Vinorelbine administration impedes the timely progression of meiotic maturation and induces aneuploidy in mouse oocytes.

Vinorelbine is a commonly used drug to treat various malignancies, such as breast cancer, non-small cell lung cancer, and metastatic pleural mesothelioma. Its side effects include severe neutropenia, local phlebitis, gastrointestinal reactions, and neurotoxicity. In view of the scarcity of research on vinorelbine's reproductive toxicity, this study evaluated the impact of vinorelbine ditartrate, a commonly used form of vinorelbine, on oocyte maturation in vitro. Our investigation revealed that vinorelbine ditartrate had no effect on oocyte meiotic resumption. However, it did reduce the rate of first polar body extrusion, suggesting that it could significantly impede the meiotic maturation of oocytes. Vinorelbine ditartrate exposure was found to disturb the regular spindle assembly and chromosome alignment, leading to the continuous activation of the spindle assembly checkpoint (SAC) and a delayed activation of the anaphase-promoting complex/cyclosome (APC/C), ultimately causing aneuploidy in oocytes. Consequently, the administration of vinorelbine is likely to result in oocyte aneuploidy, which can be helpful in providing a drug reference and fertility guidance in a clinical context.

Enzyme and Pathway Engineering for Improved Betanin Production in Saccharomyces cerevisiae.

Betanin is a water-soluble red-violet pigment belonging to the betacyanins family. It has become more and more attractive for its natural food colorant properties and health benefits. However, the commercial production of betanin, typically extracted from red beetroot, faces economic and sustainability challenges. Microbial heterologous production therefore offers a promising alternative. Here, we performed combinatorial engineering of plant P450 enzymes and precursor metabolisms to improve the de novo production of betanin in Saccharomyces cerevisiae. Semirational design by computer simulation and molecular docking was used to improve the catalytic activity of CYP76AD. Alanine substitution and site-directed saturation mutants were screened, with a combination mutant showing an approximately 7-fold increase in betanin titer compared to the wild type. Subsequently, betanin production was improved by enhancing the l-tyrosine pathway flux and UDP-glucose supply. Finally, after optimization of the fermentation process, the engineered strain BEW10 produced 134.1 mg/L of betanin from sucrose, achieving the highest reported titer of betanin in a shake flask by microbes. This work shows the P450 enzyme and metabolic engineering strategies for the efficient microbial production of natural complex products.

GARNL3 identified as a crucial target for overcoming temozolomide resistance in EGFRvIII-positive glioblastoma.

OBJECT: Amplification of the epidermal growth factor receptor (EGFR) and its active mutant type III (EGFRvIII), frequently occurr in glioblastoma (GBM), contributing to chemotherapy and radiation resistance in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in EGFRvIII GBM could offer valuable insights for cancer treatment. METHODS: To elucidate the molecular mechanisms underlying EGFRvIII-mediated resistance to TMZ in GBM, we conducted a comprehensive analysis using Gene Expression Omnibus and The cancer genome atlas (TCGA) databases. Initially, we identified common significantly differentially expressed genes (DEGs) and prioritized those correlating significantly with patient prognosis as potential downstream targets of EGFRvIII and candidates for drug resistance. Additionally, we analyzed transcription factor expression changes and their correlation with candidate genes to elucidate transcriptional regulatory mechanisms. Using estimate method and databases such as Tumor IMmune Estimation Resource (TIMER) and CellMarker, we assessed immune cell infiltration in TMZ-resistant GBM and its relationship with candidate gene expression. In this study, we examined the expression differences of candidate genes in GBM cell lines following EGFRvIII intervention and in TMZ-resistant GBM cell lines. This preliminary investigation aimed to verify the regulatory impact of EGFRvIII on candidate targets and its potential involvement in TMZ resistance in GBM. RESULTS: Notably, GTPase Activating Rap/RanGAP Domain Like 3 (GARNL3) emerged as a key DEG associated with TMZ resistance and poor prognosis, with reduced expression correlating with altered immune cell profiles. Transcription factor analysis suggested Epiregulin (EREG) as a putative upstream regulator of GARNL3, linking it to EGFRvIII-mediated TMZ resistance. In vitro experiments confirmed EGFRvIII-mediated downregulation of GARNL3 and decreased TMZ sensitivity in GBM cell lines, further supported by reduced GARNL3 levels in TMZ-resistant GBM cells. CONCLUSION: GARNL3 downregulation in EGFRvIII-positive and TMZ-resistant GBM implicates its role in TMZ resistance, suggesting modulation of EREG/GARNL3 signaling as a potential therapeutic strategy.

Asynchronous Involvement of VLPFC and DLPFC During Negative Emotion Processing: An Online Transcranial Magnetic Stimulation Study.

The ventrolateral prefrontal cortex (VLPFC) and dorsolateral prefrontal cortex (DLPFC) have been found to play important roles in negative emotion processing. However, the specific time window of their involvement remains unknown. This study addressed this issue in three experiments using single-pulse transcranial magnetic stimulation (TMS). We found that TMS applied over the VLPFC at 400 ms after negative emotional exposure significantly enhanced negative feelings compared to the vertex condition. Furthermore, TMS applied over the DLPFC at both 0 ms and 600 ms after negative emotional exposure also resulted in deteriorated negative feelings. These findings provide potential evidence for the VLPFC-dependent semantic processing (∼400 ms) and the DLPFC-dependent attentional and cognitive control (∼0/600 ms) in negative emotion processing. The asynchronous involvement of these frontal cortices not only deepens our understanding of the neural mechanisms underlying negative emotion processing but also provides valuable temporal parameters for neurostimulation therapy targeting patients with mood disorders.

Spray-Coated MoO3 Hole Transport Layer for Inverted Organic Photovoltaics.

This study focuses on the hole transport layer of molybdenum trioxide (MoO3) for inverted bulk heterojunction (BHJ) organic photovoltaics (OPVs), which were fabricated using a combination of a spray coating and low-temperature annealing process as an alternative to the thermal evaporation process. To achieve a good coating quality of the sprayed film, the solvent used for solution-processed MoO3 (S-MoO3) should be well prepared. Isopropanol (IPA) is added to the as-prepared S-MoO3 solution to control its concentration. MoO3 solutions at concentrations of 5 mg/mL and 1 mg/mL were used for the spray coating process. The power conversion efficiency (PCE) depends on the concentration of the MoO3 solution and the spray coating process parameters of the MoO3 film, such as flow flux, spray cycles, and film thickness. The results of devices fabricated from solution-processed MoO3 with various spray fluxes show a lower PCE than that based on thermally evaporated MoO3 (T-MoO3) due to a limiting FF, which gradually increases with decreasing spray cycles. The highest PCE of 2.8% can be achieved with a 1 mg/mL concentration of MoO3 solution at the sprayed flux of 0.2 mL/min sprayed for one cycle. Additionally, S-MoO3 demonstrates excellent stability. Even without any encapsulation, OPVs can retain 90% of their initial PCE after 1300 h in a nitrogen-filled glove box and under ambient air conditions. The stability of OPVs without any encapsulation still has 90% of its initial PCE after 1300 h in a nitrogen-filled glove box and under air conditions. The results represent an evaluation of the feasibility of solution-processed HTL, which could be employed for a large-area mass production method.

Causal relationship between the immune cells and ankylosing spondylitis: univariable, bidirectional, and multivariable Mendelian randomization.

Background: Ankylosing spondylitis (AS) is an autoimmune disease that affects millions of individuals. Immune cells have been recognized as having a crucial role in the pathogenesis of AS. However, their relationship has not been fully explored. Methods: We chose to employ Mendelian randomization (MR) to investigate the potential correlation between immune cells and AS. We sourced the data on immune cells from the latest genome-wide association studies (GWASs). We obtained data on AS from the FinnGen consortium. Our comprehensive univariable MR analysis covered 731 immune cells to explore its potential causal relationship with AS. The primary analysis method was inverse-variance weighted (IVW). Additionally, we used Cochran's Q test and the MR-Egger intercept test to assess the presence of pleiotropy and heterogeneity. We examined whether our results could be influenced by individual single-nucleotide polymorphisms (SNPs) using the leave-one-out test. We conducted a bidirectional MR to investigate the reverse relationship. We also applied multivariable MR to decrease the potential influence between the immune cells. Results: Overall, our univariable MR analysis revealed eight immune cells associated with AS. Among these, four immune cells contributed to an increased risk of AS, while four immune cells were identified as protective factors for AS. However, the Bonferroni test confirmed only one risk factor and one protective factor with a significance level of p < 6.84E-05. CD8 on effector memory CD8+ T cell could increase the risk of AS (p: 1.2302E-05, OR: 2.9871, 95%CI: 1.8289-4.8786). HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 1.2301E-06, OR: 0.5446, 95%CI: 0.4260-0.6962). We also identified a bidirectional relationship between CD4 on CD39+ activated CD4 regulatory T cells and AS utilizing the bidirectional MR. To address potential confounding among immune cells, we employed multivariable MR analysis, which revealed that only one immune cell had an independent effect on AS. HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 2.113E-06, OR: 0.0.5423, 95%CI: 0.4210-0.6983). Our findings were consistently stable and reliable. Conclusions: Our findings indicated a potential link between immune cells and AS, which could provide a new idea for future research. Nevertheless, the specific underlying mechanisms require further exploration.

Enhancing ventrolateral prefrontal cortex activation mitigates social pain and modifies subsequent social attitudes: Insights from TMS and fMRI.

Social pain, a multifaceted emotional response triggered by interpersonal rejection or criticism, profoundly impacts mental well-being and social interactions. While prior research has implicated the right ventrolateral prefrontal cortex (rVLPFC) in mitigating social pain, the precise neural mechanisms and downstream effects on subsequent social attitudes remain elusive. This study employed transcranial magnetic stimulation (TMS) integrated with fMRI recordings during a social pain task to elucidate these aspects. Eighty participants underwent either active TMS targeting the rVLPFC (n = 41) or control stimulation at the vertex (n = 39). Our results revealed that TMS-induced rVLPFC facilitation significantly reduced self-reported social pain, confirming the causal role of the rVLPFC in social pain relief. Functional connectivity analyses demonstrated enhanced interactions between the rVLPFC and the dorsolateral prefrontal cortex, emphasizing the collaborative engagement of prefrontal regions in emotion regulation. Significantly, we observed that negative social feedback led to negative social attitudes, whereas rVLPFC activation countered this detrimental effect, showcasing the potential of the rVLPFC as a protective buffer against adverse social interactions. Moreover, our study uncovered the impact role of the hippocampus in subsequent social attitudes, a relationship particularly pronounced during excitatory TMS over the rVLPFC. These findings offer promising avenues for improving mental health within the intricate dynamics of social interactions. By advancing our comprehension of the neural mechanisms underlying social pain relief, this research introduces novel intervention strategies for individuals grappling with social distress. Empowering individuals to modulate rVLPFC activation may facilitate reshaping social attitudes and successful reintegration into communal life.

Helicobacter pylori infection induces gastric cancer cell malignancy by targeting HOXA-AS2/miR-509-3p/MMD2 axis.

BACKGROUND: Helicobacter pylori (Hp) infection is considered to be the strongest risk factor for gastric cancer (GC). Long non-coding RNA HOXA cluster antisense RNA 2 (HOXA-AS2) has been indicated to be significantly related to Hp infection in GC patients. OBJECTIVE: To investigate the detailed role and molecular mechanism of lncRNA HOXA-AS2 in Hp-induced GC. METHODS: GC cells were treated with Hp filtrate for cell infection. Bioinformatics tools were utilized for survival analysis and prediction of HOXA-AS2 downstream molecules. Western blotting and RT-qPCR were utilized for assessing protein and RNA levels, respectively. Flow cytometry, colony formation and CCK-8 assays were implemented for testing HOXA-AS2 functions in Hp-infected GC cells. HOXA-AS2 localization in cells was determined by subcellular fractionation assay. The relationship between RNAs were measured by luciferase reporter assay. RESULTS: Hp infection induced HOXA-AS2 upregulation in GC cells. Knocking down HOXA-AS2 restrained cell proliferation but promoted cell apoptosis with Hp infection. HOXA-AS2 bound to miR-509-3p, and miR-509-3p targeted monocyte to macrophage differentiation associated 2 (MMD2). Overexpressing MMD2 reversed HOXA-AS2 depletion-mediated suppression on cell aggressiveness with Hp infection. CONCLUSION: Hp infection induces the aggressiveness of GC cells by regulating HOXA-AS2/miR-509-3p/MMD2 axis.

Subtype-Specific Association of Mitochondrial DNA Copy Number With Poststroke/TIA Outcomes in 10†241 Patients in China.

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) is associated with the severity and mortality in patients with stroke, but the associations in different stroke subtypes remain unexplored. METHODS: We conducted an observational prospective cohort analysis on patients with ischemic stroke or transient ischemic attack enrolled in the Third China National Stroke Registry. We applied logistic models to assess the association of mtDNA-CN with functional outcome (modified Rankin Scale score, 3-6 versus 0-2) and Cox proportional hazard models to assess the association with stroke recurrence (treating mortality as a competing risk) and mortality during a 12-month follow-up, adjusting for sex, age, physical activity, National Institutes of Health Stroke Scale at admission, history of stroke and peripheral artery disease, small artery occlusion, and interleukin-6. Subgroup analyses stratified by age and stroke subtypes were conducted. RESULTS: The Third China National Stroke Registry enrolled 15 166 patients, of which 10 241 with whole-genome sequencing data were retained (mean age, 62.2 [SD, 11.2] years; 68.8% men). The associations between mtDNA-CN and poststroke/transient ischemic attack outcomes were specific to patients aged ≤65 years, with lower mtDNA-CN significantly associated with stroke recurrence in 12 months (subdistribution hazard ratio, 1.15 per SD lower mtDNA-CN [95% CI, 1.04-1.27]; P=5.2×10-3) and higher all-cause mortality in 3 months (hazard ratio, 2.19 [95% CI, 1.41-3.39]; P=5.0×10-4). Across subtypes, the associations of mtDNA-CN with stroke recurrence were specific to stroke of undetermined cause (subdistribution hazard ratio, 1.28 [95% CI, 1.11-1.48]; P=6.6×10-4). In particular, lower mtDNA-CN was associated with poorer functional outcomes in stroke of undetermined cause patients diagnosed with embolic stroke of undetermined source (odds ratio, 1.53 [95% CI, 1.20-1.94]; P=5.4×10-4), which remained significant after excluding patients with recurrent stroke (odds ratio, 1.49 [95% CI, 1.14-1.94]; P=3.0×10-3). CONCLUSIONS: Lower mtDNA-CN is associated with higher stroke recurrence rate and all-cause mortality, as well as poorer functional outcome at follow-up, among stroke of undetermined cause, embolic stroke of undetermined source, and younger patients.

Posterior Lateral Endoscopic Cervical Discectomy Through a Lateral Mass Approach in the Treatment of Cervical Spondylotic Radiculopathy.

OBJECTIVE: The present study outlines the feasibility, safety, and short-term clinical outcomes of posterior lateral endoscopic cervical discectomy (PLECD) through a lateral mass approach for treating cervical spondylotic radiculopathy (CSR). METHODS: This single-center retrospective observational study involved 30 patients with single-level CSR who had failed conservative treatment and presented with clinical symptoms consistent with imaging findings undergoing PLECD via a lateral mass approach. Primary outcomes included the visual analog scale (VAS) for neck and arm pain, the Japanese Orthopedic Association (JOA) score, and the modified MacNab criteria. Radiographic follow-up consisted of static and dynamic cervical radiographs and computed tomographic scans. RESULTS: Thirty patients (13 men and 17 women; mean age 48.8 ± 11.9 years) underwent this procedure, and the mean operative time was 74.90 ± 13.52 minutes. Mean follow-up was 7.37 ± 2.17 months. The VAS scores for the neck and arm decreased significantly at the last follow-up (neck, 26.80 ± 4.75 to 9.87 ± 1.78; arm, 71.30 ± 8.48 to 14.73 ± 4.00) (P < 0.05). The JOA score also decreased from 13.47 ± 1.36 to 15.90 ± 0.92 at the last follow-up (P < 0.05). Twenty-nine patients demonstrated satisfactory outcomes based on the modified MacNab criteria at the last follow-up. All patients exhibited a positive clinical response, experiencing relief from symptoms. Postoperative computed tomography (CT) scans confirmed the complete removal of lesions. CONCLUSIONS: PLECD through a lateral mass approach, as an alternative to conventional "keyhole" approaches, proves to be a novel and viable therapeutic option for CSR, demonstrating both high efficacy and safety.

Development and validation of a nomogram to predict the risk of constipation after lumbar interbody fusion surgery.

INTRODUCTION: To understand the incidence of postoperative constipation and the risk factors of constipation in patients with lumbar interbody fusion, we constructed and verified the constipation risk prediction model, so as to provide reference for the prevention and treatment of postoperative constipation. METHODS: The data of patients undergoing lumbar interbody fusion in our hospital were retrospectively analyzed from December 2021 to December 2022. According to postoperative constipation, the patients were divided into constipation group and non-constipation group. Univariate logistic regression analysis and multivariate logistic regression analysis were used to determine independent risk factors for postoperative constipation. Based on independent risk factors, a nomogram was developed to predict the risk of constipation after lumbar interbody fusion. The prediction performance was assessed using receiver operating characteristic curve (ROC), calibration curve and decision curve analysis (DCA). Finally, bootstrapping method for internal validation was further evaluated the nomogram. RESULTS: A total of 282 patients participated in the study. 176 patients (62.41%) after lumbar interbody occurred constipation, and 106 patients were asymptomatic. Multivariate regression analysis showed independent risk factors, including the use of calcium channel blockers, polypharmacy, postoperative bed time, and constipation history. Multivariate regression analysis was used to establish the model. The C-index of the nomogram was 0.827 (95% CI 0.779-0.875), and the C-index of interval bootstrapping validation was 0.813 (95% CI 0.765-0.861), and the area under the AUC was 0.800. The nomogram showed good discrimination ability. CONCLUSIONS: The use of calcium channel blockers, polypharmacy, postoperative bed time, and history of constipation are independent risk factors for postoperative constipation in patients undergoing lumbar interbody fusion. The constructed risk prediction model has good discriminative ability.

Thermal and Magnetic Dual-Responsive Catheter-Assisted Shape Memory Microrobots for Multistage Vascular Embolization.

Catheters navigating through complex vessels, such as sharp turns or multiple U-turns, remain challenging for vascular embolization. Here, we propose a novel multistage vascular embolization strategy for hard-to-reach vessels that releases untethered swimming shape-memory magnetic microrobots (SMMs) from the prior catheter to the vessel bifurcation. SMMs, made of organo-gel with magnetic particles, ensure biocompatibility, radiopacity, thrombosis, and fast thermal and magnetic responses. An SMM is initially a linear shape with a 0.5-mm diameter at 20 °C inserted in a catheter. It transforms into a predetermined helix within 2 s at 38 °C blood temperature after being pushed out of the catheter into the blood. SMMs enable agile swimming in confined and tortuous vessels and can swim upstream using helical propulsion with rotating magnetic fields. Moreover, we validated this multistage vascular embolization in living rabbits, completing 100-cm travel and renal artery embolization in 2 min. After 4 weeks, the SMMs maintained the embolic position, and the kidney volume decreased by 36%.

Potential Protein Signatures for Recurrence Prediction of Ischemic Stroke.

BACKGROUND: Acute ischemic stroke is a major cause of mortality and disability worldwide, with approximately 7.4% to 7.7% recurrence within the first 3 months. This study aimed to identify potential biomarkers for predicting stroke recurrence. METHODS AND RESULTS: We conducted a nested case-control study using a hospital-based cohort from the Third China National Stroke Registry selecting 214 age- and sex-matched patients with ischemic stroke with hypertension and no history of diabetes or heart disease. Using data-independent acquisition for discovery and multiple reaction monitoring for quantitative validation, we identified 26 differentially expressed proteins in large-artery atherosclerosis (Causative Classification of Ischemic Stroke [CCS]1), 16 in small-artery occlusion (CCS3), and 25 in undetermined causes (CCS5) among patients with recurrent stroke. In the CCS1 and CCS3 subgroups, differentially expressed proteins were associated with platelet aggregation, neuronal death/cerebroprotection, and immune response, whereas differentially expressed proteins in the CCS5 subgroup were linked to altered metabolic functions. Validated recurrence predictors included proteins associated with neutrophil activity and vascular inflammation (TAGLN2 [transgelin 2], ITGAM [integrin subunit α M]/TAGLN2 ratio, ITGAM/MYL9 [myosin light chain 9] ratio, TAGLN2/RSU1 [Ras suppressor protein 1] ratio) in the CCS3 subgroup and proteins associated with endothelial plasticity and blood-brain barrier integrity (ITGAM/MYL9 ratio and COL1A2 [collagen type I α 2 chain]/MYL9 ratio) in the CCS3 and CCS5 subgroups, respectively. CONCLUSIONS: These findings provide a foundation for developing a blood-based biomarker panel, using causative classifications, which may be used in routine clinical practice to predict stroke recurrence.

In situ growth engineering of ultrathin dendritic PdNi nanosheets on nitrogen-doped V2CTx MXenes for efficient hydrogen evolution.

Immobilizing metal nanoparticles on a support is crucial for catalysts' stability and spatial distribution. MXenes are promising substrates for in situ growth engineering of various electrocatalysts owing to their merits. A stronger binding capacity can be achieved between the in situ-fabricated catalysts and MXenes compared to a common physical combination. Thus, synergistically utilizing morphology modulation, composition optimization, and the interfacial interaction between metal catalysts and supports will maximize the electrocatalytic activity. However, most reported in situ-formed catalysts on MXenes result in solid 0D nanoparticles and in situ growth of nanoalloy catalysts on MXenes with a precisely controlled morphology is still lacking. Herein, nanodendritic PdNi alloys are in situ grown on nitrogen-doped V2CTx, serving as efficient electrocatalysts toward the hydrogen evolution reaction (HER). Thanks to the synergistic effect of the unique nanodendritic structure of PdNi, the merits of N-TBA-V2CTx nanosheets, and the strong metal-support interaction between the PdNi and the N-TBA-V2CTx support, the in situ-formed Pd58Ni42/N-TBA-V2CTx electrocatalyst shows excellent HER performance with an ultralow overpotential of 44.1 mV to achieve 10 mA cm-2 and a lowest Tafel slope of 39.4 mV dec-1, which outperforms Pd58Ni42/TBA-V2CTx, Pd58Ni42, and Pd/C. Remarkably, the Pd58Ni42/N-TBA-V2CTx catalyst can maintain 92.3% of its initial activity even after 50 h of continuous operation.

Gut Microbiome and Stroke: a Bidirectional Mendelian Randomisation Study in East Asian and European Populations.

BACKGROUND AND AIMS: Observational studies have implicated the involvement of gut microbiome in stroke development. Conversely, stroke may disrupt the gut microbiome balance, potentially causing systemic infections exacerbated brain infarction. However, the causal relationship remains controversial or unknown. To investigate bidirectional causality and potential ethnic differences, we conducted a bidirectional two-sample Mendelian randomisation (MR) study in both East Asian (EAS) and European (EU) populations. METHODS: Leveraging the hitherto largest genome-wide association study (GWAS) summary data from the MiBioGen Consortium (n=18 340, EU) and BGI (n=2524, EAS) for the gut microbiome, stroke GWAS data from the GIGASTROKE Consortium(264 655 EAS and 1 308 460 EU), we conducted bidirectional MR and sensitivity analyses separately for the EAS and EU population. RESULTS: We identified nominally significant associations between 85 gut microbiomes taxa in EAS and 64 gut microbiomes taxa in EU with stroke or its subtypes. Following multiple testing, we observed that genetically determined 1 SD increase in the relative abundance of species Bacteroides pectinophilus decreased the risk of cardioembolic stroke onset by 28% (OR 0.72 (95% CI 0.62 to 0.84); p=4.22e-5), and that genetically determined 1 SD increase in class Negativicutes resulted in a 0.76% risk increase in small vessel stroke in EAS. No significant causal association was identified in the EU population and the reverse MR analysis. CONCLUSION: Our study revealed subtype-specific and population-specific causal associations between gut microbiome and stroke risk among EAS and EU populations. The identified causality holds promise for developing a new stroke prevention strategy, warrants further mechanistic validation and necessitates clinical trial studies.

Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation.

Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. Hence, an efficient drug delivery system could serve as a valuable tool in drug screening and potentially enhance therapeutic efficacy. However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. Accordingly, we develop a magnetic nanocarrier functionalized with PAR2-targeting hexapeptide for dual-active targeting drug delivery. We show that the nanocarriers effectively deliver XCT790-an anti-calcification drug-to the calcified aortic valve under extra magnetic field navigation. We demonstrate that the nano-cargoes consequently inhibit the osteogenic differentiation of valvular interstitial cells, and alleviate aortic valve calcification and stenosis in a high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr-/-) mouse model. This work combining PAR2- and magnetic-targeting presents an effective targeted drug delivery system for treating calcific aortic valve disease in a murine model, promising future clinical translation.

Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice.

BACKGROUND: Major depressive disorder (MDD) is a common but severe psychiatric illness characterized by depressive mood and diminished interest. Both nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 1 (NLRP1) inflammasome and autophagy have been reported to implicate in the pathological processes of depression. However, the mechanistic interplay between NLRP1 inflammasome, autophagy, and depression is still poorly known. METHODS: Animal model of depression was established by chronic social defeat stress (CSDS). Depressive-like behaviors were determined by social interaction test (SIT), sucrose preference test (SPT), open field test (OFT), forced swim test (FST), and tail-suspension test (TST). The protein expression levels of NLRP1 inflammasome complexes, pro-inflammatory cytokines, phosphorylated-phosphatidylinositol 3-kinase (p-PI3K)/PI3K, phosphorylated-AKT (p-AKT)/AKT, phosphorylated-mechanistic target of rapamycin (p-mTOR)/mTOR, brain-derived neurotrophic factor (BDNF), phosphorylated-tyrosine kinase receptor B (p-TrkB)/TrkB, Bcl-2-associated X protein (Bax)/B-cell lymphoma-2 (Bcl2) and cleaved cysteinyl aspartate-specific proteinase-3 (caspase-3) were examined by western blotting. The mRNA expression levels of pro-inflammatory cytokines were tested by quantitative real-time PCR. The interaction between proteins was detected by immunofluorescence and coimmunoprecipitation. Neuronal injury was assessed by Nissl staining. The autophagosomes were visualized by transmission electron microscopy. Nlrp1a knockdown was performed using an adeno-associated virus (AAV) vector containing Nlrp1a-shRNA-eGFP infusion. RESULTS: CSDS exposure caused a bidirectional change in hippocampal autophagy function, which was activated in the initial period but impaired at the later stage. In addition, CSDS exposure increased the expression levels of hippocampal NLRP1 inflammasome complexes, pro-inflammatory cytokines, p-PI3K, p-AKT and p-mTOR in a time-dependent manner. Interestingly, NLRP1 is immunoprecipitated with mTOR but not PI3K/AKT and CSDS exposure facilitated the immunoprecipitation between them. Hippocampal Nlrp1a knockdown inhibited the activity of PI3K/AKT/mTOR signaling, rescued the impaired autophagy and ameliorated depressive-like behavior induced by CSDS. In addition, rapamycin, an autophagy inducer, abolished NLRP1 inflammasome-driven inflammatory reactions, alleviated depressive-like behavior and exerted a neuroprotective effect. CONCLUSIONS: Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behavior in mice and the regulation of autophagy could be a valuable therapeutic strategy for the management of depression.

Neural mechanisms of sequential dependence in time perception: the impact of prior task and memory processing.

Our perception and decision-making are susceptible to prior context. Such sequential dependence has been extensively studied in the visual domain, but less is known about its impact on time perception. Moreover, there are ongoing debates about whether these sequential biases occur at the perceptual stage or during subsequent post-perceptual processing. Using functional magnetic resonance imaging, we investigated neural mechanisms underlying temporal sequential dependence and the role of action in time judgments across trials. Participants performed a timing task where they had to remember the duration of green coherent motion and were cued to either actively reproduce its duration or simply view it passively. We found that sequential biases in time perception were only evident when the preceding task involved active duration reproduction. Merely encoding a prior duration without reproduction failed to induce such biases. Neurally, we observed activation in networks associated with timing, such as striato-thalamo-cortical circuits, and performance monitoring networks, particularly when a "Response" trial was anticipated. Importantly, the hippocampus showed sensitivity to these sequential biases, and its activation negatively correlated with the individual's sequential bias following active reproduction trials. These findings highlight the significant role of memory networks in shaping time-related sequential biases at the post-perceptual stages.

A systematic review and meta-analysis of moxibustion for chronic prostatitis.

BACKGROUND: Chronic prostatitis (CP) is a common condition that affects many individuals. Previous clinical trials have explored the use of moxibustion as a potential treatment for CP. However, the evidence on the effectiveness of moxibustion for CP remains limited. Therefore, this study aimed to comprehensively assess the effects of moxibustion for CP. METHODS: In order to gather relevant and up-to-date information, we conducted a systematic literature search of databases including Cochrane Library, PUBMED, EMBASE, CNKI, and Wangfang from inception until June 30, 2023. Only randomized clinical trials (RCTs) that investigated the use of moxibustion for CP were included in this study. The primary outcomes of interest were the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) scores and the overall response rate. To evaluate the quality of the included studies, we used the Cochrane risk-of-bias tool. RESULTS: After analyzing the data from 8 RCTs involving a total of 664 patients, we found significant differences in NIH-CPSI scores between moxibustion and other treatment modalities. Specifically, when compared with herbal medicine, moxibustion was associated with a mean difference (MD) of -1.78 in NIH-CPSI scores (95% confidence interval [CI] [-2.78, -0.78], P < .001), and when compared with western medicine, moxibustion was associated with a MD of -5.24 in NIH-CPSI scores (95% CI [-7.80, -2.67], P < .08). In terms of the overall response rate, moxibustion was found to be superior to herbal medicine, with a MD of 2.36 (95% [19, 4.67], P = .01). Additionally, when moxibustion was combined with herbal medicine, it yielded a higher overall response rate with a MD of 4.07 (95% CI [1.54, 10.74], P = .005) compared to herbal medicine alone. Moxibustion also outperformed western medicine in terms of the overall response rate, with a MD of 4.56 (95% CI [2.24, 9.26], P < .001). CONCLUSION: Based on the findings of this study, moxibustion appears to be a potentially efficacious treatment for CP. The results suggest that moxibustion can improve NIH-CPSI scores and overall response rate in patients with CP. However, further high-quality studies are needed to validate these results and establish the long-term effects of moxibustion as a treatment for CP.