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ETHNOPHARMACOLOGICAL RELEVANCE: Caryopteris trichosphaera W. W. Sm., a traditional ethnic medicine, was recorded in the Compendium of Materia Medica for treating wound infection by pathogenic infection. However, its antibacterial potential and bioactive compositions against drug-resistant bacteria need to be validated. AIM OF THE STUDY: To investigate the chemical constituents of C. trichosphaera and explore its anti-MRSA component in vitro and in vivo, together with the antibacterial mechanism. MATERIALS AND METHODS: Bioactive constituents investigation was carried out by phytochemical method and antibacterial screening. The antibacterial mechanism was predicted by network pharmacology, which was further validated by time-kill analysis, membrane function tests, multigenerational resistance induction assay and biofilm test, and metabolomics analysis in vitro. In addition, MRSA-induced epidermal infection in mice was selected to evaluate its pharmacological effect in vivo. RESULTS: Six antibacterial diterpenoids against MRSA and VRE with MIC values 4-32 µg/mL from C. trichosphaera were reported for the first time, in which the major compound cativic acid (1) disrupted MRSA cell membranes by modulating permeability, depolarization, and fluidity while increasing reactive oxygen species (ROS) and malondialdehyde (MDA) levels. It also displayed remarkable anti-biofilm activity without inducing bacterial resistance or cytotoxicity. Moreover, cativic acid affected MRSA biosynthesis of cofactors, amino acid biosynthesis, nucleotide metabolism by metabolomics analysis. Furthermore, cativic acid accelerated wound healing in MRSA-infected mouse skin wounds, even better than vancomycin. CONCLUSIONS: The results supported the traditional use of C. trichosphaera, and presented unreported anti-MRSA agent, cativic acid, as a plant-derived bactericide in vitro and in vivo for the first time.

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Intrinsic superconductivity is rarely discovered in sp2-hybridized monolayer carbon allotropes. Here we design a carbon monolayer configured of pentagon, heptagon, and hexagon rings with p2 plane group symmetry. Full-sp2 hybridization is proposed to favor thermal metastability on a low Gibbs free energy. The extremely small thermal expansion coefficient is predicted to the turn negative value to positive with elevating temperature. Carbon polygon structures remain intact at a high thermal temperature of 3,000 K. The high specific surface area is found to approach 2,700 m2/g, with O2-adsorption being advantageous over pristine graphene. We reveal electronic Fermi surfaces mediated by phonon modes of carbon out-of-plane vibrations. By calculating the Eliashberg equation, we evaluate intrinsic superconductivity with a large electron-phonon coupling coefficient. The superconducting transition temperature is estimated to reach 20 K under a high logarithmic average frequency. These first-principles calculations shall stimulate experimentalists' interest in exploring low-dimensional carbon superconductors with gas sensitivity.

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With rapidly evolving high-throughput technologies and consistently decreasing costs, collecting multimodal omics data in large-scale studies has become feasible. Although studying multiomics provides a new comprehensive approach in understanding the complex biological mechanisms of human diseases, the high dimensionality of omics data and the complexity of the interactions among various omics levels in contributing to disease phenotypes present tremendous analytical challenges. There is a great need of novel analytical methods to address these challenges and to facilitate multiomics analyses. In this paper, we propose a multimodal functional deep learning (MFDL) method for the analysis of high-dimensional multiomics data. The MFDL method models the complex relationships between multiomics variants and disease phenotypes through the hierarchical structure of deep neural networks and handles high-dimensional omics data using the functional data analysis technique. Furthermore, MFDL leverages the structure of the multimodal model to capture interactions between different types of omics data. Through simulation studies and real-data applications, we demonstrate the advantages of MFDL in terms of prediction accuracy and its robustness to the high dimensionality and noise within the data.

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Aprendizaje Profundo , Genómica , Humanos , Genómica/métodos , Biología Computacional/métodos , Redes Neurales de la Computación , Algoritmos , Multiómica

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Purpose: To construct a free and accurate breast cancer mortality prediction tool by incorporating lifestyle factors, aiming to assist healthcare professionals in making informed decisions. Patients and Methods: In this retrospective study, we utilized a ten-year follow-up dataset of female breast cancer patients from a major Chinese hospital and included 1,390 female breast cancer patients with a 7% (96) mortality rate. We employed six machine learning algorithms (ridge regression, k-nearest neighbors, neural network, random forest, support vector machine, and extreme gradient boosting) to construct a mortality prediction model for breast cancer. Results: This model incorporated significant lifestyle factors, such as postsurgery sexual activity, use of totally implantable venous access ports, and prosthetic breast wear, which were identified as independent protective factors. Meanwhile, ten-fold cross-validation demonstrated the superiority of the random forest model (average AUC = 0.918; 1-year AUC = 0.914, 2-year AUC = 0.867, 3-year AUC = 0.883). External validation further supported the model's robustness (average AUC = 0.782; 1-year AUC = 0.809, 2-year AUC = 0.785, 3-year AUC = 0.893). Additionally, a free and user-friendly web tool was developed using the Shiny framework to facilitate easy access to the model. Conclusion: Our breast cancer mortality prediction model is free and accurate, providing healthcare professionals with valuable information to support their clinical decisions and potentially promoting healthier lifestyles for breast cancer patients.

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BACKGROUND: At the beginning of December 2022, the Chinese government made major adjustments to the epidemic prevention and control measures. The epidemic infection data and laboratory makers for infected patients based on this period may help with the management and prognostication of COVID-19 patients. METHODS: The COVID-19 patients hospitalized during December 2022 were enrolled. Logistic regression analysis was used to screen significant factors associated with mortality in patients with COVID-19. Candidate variables were screened by LASSO and stepwise logistic regression methods and were used to construct logistic regression as the prognostic model. The performance of the models was evaluated by discrimination, calibration, and net benefit. RESULTS: 888 patients were eligible, consisting of 715 survivors and 173 all-cause deaths. Factors significantly associated with mortality in COVID-19 patients were: lactate dehydrogenase (LDH), albumin (ALB), procalcitonin (PCT), age, smoking history, malignancy history, high density lipoprotein cholesterol (HDL-C), lactate, vaccine status and urea. 335 of the 888 eligible patients were defined as ICU cases. Seven predictors, including neutrophil to lymphocyte ratio, D-dimer, PCT, C-reactive protein, ALB, bicarbonate, and LDH, were finally selected to establish the prognostic model and generate a nomogram. The area under the curve of the receiver operating curve in the training and validation cohorts were respectively 0.842 and 0.853. In terms of calibration, predicted probabilities and observed proportions displayed high agreements. Decision curve analysis showed high clinical net benefit in the risk threshold of 0.10-0.85. A cutoff value of 81.220 was determined to predict the outcome of COVID-19 patients via this nomogram. CONCLUSIONS: The laboratory model established in this study showed high discrimination, calibration, and net benefit. It may be used for early identification of severe patients with COVID-19.

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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , COVID-19/mortalidad , COVID-19/sangre , COVID-19/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , China/epidemiología , Anciano , L-Lactato Deshidrogenasa/sangre , Modelos Logísticos , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Adulto , Polipéptido alfa Relacionado con Calcitonina/sangre , Biomarcadores/sangre , Nomogramas , Curva ROC , Factores de Riesgo

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INTRODUCTION: Acute lung injury (ALI) as one kind of acute pulmonary inflammatory disorder, manifests primarily as damage to alveolar epithelial cells and microvascular endothelial cells. Activation of the complement system is a common pathological mechanism in ALI induced by diverse factors, with the complement alternative pathway assuming a pivotal role. Baicalin, a flavonoid derived from the root of Scutellaria baicalensis Georgi, exhibits noteworthy biological activities. The present study attempted the interventional effects and underlying mechanisms of baicalin in microangiopathy in ALI induced by complement alternative pathway activation. METHODS: Activation of the complement alternative pathway by cobra venom factor (CVF). HMEC cells were pretreated with baicalin and then exposed to complement activation products. The expression of inflammatory mediators was detected by ELISA, and the intranuclear transcriptional activity of NF-κB was assessed by a dual fluorescent kinase reporter gene assay kit. Before establishing the ALI mouse model, baicalin or PDTC was gavaged for 7 d. CVF was injected into the tail vein to establish the ALI model. The levels of inflammatory mediators in BALF and serum were determined by ELISA. HE staining and immunohistochemistry evaluated pathological changes, complement activation product deposition, and NF-κB p65 phosphorylation in lung tissue. RESULTS: Baicalin reduced complement alternative activation product-induced expression of HMEC cells adhesion molecules (ICAM-1, VCAM-1, E-selectin) and cytokines (IL-6, TNF-α) as well as upregulation of NF-κB intranuclear transcriptional activity. Baicalin intervention reduced the number of inflammatory cells and protein content in the BALF and decreased the levels of IL-6, TNF-α, and ICAM-1 in serum and IL-6, TNF-α, ICAM-1, and P-selectin in BLAF. In addition, baicalin attenuated inflammatory cell infiltration in the lung of ALI mice and reduced the deposition of complement activation products (C5a, C5b-9) and phosphorylation of NF-κB p65 in lung tissue. CONCLUSION: Baicalin relieves complement alternative pathway activation-induced lung inflammation by inhibition of NF-κB pathway, delaying the progression of ALI.

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Lesión Pulmonar Aguda , Flavonoides , FN-kappa B , Animales , Flavonoides/farmacología , Ratones , FN-kappa B/metabolismo , Lesión Pulmonar Aguda/tratamiento farmacológico , Humanos , Modelos Animales de Enfermedad , Masculino , Vía Alternativa del Complemento/efectos de los fármacos , Neumonía/tratamiento farmacológico , Ratones Endogámicos C57BL , Pulmón/efectos de los fármacos , Venenos Elapídicos/farmacología

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OBJECTIVES: To investigate the effects and molecular mechanisms of inhibition of the Ras homolog gene (Rho)/Rho-associated coiled-coil forming protein kinase (ROCK) pathway on the proliferation and migration of airway smooth muscle cells involving myocardin (MYOCD). METHODS: Human airway smooth muscle cells were infected with the adenoviral vector Ad-ZsGreen-shRNA-hROCK1 in vitro. The cells were randomly divided into four groups: ROCK1 gene silencing control (shNC) group, shNC + arachidonic acid (AA, Rho/ROCK pathway activator) group, ROCK1 gene silencing (shROCK1) group, and shROCK1 + AA group (n=3 each). Quantitative real-time polymerase chain reaction and Western blot were used to detect the expression levels of ROCK1 and MYOCD mRNA and protein. ELISA was employed to measure the levels of globular actin and filamentous actin, while immunofluorescent staining and scratch assays were utilized to assess cell proliferation and migration. RESULTS: Compared to the shNC + AA group, the shROCK1 + AA group exhibited decreased levels of ROCK1 and MYOCD mRNA and protein expression, reduced expression levels of globular actin and filamentous actin, and diminished cell proliferation and migration capabilities (P<0.05). CONCLUSIONS: Inhibition of the Rho/ROCK pathway suppresses the proliferation and migration of airway smooth muscle cells, which may be associated with the downregulation of MYOCD.

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Movimiento Celular , Proliferación Celular , Miocitos del Músculo Liso , Transducción de Señal , Transactivadores , Quinasas Asociadas a rho , Quinasas Asociadas a rho/metabolismo , Quinasas Asociadas a rho/fisiología , Quinasas Asociadas a rho/genética , Humanos , Miocitos del Músculo Liso/fisiología , Miocitos del Músculo Liso/metabolismo , Células Cultivadas , Transactivadores/genética , Transactivadores/fisiología , Transactivadores/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Proteínas Nucleares/metabolismo , Proteínas de Unión al GTP rho/fisiología , Proteínas de Unión al GTP rho/genética , Proteínas de Unión al GTP rho/metabolismo

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OBJECTIVE: To identify the spatial-temporal pattern variation of whole-brain functional connectivity (FC) during reward processing in melancholic major depressive disorder (MDD) patients, and to determine the clinical correlates of connectomic differences. METHODS: 61 MDD patients and 32 healthy controls were enrolled into the study. During magnetoencephalography (MEG) scanning, all participants completed the facial emotion recognition task. The MDD patients were further divided into two groups: melancholic (n = 31) and non-melancholic (n = 30), based on the Mini International Neuropsychiatric Interview (M.I.N.I.) assessment. Melancholic symptoms were examined by using the 6-item melancholia subscale from the Hamilton Depression Rating Scale (HAM-D6). The whole-brain orthogonalized power envelope connections in the high-beta band (20-35 Hz) were constructed in each period after the happy emotional stimuli (0-200 ms, 100-300 ms, 200-400 ms, 300-500 ms, and 400-600 ms). Then, the network-based statistic (NBS) was used to determine the specific abnormal connection patterns in melancholic MDD patients. RESULTS: The NBS identified a sub-network difference at the mid-late period (300-500 ms) in response to happy faces among the three groups (corrected P = 0.035). Then, the post hoc and correlation analyses found five FCs were decreased in melancholic MDD patients and were related to HAM-D6 score, including FCs of left fusiform gyrus-right orbital inferior frontal gyrus (r = -0.52, P < 0.001), left fusiform gyrus-left amygdala (r = -0.26, P = 0.049), left posterior cingulate gyrus-right precuneus (r = -0.32, P = 0.025), left precuneus-right precuneus (r = -0.27, P = 0.049), and left precuneus-left inferior occipital gyrus (r = -0.32, P = 0.025). CONCLUSION: In response to happy faces, melancholic MDD patients demonstrated a disrupted functional connective pattern (20-35 Hz, 300-500 ms), which involved brain regions in visual information processing and the limbic system. The aberrant functional connective pattern in reward processing might be a biomarker of melancholic MDD.

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Trastorno Depresivo Mayor , Magnetoencefalografía , Recompensa , Humanos , Femenino , Masculino , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/diagnóstico por imagen , Adulto , Persona de Mediana Edad , Reconocimiento Facial/fisiología , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Ritmo beta/fisiología , Conectoma/métodos , Red Nerviosa/fisiopatología , Red Nerviosa/diagnóstico por imagen , Adulto Joven , Expresión Facial , Emociones/fisiología

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An improved understanding of the factors associated with suicidal attempts in youth suffering from depression is crucial for the identification and prevention of future suicide risk. However, there is limited understanding of how neural activity is modified during the process of decision-making. Our study aimed to investigate the neural responses in suicide attempters with major depressive disorder (MDD) during decision-making. Electroencephalography (EEG) was recorded from 79 individuals aged 16-25 with MDD, including 39 with past suicide attempts (SA group) and 40 without (NSA group), as well as from 40 age- and sex- matched healthy controls (HCs) during the Iowa Gambling Task (IGT). All participants completed diagnostic interviews, self-report questionnaires. Our study examined feedback processing by measuring the feedback-related negativity (FRN), ΔFN (FRN-loss minus FRN-gain), and the P300 as electrophysiological indicators of feedback evaluation. The SA group showed poorest IGT performance. SA group and NSA group, compared with HC group, exhibited specific deficits in decision-making (i.e., exhibited smaller (i.e., blunted) ΔFN). Post hoc analysis found that the SA group was the least sensitive to gains and the most sensitive to losses. In addition, we also found that the larger the value of ΔFN, the better the decision-making ability and the lower the impulsivity. Our study highlights the link between suicide attempts and impaired decision-making in individuals with major depressive disorder. These findings constitute an important step in gaining a better understanding of the specific reward-related abnormalities that could contribute to the young MDD patients with suicide attempts.

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Toma de Decisiones , Trastorno Depresivo Mayor , Electroencefalografía , Intento de Suicidio , Humanos , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/psicología , Masculino , Femenino , Adolescente , Intento de Suicidio/psicología , Toma de Decisiones/fisiología , Adulto Joven , Adulto , Potenciales Evocados/fisiología , Encéfalo/fisiopatología

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Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer survival but are associated with treatment-limiting hypertension, often attributed to endothelial cell (EC) dysfunction. Using phosphoproteomic profiling of VEGFRi-treated ECs, drugs were screened for mitigators of VEGFRi-induced EC dysfunction and validated in primary aortic ECs, mice, and canine cancer patients. VEGFRi treatment significantly raised systolic blood pressure (SBP) and increased markers of endothelial and renal dysfunction in mice and canine cancer patients. α-Adrenergic-antagonists were identified as drugs that most oppose the VEGFRi proteomic signature. Doxazosin, one such α-antagonist, prevented EC dysfunction in murine, canine, and human aortic ECs. In mice with sorafenib-induced-hypertension, doxazosin mitigated EC dysfunction but not hypertension or glomerular endotheliosis, while lisinopril mitigated hypertension and glomerular endotheliosis without impacting EC function. Hence, reversing EC dysfunction was insufficient to mitigate VEGFRi-induced-hypertension in this mouse model. Canine cancer patients with VEGFRi-induced-hypertension were randomized to doxazosin or lisinopril and both agents significantly decreased SBP. The canine clinical trial supports safety and efficacy of doxazosin and lisinopril as antihypertensives for VEGFRi-induced-hypertension and the potential of trials in canines with spontaneous cancer to accelerate translation. The overall findings demonstrate the utility of phosphoproteomics to identify EC-protective agents to mitigate cardio-oncology side effects.

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Doxazosina , Células Endoteliales , Hipertensión , Receptores de Factores de Crecimiento Endotelial Vascular , Animales , Perros , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Doxazosina/farmacología , Doxazosina/uso terapéutico , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Proteómica/métodos , Presión Sanguínea/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Lisinopril/farmacología , Lisinopril/uso terapéutico , Masculino , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Sorafenib/farmacología , Sorafenib/uso terapéutico

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Single-cell ATAC-seq sequencing data (scATAC-seq) has been widely used to investigate chromatin accessibility on the single-cell level. One important application of scATAC-seq data analysis is differential chromatin accessibility (DA) analysis. However, the data characteristics of scATAC-seq such as excessive zeros and large variability of chromatin accessibility across cells impose a unique challenge for DA analysis. Existing statistical methods focus on detecting the mean difference of the chromatin accessible regions while overlooking the distribution difference. Motivated by real data exploration that distribution difference exists among cell types, we introduce a novel composite statistical test named "scaDA", which is based on zero-inflated negative binomial model (ZINB), for performing differential distribution analysis of chromatin accessibility by jointly testing the abundance, prevalence and dispersion simultaneously. Benefiting from both dispersion shrinkage and iterative refinement of mean and prevalence parameter estimates, scaDA demonstrates its superiority to both ZINB-based likelihood ratio tests and published methods by achieving the highest power and best FDR control in a comprehensive simulation study. In addition to demonstrating the highest power in three real sc-multiome data analyses, scaDA successfully identifies differentially accessible regions in microglia from sc-multiome data for an Alzheimer's disease (AD) study that are most enriched in GO terms related to neurogenesis and the clinical phenotype of AD, and AD-associated GWAS SNPs.

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Cromatina , Análisis de la Célula Individual , Cromatina/genética , Cromatina/metabolismo , Cromatina/química , Análisis de la Célula Individual/métodos , Análisis de la Célula Individual/estadística & datos numéricos , Humanos , Biología Computacional/métodos , Enfermedad de Alzheimer/genética , Modelos Estadísticos , Secuenciación de Inmunoprecipitación de Cromatina/métodos , Simulación por Computador , Animales , Análisis de Secuencia de ADN/métodos , Algoritmos

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BACKGROUND: Current clinical studies have indicated that major depressive disorder (MDD) with adverse childhood experiences (ACEs) is associated with greater anhedonia. However, little is known about whether the change in reward sensitivity among young MDD individuals with ACEs are related to anhedonia. METHODS: We evaluated anhedonia and ACEs of each patient. Then, we performed Iowa gambling task during EEG to measure the reward positivity (RewP) and its difference (ΔRewP) in 86 MDD patients (31 with no or one ACE and 55 with two or more ACEs) and 44 healthy controls (HCs). Furthermore, we constructed a mediation model to assessed whether aberrant ΔRewP could mediate the relationship between ACEs and anhedonia. RESULTS: Compared with healthy controls and MDD patients with no or one ACE, MDD patients with two or more ACEs had the most severe symptoms of anhedonia and impaired decision-making, and showed significantly reduced reward sensitivity (most blunted ΔRewP). More importantly, ΔRewP mediated relationship between ACEs and anhedonia in MDD. CONCLUSIONS: We found that the ΔRewP partially mediates the association between ACEs and anhedonia in MDD patients, which provides evidence for the neurobiological basis of abnormal changes in the reward system in MDD individuals with early adverse experiences.

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Endothelial cAMP-specific phosphodiesterase PDE3A is one of the major negative regulators of the endothelial barrier function in acute lung injury (ALI) models. However, the mechanisms underlying its regulation still need to be fully resolved. We show here that the PDE3A is a newly described client of the molecular chaperone hsp90. In endothelial cells (EC), hsp90 inhibition by geldanamycin (GA) led to a disruption of the hsp90/PDE3A complex, followed by a significant decrease in PDE3A protein levels. The decrease in PDE3A protein levels was ubiquitin-proteasome-dependent and required the activity of the E3 ubiquitin ligase C-terminus of Hsc70-interacting protein (CHIP). GA treatment also enhanced the association of PDE3A with hsp70, which partially prevented PDE3A degradation. GA-induced decreases in PDE3A protein levels correlated with decreased PDE3 activity and increased cAMP levels in EC. We also demonstrated that PKG-dependent phosphorylation of PDE3A at Ser654 can signal the dissociation of PDE3A from hsp90 and PDE3A degradation. This was confirmed by endogenous PDE3A phosphorylation and degradation in 8-Br-cGMP- or 8-CPT-cGMP- and Bay 41-8543 -stimulated EC and comparisons of wildtype- and phospho-mimic S654D mutant PDE3A protein stability in transiently transfected HEK293 cells. In conclusion, we have identified a new mechanism of PDE3A regulation mediated by the ubiquitin-proteasome system. Further, the degradation of PDE3A is controlled by the phosphorylation of S654 and the interaction with hsp90. We speculate that targeting the PDE3A/hsp90 complex could be a therapeutic approach for ALI.

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BACKGROUND: Cholangiocarcinoma (CCA) is one of the most deadly cancers in the world. It usually has a bad prognosis and is challenging to identify in its early stages. Long noncoding RNAs (lncRNAs) have been shown in an increasing number of studies to be important in the control of signaling pathways, cell behaviors, and epigenetic modification that contribute to the growth of tumors. The purpose of this work was to examine the relationship between CCA and lncRNA AL161431.1. METHODS: Using TCGA clinical survival data, we evaluated the association between AL161431.1 expression and patient prognosis. Using the program cluster Profiler R, enrichment analysis was performed. Additionally, the association between immune cell infiltration and AL161431.1 expression was evaluated by a review of the TCGA database. Next, to ascertain if AL161431.1 influences tumor growth, migration, and invasion in CCA, functional in vitro assays were conducted. Quantitative real-time polymerase chain reaction (qPCR) was employed to gauge AL161431.1 expression levels in CCA cells. Western blot was used to measure protein levels. RESULTS: In CCA, AL161431.1 was extremely expressed. The patients in the high-risk group had a significantly poorer overall survival (OS) than the patients in the low-risk group. A more thorough look at the TCGA data showed a relationship between high expression levels of AL161431.1 and increased infiltration of T cells, T helper cells, and NK CD56dim cells. Furthermore, AL161431.1 knockdown in CCA cells impeded invasion, migration, and proliferation and also lowered the expression of phosphorylated Smad2/Smad3 to restrain the TGFß/SMAD signaling pathway. CONCLUSIONS: Our results indicate that the lncRNA AL161431.1 activates the TGFß/SMAD signaling pathway to enhance CCA development and metastasis. AL161431.1 could be a novel target for cholangiocarcinoma treatment or a diagnostic marker.

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Neoplasias de los Conductos Biliares , Movimiento Celular , Colangiocarcinoma , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , ARN Largo no Codificante , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Colangiocarcinoma/metabolismo , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Técnicas de Silenciamiento del Gen , Pronóstico , Femenino , Masculino , Invasividad Neoplásica

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BACKGROUND: The widespread problem of suicide and its severe burden in bipolar disorder (BD) necessitate the development of objective risk markers, aiming to enhance individual suicide risk prediction in BD. METHODS: This study recruited 123 BD patients (61 patients with prior suicide attempted history (PSAs), 62 without (NSAs)) and 68 healthy controls (HEs). The Latent Dirichlet Allocation (LDA) model was used to decompose the resting state functional connectivity (RSFC) into multiple hyper/hypo-RSFC patterns. Thereafter, according to the quantitative results of individual heterogeneity over latent factor dimensions, the correlations were analyzed to test prediction ability. RESULTS: Model constructed without introducing suicide-related labels yielded three latent factors with dissociable hyper/hypo-RSFC patterns. In the subsequent analysis, significant differences in the factor distributions of PSAs and NSAs showed biases on the default-mode network (DMN) hyper-RSFC factor (factor 3) and the salience network (SN) and central executive network (CEN) hyper-RSFC factor (factor 1), indicating predictive value. Correlation analysis of the individuals' expressions with their Nurses' Global Assessment of Suicide Risk (NGASR) revealed factor 3 positively correlated (r = 0.4180, p < 0.0001) and factor 1 negatively correlated (r = - 0.2492, p = 0.0055) with suicide risk. Therefore, it could be speculated that patterns more associated with suicide reflected hyper-connectivity in DMN and hypo-connectivity in SN, CEN. CONCLUSIONS: This study provided individual suicide-associated risk factors that could reflect the abnormal RSFC patterns, and explored the suicide related brain mechanisms, which is expected to provide supports for clinical decision-making and timely screening and intervention for individuals at high risks of suicide.

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Trastorno Bipolar , Encéfalo , Imagen por Resonancia Magnética , Humanos , Trastorno Bipolar/psicología , Trastorno Bipolar/fisiopatología , Trastorno Bipolar/diagnóstico por imagen , Femenino , Masculino , Adulto , Factores de Riesgo , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Suicidio/psicología , Persona de Mediana Edad , Intento de Suicidio/psicología , Descanso/fisiología , Adulto Joven

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Vancomycin-resistant enterococcus (VRE) is a major nosocomial pathogen that exhibits enhanced infectivity due to its robust virulence and biofilm-forming capabilities. In this study, 6-methoxyldihydrochelerythrine chloride (6-MDC) inhibited the growth of exponential-phase VRE and restored VRE's sensitivity to vancomycin. 6-MDC predominantly suppressed the de novo biosynthetic pathway of pyrimidine and purine in VRE by the RNA-Seq analysis, resulting in obstructed DNA synthesis, which subsequently weakened bacterial virulence and impeded intracellular survival. Furthermore, 6-MDC inhibited biofilm formation, eradicated established biofilms, reduced virulence, and enhanced the host immune response to prevent intracellular survival and replication of VRE. Finally, 6-MDC reduced the VRE load in peritoneal fluid and cells significantly in a murine peritoneal infection model. This paper provides insight into the potential antimicrobial target of benzophenanthridine alkaloids for the first time.

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Antibacterianos , Benzofenantridinas , Biopelículas , Pruebas de Sensibilidad Microbiana , Enterococos Resistentes a la Vancomicina , Animales , Ratones , Antibacterianos/farmacología , Antibacterianos/química , Benzofenantridinas/farmacología , Benzofenantridinas/química , Enterococos Resistentes a la Vancomicina/efectos de los fármacos , Biopelículas/efectos de los fármacos , Virulencia/efectos de los fármacos , Vancomicina/farmacología , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Femenino

RESUMEN

BACKGROUND AND OBJECTIVES: Congenital heart defect (CHD) is one of the most common birth defects. The aim of this cohort study was to evaluate the prevalence of chromosomal abnormalities and the clinical utility of chromosomal microarray analysis (CMA) in fetuses with different types of CHD, aiming to assist genetic counseling and clinical decision-making. METHODS: In this study, 642 fetuses with CHD were enrolled from a single center over a six-year period (2017-2022). Both conventional karyotyping and CMA were performed simultaneously on these fetuses. RESULTS: The diagnostic yield of CMA in fetuses with CHD in our study was 15.3% (98/642). Our findings revealed a significant increase in the diagnostic yield of CMA compared to karyotyping in fetuses with CHD. Among CHD subgroups, the diagnostic yields were high in complex CHD (34.9%), conotruncal defects (28.6%), right ventricular outflow tract obstructive defects (RVOTO) (25.9%), atrioventricular septal defects (AVSD) (25.0%) and left ventricular outflow tract obstructive defects (LVOTO) (24.1%), while those in other CHD (10.6%) and septal defects (10.9%) were relatively low. The overall detection rate of clinically significant chromosomal abnormalities was significantly higher in the non-isolated CHD group compared to the isolated CHD group (33.1% vs. 9.9%, P < 0.0001). Interestingly, numerical chromosomal abnormalities were more likely to occur in the non-isolated CHD group than in the isolated CHD group (20.3% vs. 2.0%, P < 0.0001). The rate of termination of pregnancy (TOP)/Still birth in the non-isolated CHD group was significantly higher than that in the isolated CHD group (40.5% vs. 20.6%, P < 0.0001). Compared to the isolated CHD group, the detection rate of clinically significant chromosomal abnormalities was significantly higher in the group of CHD with soft markers (35.6% vs. 9.9%, P < 0.0001) and in the group of CHD with additional structural anomalies (36.1% vs. 9.9%, P < 0.0001). CONCLUSIONS: CMA is a reliable and high-resolution technique that should be recommended as the front-line test for prenatal diagnosis of fetuses with CHD. The prevalence of chromosomal abnormalities varies greatly among different subgroups of CHD, and special attention should be given to prenatal non-isolated cases of CHD, especially those accompanied by additional structural anomalies or soft markers.

Asunto(s)

Cardiopatías Congénitas , Análisis por Micromatrices , Diagnóstico Prenatal , Humanos , Cardiopatías Congénitas/genética , Femenino , Análisis por Micromatrices/métodos , Embarazo , Diagnóstico Prenatal/métodos , Aberraciones Cromosómicas , Estudios de Cohortes , Adulto , Cariotipificación/métodos , Feto , China/epidemiología , Pueblos del Este de Asia

RESUMEN

An interesting question is whether chalcogen atoms can emulate the role of carbon or boron elements stabilized between two transition metal layers, as observed in MXenes or MBenes. Here, we predict a new family of two-dimensional ternary compounds M4XY2 (where M = Pd, Y, Zr, etc.; X = S, Se, Te; and Y = Cl, Br, I), named M-chalcogene. Through first-principles calculations, we reveal diverse physical properties in these compounds, including superconducting, topological, and magnetic characteristics, where the bilayer transition metals play crucial roles. Moreover, the expected helical edge states and superconducting transition temperatures in Pd4SCl2 can be finely tuned by strains. Additionally, the Ti4SCl2 is predicted to be a topological insulator and shows promise as a gas sensor candidate for certain exotic gases. Our findings expand two-dimensional material families and provide promising platforms for diverse physical phenomena with efficient tunability by external stimuli for various applications.

RESUMEN

OBJECTIVES: Postdoctoral researchers in Chinese universities commonly face a high risk of mental health issues, such as depression, yet the underlying causes and mechanisms remain unclear. This study aims to explore the influence of childhood socioeconomic status (SES) on depression among postdoctoral researchers and the mediating roles of current subjective SES and perceived stress in this process. METHODS: An online survey was conducted among postdoctoral researchers at a university. The survey included a general information questionnaire, the Childhood Socioeconomic Status Scale, the Subjective Socioeconomic Status Scale, the Perceived Stress Scale, and the Patient Health Questionnaire. A total of 505 valid responses were collected. Pearson correlation analysis was used to analyze the data, and the PROCESS macro was employed for chain mediation analysis. RESULTS: Childhood SES was significantly positively correlated with current subjective SES (P<0.05) and significantly negatively correlated with postdoctoral tenure, perceived stress, and depression (all P<0.05). Current subjective SES was significantly negatively correlated with perceived stress and depression (both P<0.05), while perceived stress was significantly positively correlated with depression (P<0.05). The chain mediation effect of childhood SES → current subjective SES → perceived stress → depression was significant (P<0.05). CONCLUSIONS: Childhood socioeconomic status can influence depression among postdoctoral researchers through the mediating roles of current subjective socioeconomic status and perceived stress. These findings provide a target for the prevention and intervention of depression in postdoctoral populations and offer a reference for the development of mental health promotion strategies for young university faculty.

Asunto(s)

Depresión , Clase Social , Estrés Psicológico , Humanos , Estrés Psicológico/psicología , Universidades , Depresión/etiología , Depresión/psicología , Encuestas y Cuestionarios , Femenino , Masculino , Investigadores/psicología , Investigadores/estadística & datos numéricos , China/epidemiología , Adulto

RESUMEN

Background: The decline in the number of new HIV infections among adults has slowed down, gradually becoming the biggest obstacle to achieving the 2030 target of ending the HIV/AIDS epidemic. Thus, a political declaration to ensure that 90% of people at high risk of HIV infection can access comprehensive prevention services was proposed by the United Nations General Assembly. Therefore, obtaining an accurate estimated size of high-risk populations is required as a prior condition to plan and implement HIV prevention services. The network scale-up method (NSUM) was recommended by the United Nations Programme on HIV/AIDS and the World Health Organization to estimate the sizes of populations at high risk of HIV infection; however, we found that the NSUM also revealed underlying population characteristics of female sex workers in addition to being used to estimate the population size. Such information on underlying population characteristics is very useful in improving the planning and implementation of HIV prevention services. This is especially relevant for people who inject drugs, where in addition to stigma and discrimination, criminalization further hinders access to HIV prevention services. Objective: We aimed to conduct a further exploration of the public health implications of the NSUM by using it to estimate the population size, popularity ratio, and information transmission rate among people who inject drugs. Methods: A stratified 2-stage cluster survey of the general population and a respondent-driven sampling survey of people who inject drugs were conducted in the urban district of Taiyuan, China, in 2021. Results: The estimated size of the population of people who inject drugs in Taiyuan was 1241.9 (95% CI 1009.2-1474.9), corresponding to 4.4×10-2% (95% CI 3.6×10-2% to 5.2×10-2%) of the adult population aged 15-64 years. The estimated popularity ratio of people who inject drugs was 53.6% (95% CI 47.2%-60.1%), and the estimated information transmission rate was 87.9% (95% CI 86.5%-89.3%). Conclusions: In addition to being used to estimate the size of the population of people who inject drugs, the NSUM revealed that they have smaller-sized personal social networks while concealing their drug use, and these underlying population characteristics are extremely useful for planning appropriate service delivery approaches with the fewest barriers for people who inject drugs to access HIV prevention services. Therefore, more cost-effectiveness brings new public health implications for the NSUM, which makes it even more promising for its application.

Asunto(s)

Infecciones por VIH , Salud Pública , Humanos , Estudios Transversales , Adulto , Femenino , Infecciones por VIH/prevención & control , Infecciones por VIH/epidemiología , Masculino , Persona de Mediana Edad , Adolescente , China/epidemiología , Adulto Joven , Encuestas y Cuestionarios