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PURPOSE: This study aimed to develop a Quality of Life (QOL) assessment scale for older patients with Neuro-co-Cardiological Diseases (NCCD) and to evaluate the reliability and validity of the scale. METHOD: The study participants were derived from the Elderly Individuals with NCCD Registered Cohort Study (EINCCDRCS), a multicenter registry of patients with NCCD. The preliminary testing of the questionnaire was conducted among 10 older individuals aged 65 years and older who had NCCD and were recruited from the registry. Other patients who met the inclusion criteria participated in the field testing. After verifying the unidimensionality, local independence, and monotonicity assumptions of the scale, we employed the Rasch model within Item Response Theory framework to assess the quality of the scale through methods including internal consistency, criterion validity, Wright map, and item functioning differential. Subsequently, we assessed the construct validity of the scale by combining exploratory factor analysis with confirmatory factor analysis. RESULTS: Based on well-validated scales such as the short-form WHOQOL-OLD, HeartQOL, IQCODE, and SF-36, an original Neuro-co-Cardiological Diseases Quality of Life scale (NCCDQOL) was developed. 196 individuals from the EINCCDRCS were included in the study, with 10 participating in the preliminary testing and 186 in the field testing. Based on the results of the preliminary testing, the original questionnaire was refined through item deletion and adjustment, resulting in an 11-item NCCDQOL questionnaire. The Rasch analysis of the field testing data led to the removal of 21 misfitting individuals. The NCCDQOL demonstrated a four-category structure, achieved by combining two response categories. This structure aligned with the assumptions of unidimensionality, local independence, and monotonicity. The NCCDQOL also exhibited good validity and reliability. CONCLUSION: The revised NCCDQOL questionnaire demonstrated good reliability and validity in the Rasch model, indicating promising potential for clinical application.
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Calidad de Vida , Humanos , Calidad de Vida/psicología , Anciano , Masculino , Femenino , Encuestas y Cuestionarios/normas , Estudios de Cohortes , Anciano de 80 o más Años , Enfermedades del Sistema Nervioso/psicología , Enfermedades del Sistema Nervioso/diagnóstico , Cardiopatías/psicología , Cardiopatías/diagnóstico , Reproducibilidad de los Resultados , Sistema de Registros , ComorbilidadRESUMEN
The association between the red blood cell distribution width-platelet ratio (RPR) and mortality in heart failure patients remains unclear. We aimed to investigate the potential non-linear relationship between RPR and 1-year mortality risk. A retrospective cohort study was conducted involving 6982 participants from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Multivariable Cox regression and restricted cubic spline analyses were performed to evaluate the association between RPR and 1-year mortality, adjusting for potential confounders. We observed 1091 patients died in hospital and 2535 patients died during 1 year follow-up period. The prevalence or incidence of mortality did not show statistically significant differences among RPR groups in the overall study population. However, a positive association between RPR and the risk of mortality was noted after adjusting for multiple variables (HR = 1.38, 95 % CI = 1.06-1.81, P = 0.018). Analysis using restricted cubic splines indicated a U-shaped relationship between RPR levels and the risk of mortality (P nonlinearity <0.05), with the point of lowest risk at 0.104. Compared to this level, lower RPR (<0.104) was associated with increased mortality (HR = 0.046, 95 % CI: 0.004-0.546), as was higher RPR (>0.104) (HR = 2.656, 95 % CI: 1.692-4.170).This U-shaped association was consistent across subgroup analyses (all interaction P values > 0.05). RPR exhibits a U-shaped association with 1-year mortality in heart failure patients, suggesting both low and high RPR levels are linked to increased risk. RPR may serve as a relevant biomarker for risk stratification in this population. We incorporated RPR into the SOFA (AUC 0.731) and SAPS II (AUC 0.746) models, which significantly improved their predictive ability for in-hospital mortality. For 1-year mortality prediction, RPR + SAPS II (AUC 0.683) showed significantly improved accuracy, while RPR + SOFA (AUC 0.626) did not improve significantly.
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BACKGROUND: Extrachromosomal circular DNAs (eccDNAs), a type of double-stranded DNAs (dsDNAs) that facilitate the activation of the DNA sensing machinery, have been implicated in the progression and prognosis of various diseases. While the roles of eccDNAs remain contentious, their significance in diffuse large B-cell lymphoma (DLBCL) has not been reported. METHODS: Circular DNA sequencing (circle-seq) was used to demonstrate the expression profile of eccDNAs in DLBCL, and atomic force microscopy to validate the presence of eccDNAs. CCK-8 and scRNA-seq techniques were employed to uncover the activation of eccDNA in the STING pathway, leading to enhanced cell proliferation. Chemotherapeutic drugs were used to test the hypothesis that DNA damage induces the production of eccDNA, thereby activating the STING pathway independent of cGAS. GEO databases were used for verification of the prognosis of the eccDNA-related genes, and animal models were used to investigate the synergistic effects of DNA damage therapy in combination with STING inhibitors on anti-tumour responses. RESULTS: EccDNAs were widely expressed in DLBCL and associated with the prognosis of patients. Elevated abundance of eccDNAs promoted the progression of DLBCL. Chemotherapeutic drugs-induced DNA damage triggered the generation of eccDNAs, resulting in the activation of the STING signalling in a cGAS-independent manner. Moreover, inhibition of STING exerted a synergistic anti-tumour effect with cisplatin. CONCLUSIONS: EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. This finding offers a rational therapeutic strategy combining chemotherapy with targeting STING. HIGHLIGHTS: EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. The combined treatment of chemotherapeutic drugs with STING inhibitor significantly delayed the tumor progression, providing new insights into the therapeutic strategy for patients with DLBCL, particularly the relapsed and/or refractory (R/R) ones.
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Linfoma de Células B Grandes Difuso , Proteínas de la Membrana , Transducción de Señal , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Transducción de Señal/genética , Animales , Ratones , MultiómicaRESUMEN
BACKGROUND: Intracranial haemorrhage (ICH) poses a significant threat to patients on Direct Oral Anticoagulants (DOACs), with existing risk scores inadequately predicting ICH risk in these patients. We aim to develop and validate a predictive model for ICH risk in DOAC-treated patients. METHODS: 24,794 patients treated with a DOAC were identified in a province-wide electronic medical and health data platform in Tianjin, China. The cohort was randomly split into a 4:1 ratio for model development and validation. We utilized forward stepwise selection, Least Absolute Shrinkage and Selection Operator (LASSO), and eXtreme Gradient Boosting (XGBoost) to select predictors. Model performance was compared using the area under the curve (AUC) and net reclassification index (NRI). The optimal model was stratified and compared with the DOAC model. RESULTS: The median age is 68.0 years, and 50.4% of participants are male. The XGBoost model, incorporating six independent factors (history of hemorrhagic stroke, peripheral artery disease, venous thromboembolism, hypertension, age, low-density lipoprotein cholesterol levels), demonstrated superior performance in the development dateset. It showed moderate discrimination (AUC: 0.68, 95% CI: 0.64-0.73), outperforming existing DOAC scores (ΔAUC = 0.063, P = 0.003; NRI = 0.374, P < 0.001). Risk categories significantly stratified ICH risk (low risk: 0.26%, moderate risk: 0.74%, high risk: 5.51%). Finally, the model demonstrated consistent predictive performance in the internal validation. CONCLUSION: In a real-world Chinese population using DOAC therapy, this study presents a reliable predictive model for ICH risk. The XGBoost model, integrating six key risk factors, offers a valuable tool for individualized risk assessment in the context of oral anticoagulation therapy.
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Hemorragias Intracraneales , Humanos , Masculino , Femenino , Anciano , Hemorragias Intracraneales/inducido químicamente , Persona de Mediana Edad , Administración Oral , Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Factores de Riesgo , Medición de Riesgo/métodosRESUMEN
Parkinson's disease (PD) is a multifactorial degenerative disease in the elder. Given the involvement of mammalian sterile 20-like kinase 1 (MST1) in PD, this article was to illustrate the mechanism of MST1 in 1-methyl-4-phenylpyridinium ion (MPP+)-induced PD cell model. Cells were treated with different concentrations of MPP+ to establish a PD cell model. Reverse transcription-quantitative polymerase chain reaction and Western blot revealed that MST1 expression and iron ion concentration increased, but cellular viability decreased with MPP+ concentration. Inhibition of MST1 decreased ferroptosis; increased cellular viability, iron ion content, and levels of glutathione peroxidase 4; and decreased reactive oxygen species and lactate dehydrogenase release. Upregulation of ferroptosis levels using ferroptosis agonist Erastin reduced the protective effect of MST1 inhibition on PD cells. Mechanistically, dual-luciferase analysis identified that miR-23b-3p targeted MST1 and inhibited its expression. Overexpression of miR-23b-3p inhibited MST1 levels, thereby reducing cellular ferroptosis and attenuating MPP+-induced cell injury. Collectively, MST1 expression increased with increasing MPP+ concentration, and miR-23b-3p targeted MST1 to reduce ferroptosis and MPP+-induced cell injury.
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BACKGROUND: Direct oral anticoagulants (DOACs) reduce stroke risk in patients with device-detected atrial fibrillation (DD-AFib) but increase major bleeding risk. The time to benefit (TTB) and time to harm (TTH) are not well quantified. OBJECTIVE: The purpose of this study was to determine TTB and TTH in DOAC-treated patients with DD-AFib. METHODS: Studies were identified from PubMed searching until November 2023. The primary efficacy outcome was the time to the first stroke event, and the primary safety outcome was the time to the first major bleeding event. Pooled hazard ratio (HR) and its confidence interval (CI) were calculated through reconstructed patient-level data and study-level data. Weibull model and Markov chain Monte Carlo simulation were applied to determine time to specific absolute risk change thresholds. RESULTS: Two trials involving DOACs-NOAH-AFNET 6 (Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes) and ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation)-were identified, which randomized 6548 adults with a mean age of >75 years and a median atrial high-rate episode duration ranging from 1.5 to 2.8 hours. DOACs decreased the risk of stroke (HR 0.67; 95% CI 0.50-0.90) but increased the risk of major bleeding (HR 1.57; 95% CI 1.21-2.04). A TTB of 2.67 years was needed to prevent 1 stroke per 100 DOAC-treated patients, while a TTH of 1.67 years was needed to observe 1 major bleeding. CONCLUSION: In elderly patients with low durations of DD-AFib, DOACs result in a delayed and restricted stroke-preventive benefit while posing an early-onset bleeding risk. Our findings offer new insights into the risk-benefit profile and provide clinicians an additional dimension to facilitate shared decision-making discussions with patients.
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In this work, rate coefficients of four prototypical insertion reactions, X + H2 â H + XH (X = C(1D), N(2D), O(1D), S(1D)), and associated isotope reactions are calculated based on ring polymer molecular dynamics (RPMD) with Cayley propagator (Cayley-RPMD). The associated kinetic isotope effects are systematically studied too. The Cayley propagator used in this work increases the stability of numerical integration in RPMD calculations and also supports a larger evolution time interval, allowing us to reach both high accuracy and efficiency. So, our results do not only provide chemical kinetic data for the title reactions in an extended temperature range but also consist of experimental results, standard RPMD, and other theoretical methods. The results in this work also reflect that Cayley-RPMD has strong consistency and high reliability in its investigations of chemical dynamics for insertion reactions.
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This work aims to expand the structure-property relationships of bromo-containing polyimides and the influence of bromine atoms on the gas separation properties of such materials. A series of intrinsically microporous polyimides were synthesized from 2,2'-dibromo-4,4',5,5'-bipohenyltetracarboxylic dianhydride (Br-BPDA) and five bulky diamines, (7,7'-(mesitylmethylene)bis(8-methyldibenzo[b,e][1,4]dioxin-2-amine) (MMBMA), 7,7'-(Mesitylmethylene)bis(1,8-dimethyldibenzo[b,e][1,4] dioxin-2-amine) (MMBDA), 4,10-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diamine (TBDA1), 4,10-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-3,9-diamine (TBDA2), and (9R,10R)-9,10-dihydro-9,10-[1,2]benzenoanthracene-2,6-diamine (DAT). The Br-BPDA-derived polyimides exhibited excellent solubility, high thermal stability, and good mechanical properties, with their tensile strength and modulus being 59.2-109.3 MPa and 1.8-2.2 GPa, respectively. The fractional free volumes (FFVs) and surface areas (SBET) of the Br-BPDA-derived polyimides were in the range of 0.169-0.216 and 211-342 m2 g-1, following the order of MMBDA > MMBMA > TBDA2 > DAT > TBDA1, wherein the Br-BPDA-MMBDA exhibited the highest SBET and FFV and thus highest CO2 permeability of 724.5 Barrer. Moreover, Br-BPDA-DAT displayed the best gas separation performance, with CO2, H2, O2, N2, and CH4 permeabilities of 349.8, 384.4, 69.8, 16.3, and 19.7 Barrer, and H2/N2 selectivity of 21.4. This can be ascribed to the ultra-micropores (<0.7 nm) caused by the high rigidity of Br-BPDA-DAT. In addition, all the bromo-containing polymers of intrinsic microporosity membranes exhibited excellent resistance to physical ageing.
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OBJECTIVE: The aim of this research was to examine how penehyclidine hydrochloride (PHC) impacts the occurrence of pyroptosis in lung tissue cells within a rat model of lung ischemia-reperfusion injury. METHODS: Twenty-four Sprague Dawley (SD) rats, weighing 250 g to 270 g, were randomly distributed into three distinct groups as outlined below: a sham operation group (S group), a control group (C group), and a test group (PHC group). Rats in the PHC group received a preliminary intravenous injection of PHC at a dose of 3 mg/kg. At the conclusion of the experiment, lung tissue and blood samples were collected and properly stored for subsequent analysis. The levels of malondialdehyde, superoxide dismutase, and myeloperoxidase in the lung tissue, as well as IL-18 and IL-1ß in the blood serum, were assessed using an Elisa kit. Pyroptosis-related proteins, including Caspase1 p20, GSDMD-N, and NLRP3, were detected through the western blot method. Additionally, the dry-to-wet ratio (D/W) of the lung tissue and the findings from the blood gas analysis were also documented. RESULTS: In contrast to the control group, the PHC group showed enhancements in oxygenation metrics, reductions in oxidative stress and inflammatory reactions, and a decrease in lung injury. Additionally, the PHC group exhibited lowered levels of pyroptosis-associated proteins, including the N-terminal segment of gasdermin D (GSDMD-N), caspase-1p20, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3). CONCLUSION: Pre-administration of PHC has the potential to mitigate lung ischemia-reperfusion injuries by suppressing the pyroptosis of lung tissue cells, diminishing inflammatory reactions, and enhancing lung function. The primary mechanism behind anti-pyroptotic effect of PHC appears to involve the inhibition of oxidative stress.
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Gasderminas , Pulmón , Piroptosis , Quinuclidinas , Ratas Sprague-Dawley , Daño por Reperfusión , Animales , Piroptosis/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Ratas , Quinuclidinas/farmacología , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Masculino , Malondialdehído/metabolismo , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-18/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Superóxido Dismutasa/metabolismo , Peroxidasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Caspasa 1/metabolismo , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/metabolismoRESUMEN
Essential hypertension is a notable threat for the older (age, ≥65 years) population. However, to the best of our knowledge, a real-world study assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablets in older Chinese patients with essential hypertension has not been performed. Therefore, the present study aimed to evaluate the efficacy and safety of OM-AML tablets in these patients. A total of 463 older Chinese patients with essential hypertension treated with OM-AML (20/5 mg) tablets (Sevikar®) were analyzed in a prospective, single-arm, multi-center, real-world study. Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, and at week (W)4 and W8 after OM-AML tablet administration were measured. The mean ± standard error change of SeSBP/SeDBP was -10.3±0.8/-4.6±0.5 and -12.5±0.8/-5.6±0.5 mmHg at W4 and W8, respectively. At W4, 74.1 and 26.8% of patients achieved BP target according to the China and American Heart Association (AHA) criteria, while at W8, 78.0 and 38.7% of patients reached these BP targets accordingly. Finally, 76.5 and 80.5% of patients achieved BP response at W4 and W8, respectively. Furthermore, home-measured SeSBP and SeDBP were significantly decreased from W1 to W8 (both P<0.001). Additionally, the satisfaction of both patients and physicians was elevated at W8 compared with at W0 (both P<0.001). The medication possession rate from baseline to W4 and W8 was 95.5 and 92.5%. The most common drug-associated adverse events by system organ classes were nervous system disorder (4.5%), vascular disorder (2.8%), and general disorder and administration site conditions (2.6%), which were generally mild. In conclusion, OM-AML tablets may be considered effective and safe in lowering BP, enabling the achievement of guideline-recommended BP targets in older Chinese patients with essential hypertension.
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Congenital anomalies of the kidney and urinary tract (CAKUT) are primarily causal for end-stage renal disease and have significant implications for long-term survival. A total of 39 healthy controls and 94 children with chronic kidney disease (CKD) were enrolled (3-12 years old as children, 13-18 years old as adolescents), who were divided into CAKUT and Non-CAKUT according to the etiology of CKD. CKD group was further classified according to estimating glomerular filtration rate (eGFR). Circulating levels of inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemokine-1 (MCP-1), and transforming growth factor-ß1 (TGF-ß1) were analyzed. The relationship between these inflammatory markers with eGFR and the kidney injury parameter (urine protein) was investigated to assess their potential as early markers of disease progression. All circulating levels of these inflammatory cytokines were increased in CKD patients (including CAKUT and Non-CAKUT) compared with healthy subjects. The circulating levels of MCP-1 and TGF-ß1 were increased in CAKUT adolescents compared with CAKUT children. In CAKUT children, levels of MCP-1 and TGF-ß1 increased as CKD progressed, and MCP-1 and TGF-ß1 were negatively and significantly correlated with eGFR and positively with urine protein. MCP-1 and TGF-ß1 may contribute to the early detection of CKD and disease stage/progression in CAKUT children.
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There lacks real-world study with a large sample size assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM-AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM-AML (20/5 mg) tablet were analyzed in the current prospective, single-arm, multi-center, real-world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was -10.8 ± 0.4/-6.6 ± 0.3 mmHg at W4 and -12.7 ± 0.5/-7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home-measured SeSBP and SeDBP decreased from W1 to W8 (both p < .001). Besides, patients' and physicians' satisfaction were elevated at W8 compared with W0 (both p < .001). The medication possession rate was 94.8% from baseline to W4 and 91.3% from baseline to W8. The most common drug-related adverse events were nervous system disorders (4.6%), vascular disorders (2.6%), and general disorders and administration site conditions (2.3%) by system organ class, which were generally mild and manageable. In conclusion, OM-AML tablet is one of the best antihypertensive agents in patients with essential hypertension.
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Combinación Besilato de Amlodipino y Olmesartán Medoxomilo , Hipertensión , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Hipertensión/inducido químicamente , Olmesartán Medoxomilo/farmacología , Amlodipino/efectos adversos , Hidroclorotiazida/uso terapéutico , Tetrazoles/farmacología , Imidazoles/efectos adversos , Quimioterapia Combinada , Método Doble Ciego , Antihipertensivos/efectos adversos , Presión Sanguínea/fisiología , Hipertensión Esencial/tratamiento farmacológico , Leucemia Mieloide Aguda/inducido químicamente , Leucemia Mieloide Aguda/tratamiento farmacológicoRESUMEN
This work developed an optofluidic immunochip that uses whispering gallery mode with fiber laser enhancement, for the rapid detection of a key biomarker cardiac troponin I for acute myocardial infarction (AMI). The immunochip adopted an innovative design, using perforated hollow glass microspheres (HGMS) as carriers, with antibodies immobilized on the inner surface of the HGMS, thereby achieving ultra-low sample consumption. The performance of the immunochip was improved by fiber laser, including spectral width compression to 0.019 nm, optical signal-to-noise ratio amplification to 63.17 dB, and an enhancement in the limit of detection to 5 pg/mL. Moreover, this immunochip can provide results within 15 min, making it highly suitable for early AMI risk management. Compared to the standard electrochemiluminescence detection method, although some differences exist in the results of the immunochip due to the principle of detection and differences in antibody affinity, its positive reference value can be calculated as 0.0754 ng/mL, with a successful recognition rate of 88% for positive patients. The immunosensor is integrated on a polydimethylsiloxane substrate, with a compact size suitable for use in point-of-care devices and AMI self-screening, as well as rapid disease screening and microanalysis of various biomarkers, offering new possibilities for applications in these fields.
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Técnicas Biosensibles , Infarto del Miocardio , Humanos , Microesferas , Inmunoensayo , Infarto del Miocardio/diagnóstico , BiomarcadoresRESUMEN
An in-depth understanding of the pathogenesis and mechanisms of sleep disorders is important for finding reliable treatments and interventions in the future. This study aims to explore the effect of sleep deprivation by modified multiple platform-water maze (MMP-WM) on rat neurological function and Tau protein in the hippocampus, as well as the intervention effect of remimazolam. First, 40 Sprague Dawley (SD) rats were divided into a control group (no treatment), a Rem group (remimazolam), an MMP-WM group (sleep deprivation model in rats established by MMP-WM), and a combined group (MMP-WM + remimazolam). Five rats were randomly selected from each group for behavior tests at 1 d and 7 d of drug administration or sleep deprivation for Morris water maze and open field test. After that, the rats were executed, the hippocampus was isolated for Nissl staining, and the protein expression of phosphorylated Tau (p-Tau) in the CA1 region of the hippocampus was measured by immunohistochemistry. At 1 d, the status in the MMP-WM group was more similar to that in the control group The MMP-WM group showed sparsely arranged hippocampal CA1 neurons, reduced number of Nissl bodies, prolonged escape latency, decreased number of platform crossings and percentage of activity time in the central region, substantially increased p-Tau expression. In contrast, the combined group showed significant improvement in nerve injury, behavior test results, p-Tau at 7 d compared with the MMP-WM group and the same group at 1 d. In addition, detection of brain-derived neurotrophic factor (BDNF) and neurotransmitter levels in the cerebrospinal fluid also showed improved neurologic function in the combined group. These results confirm tha MMP-WM was effective in the establishment of sleep deprivation rat model that accurately reflects the pathological manifestations of sleep disorders in human, and the use of remimazolam effectively reversed the pathological damage in sleep-deprived rats.
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Privación de Sueño , Trastornos del Sueño-Vigilia , Humanos , Ratas , Animales , Proteínas tau , Ratas Sprague-Dawley , HipocampoRESUMEN
Chronic lymphocytic leukemia (CLL) is a hematological malignancy with high metabolic heterogeneity. N6-methyladenosine (m6A) modification plays an important role in metabolism through regulating circular RNAs (circRNAs). However, the underlying mechanism is not yet fully understood in CLL. Herein, an m6A scoring system and an m6A-related circRNA prognostic signature are established, and circTET2 as a potential prognostic biomarker for CLL is identified. The level of m6A modification is found to affect the transport of circTET2 out of the nucleus. By interacting with the RNA-binding protein (RBP) heterogeneous nuclear ribonucleoprotein C (HNRNPC), circTET2 regulates the stability of CPT1A and participates in the lipid metabolism and proliferation of CLL cells through mTORC1 signaling pathway. The mTOR inhibitor dactolisib and FAO inhibitor perhexiline exert a synergistic effect on CLL cells. In addition, the biogenesis of circTET2 can be affected by the splicing process and the RBPs RBMX and YTHDC1. CP028, a splicing inhibitor, modulates the expression of circTET2 and shows pronounced inhibitory effects. In summary, circTET2 plays an important role in the modulation of lipid metabolism and cell proliferation in CLL. This study demonstrates the clinical value of circTET2 as a prognostic indicator as well as provides novel insights in targeting treatment for CLL.
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Ácidos Grasos , Ribonucleoproteína Heterogénea-Nuclear Grupo C , Leucemia Linfocítica Crónica de Células B , ARN Circular , Humanos , Proliferación Celular , Ácidos Grasos/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo C/metabolismo , Leucemia Linfocítica Crónica de Células B/genética , Metabolismo de los Lípidos/genética , ARN Circular/metabolismoRESUMEN
In this work, the dynamics of a prototypical heavy-light-heavy abstract reaction, Cl(2P) + HCl â HCl + Cl(2P), is investigated both by constructing a new potential energy surface (PES) and by rate coefficient calculations. Both the permutation invariant polynomial neural network method and the embedded atom neural network (EANN) method, based on ab initio MRCI-F12+Q/AVTZ level points, are used for obtaining globally accurate full-dimensional ground state PES, with the corresponding total root mean square error being only 0.043 and 0.056 kcal/mol, respectively. In addition, this is also the first application of the EANN in a gas-phase bimolecular reaction. The saddle point of this reaction system is confirmed to be nonlinear. In comparison with both the energetics and rate coefficients obtained on both PESs, we find that the EANN is reliable in dynamic calculations. A full-dimensional approximate quantum mechanical method, ring-polymer molecular dynamics with a Cayley propagator, is employed to obtain the thermal rate coefficients and kinetic isotopic effects of the title reaction Cl(2P) + XClâ XCl + Cl(2P) (H, D, Mu) on both new PESs, and the kinetic isotope effect (KIE) is also obtained. The rate coefficients reproduce the experimental results at high temperatures perfectly but with moderate accuracy at lower temperatures, but the KIE is with high accuracy. The similar kinetic behavior is supported by quantum dynamics using wave packet calculations as well.
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Elementary gas-surface processes are essential steps in heterogeneous catalysis. A predictive understanding of catalytic mechanisms remains challenging due largely to difficulties in accurately characterizing the kinetics of such steps. Experimentally, thermal rates for elementary surface reactions can now be measured using a novel velocity imaging technique, providing a stringent testing ground for ab initio rate theories. Here, we propose to combine ring polymer molecular dynamics (RPMD) rate theory with state-of-the-art first-principles-determined neural network potential to calculate surface reaction rates. Taking NO desorption from Pd(111) as an example, we show that the harmonic approximation and the neglect of lattice motion in the commonly-used transition state theory overestimates and underestimates the entropy change during the desorption process, respectively, leading to opposite errors in rate coefficient predictions and artificial error cancellations. Including anharmonicity and lattice motion, our results reveal a generally neglected surface entropy change due to significant local structural change during desorption and obtain the right answer for the right reasons. Although quantum effects are found to be less important in this system, the proposed approach establishes a more reliable theoretical benchmark for accurately predicting the kinetics of elementary gas-surface processes.
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Since the western region of China, which is typical of extraordinary resource endowments, has gradually emerged as the major mining zone in China, the mining of thick coal seams and roadways with coal-rock composite roof have become more and more common in this region. However, it is extremely difficult to realize safe and effective maintenance and control of such roadways due to the differences in natural endowments of coal-rock masses. With the roadway with coal-rock composite roof of Hulusu Coal Mine in western China as the engineering background, experiment research on large-scale similarity model was conducted through comprehensive measures such as the pneumatic loading system, the surrounding rock stress monitoring system, the roadway deformation monitoring system, the bolt load monitoring system, and the displacement field monitoring system in this paper. According to the results of the experiment, the control effects of the three support systems on the roadway with coal-rock composite roof were significantly different. When the single support of short anchor bolts was applied, the comparatively low initial anchor-hold failed to constrain the initial micro deformation of the roof. Consequently, wide-range fractures of the roof were triggered at a loading pressure of 0.8 MPa. In the meanwhile, the deep surrounding rocks witnessed a downward inflection point in stress, accompanied by the possibility of the collapse of the thin-layer anchorage zone at any time. As for the support combining both short anchor bolts and long anchor cables, though a reinforced effect on the bolt anchorage zone could be achieved with the help of the cables, the active reinforcement capacity of the bolt was limited. The bolt anchorage zone was the first to be damaged at a loading pressure of 0.9 MPa, which would subsequently affect the effective bearing capacity of the deep surrounding rocks. In the application of the single support of high-strength long anchor bolts, the long bolts with high pre-tightening force were able to lock multiple groups of coal-rock strata to form a thick-layer anchorage bearing structure capable of withstanding a load as high as 1.0 MPa. The crash and collapse of the coal wall eventually caused the subsidence of the roof. Based on the intense dynamic load experiment and the feedbacks of engineering application outcomes in the field, it was concluded that the high-pretension thick-layer (HPTL) anchoring technology can effectively constrain the deformation of roadways with coal-rock composite roof with favorable application outcomes.
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ABSTRACT: The clinical efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in reducing major cardiovascular adverse events related to atherosclerotic cardiovascular disease (ASCVD) has been well established in recent large randomized outcome trials. Although the cardiovascular and all-cause mortality benefit of PCSK9i remains inconclusive, current cholesterol management guidelines have been modified toward more aggressive goals for lowering low-density lipoprotein cholesterol (LDL-C). Consequently, the emerging concept of "the lower the better" has become the paradigm of ASCVD prevention. However, there is evidence from observational studies of a U-shaped association between baseline LDL-C levels and all-cause mortality in population-based cohorts. Among East Asian populations, low LDL-C was associated with an increased risk for hemorrhagic stroke in patients not on antithrombotic therapy. Accumulating evidence showed that low LDL-C was associated with an enhanced bleeding risk in patients on dual antiplatelet therapy following percutaneous coronary intervention. Additionally, low LDL-C was associated with a higher risk for incident atrial fibrillation and thereby, a possible increase in the risk for intracranial hemorrhage after initiation of anticoagulation therapy. The mechanism of low-LDL-C-related bleeding risk has not been fully elucidated. This review summarizes recent evidence of low-LDL-C-related bleeding risk in patients on antithrombotic therapy and discusses potential measures for reducing this risk, underscoring the importance of carefully weighing the pros and cons of aggressive LDL-C lowering in patients on antithrombotic therapy.