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SUMMARY: Recent technical advancements in single-cell chromatin accessibility sequencing (scCAS) have brought new insights to the characterization of epigenetic heterogeneity. As single-cell genomics experiments scale up to hundreds of thousands of cells, the demand for computational resources for downstream analysis grows intractably large and exceeds the capabilities of most researchers. Here, we propose EpiCarousel, a tailored Python package based on lazy loading, parallel processing, and community detection for memory- and time-efficient identification of metacells, i.e. the emergence of homogenous cells, in large-scale scCAS data. Through comprehensive experiments on five datasets of various protocols, sample sizes, dimensions, number of cell types, and degrees of cell-type imbalance, EpiCarousel outperformed baseline methods in systematic evaluation of memory usage, computational time, and multiple downstream analyses including cell type identification. Moreover, EpiCarousel executes preprocessing and downstream cell clustering on the atlas-level dataset with 707 043 cells and 1 154 611 peaks within 2 h consuming <75 GB of RAM and provides superior performance for characterizing cell heterogeneity than state-of-the-art methods. AVAILABILITY AND IMPLEMENTATION: The EpiCarousel software is well-documented and freely available at https://github.com/biox-nku/epicarousel. It can be seamlessly interoperated with extensive scCAS analysis toolkits.
Subject(s)
Chromatin , Single-Cell Analysis , Software , Chromatin/metabolism , Single-Cell Analysis/methods , Humans , Genomics/methods , Computational Biology/methodsABSTRACT
Perovskite oxides are proven as a striking platform for developing high-performance electrocatalysts. Nonetheless, a significant portion of them show CO2 electroreduction (CO2RR) inertness. Here a simple but effective strategy is reported to activate inert perovskite oxides (e.g., SrTiO3) for CO2RR through slight Cu2+ doping in B-sites. For the proof-of-concept catalysts of SrTi1-xCuxO3 (x = 0.025, 0.05, and 0.1), Cu2+ doping (even in trace amount, e.g., x = 0.025) can not only create active, stable CuO6 octahedra, increase electrochemical active surface area, and accelerate charge transfer, but also significantly regulate the electronic structure (e.g., up-shifted band center) to promote activation/adsorption of reaction intermediates. Benefiting from these merits, the stable SrTi1-xCuxO3 catalysts feature great improvements (at least an order of magnitude) in CO2RR activity and selectivity for high-order products (i.e., CH4 and C2+), compared to the SrTiO3 parent. This work provides a new avenue for the conversion of inert perovskite oxides into high-performance electrocatalysts toward CO2RR.
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All-hydrogel supercapacitors are emerging as promising power sources for next-generation wearable electronics due to their intrinsic mechanical flexibility, eco-friendliness, and enhanced safety. However, the insufficient interfacial adhesion between the electrode and electrolyte and the frozen hydrogel matrices at subzero temperatures largely limit the practical applications of all-hydrogel supercapacitors. Here, an all-hydrogel supercapacitor is reported with robust interfacial contact and anti-freezing property, fabricated by in situ polymerizing hydrogel electrolyte onto hydrogel electrodes. The robust interfacial adhesion is developed by the synergistic effect of a tough hydrogel matrix and topological entanglements. Meanwhile, the incorporation of zinc chloride (ZnCl2) in the hydrogel electrolyte prevents the freezing of water solvents and endows the all-hydrogel supercapacitor with mechanical flexibility and fatigue resistance across a wide temperature range of 20 °C to -60 °C. Such all-hydrogel supercapacitor demonstrates satisfactory low-temperature electrochemical performance, delivering a high energy density of 11 mWh cm-2 and excellent cycling stability with a capacitance retention of 90% over 10000 cycles at -40 °C. Notably, the fabricated all-hydrogel supercapacitor can endure dynamic deformations and operate well under 2000 tension cycles even at -40 °C, without experiencing delamination and electrochemical failure. This work offers a promising strategy for flexible energy storage devices with low-temperature adaptability.
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A highly viable alternative to lithium-ion batteries for stationary electrochemical energy-storage systems is the potassium dual-ion hybrid capacitor (PIHC), especially toward fast-charging capability. However, the sluggish reaction kinetics of negative electrode materials seriously impedes their practical implementation. In this paper, a new negative electrode Bi@RPC (Nano-bismuth confined in nitrogen- and oxygen-doped carbon with rationally designed pores, evidenced by advanced characterization) is developed, leading to a remarkable electrochemical performance. PIHCs building with the active carbon YP50F positive electrode result in a high operation voltage (0.1-4 V), and remarkably well-retained energy density at a high-power density (11107 W kg-1 at 98 Wh kg-1). After 5000 cycles the proposed PHICs still show a superior capacity retention of 92.6%. Moreover, a reversible mechanism of "absorption-alloying" of the Bi@RPC nanocomposite is revealed by operando synchrotron X-ray diffraction and Raman spectroscopy. With the synergistic potassium ions storage mechanism arising from the presence of well-structured pores and nano-sized bismuth, the Bi@RPC electrode exhibits an astonishingly rapid kinetics and high energy density. The results demonstrate that PIHCs with Bi@RPC-based negative electrode is the promising option for simultaneously high-capacity and fast-charging energy storage devices.
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BACKGROUND: The treatment regimen for tuberculous meningitis (TBM) remains unclear and requires optimization. There are some reports on successful adjunct intrathecal dexamethasone and isoniazid (IDI) treatment strategies for TBM, however, there is equivocal evidence on their efficacy and safety. METHODS: A comprehensive search of English and Chinese databases was conducted from inception to February 2024. A meta-analysis was performed on randomized controlled trials (RCTs) estimating the effects of adjunct IDI on conventional anti-TB (C anti-TB) treatments or C anti-TB alone. Efficacy, adverse reaction rate, cerebrospinal fluid (CSF) leukocytes, and CSF protein were used as primary outcome indicators. CSF glucose, CSF chlorides, CSF pressure, recovery time for laboratory indicators and recovery time for clinical symptoms were used as secondary outcome indicators. RESULTS: A total of 17 studies involving 1360 (IDI group vs. C anti-TB group: 392 vs. 372; higher-dose IDI group vs. lower-dose IDI group: 319 vs. 277) patients were included in our analysis. Efficacy was significantly higher (RR 1.3, 95% CI 1.2-1.4, P < 0.001) and adverse reaction rate was significantly lower in the IDI groups (RR 0.59, 95% CI 0.37-0.92, P = 0.021). Furthermore, CSF leukocytes (WMD - 29.33, 95% CI [- 40.64 to-18.02], P < 0.001) and CSF protein (WMD - 0.79, 95%CI [-0.96 to-0.61], P < 0.001) were significantly lower in the IDI groups. Recovery time indicators were all shorter in the IDI groups, fever (SMD - 2.45, 95% CI [-3.55 to-1.35], P < 0.001), coma (SMD-3.75, 95% CI [-4.33 to-3.17], P < 0.001), and headache (SMD - 3.06, 95% CI [- 4.05 to-2.07], P < 0.001), respectively. Higher-dose IDI was more effective than lower-dose IDI (RR 1.23, 95% CI 1.14-1.33, P < 0.001), with no significant difference in adverse reaction rate between the two (RR 0.82, 95%CI 0.43-1.56, P = 0.544). CONCLUSION: Adjunct IDI with C anti-TB can enhance therapeutic outcomes and reduce adverse reaction rate in adult TBM patients, with higher-dose IDI showing superior efficacy. These findings highlight the potential of IDI as an adjunctive therapy in TBM management. However, more high-quality RCTs from more regions should be conducted to support our results. TRIAL REGISTRATION: Retrospectively registered in PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023388860 .
Subject(s)
Antitubercular Agents , Dexamethasone , Drug Therapy, Combination , Injections, Spinal , Isoniazid , Tuberculosis, Meningeal , Humans , Tuberculosis, Meningeal/drug therapy , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Isoniazid/administration & dosage , Isoniazid/therapeutic use , Isoniazid/adverse effects , Antitubercular Agents/administration & dosage , Antitubercular Agents/adverse effects , Antitubercular Agents/therapeutic use , Injections, Spinal/methods , Treatment Outcome , Randomized Controlled Trials as Topic/methodsABSTRACT
Lithium, a representative alkali metal, holds the coveted status of the "holy grail" in the realm of next-generation rechargeable batteries, owing to its remarkable theoretical specific capacity and low electrode potential. However, the inherent reactivity of Li metal inevitably results in the formation of the solid-electrolyte interphase (SEI) on its surface, adding complexity to the Li electrodeposition process compared to conventional metal electrodeposition. Attaining uniform Li deposition is crucial for ensuring stable, long-cycle performance and high Coulombic efficiency in Li metal batteries, which requires a comprehensive understanding of the underlying factors governing the electrodeposition process. This review delves into the intricate kinetics of Li electrodeposition, elucidating the multifaceted factors that influence charge and mass transfer kinetics. The intrinsic relationship between charge transfer kinetics and Li deposition is scrutinized, exploring how parameters such as current density and electrode potential impact Li nucleation and growth, as well as dendrite formation. Additionally, the applicability of classical mass-transfer-controlled electrodeposition models to Li anode systems is evaluated, considering the influence of ionic concentration and solvation structure on Li+ transport, SEI formation, and subsequent deposition kinetics. The pivotal role of SEI compositional structure and physicochemical properties in governing charge and mass transfer processes is underscored, with an emphasis on strategies for regulating Li deposition kinetics from both electrolyte and SEI perspectives. Finally, future directions in Li electrodeposition research are outlined, emphasizing the importance of ongoing exploration from a kinetic standpoint to fully unlock the potential of Li metal batteries.
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Cannabidiol (CBD), one of the major components extracted from the plant Cannabis sativa L., has been used as a prescription drug to treat seizures in many countries. CBD-induced male reproductive toxicity has been reported in animal models; however, the underlying mechanisms remain unclear. We previously reported that CBD induced apoptosis in primary human Leydig cells, which constitute the primary steroidogenic cell population in the testicular interstitium. In this study, we investigated the effects of CBD and its metabolites on TM3 mouse Leydig cells. CBD, at concentrations below 30 µM, reduced cell viability, induced G1 cell cycle arrest, and inhibited DNA synthesis. CBD induced apoptosis after exposure to high concentrations (≥ 50 µM) for 24 h or a low concentration (20 µM) for 6 days. 7-Hydroxy-CBD and 7-carboxy-CBD, the main CBD metabolites of CBD, exhibited the similar toxic effects as CBD. In addition, we conducted a time-course mRNA-sequencing analysis in both primary human Leydig cells and TM3 mouse Leydig cells to understand and compare the mechanisms underlying CBD-induced cytotoxicity. mRNA-sequencing analysis of CBD-treated human and mouse Leydig cells over a 5-day time-course indicated similar responses in both cell types. Mitochondria and lysosome dysfunction, oxidative stress, and autophagy were the major enriched pathways in both cell types. Taken together, these findings demonstrate comparable toxic effects and underlying mechanisms in CBD-treated mouse and primary human Leydig cells.
Subject(s)
Apoptosis , Cannabidiol , Cell Survival , Leydig Cells , Cannabidiol/toxicity , Leydig Cells/drug effects , Leydig Cells/metabolism , Male , Animals , Humans , Mice , Cell Survival/drug effects , Apoptosis/drug effects , Oxidative Stress/drug effects , Cell Line , Mitochondria/drug effects , Mitochondria/metabolism , Cells, CulturedABSTRACT
Abundant studies have explored the relations among deviant peer affiliation, self-control, and aggression without separating within-person from between-person effects. Moreover, it is unclear whether self-control mediates the associations between deviant peer affiliation and aggression during early adolescence. This longitudinal study used Random Intercept Cross-Lagged Panel Model to examine the dynamic relations among deviant peer affiliation, self-control, and aggression within individuals, including examining whether self-control mediated the relations between deviant peer affiliation and aggression. A total of 4078 early adolescents (54% boys, Mage = 9.91, SD = 0.73) completed questionnaires on four occasions across 2 years. Results indicated: (a) Deviant peer affiliation and aggression positively predicted each other; (b) Self-control and aggression negatively predicted each other but were unstable; (c) Deviant peer affiliation and self-control negatively predicted each other; and (d) Self-control mediated the path from aggression to deviant peer affiliation, but not vice versa. The results more precisely identify the relations among deviant peer affiliation, self-control, and aggression within individuals, providing valuable information for prevention and intervention programs targeted at alleviating early adolescent aggression.
Subject(s)
Adolescent Behavior , Aggression , Peer Group , Self-Control , Humans , Aggression/psychology , Male , Female , Self-Control/psychology , Child , Longitudinal Studies , Adolescent , Adolescent Behavior/psychology , Surveys and QuestionnairesABSTRACT
The action of wind and waves has a significant effect on the ship's roll, which can be a source of chaos and even capsize. The influence of random wave excitation is considered in order to investigate complex dynamic behavior by analytical and numerical methods. Chaotic rolling motions are theoretically studied in detail by means of the relevant Melnikov method with or without noise excitation. Numerical simulations are used to verify and analyze the appropriate parameter excitation and noise conditions. The results show that by changing the parameters of the excitation amplitude or the noise intensity, chaos can be induced or suppressed.
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A graphene-based tunable polarization conversion metasurface (PCM) was designed and analyzed for the purpose of reducing the radar cross-section (RCS) of array antennas. The metasurface comprises periodic shuttle-shaped metal patches, square-patterned graphene, and inclined grating-patterned graphene. By adjusting the Fermi energy levels of the upper (µ1) and lower (µ2) graphene layers, different states were achieved. In State 1, with µ1 = 0 eV and µ2 = 0.5 eV, the polarization conversion ratio (PCR) exceeded 0.9 in the bandwidths of 1.65-2.19 THz and 2.29-2.45 THz. In State 2, with µ1 = µ2 = 0.5 eV, the PCR was greater than 0.9 in the 1.23-1.85 THz and 2.24-2.60 THz bands. In State 3, with µ1 = µ2 = 1 eV, the PCR exceeded 0.9 in the 2.56-2.75 THz and 3.73-4.05 THz bands. By integrating the PCM with the array antenna, tunable RCS reduction was obtained without affecting the basic radiation functionality of the antenna. In State 1, RCS reduction was greater than 10 dB in the 1.60-2.43 THz and 3.63-3.72 THz frequency ranges. In State 2, the RCS reduction exceeded 10 dB in the 2.07-2.53 THz, 2.78-2.98 THz, and 3.70-3.81 THz bands. In State 3, RCS reduction was greater than 10 dB in the 1.32-1.43 THz, 2.51-2.76 THz, and 3.76-4.13 THz frequency ranges. This polarization conversion metasurface shows significant potential for applications in switchable and tunable antenna RCS reduction.
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Foodborne contaminants refer to substances that are present in food and threaten food safety. Due to the progress in detection technology and the rising concerns regarding public health, there has been a surge in research focusing on the dangers posed by foodborne contaminants. These studies aim to explore and implement strategies that are both safe and efficient in mitigating the associated risks. Anthocyanins, a class of flavonoids, are abundantly present in various plant species, such as blueberries, grapes, purple sweet potatoes, cherries, mulberries, and others. Numerous epidemiological and nutritional intervention studies have provided evidence indicating that the consumption of anthocyanins through dietary intake offers a range of protective effects against the detrimental impact of foodborne contaminants. The present study aims to differentiate between two distinct subclasses of foodborne contaminants: those that are generated during the processing of food and those that originate from the surrounding environment. Furthermore, the impact of anthocyanins on foodborne contaminants was also summarized based on a review of articles published within the last 10 years. However, further investigation is warranted regarding the mechanism by which anthocyanins target foodborne contaminants, as well as the potential impact of individual variations in response. Additionally, it is important to note that there is currently a dearth of clinical research examining the efficacy of anthocyanins as an intervention for mitigating the effects of foodborne pollutants. Thus, by exploring the detoxification effect and mechanism of anthocyanins on foodborne pollutants, this review thereby provides evidence, supporting the utilization of anthocyanin-rich diets as a means to mitigate the detrimental effects of foodborne contaminants.
Subject(s)
Anthocyanins , Environmental Pollutants , Anthocyanins/pharmacology , Diet , Food Safety , FruitABSTRACT
Objective: The aims of this study were to examine the effect of SARS-CoV-2 infection on cardiorespiratory fitness (CRF) and time-trial performance in vaccinated well-trained young kayak athletes. Methods: This is a longitudinal observational study. Sixteen (7 male, 9 female) vaccinated kayakers underwent body composition assessment, maximal graded exercise test, and 1000-m time-trial tests 21.9 ± 1.7 days before and 66.0 ± 2.2 days after the SARS-CoV-2 infection. The perception of training load was quantified with Borg's CR-10 scale before and after the infection return to sport period. Results: There were significant decreases in peak oxygen uptake (-9.7 %; effect size [ES] = 1.38), peak oxygen pulse (-5.7 %; ES = 0.96), and peak heart rate (-1.9 %; ES = 0.61). Peak minute ventilation, and minute ventilation/carbon dioxide production slope were unchanged after infection compared to the pre-infection values. In the entire 1000-m, the impaired tendencies were found in completion time, mean power, and mean speed (-2.4 to 1.2 %; small ESs = -0.40 to 0.47) as well as significant changes in stroke rate and stroke length (-4.5 to 3.7 %; ESs = -0.60 to 0.73). Conclusion: SARS-CoV-2 infection decreased CRF and time-trial performance even two months after return to regular training in vaccinated athletes.
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OBJECTIVE: To evaluate the impact of combining action research theory with focus-solving short-term psychotherapy on the psychological stress, adjustment, and rehabilitation of patients with acute myocardial infarction (AMI) following percutaneous coronary intervention (PCI). METHODS: Between January 2022 and January 2023, a prospective study was conducted involving 300 AMI patients at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Participants were divided into a control group and a study group, with 150 patients in each. The control group received standard treatment and rehabilitation guidance, while the study group also received interventions based on action research theory and focus-solving short-term psychotherapy. Outcomes measured included scores from the Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Mental Health Inventory (MHI), National Institutes of Health Stroke Scale (NIHSS), Fugl-Meyer Assessment (FMA), Essential Skills for Caregivers Assessment (ESCA), and patient satisfaction. Prognostic factors were also analyzed. RESULTS: Post-intervention, the study group demonstrated significantly lower scores in HAMA and HAMD and reported less psychological pain, alongside higher scores in psychological well-being, compared to the control group (all P < 0.05). Additionally, the study group showed improved neurological function (NIHSS scores) and motor skills (FMA scores) as well as enhanced self-care abilities (higher ESCA scores) (all P < 0.05). Patient satisfaction was also notably higher in the study group (P < 0.05). Key prognostic factors included history of diabetes, Killip classification, and door-to-balloon (DTB) time. CONCLUSION: The integration of action research theory with focus-solving short-term psychotherapy significantly alleviated anxiety and depression in AMI patients post-PCI, enhanced their psychological adjustment, and facilitated the recovery of neurological and motor functions. This approach also improved self-care capabilities. Effective management of underlying conditions, vigilant monitoring of Killip classification, and minimization of DTB time are critical to reducing major adverse cardiac events and improving patient outcomes.
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BACKGROUND: Intervertebral disc degeneration (IDD) is an increasingly important cause of low back pain (LBP) that results in substantial health and economic burdens. Inflammatory pathway activation and the production of reactive oxygen species (ROS) play vital roles in the progression of IDD. Several studies have suggested that phillyrin has a protective role and inhibits inflammation and the production of ROS. However, the role of phillyrin in IDD has not been confirmed. PURPOSE: The purpose of this study was to investigate the role of phillyrin in IDD and its mechanisms. STUDY DESIGN: To establish IDD models in vivo, ex-vivo, and in vitro to verify the function of phillyrin in IDD. METHOD: The effects of phillyrin on extracellular matrix (ECM) degeneration, inflammation, and oxidation in nucleus pulposus (NP) cells were assessed using immunoblotting and immunofluorescence analysis. Additionally, the impact of phillyrin administration on acupuncture-mediated intervertebral disc degeneration (IDD) in rats was evaluated using various techniques such as MRI, HE staining, S-O staining, and immunohistochemistry (IHC). RESULT: Pretreatment with phillyrin significantly inhibited the IL-1ß-mediated reduction in the degeneration of ECM and apoptosis by alleviating activation of the NF-κB inflammatory pathway and the generation of ROS. In addition, in vivo and ex-vivo experiments verified the protective effect of phillyrin against IDD. CONCLUSION: Phillyrin can attenuate the progression of IDD by reducing ROS production and activating inflammatory pathways.
Subject(s)
Disease Progression , Intervertebral Disc Degeneration , NF-kappa B , Rats, Sprague-Dawley , Reactive Oxygen Species , Intervertebral Disc Degeneration/metabolism , Intervertebral Disc Degeneration/pathology , Animals , Reactive Oxygen Species/metabolism , NF-kappa B/metabolism , Rats , Male , Nucleus Pulposus/metabolism , Nucleus Pulposus/drug effects , Nucleus Pulposus/pathology , Signal Transduction/drug effects , Extracellular Matrix/metabolism , Extracellular Matrix/drug effects , Disease Models, Animal , Cells, Cultured , Humans , Apoptosis/drug effectsABSTRACT
Islet or ß-cell transplantation is currently considered to be the ideal treatment for diabetes, and three-dimensional (3D) bioprinting of a bionic pancreas with physiological stiffness is considered to be promising for the encapsulation and transplantation of ß-cells. In this study, a 5%GelMA/2%AlgMA hybrid hydrogel with pancreatic physiological stiffness was constructed and used for ß-cell encapsulation, 3D bioprinting, and in vivo transplantation to evaluate glycemic control in diabetic mice. The hybrid hydrogel had good cytocompatibility and could induce insulin-producing cells (IPCs) to form pseudoislet structures and improve insulin secretion. Furthermore, we validated the importance of betacellulin (BTC) in IPCs differentiation and confirmed that IPCs self-regulation was achieved by altering the nuclear and cytoplasmic distributions of BTC expression. In vivo transplantation of diabetic mice quickly restored blood glucose levels. In the future, 3D bioprinting of ß-cells using biomimetic hydrogels will provide a promising platform for clinical islet transplantation for the treatment of diabetes.
Subject(s)
Diabetes Mellitus, Experimental , Insulin-Secreting Cells , Mice , Animals , Diabetes Mellitus, Experimental/therapy , Hydrogels/pharmacology , Hydrogels/chemistry , Glycemic Control , Biomimetics , Insulin-Secreting Cells/metabolismABSTRACT
Hydroxychloroquine (HCQ), a derivative of chloroquine (CQ), is an antimalarial and antirheumatic drug. Since there is limited data available on the genotoxicity of HCQ, in the current study, we used a battery of in vitro assays to systematically examine the genotoxicity of HCQ in human lymphoblastoid TK6 cells. We first showed that HCQ is not mutagenic in TK6 cells up to 80 µM with or without exogenous metabolic activation. Subsequently, we found that short-term (3-4 h) HCQ treatment did not cause DNA strand breakage as measured by the comet assay and the phosphorylation of histone H2A.X (γH2A.X), and did not induce chromosomal damage as determined by the micronucleus (MN) assay. However, after 24-h treatment, both CQ and HCQ induced comparable and weak DNA damage and MN formation in TK6 cells; upregulated p53 and p53-mediated DNA damage responsive genes; and triggered apoptosis and mitochondrial damage that may partially contribute to the observed MN formation. Using a benchmark dose (BMD) modeling analysis, the lower 95% confidence limit of BMD50 values (BMDL50) for MN induction in TK6 cells were about 19.7 µM for CQ and 16.3 µM for HCQ. These results provide additional information for quantitative genotoxic risk assessment of these drugs.
Subject(s)
Hydroxychloroquine , Tumor Suppressor Protein p53 , Humans , Hydroxychloroquine/toxicity , Hydroxychloroquine/therapeutic use , Tumor Suppressor Protein p53/genetics , DNA Damage , Chloroquine/toxicity , Comet AssayABSTRACT
RATIONALE AND OBJECTIVES: This study aimed to investigate the prognostic value of preoperative CT scan-derived myocardial biomarkers in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). MATERIALS AND METHODS: In April 2024, three databases (PubMed, Web of Science and Embase) were searched to identify studies. A random-effects model for meta-analysis was conducted to calculate pooled hazard ratios (HR) and 95% confidence intervals (CI) to assess the prognostic value. The I2 statistic was used to assess heterogeneity. Meta-regression analysis was conducted to appraise which variables yielded a significant impact on the HR of included biomarkers. RESULTS: 11 studies were identified, of which six studies involved 678 patients reporting extracellular volume fraction (ECV), one study involved 300 patients reporting ECV and left ventricular global longitudinal strain (LVGLS), three studies involved 868 patients reporting LVGLS and one study involved 376 patients reporting LVGLS and peak left atrial longitudinal strain (PALS). The endpoints included all-cause mortality, major adverse cardiovascular events (MACE) and a composite outcome of the previous two. The meta-analysis revealed that ECV, whether considered as a dichotomous variable (pooled HR: 3.87, 95% CI: 2.63-5.70, I2 = 0%), or as a continuous variable (pooled HR: 1.12, 95% CI: 1.05-1.19, I2 = 66%), and LVGLS, whether considered as a dichotomous variable (pooled HR: 1.70, 95% CI: 1.30-2.22, I2 = 0%) or a continuous variable (pooled HR: 1.07, 95% CI: 1.04-1.10, I2 = 0%) were all significant predictors for outcomes in patients with severe AS after TAVR. Age, sex, follow-up time and mean pressure gradient had a significant impact on the model of ECV (continuous). CONCLUSION: The higher CT-derived ECV and impaired LVGLS are able to predict worse outcomes in patients with severe AS who have undergone TAVR.
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The epidermal growth factor (EGF)-like factors, comprising amphiregulin (AREG), betacellulin (BTC), and epiregulin (EREG), play a critical role in regulating the ovulatory process. Pentraxin 3 (PTX3), an essential ovulatory protein, is necessary for maintaining extracellular matrix (ECM) stability during cumulus expansion. The aim of this study was to investigate the impact of EGF-like factors, AREG, BTC, and EREG on the expression and production of PTX3 in human granulosa-lutein (hGL) cells and the molecular mechanisms involved. Our results demonstrated that AREG, BTC, and EREG could regulate follicular function by upregulating the expression and increasing the production of PTX3 in both primary (obtained from 20 consenting patients undergoing IVF treatment) and immortalized hGL cells. The upregulation of PTX3 expression was primarily facilitated by the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling pathway, induced by these EGF-like factors. In addition, we found that the upregulation of PTX3 expression triggered by the EGF-like factors was completely reversed by either pretreatment with the epidermal growth factor receptor (EGFR) inhibitor, AG1478, or knockdown of EGFR, suggesting that EGFR is crucial for activating the ERK1/2 signaling pathway in hGL cells. Overall, our findings indicate that AREG, BTC, and EREG may modulate human cumulus expansion during the periovulatory stage through the upregulation of PTX3.
Subject(s)
Amphiregulin , Betacellulin , C-Reactive Protein , Epiregulin , Luteal Cells , Serum Amyloid P-Component , Up-Regulation , Female , Humans , Amphiregulin/metabolism , Amphiregulin/genetics , Betacellulin/metabolism , C-Reactive Protein/metabolism , C-Reactive Protein/genetics , Epidermal Growth Factor/metabolism , Epidermal Growth Factor/pharmacology , Epiregulin/metabolism , Epiregulin/genetics , ErbB Receptors/metabolism , Luteal Cells/metabolism , MAP Kinase Signaling System , Serum Amyloid P-Component/metabolism , Serum Amyloid P-Component/geneticsABSTRACT
Increasing public interest has resulted in the widespread use of non-pharmaceutical cannabidiol (CBD) products. The sales of CBD products continue to rise, accompanied by concerns regarding unsubstantiated benefits, lack of product quality control, and potential health risks. Both animal and human studies have revealed a spectrum of toxicological effects linked to the use of CBD. Adverse effects related to exposure of humans to CBD include changes in appetite, gastrointestinal discomfort, fatigue, and elevated liver aminotransferase enzymes. Animal studies reported changes in organ weight, reproduction, liver function, and the immune system. This review centers on human-derived data, including clinical studies and in vitro investigations. Animal studies are also included when human data is not available. The objective is to offer an overview of CBD-related hepatotoxicity, metabolism, and potential CBD-drug interactions, thereby providing insights into the current understanding of CBD's impact on human health. It's important to note that this review does not serve as a risk assessment but seeks to summarize available information to contribute to the broader understanding of potential toxicological effects of CBD on the liver.
Subject(s)
Cannabidiol , Liver , Cannabidiol/toxicity , Humans , Liver/drug effects , Animals , Chemical and Drug Induced Liver InjuryABSTRACT
BACKGROUND: Several studies have suggested an association between major depressive disorder (MDD) and abnormal brain structure. However, it is unclear whether MDD affects cortical gray matter volume, a common indicator of cognitive function. We aimed to determine whether MDD was associated with decreased cortical gray matter volume (GMV) through a Mendelian randomization (MR) study. METHODS: We obtained summary genetic data from a study conducted by the Psychiatric Genomics Consortium, which recruited a total of 480,359 participants (135,458 cases and 344,901 controls). Genetic tools-single nucleotide polymorphisms (SNPs)-of MDD were extracted from the study and their effects on gray matter volumes of the cortex and total brain were evaluated in a large cohort from the UK Biobank (n = 8427). The effects of the SNPs were pooled using inverse variance weighted (IVW) analysis and further tested in several sensitivity analyses. We tested whether C-reactive protein (CRP) levels and interleukin-6 signaling were the mediators of the effects using a multivariate MR model. RESULTS: Thirty-three SNPs were identified and adopted as genetic tools for predicting MDD. IVW analysis showed that MDD was associated with lower overall GMV (beta value -0.106, 95%CI -0.188 to -0.023, p = 0.011) in the frontal pole (left frontal pole, -0.152, 95%CI -0.177 to -0.127, p = 0.013; right frontal pole, -0.133, 95%CI -0.253 to -0.013, p = 0.028). Multivariate and mediation analysis showed that interleukin-6 was an important mediator of GMV reduction. Reverse causality analysis found no evidence that total GMV affected the risk of MDD, but showed that increased left precuneus cortex volume and left posterior cingulate cortex volume were associated with increased risk of MDD. LIMITATIONS: Potential pleiotropic effects and overestimation of real-world effects. Key assumptions for MR analysis may not be satisfactorily met. CONCLUSION: MDD was associated with a reduced GMV, and interleukin-6 might be a mediator of GMV reduction.