Phosphoribosylpyrophosphate synthetase as a metabolic valve advances Methylobacterium/Methylorubrum phyllosphere colonization and plant growth.

The proficiency of phyllosphere microbiomes in efficiently utilizing plant-provided nutrients is pivotal for their successful colonization of plants. The methylotrophic capabilities of Methylobacterium/Methylorubrum play a crucial role in this process. However, the precise mechanisms facilitating efficient colonization remain elusive. In the present study, we investigate the significance of methanol assimilation in shaping the success of mutualistic relationships between methylotrophs and plants. A set of strains originating from Methylorubrum extorquens AM1 are subjected to evolutionary pressures to thrive under low methanol conditions. A mutation in the phosphoribosylpyrophosphate synthetase gene is identified, which converts it into a metabolic valve. This valve redirects limited C1-carbon resources towards the synthesis of biomass by up-regulating a non-essential phosphoketolase pathway. These newly acquired bacterial traits demonstrate superior colonization capabilities, even at low abundance, leading to increased growth of inoculated plants. This function is prevalent in Methylobacterium/Methylorubrum strains. In summary, our findings offer insights that could guide the selection of Methylobacterium/Methylorubrum strains for advantageous agricultural applications.

Dietary Intake of Nutrients Involved in Serotonin and Melatonin Synthesis and Prenatal Maternal Sleep Quality and Affective Symptoms.

Poor sleep quality and psychological distress in pregnancy are important health concerns. Serotonin and melatonin levels may underlie variation in these adverse outcomes. In this study, we examined dietary nutrients involved in serotonin and melatonin synthesis in relation to maternal sleep quality and affective symptoms during pregnancy. Pregnant women at no greater than normal medical risk at enrollment completed 24-hour dietary recalls in mid-late pregnancy. Usual intakes of vitamin B6, vitamin D, eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), and tryptophan were estimated from dietary intake of foods and supplements using the National Cancer Institute (NCI) method. Sleep quality, depression, and anxiety were measured using validated questionnaires. Associations between nutrient intakes, sleep quality, and affective symptoms were estimated using generalized estimating equation models adjusting for potential confounding factors. In minimally adjusted models, EPA + DHA and tryptophan intakes were associated with a lower score indicating better sleep quality (b: -1.07, 95% CI: -2.09, -0.05) and (b: -12.40, 95% CI: -24.60, -0.21), respectively. EPA + DHA and tryptophan intakes were also associated with a lower odds of shorter sleep duration and sleep disturbances. In addition, tryptophan was associated with a lower odds of higher sleep latency. However, associations were attenuated and nonsignificant after adjustment for demographic and lifestyle factors. In conclusion, intakes of EPA + DHA and tryptophan were associated with improved sleep quality, but these associations were confounded by maternal demographic and lifestyle characteristics. This study highlights the need to consider dietary intake and pregnancy health in the context of demographic characteristics and lifestyle behaviors.

Targeting delivery of miR-146a via IMTP modified milk exosomes exerted cardioprotective effects by inhibiting NF-κB signaling pathway after myocardial ischemia-reperfusion injury.

Reperfusion therapy is critical for saving heart muscle after myocardial infarction, but the process of restoring blood flow can itself exacerbate injury to the myocardium. This phenomenon is known as myocardial ischemia-reperfusion injury (MIRI), which includes oxidative stress, inflammation, and further cell death. microRNA-146a (miR-146a) is known to play a significant role in regulating the immune response and inflammation, and has been studied for its potential impact on the improvement of heart function after myocardial injury. However, the delivery of miR-146a to the heart in a specific and efficient manner remains a challenge as extracellular RNAs are unstable and rapidly degraded. Milk exosomes (MEs) have been proposed as ideal delivery platform for miRNA-based therapy as they can protect miRNAs from RNase degradation. In this study, the effects of miR-146a containing MEs (MEs-miR-146a) on improvement of cardiac function were examined in a rat model of MIRI. To enhance the targeting delivery of MEs-miR-146a to the site of myocardial injury, the ischemic myocardium-targeted peptide IMTP was modified onto the surfaces, and whether the modified MEs-miR-146a could exert a better therapeutic role was examined by echocardiography, myocardial injury indicators and the levels of inflammatory factors. Furthermore, the expressions of miR-146a mediated NF-κB signaling pathway-related proteins were detected by western blotting and qRT-PCR to further elucidate its mechanisms. MiR-146 mimics were successfully loaded into the MEs by electroporation at a square wave 1000 V voltage and 0.1 ms pulse duration. MEs-miR-146a can be up-taken by cardiomyocytes and protected the cells from oxygen glucose deprivation/reperfusion induced damage in vitro. Oral administration of MEs-miR-146a decreased myocardial tissue apoptosis and the expression of inflammatory factors and improved cardiac function after MIRI. The miR-146a level in myocardium tissues was significantly increased after the administration IMTP modified MEs-miR-146a, which was higher than that of the MEs-miR-146a group. In addition, intravenous injection of IMTP modified MEs-miR-146a enhanced the targeting to heart, improved cardiac function, reduced myocardial tissue apoptosis and suppressed inflammation after MIRI, which was more effective than the MEs-miR-146a treatment. Moreover, IMTP modified MEs-miR-146a reduced the protein levels of IRAK1, TRAF6 and p-p65. Therefore, IMTP modified MEs-miR-146a exerted their anti-inflammatory effect by inhibiting the IRAK1/TRAF6/NF-κB signaling pathway. Taken together, our findings suggested miR-146a containing MEs may be a promising strategy for the treatment of MIRI with better outcome after modification with ischemic myocardium-targeted peptide, which was expected to be applied in clinical practice in future.

Comparison of the Efficacy and Safety of Nivolumab Plus Cabozantinib versus Sunitinib in the Treatment of Elderly Patients with Advanced Clear Cell Renal Cell Carcinoma.

OBJECTIVE: Advanced clear cell renal cell carcinoma (ccRCC) seriously affects the life and health of patients, but effective treatment for this disease is still lacking in clinic. This study investigated the efficacy of nivolumab plus cabozantinib versus sunitinib in the treatment of elderly patients with advanced ccRCC. METHODS: The clinical data of 216 elderly patients with advanced ccRCC in our hospital from January 2020 to January 2022 were retrospectively analysed. On the basis of different treatment regimens, patients were divided into the cabozantinib group (n = 111, receiving nivolumab and cabozantinib) and the sunitinib group (n = 105, receiving nivolumab and sunitinib). The overall survival time, disease control rates, health status, incidence of adverse events and identification of prognostic risk were compared between the two groups. RESULTS: The cabozantinib group had higher overall survival time, disease control rate and scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index and EuroQol-Five Dimensions-Three Levels Questionnaire than the sunitinib group. The incidence of adverse events in the cabozantinib group was lower than that in the sunitinib group (p < 0.001). However, no difference existed in the identification of prognostic risk between the two groups (p > 0.05). CONCLUSIONS: The effect of nivolumab plus cabozantinib on the treatment of elderly patients with advanced ccRCC is better than that of nivolumab plus sunitinib, with fewer adverse reactions and higher safety. However, the research results require further clinical studies to confirm and promote.

Trends in electrocardiographic and cardiovascular manifestations of patients hospitalised with COVID-19.

INTRODUCTION: Early in the coronavirus disease 2019 (COVID-19) pandemic, a low incidence of cardiovascular complications was reported in Singapore. Little was known about the trend of cardiovascular complications as the pandemic progressed. In this study, we examined the evolving trends in electrocardiographic and cardiovascular manifestations in patients hospitalised with COVID-19. METHODS: We examined the first 1781 consecutive hospitalised patients with polymerase chain reaction-confirmed COVID-19. We divided the population based on whether they had abnormal heart rate (HR) or electrocardiography (ECG) or normal HR and ECG, comparing the baseline characteristics and outcomes. Cardiovascular complications were defined as acute myocardial infarction, stroke, pulmonary embolism, myocarditis and mortality. RESULTS: The 253 (14.2%) patients who had abnormal HR/ECG at presentation were more likely to be symptomatic. Sinus tachycardia was commonly observed. Troponin I levels (97.0 ± 482.9 vs. 19.7 ± 68.4 ng/L, P = 0.047) and C-reactive protein levels (20.1 ± 50.7 vs. 13.9 ± 24.1 µmol/L, P = 0.003) were significantly higher among those with abnormal HR/ECGs, with a higher prevalence of myocarditis (2.0% vs. 0.5%, P = 0.019), pulmonary embolism (2.0% vs. 0.3%, P = 0.008) and acute myocardial infarction (1.2% vs. 0.1%, P = 0.023). After adjusting for age and comorbidities, abnormal HR/ECG (adjusted odds ratio 4.41, 95% confidence interval 2.21-8.77; P < 0.001) remained independently associated with adverse cardiovascular complications. Over time, there was a trend towards a higher proportion of hospitalised patients with cardiovascular complications. CONCLUSION: Cardiovascular complications appear to be increasing in proportion over time among hospitalised patients with COVID-19. A baseline ECG and HR measurement may be helpful for predicting these complications.

Cancer cell extravasation requires iplectin-mediated delivery of MT1-MMP at invadopodia.

BACKGROUND: Invadopodia facilitate cancer cell extravasation, but the molecular mechanism whereby invadopodia-specific proteases such as MT1-MMP are called to invadopodia is unclear. METHODS: Mass spectrometry and immunoprecipitation were used to identify interactors of MT1-MMP in metastatic breast cancer cells. After identification, siRNA and small molecule inhibitors were used to assess the effect these interactors had on cellular invasiveness. The chicken embryo chorioallantoic membrane (CAM) model was used to assess extravasation and invadopodia formation in vivo. RESULTS: In metastatic breast cancer cells, MT1-MMP was found to associate with plectin, a cytolinker and scaffolding protein. Complex formation between plectin and MT1-MMP launches invadopodia formation, a subtype we termed iplectin (i = invadopodial). iPlectin delivers MT1-MMP to invadopodia and is indispensable for regulating cell surface levels of the enzyme. Genetic depletion of plectin with siRNA reduced invadopodia formation and cell invasion in vitro. In vivo extravasation efficiency assays and intravital imaging revealed iplectin to be a key contributor to invadopodia ultrastructure and essential for extravasation. Pharmacologic inhibition of plectin using the small molecule Plecstatin-1 (PST-1) abrogated MT1-MMP delivery to invadopodia and extravasation efficiency. CONCLUSIONS: Anti-metastasis therapeutic approaches that target invadopodia are possible by disrupting interactions between MT1-MMP and iplectin. CLINICAL TRIAL REGISTRATION NUMBER: NCT04608357.

Precision therapy for ulcerative colitis: insights from mitochondrial dysfunction interacting with the immune microenvironment.

Background: Accumulating evidence reveals mitochondrial dysfunction exacerbates intestinal barrier dysfunction and inflammation. Despite the growing knowledge of mitochondrial dysfunction and ulcerative colitis (UC), the mechanism of mitochondrial dysfunction in UC remains to be fully explored. Methods: We integrated 1137 UC colon mucosal samples from 12 multicenter cohorts worldwide to create a normalized compendium. Differentially expressed mitochondria-related genes (DE-MiRGs) in individuals with UC were identified using the "Limma" R package. Unsupervised consensus clustering was utilized to determine the intrinsic subtypes of UC driven by DE-MiRGs. Weighted gene co-expression network analysis was employed to investigate module genes related to UC. Four machine learning algorithms were utilized for screening DE-MiRGs in UC and construct MiRGs diagnostic models. The models were developed utilizing the over-sampled training cohort, followed by validation in both the internal test cohort and the external validation cohort. Immune cell infiltration was assessed using the Xcell and CIBERSORT algorithms, while potential biological mechanisms were explored through GSVA and GSEA algorithms. Hub genes were selected using the PPI network. Results: The study identified 108 DE-MiRGs in the colonic mucosa of patients with UC compared to healthy controls, showing significant enrichment in pathways associated with mitochondrial metabolism and inflammation. The MiRGs diagnostic models for UC were constructed based on 17 signature genes identified through various machine learning algorithms, demonstrated excellent predictive capabilities. Utilizing the identified DE-MiRGs from the normalized compendium, 941 patients with UC were stratified into three subtypes characterized by distinct cellular and molecular profiles. Specifically, the metabolic subtype demonstrated enrichment in epithelial cells, the immune-inflamed subtype displayed high enrichment in antigen-presenting cells and pathways related to pro-inflammatory activation, and the transitional subtype exhibited moderate activation across all signaling pathways. Importantly, the immune-inflamed subtype exhibited a stronger correlation with superior response to four biologics: infliximab, ustekinumab, vedolizumab, and golimumab compared to the metabolic subtype. Conclusion: This analysis unveils the interplay between mitochondrial dysfunction and the immune microenvironment in UC, thereby offering novel perspectives on the potential pathogenesis of UC and precision treatment of UC patients, and identifying new therapeutic targets.

AQDS-functionalized biochar enhances the bioreduction of Cr(VI) by Shewanella putrefaciens CN32.

The bioreduction of toxic chromium(VI) to sparingly soluble chromium(III) represents an environmentally friendly and cost-effective method for remediating Cr contamination. Usually, this bioreduction process is slow and requires the addition of quinone compounds as electron shuttles to enhance the reaction rate. However, the dissolved quinone compounds are susceptible to loss with water flow, thereby limiting their effectiveness. To address this challenge, this study loaded anthraquinone-2,6-disulfonate (AQDS), a typical quinone compound, onto biochar (BC) to create a novel solid-phase electron mediator (BC-AQDS) that can sustainably promote Cr(VI) bioreduction. The experimental results demonstrated that BC-AQDS significantly promoted the bioreduction of Cr(VI), where the reaction rate constant increased by 4.81 times, and the reduction extent increased by 38.31%. X-ray photoelectron spectroscopy and Fourier-Transform Infrared Spectroscopy analysis revealed that AQDS replaced the -OH functional groups on the BC surface to form BC-AQDS. Upon receiving electrons from Shewanella putrefaciens CN32, BC-AQDS was reduced to BC-AH2DS, which subsequently facilitated the reduction of Cr(VI) to Cr(III). This redox cycle between BC-AQDS and BC-AH2DS effectively enhanced the bioreduction rate of Cr(VI). Our study also found that a lower carbonization temperature of BC resulted in a higher surface -OH functional group content, enabling a greater load of AQDS and a more pronounced enhancement effect on the bioreduction of Cr(VI). Additionally, a smaller particle size of BC and a higher dosage of BC-AQDS further contributed to the enhancement of Cr(VI) bioreduction. The preparation of BC-AQDS in this study effectively improve the utilization of quinone compounds and offer a promising approach for enhancing the bioreduction of Cr(VI). It provides a more comprehensive reference for understanding and solving the problem of Cr pollution in groundwater.

The Effects of Breastfeeding on Childhood Behavioral and Emotional Development: A Prospective Cohort Study in China.

BACKGROUND: Breastfeeding could improve a child's health early on, but its long-term effects on childhood behavioral and emotional development remain inconclusive. We aimed to estimate the associations of feeding practice with childhood behavioral and emotional development. METHODS: In this population-based birth cohort study, data on feeding patterns for the first 6 mo of life, the duration of breastfeeding, and children's emotional and behavioral outcomes were prospectively collected from 2489 mother-child dyads. Feeding patterns for the first 6 mo included exclusive breastfeeding (EBF) and non-exclusive breastfeeding (non-EBF, including mixed feeding or formula feeding), and the duration of breastfeeding (EBF or mixed feeding) was categorized into ≤6 mo, 7-12 mo, 13-18 mo, and >18 mo. Externalizing problems and internalizing problems were assessed with the Child Behavior Checklist (CBCL) and operationalized according to recommended clinical cutoffs, corresponding to T scores ≥64. Multivariable linear regression and logistic regression were used to evaluate the association of feeding practice with CBCL outcomes. RESULTS: The median (interquartile range) age of children at the outcome measurement was 32.0 (17.0) mo. Compared with non-EBF for the first 6 mo, EBF was associated with a lower T score of internalizing problems [adjusted mean difference (aMD): -1.31; 95% confidence interval (95% CI): -2.53, -0.10], and it was marginally associated with T scores of externalizing problems (aMD: -0.88; 95% CI: -1.92, 0.15). When dichotomized, EBF versus non-EBF was associated with a lower risk of externalizing problems (aOR: 0.54, 95% CI: 0.34, 0.87), and it was marginally associated with internalizing problems (aOR: 0.75, 95% CI: 0.54, 1.06). Regarding the duration of breastfeeding, breastfeeding for 13-18 mo versus ≤6 mo was associated with lower T scores of internalizing problems (aMD: -2.50; 95% CI: -4.43, -0.56) and externalizing problems (aMD: -2.75; 95% CI: -4.40, -1.10), and breastfeeding for >18 mo versus ≤6 mo was associated with lower T scores of externalizing problems (aMD: -1.88; 95% CI: -3.68, -0.08). When dichotomized, breastfeeding for periods of 7-12 mo, 13-18 mo, and >18 mo was associated with lower risks of externalizing problems [aOR (95% CI): 0.96 (0.92, 0.99), 0.94 (0.91, 0.98), 0.96 (0.92, 0.99), respectively]. CONCLUSIONS: Exclusive breastfeeding for the first 6 mo and a longer duration of breastfeeding, exclusively or partially, are beneficial for childhood behavioral and emotional development.

Seven-year long-term inoculation with Funneliformis mosseae increases maize yield and soil carbon storage evidenced by in situ 13C-labeling in a dryland.

Arbuscular mycorrhizal fungi (AMF) establish symbiotic relationships with roots of most plants, contributing to plant water uptake and soil carbon (C) sequestration. However, the interactive contribution and of long-term field AMF inoculation and water conservation on maize yield and soil organic carbon (SOC) sequestration in drylands remain largely unknown. After 7-year long-term field inoculation with AMF Funneliformis mosseae, AMF suppression by fungicide benomyl, and no-AMF/no-benomyl control, and two water conservation practices of half-film and full-film mulching (∼50 % and ∼100 crop planted area covered with plastic film), this study thus applied in situ 13CO2-C labeling and high-throughput sequencing to quantify newly photosynthetically assimilated C into different soil C pools including soil aggregates and respiration, and their effects on maize growth and productivity. Results showed that 7-year long-term AMF inoculation significantly increased the relative abundance of F. mosseae in rhizosphere soil and root AMF colonization, indicating that F. mosseae successfully dominated in AMF communities. Compared to no-AMF/no-benomyl control, AMF colonization significantly increased shoot biomass and maize yield by 17.9 % and 20.3 % while mitigated the less water conservation effects of half-film mulching on maize performance. The SOC content under field AMF inoculation SOC was increased from 7.9 to 8.4 g kg-1 and also the mean weight diameter of aggregates (1.21 to 1.35), e.g. aggregate stability. After 1 and/or 40 days 13C labeling, the enhanced 13C translocations into macro-aggregates with decreased 13C emissions from microbial decomposition under field AMF inoculation had contributed to SOC conservation in bulk soil. These results suggest that AMF inoculation in dryland crops is promising to increase crop yield while promoting more atmospheric CO2 fixation in soil aggregates. A long-term field AMF inoculation will enhance our understanding of applying beneficial mycorrhizal fungi to enhance soil C sequestration and also crop yield via plant-fixed atmospheric CO2 in semi-arid and arid farmlands.

Subsequent maternal sleep deprivation aggravates cognitive impairment by modulating hippocampal neuroinflammatory responses and synaptic function in maternal isoflurane-exposed offspring mice.

INTRODUCTION: Pregnant women may need to undergo non-obstetric surgery under general anesthesia owing to medical needs, and pregnant women frequently experience sleep disturbances during late gestation. Preclinical studies demonstrated that maternal isoflurane exposure (MISO) or maternal sleep deprivation (MSD) contributed to cognitive impairments in offspring. Research studies in mice have revealed that SD can aggravate isoflurane-induced cognitive deficits. However, it remains unclear whether MSD aggravates MISO-induced cognitive deficits in offspring. The purpose of this research was to explore the combined effects of MSD and MISO on offspring cognitive function and the role of neuroinflammation and synaptic function in the process of MSD + MISO. METHODS: Pregnant mice were exposed to 1.4% isoflurane by inhalation for 4 h on gestational day (GD) 14. Dams were then subjected to SD for 6 h (12:00-18:00 h) during GD15-21. At 3 months of age, the offspring mice were subjected to the Morris water maze test to assess cognitive function. Then the levels of inflammatory and anti-inflammatory markers and synaptic function-related proteins were assessed using molecular biology methods. RESULTS: The results of this study demonstrated that MISO led to cognitive dysfunction, an effect that was aggravated by MSD. In addition, MSD exacerbated the maternal isoflurane inhalation, leading to an enhancement in the expression levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha and a reduction in the hippocampal levels of IL-10, synaptophysin, post-synaptic density-95, growth-associated protein-43, and brain-derived neurotrophic factor. CONCLUSION: Our findings revealed that MSD aggravated the cognitive deficits induced by MISO in male offspring mice, and these results were associated with neuroinflammation and alternations in synaptic function.

Macrophage biomimetic nanoparticle-targeted functional extracellular vesicle micro-RNAs revealed via multiomics analysis alleviate sepsis-induced acute lung injury.

Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI. However, strategies to screen more effective EV-miRNAs as therapeutic targets are yet to be elucidated. In this study, functional EV-miRNAs were identified based on multiomics analysis of single-cell RNA sequencing of targeted organs and serum EV (sEV) miRNA profiles in patients with sepsis. The proportions of neutrophils and macrophages were increased significantly in the lungs of mice receiving sEVs from patients with sepsis compared with healthy controls. Macrophages released more EVs than neutrophils. MiR-125a-5p delivery by sEVs to lung macrophages inhibited Tnfaip3, while miR-221-3p delivery to lung neutrophils inhibited Fos. Macrophage membrane nanoparticles (MM NPs) loaded with an miR-125a-5p inhibitor or miR-221-3p mimic attenuated the response to lipopolysaccharide (LPS)-induced ALI. Transcriptome profiling revealed that EVs derived from LPS-stimulated bone marrow-derived macrophages (BMDMs) induced oxidative stress in neutrophils. Blocking toll-like receptor, CXCR2, or TNFα signaling in neutrophils attenuated the oxidative stress induced by LPS-stimulated BMDM-EVs. This study presents a novel method to screen functional EV-miRNAs and highlights the pivotal role of macrophage-derived EVs in ALI. MM NPs, as delivery systems of key sEV-miRNA mimics or inhibitors, alleviated cellular responses observed in sepsis-induced ALI. This strategy can be used to reduce septic organ damage, particularly lung damage, by targeting EVs.

Current Progress in Magnetic Resonance-Guided Focused Ultrasound to Facilitate Drug Delivery across the Blood-Brain Barrier.

This review discusses the current progress in the clinical use of magnetic resonance-guided focused ultrasound (MRgFUS) and other ultrasound platforms to transiently permeabilize the blood-brain barrier (BBB) for drug delivery in neurological disorders and neuro-oncology. Safety trials in humans have followed on from extensive pre-clinical studies, demonstrating a reassuring safety profile and paving the way for numerous translational clinical trials in Alzheimer's disease, Parkinson's disease, and primary and metastatic brain tumors. Future directions include improving ultrasound delivery devices, exploring alternative delivery approaches such as nanodroplets, and expanding the application to other neurological conditions.

Porous Chitosan/Hydroxyapatite Composite Microspheres for Vancomycin Loading and Releasing.

Porous chitosan/hydroxyapatite (Chi-HAp) composite microspheres were prepared in an aqueous solution containing chitosan, calcium nitrate, and ammonium dihydrogen phosphate by using a hydrothermal method at various temperatures. The investigation indicated that temperature significantly impacted the final product's appearance. Hydroxyapatite (HAp) coupled with dicalcium phosphate dihydrate (DCPD) flakes were obviously found at 65 and 70 °C, while the latter gradually disappeared at higher temperatures. Conversely, synthesis at 90 °C led to smaller particle sizes due to the broken chitosan chains. The microspheres synthesized at 75 °C were selected for further analysis, revealing porous structures with specific surface areas of 36.66 m2/g, pores ranging from 3 to 100 nm, and pore volumes of 0.58 cm3/g. Vancomycin (VCM), an antibiotic, was then absorbed on and released from the microspheres derived at 75 °C, with a drug entrapment efficiency of 20% and a release duration exceeding 20 days. The bacteriostatic activity of the VCM/composite microspheres against Staphylococcus aureus increased with the VCM concentration and immersion time, revealing a stable inhibition zone diameter of approximately 4.3 mm from 24 to 96 h, and this indicated the retained stability and efficacy of the VCM during the encapsulating process.

Biomechanism of abnormal stress on promoting osteoarthritis of temporomandibular joint through Piezo1 ion channel.

OBJECTIVE: This study aimed to investigate whether flow fluid shear stress (FFSS)-mediated signal transduction affects the function of Piezo1 ion channel in chondrocyte and to further explore the role of mechanical overloading in development of temporomandibular joint osteoarthritis (TMJ OA). METHODS: Immunohistochemical staining was used to determine the expression of Piezo1 in TMJ OA tissue collected from rat unilateral anterior crossbite (UAC) models. Chondrocytes harvested from normal adult SD rats were treated with FFSS (0, 4, 8, 12 dyn/cm2) in vitro. Immunofluorescent staining, real-time polymerase chain reaction, western blotting, flow cytometry and phalloidin assay were performed to detect the changes of cellular morphology as well as the expression of Piezo1 and certain pro-inflammatory and degradative factors in chondrocyte. RESULTS: Immunohistochemical analysis revealed that significantly increased Piezo1 expression was associated with UAC stimulation (p < .05). As applied FFSS escalated (4, 8 and 12 dyn/cm2), the expression levels of Piezo1, ADAMTS-5, MMP-13 and Col-X gradually increased, compared with the non-FFSS group (p < .05). Administering Piezo1 ion channel inhibitor to chondrocytes beforehand, it was observed that expression of ADAMTS-5, MMP-13 and Col-X was substantially decreased following FFSS treatment (p < .05) and the effect of cytoskeletal thinning was counteracted. The activated Piezo1 ion channel enhanced intracellular Ca2+ excess in chondrocytes during abnormal mechanical stimulation and the increased intracellular Ca2+ thinned the cytoskeleton of F-actin. CONCLUSIONS: Mechanical overloading activates Piezo1 ion channel to promote pro-inflammation and degradation and to increase Ca2+ concentration in chondrocyte, which may eventually result in TMJ OA.

Insight into the diurnal variations and potential sources of ambient PM2.5-bound polycyclic aromatic hydrocarbons during spring in Northern Taiwan.

In recent decades, polycyclic aromatic hydrocarbons (PAHs), the primary organic pollutants associated with particulate matter (PM), have attracted significant attention due to their carcinogenic and mutagenic potential. However, past studies have lacked exploration into the diurnal variation characteristics of PAHs, primarily due to limited analytical technical capabilities. This study utilized a thermal-desorption device coupled with gas chromatography/mass spectrometry (TD-GC/MS) to identify the levels of PAHs in PM2.5 during short periods (3-hr) and aimed to investigate the diurnal variations, possible sources, and potential health risks associated with PM2.5-bound PAHs in northern Taiwan. The mean concentration of total PAHs in PM2.5 was 1.22 ± 0.69 ng m-3 during the sampling period, with high molecular weight PAHs dominating. Source apportionment by the positive matrix factorization (PMF) model indicated that industrial emissions and traffic emissions (57.7 %) were the predominant sources of PAHs, with petroleum volatilization and coal/biomass combustion (42.3 %) making a lesser contribution. Diurnal variations of industrial and traffic emissions showed higher concentrations during traffic rush hours, while petroleum volatilization and coal/biomass combustion displayed higher concentrations at noon. Results from the potential source contribution function (PSCF) and the concentration weighted trajectory (CWT) model suggested that industrial emissions and traffic emissions mostly originated from local sources and were concentrated in the vicinity of the sampling site and the coastal area of western Taiwan. Source-attributed excess cancer risk (ECR) showed that industrial and traffic emissions had the highest cancer risks during morning traffic peak hours (1.69 ×10-5), while petroleum volatilization and coal/biomass combustion reached the maximum at noon (4.75 ×10-6). As a result, efforts to reduce PAH emissions from industrial and vehicle exhaust sources, especially during morning traffic hours, can help mitigate their adverse impact on human health.

Targeting a mTOR/autophagy axis: a double-edged sword of rapamycin in spontaneous miscarriage.

Immune dysfunction is a primary culprit behind spontaneous miscarriage (SM). To address this, immunosuppressive agents have emerged as a novel class of tocolytic drugs, modulating the maternal immune system's tolerance towards the embryo. Rapamycin (PubChem CID:5284616), a dual-purpose compound, functions as an immunosuppressive agent and triggers autophagy by targeting the mTOR pathway. Its efficacy in treating SM has garnered significant research interest in recent times. Autophagy, the cellular process of self-degradation and recycling, plays a pivotal role in numerous health conditions. Research indicates that autophagy is integral to endometrial decidualization, trophoblast invasion, and the proper functioning of decidual immune cells during a healthy pregnancy. Yet, in cases of SM, there is a dysregulation of the mTOR/autophagy axis in decidual stromal cells or immune cells at the maternal-fetal interface. Both in vitro and in vivo studies have highlighted the potential benefits of low-dose rapamycin in managing SM. However, given mTOR's critical role in energy metabolism, inhibiting it could potentially harm the pregnancy. Moreover, while low-dose rapamycin has been deemed safe for treating recurrent implant failure, its potential teratogenic effects remain uncertain due to insufficient data. In summary, rapamycin represents a double-edged sword in the treatment of SM, balancing its impact on autophagy and immune regulation. Further investigation is warranted to fully understand its implications.

Augmented microglial endoplasmic reticulum-mitochondria contacts mediate depression-like behavior in mice induced by chronic social defeat stress.

Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1CreER/+Hspa9f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.

Validation of the Weight-Related Eating Questionnaire in pregnancy.

The Weight-Related Eating Questionnaire (WREQ), designed for assessing distinct constructs of dietary restraint and disinhibition-related eating behaviors, has not been validated in pregnancy. This secondary data analysis aimed to evaluate the WREQ's psychometrics in a diverse sample of pregnant women from the eMoms randomized controlled trial (N = 1399), randomly split for exploratory (EFA, n = 691) and confirmatory factor analysis (CFA, n = 708). Cronbach's alpha and corrected item-total correlation was used to examine internal consistency reliability. Sequential multiple regression analyses were used to assess criterion validity. EFA revealed three factors - dietary restraint, susceptibility to external cues, and emotional eating - accounting for 65.6 % of total variances. Parallel analysis confirmed a combination of two restraint subtypes (routine restraint and compensatory restraint). CFA showed that item 3 for assessing routine restraint had the lowest squared multiple correlation (0.22). The overall Cronbach's alpha of 0.87 demonstrated good internal consistency. Dietary restraint was negatively associated with the intake of energy (p = .03) and carbohydrates (p = .02), whereas susceptibility to external cues was positively associated with the intake of energy (p < .001), carbohydrates (p < .001), and total fat (p = .003). Additionally, emotional eating was positively associated with early-pregnancy body mass index (BMI) after adjustment for covariates (p < .001). These findings confirmed the reliability of the WREQ, the construct validity for susceptibility to external cues and emotional eating, and demonstrated its criterion validity regarding nutritional intake in pregnant women.

Inhibiting the activation of enteric glial cells alleviates intestinal inflammation and comorbid anxiety- and depressive-like behaviors in the ulcerative colitis mice.

Ulcerative colitis (UC) is a common inflammatory bowel disease with a complex origin in clinical settings. It is frequently accompanied by negative emotional responses, including anxiety and depression. Enteric glial cells (EGCs) are important components of the gut-brain axis and are involved in the development of the enteric nervous system (ENS), intestinal neuroimmune, and regulation of intestinal motor functions. Since there is limited research encompassing the regulatory function of EGCs in anxiety- and depression-like behaviors induced by UC, this study aims to reveal their regulatory role in such behaviors and associated intestinal inflammation. This study applied morphological, molecular biological, and behavioral methods to observe the morphological and functional changes of EGCs in UC mice. The results indicated a significant activation of EGCs in the ENS of dextran sodium sulfate -induced UC mice. This activation was evidenced by morphological alterations, such as elongation or terminal swelling of processes. Besides EGCs activation, UC mice exhibited significantly elevated expression levels of pro-inflammatory cytokines in the peripheral blood, accompanied by anxiety- and depression-like behaviors. The inhibition of EGCs activity within the ENS can ameliorate the anxiety- and depression-like behaviors caused by UC. Our data suggest that UC and its resulting behaviors may be related to the activation of EGCs within the ENS. Moreover, the modulation of intestinal inflammation through inhibition of EGCs activation emerges as a promising clinical approach for alleviating UC-induced anxiety- and depression-like behaviors.