP8 overexpression impaired ER-phagy and caused protein aggregation medicated by reduced FAM134B and LC3II expression (key proteins involved in ER-phagy) via activating AKT/mTOR signaling pathway. The increased level of FAM134B significantly reversed the inhibitory effect of DUXAP8 overexpression on the proliferation, migration, and invasion of trophoblasts. In vivo, DUXAP8 overexpression through tail vein injection of adenovirus induced PE-like phenotypes in pregnant rats accompanied with activated AKT/mTOR signaling, decreased expression of FAM134B and LC3-II proteins and increased protein aggregation in placental tissues. Our study reveals the important role of lncRNA DUXAP8 in regulating trophoblast biological behaviors through FAM134B-mediated ER-phagy, providing a new theoretical basis for understanding the pathogenesis of PE.

Efficacy and safety of levetiracetam for migraine prophylaxis in children: a systematic review and meta-analysis.

Background: Levetiracetam (LEV), an antiepileptic drug, has been effective in adult migraine prevention but lacks extensive research in children. This study evaluates LEV's efficacy and safety for pediatric migraine prophylaxis. Methods: We reviewed randomized controlled trials (RCTs) and non-RCTs in major databases through 8 January 2024, focusing on four efficacy endpoints and adverse drug reactions (ADRs). Data synthesis involved pooled relative risks or odds ratios for dichotomous outcomes and mean differences for continuous outcomes, using fixed- or random-effects models as appropriate. Results: Eight studies with 190 participants showed that after taking LEV, the mean headache frequency decreased 5.19 per month (MD: -5.19, 95% CI: -7.11 to -3.27, p < 0.00001) and improved headache-free rates to 28% (95% CI: 0.17-0.41). More than 83% experienced a >50% reduction in monthly headache frequency. The migraine disability score decreased by 33.51 points (MD: -33.51, 95% CI: -38.46 to -28.55, p < 0.00001). ADR incidence did not significantly differ between LEV and control groups (RR: 1.06, 95% CI: 0.39 to 2.85, p = 0.91), with an overall ADR rate of 18% (95% CI: 0.13-0.24). The most common ADR was irritability (12%), leading to treatment discontinuation in 13% of cases (95% CI: 0.05-0.30). Conclusion: LEV has shown good efficacy in preventing pediatric migraines. However, its safety requires further confirmation through more extensive and well-designed RCTs. Systematic Review Registration: Identifier PROSPERO CRD42024497643.

Combating coal-burning-borne endemic arsenism in Shaanxi Province, Northwest China: The impact of high-arsenic coal ban, improved cook-stoves, and health education.

To eliminate the epidemic of coal-burning-borne endemic arsenism (CBBA), our study organized and implemented comprehensive measures including high-arsenic coal ban, improved cook-stoves, and health education. We also aimed to promote the application value of these measures in preventing and controlling CBBA to the world. From 2004 to 2005, through a stratified random sampling method, we selected 58,256 individuals to investigate the prevalence of CBBA and the arsenic levels in 1287 environmental and biological specimens. The prevalence of CBBA was 19.26 % and significantly associated with the arsenic levels in coal, pepper, corn and hair, which were at or exceeded national upper limits. To timely prevent and control the disease, the comprehensive measures have been implemented since 2005 to present. Comparison and correlation analyses were utilized to evaluate the effectiveness of these measures in reducing the prevalence of CBBA. According to statistics, 73 high-arsenic coal mines were banned and over 99 % households in endemic areas accepted stove improvements and diversified health education. Monitoring studies during 2010-2019 has confirmed that these measures led to a decrease in urine arsenic levels among endemic residents, and they developed novel dietary practices, such as properly drying, storage, and washing of food. Additionally, the awareness rate of CBBA increased from less than 70 % to over 95 %. Finally, the prevalence of CBBA has decreased to 0.153 % investigated by a census involving 2.076 million endemic residents in 2019. In summary, CBBA in northwest China has been successfully controlled through banning on high-arsenic coal, introducing improved cook-stoves, and providing health education.

Cxcr4a regulates heart progenitor development and cardiac rhythm in zebrafish.

Cxcr4a is involved in multiple organ development including coronary vasculature formation and heart left-right (LR) patterning, whether it is involved in heart progenitor determination and cardiac rhythm regulation is not addressed. Here we showed that in cxcr4a mutants, from 2 days post fertilization (dpf) to 4dpf the embryos transiently displayed pericardial edema and increased cardiac rhythm. While from 5dpf, the heart phenotype disappeared. Detailed analysis demonstrated that, at 36hpf and 48hpf, even though there was no distinct difference in the heart size between cxcr4a mutants and controls, the expression of myl7 was decreased. Further data showed that, the heart progenitors were decreased at 18SS(Somite Stage). Mechanically, RNA-seq, RT-qPCR and in situ experiments showed that the retinoic acid (RA) signaling was upregulated, and the up-regulation of RA signaling may mediate the role of cxcr4a in regulating heart progenitor development. In addition, we also identified that low dose of RA treatment accelerated the cardiac rhythm, being similar to that in cxcr4a mutants. Decreasing RA signaling partially restored the rapid cardiac rhythm in cxcr4a mutants, implying the possibility that RA signaling partially mediates the role of cxcr4a in regulating cardiac rhythm. In conclusion, our study identified cxcr4a simultaneously regulates heart progenitor determination and cardiac rhythm.