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An unexpected, divergent and efficient approach toward furanoid-bridged fullerene dimers C120O and C120O2 was established under different solvent-free ball-milling conditions by simply using pristine C60 as the starting material, water as the oxygen source and FeCl3 as the mediator. The structures of C120O and C120O2 were unambiguously established by single-crystal X-ray crystallography. A plausible reaction mechanism is proposed on the basis of control experiments. Furthermore, C120O2 has been applied in organic solar cells as the third component and exhibits good performance.
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Background: China exited strict Zero-COVID policy with a surge in Omicron variant infections in December 2022. Given China's pandemic policy and population immunity, employing Baidu Index (BDI) to analyze the evolving disease landscape and estimate the nationwide pneumonia hospitalizations in the post Zero COVID period, validated by hospital data, holds informative potential for future outbreaks. Methods: Retrospective observational analyses were conducted at the conclusion of the Zero-COVID policy, integrating internet search data alongside offline records. Methodologies employed were multidimensional, encompassing lagged Spearman correlation analysis, growth rate assessments, independent sample T-tests, Granger causality examinations, and Bayesian structural time series (BSTS) models for comprehensive data scrutiny. Results: Various diseases exhibited a notable upsurge in the BDI after the policy change, consistent with the broader trajectory of the COVID-19 pandemic. Robust connections emerged between COVID-19 and diverse health conditions, predominantly impacting the respiratory, circulatory, ophthalmological, and neurological domains. Notably, 34 diseases displayed a relatively high correlation (r > 0.5) with COVID-19. Among these, 12 exhibited a growth rate exceeding 50% post-policy transition, with myocarditis escalating by 1,708% and pneumonia by 1,332%. In these 34 diseases, causal relationships have been confirmed for 23 of them, while 28 garnered validation from hospital-based evidence. Notably, 19 diseases obtained concurrent validation from both Granger causality and hospital-based data. Finally, the BSTS models approximated approximately 4,332,655 inpatients diagnosed with pneumonia nationwide during the 2 months subsequent to the policy relaxation. Conclusion: This investigation elucidated substantial associations between COVID-19 and respiratory, circulatory, ophthalmological, and neurological disorders. The outcomes from comprehensive multi-dimensional cross-over studies notably augmented the robustness of our comprehension of COVID-19's disease spectrum, advocating for the prospective utility of internet-derived data. Our research highlights the potential of Internet behavior in predicting pandemic-related syndromes, emphasizing its importance for public health strategies, resource allocation, and preparedness for future outbreaks.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/epidemiología , China/epidemiología , Estudios Retrospectivos , Hospitalización/estadística & datos numéricos , Teorema de Bayes , Política de Salud , PandemiasRESUMEN
This paper analyzes the potential shortsightedness of enterprise managers through annual reports. Additionally, we use corporate financial statement data to measure enterprises over-financialization in terms of resource allocation. After testing with a causal inference model, we find that firms with managerial myopia significantly contribute to over-financialization. It remains robust even after the instrumental variable of whether the manager has experienced a famine is used. Furthermore, financial distress and financing constraints amplify the inclination of short-term-focused managers to amass greater financial assets.
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Administración Financiera , China , Humanos , Comercio/economíaRESUMEN
BACKGROUND: Detection of precachexia is important for the prevention and treatment of cachexia. However, how to identify precachexia is still a challenge. OBJECTIVE: This study aimed to detect cancer precachexia using a simple method and distinguish the different characteristics of precachexia and cachexia. METHODS: We included 3896 participants in this study. We used all baseline characteristics as input variables and trained machine learning (ML) models to calculate the importance of the variables. After filtering the variables based on their importance, the models were retrained. The best model was selected based on the receiver operating characteristic value. Subsequently, we used the same method and process to identify patients with precachexia in a noncachexia population using the same method and process. RESULTS: Participants in this study included 2228 men (57.2%) and 1668 women (42.8%), of whom 471 were diagnosed with precachexia, 1178 with cachexia, and the remainder with noncachexia. The most important characteristics of cachexia were eating changes, arm circumference, high-density lipoprotein (HDL) level, and C-reactive protein albumin ratio (CAR). The most important features distinguishing precachexia were eating changes, serum creatinine, HDL, handgrip strength, and CAR. The two logistic regression models for screening for cachexia and diagnosing precachexia had the highest area under the curve values of 0.830 and 0.701, respectively. Calibration and decision curves showed that the models had good accuracy. CONCLUSION: We developed two models for identifying precachexia and cachexia, which will help clinicians detect and diagnose precachexia.
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Caquexia , Aprendizaje Automático , Neoplasias , Humanos , Caquexia/etiología , Caquexia/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias/complicaciones , Anciano , Estudios de Cohortes , Proteína C-Reactiva/análisis , AdultoRESUMEN
INTRODUCTION: Hemolysis, elevated liver enzyme levels, and low platelet count (HELLP) syndrome is a pregnancy-related clinical condition characterized by hemolysis, elevated liver enzymes, and thrombocytopenia, posing significant risks to maternal and fetal safety. Hepatic hematoma with spontaneous rupture and bleeding is a rare but severe complication of HELLP syndrome, with limited reports of hepatic artery intervention and embolization therapy. PRESENTATION OF CASE: We present the case of a 35-year-old pregnant woman who developed worsening pain under the xiphoid process the night following a cesarean section. Her blood pressure dropped from 189/110 mmHg to 90/60 mmHg within 40 min. Vaginal exploration revealed no blood flow, and subsequent laparotomy uncovered multiple small liver surface lacerations actively bleeding. Emergency transcatheter arterial embolization (TAE) was promptly performed, stabilizing her condition. She was discharged 37 days post-admission. DISCUSSION: TAE plays an important role in the treatment of HELLP syndrome with spontaneous liver rupture, with characteristics of minimal trauma and good efficacy, but the evidence supporting this recommendation is somewhat limited. CONCLUSION: This case underscores TAE as a potentially effective and less invasive alternative to surgical interventions for managing HELLP syndrome with spontaneous liver rupture. Further research is needed to better clarify the safety and efficacy of TAE in the treatment of HELLP syndrome with spontaneous liver rupture.
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In this study, we redefine the diagnostic landscape of diabetic ulcers (DUs), a major diabetes complication. Our research uncovers new biomarkers linked to immunogenic cell death (ICD) in DUs by utilizing RNA-sequencing data of Gene Expression Omnibus (GEO) analysis combined with a comprehensive database interrogation. Employing a random forest algorithm, we have developed a diagnostic model that demonstrates improved accuracy in distinguishing DUs from normal tissue, with satisfactory results from ROC analysis. Beyond mere diagnosis, our model categorizes DUs into novel molecular classifications, which may enhance our comprehension of their underlying pathophysiology. This study bridges the gap between molecular insights and clinical practice. It sets the stage for transformative strategies in DUs management, marking a significant step forward in personalized medicine for diabetic patients.
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AIM: To assess the research capacity of 3014 clinical nurses in northeastern China, examining their participation in research and self-assessed competencies to advance nursing practice. BACKGROUND: Nursing research is essential for the development of the nursing discipline, yet significant progress in enhancing the research capabilities of nursing staff has been limited over the past decades. Clinical nurses, central to the execution of research activities, need improved research skills to identify relevant topics and synthesise clinical experiences with the literature. DESIGN: A cross-sectional survey. METHODS: In 2023, using a convenience sampling method, a cross-sectional questionnaire survey was conducted on 3014 nurses in a Grade A tertiary hospital. The questionnaire included questions on basic information and scientific research, as well as a self-evaluation scale assessing the nurses' capability for conducting scientific research. RESULTS: Among the nurses participating in the survey, 29.66% (894) had published academic papers in Chinese, 2.06% (62) had published papers in Science Citation Index journals, 2.39% (72) had hosted nursing research projects, 5.87% (177) had participated in nursing research projects and 71% (2140) expressed their willingness to participate in nursing research activities. The average score on the self-evaluation of research capability was 54.08 ± 24.55, with scores ranging from 0 to 120. CONCLUSION: The clinical nurses' research capacity scores are at the midpoint of the scale (0-120), indicating basic research capabilities with room for improvement. There is a high willingness to engage in research. Nursing managers should consider these factors in training programmes and promote research activities to improve the team's scientific capability. RELEVANCE TO CLINICAL PRACTICE: This study reveals a critical gap between nurses' willingness and actual involvement in research, emphasising the need for enhanced research skills to improve nursing practice. PATIENT OR PUBLIC CONTRIBUTION: This study did not require patient or public involvement in its design, outcome measures or execution. The contribution of patients/members of the public was limited solely to data collection.
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STUDY DESIGN: A retrospective, cross-sectional cohort study. OBJECTIVE: This study aims to investigate the association between paraspinal muscle parameters and single-segment degenerative lumbar spondylolisthesis (DLS). SUMMARY OF BACKGROUND DATA: The relationship between lumbar paraspinal muscles morphology and single-segment DLS remains unclear. METHODS: A retrospective review was conducted on 115 patients with L4/5 single-segment DLS and 105 subjects without DLS. Two independent investigators assessed the relative cross-sectional area and fat infiltration rate of the multifidus, erector spinae, and psoas major at L3/4, L4/5, and L5/S1 levels, comparing these measurements between the two groups. Additionally, binary logistic regression analysis was performed with DLS as the dependent variable to analyze the relative cross-sectional area and fat infiltration rate of different paraspinal muscles. Within the DLS group, the correlation between paraspinal muscle characteristics and the anteroposterior diameter of the spinal canal was examined. RESULTS: The fat infiltration rate of multifidus, erector spinae, and psoas major were higher in the DLS group than in the control group, while the relative cross-sectional area of multifidus and psoas major were lower in the DLS group. Binary logistic regression analysis revealed a significant correlation between fat infiltration rate of multifidus and psoas major and DLS. The relative cross-sectional area of multifidus and erector spinae was significantly smaller below the affected segment in the DLS group compared to the control group. A significant positive correlation was observed between the relative cross-sectional area of multifidus and erector spinae and the anteroposterior diameter of the spinal canal. CONCLUSION: There is a close association between paraspinal muscle degeneration and single-segment DLS, with increased relative cross-sectional area of the multifidus and psoas major possibly being risk factors for single-segment DLS. The restoration or enhancement of paraspinal muscle function could potentially serve as a pivotal target for the prevention and treatment of single-segment DLS. LEVEL OF EVIDENCE: III.
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INTRODUCTION: Evidence on the association between early-life malnutrition exposure at different developmental stages and the subsequent risk of osteoporosis and fractures in adulthood remains sparse and equivocal. This study sought to elucidate the relationship between malnutrition exposure in early life and the occurrence of osteoporosis and fractures later in life. METHODS: This research is a cross-sectional analysis carried out within the framework of the China Community-based Cohort of Osteoporosis (CCCO), an ongoing community-based cohort study. Participants were stratified by birthdate into several categories: non-exposed, fetal, early childhood, mid-childhood, late childhood, and adolescence exposure groups. The non-exposure and adolescence exposure groups were consolidated into an "age-matched group" to provide a robust comparative framework for analyzing the probability of developing osteoporosis (defined as a T-score ≤ -2.5 in bone mineral density) and the frequency of self-reported fracture. Multiple logistic regression models were utilized to investigate the association between early-life malnutrition exposure and the risks of osteoporosis and fracture. Additionally, we validated our findings using the China Northwest Cohort (CNC). RESULTS: A total of 12,789 participants were included into the final analysis. After adjusting for various covariates, individuals exposed to malnutrition during their fetal and childhood stages (early, middle, and late) increased the likelihood of developing osteoporosis in adulthood, compared to their age-matched counterparts. In these four groups, the ORs (95% CI) for osteoporosis risk were 1.223 (1.035 to 1.445), 1.208 (1.052 to 1.386), 1.249 (1.097 to 1.421), and 1.101 (1.001 to 1.210), respectively (all P values < 0.05). Specifically, the late childhood exposure group showed a heightened risk of fracture, with an OR (95% CI) of 1.155 (1.033 to 1.291) and a P-value of 0.01127. Stratified analyses further found a significant correlation between early-life exposure to malnutrition and an elevated risk of osteoporosis in participants with lower educational attainment, overweight or obese participants. Additionally, corroborating evidence from the CNC confirmed the influence of malnutrition exposure on osteoporosis risk. CONCLUSIONS: Early-life exposure to malnutrition had a detrimental impact on bone health. Individuals who had experienced malnutrition during fetal and childhood stages (early, middle, and late) exhibited a high susceptibility to osteoporosis in adulthood, compared to age-matched cohorts. This susceptibility was particularly pronounced in women, and individuals who were overweight or obese, or had lower levels of education.
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Four undescribed butanolides, linderangolides A-D (1-4), along with four known congeners, lincomolide A (5), (-)-epilitsenolide C2 (6), (-)-epilitsenolide C1 (7) and litseakolide H (8), were isolated from the roots of Lindera angustifolia. The planar structures of 1-4 were elucidated based on extensive spectroscopic analyses, the relative and absolute configurations of 1-4 were determined by the NOESY spectra and the comparison of calculated and experimental ECD. The cytotoxic activities of all isolated compounds were tested, 4 showed inhibitory activity against SGC-7 cells with IC50 value of 6.62 µM.
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Analysis of bacterial carbohydrate-active enzymes (CAZymes) contributes significantly to comprehending the response exhibited by coral symbionts to the external environment. This study explored the impact of bleaching on the bacteria and their CAZymes in coral Favites sp. through metagenomic sequencing. Notably, principal coordinates analysis (PCoA) unveiles substantial difference in bacterial communities between bleached and unbleached corals. Proteobacteria, Actinobacteria, Acidobacteria, Bacteroidota, and Chloroflexi, exhibit noteworthy alterations during coral bleaching. CAZymes profiles in bleached coral disclosed a significant increase in Glycosyltransferases (GTs) abundance, suggesting an intensified biosynthesis of polysaccharides. Conversely, there is a marked reduction in other CAZymes abundance in bleached coral. Proteobacteria, Bacteroidota, Chlorobi, and Planctomycetota exhibit greater contributions to CAZymes in bleached corals, with Rhodobacterales, Cytophagales, Burkholderiales, Caulobacterales, and Hyphomicrobiales being the main contributors. While Acidobacteria, Actinobacteria, and Chloroflexi demonstrate higher contributions to CAZymes in unbleached corals. The changes in bacteria and their CAZymes reflect the ecological adaptability of coral holobionts when facing environmental stress. The alterations in CAZymes composition caused by bleaching events may have profound impacts on coral nutrient absorption and ecosystem stability. Therefore, understanding the dynamic changes in CAZymes is crucial for assessing the health and recovery potential of coral ecosystems.
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Antozoos , Bacterias , Animales , Antozoos/microbiología , Bacterias/genética , Bacterias/enzimología , Simbiosis , MicrobiotaRESUMEN
Calcination of MgCO3 is an important industrial reaction, but it causes significant and unfavorable CO2 production. Calcination in a reducing green hydrogen atmosphere can substantially reduce CO2 release and produce high value-added products such as CO or hydrocarbons, but the mechanism is still unclear. Here, the in situ transformation process of MgCO3 interacting with hydrogen and the specific formation mechanism of the high value-added products are thoroughly investigated based on reaction thermodynamic, ab initio molecular dynamics (AIMD) simulations, and density functional theory (DFT) calculations. The reaction thermodynamic parameters of MgCO3 coupled with hydrogen to produce CO or methane are calculated, revealing that increasing and decreasing the thermal reductive decomposition temperature favors the production of CO and methane, respectively. Kinetically, the energy barriers of each possible production pathway for the dominant products CO and methane are further calculated in conjunction with the AIMD simulation results of the transformation process. The results suggest that CO is produced via the MgO catalytic-carboxyl pathway (CO2*â COOH*transâ COOH*cisâ CO*â CO), which is autocatalyzed by MgO derived from the thermal reductive decomposition of MgCO3. For the mechanism of methane formation, it prefers to be produced by the stepwise interaction of carbonates in the MgCO3 laminates with hydrogen adsorbed on their surfaces (direct conversion pathway: sur-O-CO â sur-O-HCO â sur-O-HCOH â sur-O-HC â sur-O-CH2 â sur-O-CH3 â sur-O + CH4*).
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BACKGROUND: Focal cortical dysplasia (FCD) is the most common epileptogenic developmental malformation. The diagnosis of FCD is challenging. We generated a radiomics nomogram based on multiparametric magnetic resonance imaging (MRI) to diagnose FCD and identify laterality early. METHODS: Forty-three patients treated between July 2017 and May 2022 with histopathologically confirmed FCD were retrospectively enrolled. The contralateral unaffected hemispheres were included as the control group. Therefore, 86 ROIs were finally included. Using January 2021 as the time cutoff, those admitted after January 2021 were included in the hold-out set (n = 20). The remaining patients were separated randomly (8:2 ratio) into training (n = 55) and validation (n = 11) sets. All preoperative and postoperative MR images, including T1-weighted (T1w), T2-weighted (T2w), fluid-attenuated inversion recovery (FLAIR), and combined (T1w + T2w + FLAIR) images, were included. The least absolute shrinkage and selection operator (LASSO) was used to select features. Multivariable logistic regression analysis was used to develop the diagnosis model. The performance of the radiomic nomogram was evaluated with an area under the curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration and clinical utility. RESULTS: The model-based radiomics features that were selected from combined sequences (T1w + T2w + FLAIR) had the highest performances in all models and showed better diagnostic performance than inexperienced radiologists in the training (AUCs: 0.847 VS. 0.664, p = 0.008), validation (AUC: 0.857 VS. 0.521, p = 0.155), and hold-out sets (AUCs: 0.828 VS. 0.571, p = 0.080). The positive values of NRI (0.402, 0.607, 0.424) and IDI (0.158, 0.264, 0.264) in the three sets indicated that the diagnostic performance of Model-Combined improved significantly. The radiomics nomogram fit well in calibration curves (p > 0.05), and decision curve analysis further confirmed the clinical usefulness of the nomogram. Additionally, the contrast (the radiomics feature) of the FCD lesions not only played a crucial role in the classifier but also had a significant correlation (r = -0.319, p < 0.05) with the duration of FCD. CONCLUSION: The radiomics nomogram generated by logistic regression model-based multiparametric MRI represents an important advancement in FCD diagnosis and treatment.
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Displasia Cortical Focal , Imágenes de Resonancia Magnética Multiparamétrica , Nomogramas , Radiómica , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Adulto Joven , Displasia Cortical Focal/diagnóstico por imagen , Lateralidad Funcional , Imágenes de Resonancia Magnética Multiparamétrica/métodos , Estudios RetrospectivosRESUMEN
Glioblastoma (GBM), known as the most malignant and common primary brain tumor of the central nervous system, has finite therapeutic options and a poor prognosis. Studies have shown that host intestinal microorganisms play a role in the immune regulation of parenteral tumors in a number of different ways, either directly or indirectly. However, the potential impact of gut microbiota on tumor microenvironment, particularly glioma immunological milieu, has not been clarified exactly. In this study, by using an orthotopic GBM model, we found gut microbiota dysbiosis caused by antibiotic cocktail treatment boosted the tumor process in vivo. An obvious change that followed gut microbiota dysbiosis was the enhanced percentage of M2-like macrophages in the TME, in parallel with a decrease in the levels of gut microbial metabolite, short-chain fatty acids (SCFAs) in the blood and tumor tissues. Oral supplementation with SCFAs can increase the proportion of M1-like macrophages in the TME, which improves the outcomes of glioma. In terms of mechanism, SCFAs-activated glycolysis in the tumor-associated macrophages may be responsible for the elevated M1 polarization in the TME. This study will enable us to better comprehend the "gut-brain" axis and be meaningful for the development of TAM-targeting immunotherapeutic strategies for GBM patients.
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Neoplasias Encefálicas , Disbiosis , Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Glioblastoma , Microambiente Tumoral , Glioblastoma/tratamiento farmacológico , Glioblastoma/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Disbiosis/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Ácidos Grasos Volátiles/metabolismo , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/metabolismo , Humanos , Ratones , Línea Celular Tumoral , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Progresión de la Enfermedad , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Ratones Endogámicos C57BL , Regulación hacia Arriba/efectos de los fármacos , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/metabolismo , MasculinoRESUMEN
Organic amides as solvents and structure directing agents (SDAs) are crucial for synthesizing zeolitic imidazolate frameworks (ZIFs). However, current research focuses only on the use of short alkyl-chain amides as solvents/SDAs. Here, we investigate the role of amides with varying alkyl-chain lengths on the structures and topologies of Zn(Im)2 polymorphs. Using short alkyl-chain amides as solvents, the Zn(Im)2 topological structures are affected by the synthesis conditions, leading to "one SDA/multiple topological structures". In contrast, when long alkyl-chain amides are used as solvents, the Zn(Im)2 topological structures are essentially unaffected by other synthesis conditions. Thus, long alkyl-chain amides are shown for the first time to exhibit a significant template role, leading to "one template/one topological structure". Specifically, the use of long alkyl-chain N,N-dimethyl-Cn amides (abbreviated as DM-Cn amides, n = 3, 4, 6, 8, and 10) can lead to only DTF-type Zn(Im)2 frameworks under broad crystallization conditions. Single-crystal X-ray diffraction confirmed that the exquisite structural compatibility between long alkyl-chain DM-Cn amides and the DFT-type Zn(Im)2 framework results in a highly regular head-to-tail arrangement of amides along the (kaa-lov) n chain of the DFT framework. The template role for long alkyl-chain amides was further identified to be multiple C-H···π interactions between DM-Cn amides and Zn(Im)2 frameworks thanks to molecular simulations.
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BACKGROUND: The prognostic value and clinical relevance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) in esophageal squamous cell carcinoma (ESCC) remain unclear. AIMS: To investigate the prognostic value and functional involvement of TILs in ESCC. METHODS: We included 40 patients across different stages of ESCC from Xinjiang. Multiplex fluorescent immunohistochemistry characterized TILs and TAMs. TILs in different tumor regions were quantified and correlated with overall survival (OS) using log-rank test and Cox regression analyses. RESULTS: Invasive ESCC exhibited increased CD4 T cells and Tregs compared to carcinoma in situ, with a higher Tregs/CD4 T cells ratio (p < 0.05). TAMs, primarily in stromal regions, were significantly associated with Foxp3+ cells (p < 0.05). Higher infiltration of stromal TAMs and a higher CD4/CD8 T cells ratio correlated with poorer OS, while a higher CD8 T/Foxp3+ cells ratio indicated better survival. Multivariate Cox analysis revealed TNM stage, tumor length, and stromal CD4/CD8 T cells ratio as independent prognostic factors (p < 0.05). An immune prognostic risk score-based nomogram was constructed to predict patient outcomes. CONCLUSIONS: The spatial distribution and abundance of TILs significantly correlated with prognosis, providing a useful immune classification for ESCC.
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BACKGROUND: Aging is an inevitable biological process. Accelerated aging renders adults more susceptible to chronic diseases and increases their mortality rates. Previous studies have reported the relationship between lifestyle factors and phenotypic aging. However, the relationship between intrinsic factors, such as reproductive factors, and phenotypic aging remains unclear. METHODS: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), spanning from 1999 to 2010 and 2015-2018, with 14,736 adult women. Random forest imputation was used to handle missing covariate values in the final cohort. Weighted linear regression was utilized to analyze the relationship between women-specific reproductive factors and PhenoAgeAccel. Considering the potential impact of menopausal status on the results, additional analyses were conducted on premenopausal and postmenopausal participants. Additionally, the Life's Essential 8 (LE8) was used to investigate the impact of healthy lifestyle and other factors on the relationship between women-specific reproductive factors and PhenoAgeAccel. Stratified analyses were conducted based on significant interaction p-values. RESULTS: In the fully adjusted models, delayed menarche and gynecological surgery were associated with increased PhenoAgeAccel, whereas pregnancy history were associated with a decrease. Additionally, early or late ages of menopause, first live birth, and last live birth can all negatively impact PhenoAgeAccel. The relationship between women-specific reproductive factors and PhenoAgeAccel differs between premenopausal and postmenopausal women. High LE8 scores positively impacted the relationship between certain reproductive factors (age at menarche, age at menopause, age at first live birth, and age at last live birth) and phenotypic age acceleration. Stratified analysis showed significant interactions for the following variables: BMI with age at menarche, pregnancy history, and age at menopause; ethnicity with age at menopause, age at first live birth, and parity; smoking status with use of contraceptive pills and gynecologic surgery; hypertension with use of contraceptive pills, pregnancy history, and age at menopause. CONCLUSION: Delayed menarche, gynecological surgery, and early or late ages of menopause, first live birth, and last live birth are associated with accelerated phenotypic aging. High LE8 score may alleviate the adverse effects of reproductive factors on phenotypic aging.
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Envejecimiento , Menarquia , Menopausia , Encuestas Nutricionales , Fenotipo , Humanos , Femenino , Adulto , Envejecimiento/fisiología , Persona de Mediana Edad , Encuestas Nutricionales/estadística & datos numéricos , Encuestas Nutricionales/métodos , Menopausia/fisiología , Menarquia/fisiología , Embarazo , Anciano , Reproducción/fisiología , Historia Reproductiva , Estilo de VidaRESUMEN
Efgartigimod was the first-in-class neonatal Fc receptor antagonist approved for the treatment of acetylcholine receptor antibody positive (AChR+), Myasthenia Gravis Foundation of America (MGFA) Class II-IV generalized myasthenia gravis (gMG) patients. As a novel therapy, the clinical experiences are still lacking, especially for the use of efgartigimod in manifest and impending myasthenic crisis (IMC). We reported three AChR+, gMG patients, two with myasthenic crisis (MC) and one with IMC, treated with efgartigimod. MGFA class, MG-Activity of Daily Living score (MG-ADL), Quantitative MG score (QMG), and Muscle Research Council sum score (MRC), concentration of anti-AChR antibody, IgG, globulin, and albumin, subsets of T and B lymphocyte were evaluated or measured before, during and after efgartigimod treatment. All patients showed fast and robust response to efgartigimod with marked improvement in MGFA, MG-ADL, QMG, and MRC scores. Patient 1 did not respond effectively to IVIg but was successfully rescued by add-on efgartigimod. She extubated at 7 days after the first infusion and got rid of NIV after 14-days treatment. Patient 2 and patient 3 directly used efgartigimod when symptoms were not ameliorated by adjusting of oral drugs. Patient 2 wean from BiPAP at seven days after the first infusion. Patient 3 in IMC status, overcame the severe dysphagia at three days after the first infusion. Clinical symptoms continued to improve 1-2 weeks after discharge. Concentration of anti-AChR antibody, IgG and globulin were remarkably reduced by efgartigimod treatment. Our study supported that efgartigimod could act as a fast-acting rescue therapy for patients with MC or IMC. Larger studies from multicenter are required to provide further evidence.
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Diversity, a hallmark of G protein-coupled receptor (GPCR) signaling, partly stems from alternative splicing of a single gene generating more than one isoform for a receptor. Additionally, receptor responses to ligands can be attenuated by desensitization upon prolonged or repeated ligand exposure. Both phenomena have been demonstrated and exemplified by the deuterostome tachykinin signaling system, although the role of phosphorylation in desensitization remains a subject of debate. Here, we describe the signaling system for tachykinin-related peptides (TKRPs) in a protostome, mollusk Aplysia. We cloned the Aplysia TKRP precursor, which encodes three TKRPs (apTKRP-1, apTKRP-2a, and apTKRP-2b) containing the FXGXR-amide motif. In situ hybridization and immunohistochemistry showed predominant expression of TKRP mRNA and peptide in the cerebral ganglia. TKRPs and their posttranslational modifications were observed in extracts of central nervous system ganglia using mass spectrometry. We identified two Aplysia TKRP receptors (apTKRPRs), named apTKRPR-A and apTKRPR-B. These receptors are two isoforms generated through alternative splicing of the same gene and differ only in their intracellular C termini. Structure-activity relationship analysis of apTKRP-2b revealed that both C-terminal amidation and conserved residues of the ligand are critical for receptor activation. C-terminal truncates and mutants of apTKRPRs suggested that there is a C-terminal phosphorylation-independent desensitization for both receptors. Moreover, apTKRPR-B also exhibits phosphorylation-dependent desensitization through the phosphorylation of C-terminal Ser/Thr residues. This comprehensive characterization of the Aplysia TKRP signaling system underscores the evolutionary conservation of the TKRP and TK signaling systems, while highlighting the intricacies of receptor regulation through alternative splicing and differential desensitization mechanisms.
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Aplysia , Isoformas de Proteínas , Animales , Aplysia/metabolismo , Fosforilación , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/genética , Receptores de Taquicininas/metabolismo , Receptores de Taquicininas/genética , Taquicininas/metabolismo , Taquicininas/genética , Secuencia de Aminoácidos , Transducción de Señal , Empalme Alternativo , HumanosRESUMEN
The regulation of the cancer cell cycle heavily relies on cyclin-dependent kinases (CDKs). Targeting CDKs has been identified as a promising approach for effective cancer therapy. In recent years, there has been significant attention paid towards developing small-molecule CDK inhibitors in the field of drug discovery. Notably, five such inhibitors have already received regulatory approval for the treatment of different cancers, including breast tumors, lung malignancies, and hematological malignancies. This review provides an overview of the synthetic routes used to produce 17 representative small-molecule CDK inhibitors that have obtained regulatory approval or are currently being evaluated through clinical trials. It also discusses their clinical applications for treating CDK-related diseases and explores the challenges and limitations associated with their use in a clinical setting, which will stimulate the further development of novel CDK inhibitors. By integrating therapeutic applications, synthetic methodologies, and mechanisms of action observed in various clinical trials involving these CDK inhibitors, this review facilitates a comprehensive understanding of the versatile roles and therapeutic potential offered by interventions targeting CDKs.