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Pyroptosis is a type of programmed cell death mediated by gasdermines (GSDMs). The N-terminal domain of GSDMs forms pores in the plasma membrane, causing cell membrane rupture and the release of cell contents, leading to an inflammatory response and mediating pyrodeath. Pyroptosis plays an important role in inflammatory diseases and malignant tumors. With the further study of pyroptosis, an increasing number of studies have shown that the pyroptosis pathway can regulate the tumor microenvironment and antitumor immunity of colorectal cancer and is closely related to the occurrence, development, treatment and prognosis of colorectal cancer. This review aimed to explore the molecular mechanism of pyroptosis and the role of pyroptosis in the occurrence, development, treatment and prognosis of colorectal cancer (CRC) and to provide ideas for the clinical diagnosis and treatment of CRC.
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αß T cells are critical components of the adaptive immune system; they maintain tissue and immune homeostasis during health, provide sterilizing immunity after pathogen infection, and are capable of eliminating transformed tumor cells. Fundamental to these distinct functions is the ligand specificity of the unique antigen receptor expressed on each mature T cell (TCR), which endows lymphocytes with the ability to behave in a cell-autonomous, disease context-specific manner. Clone-specific behavioral properties are initially established during T cell development when thymocytes use TCR recognition of major histocompatibility complex (MHC) and MHC-like ligands to instruct survival versus death and to differentiate into a plethora of inflammatory and regulatory T cell lineages. Here, we review the ligand specificity of the preselection thymocyte repertoire and argue that developmental stage-specific alterations in TCR signaling control cross-reactivity and foreign versus self-specificity of T cell sublineages.
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Timo , Humanos , Animales , Timo/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/inmunología , Timocitos/inmunología , Timocitos/metabolismo , Linfocitos T/inmunología , Diferenciación Celular/inmunología , Complejo Mayor de Histocompatibilidad/inmunologíaRESUMEN
Accurately assessing the changes in soil organic carbon storage ï¼SOCSï¼ before and after the Grain for Green Project ï¼GFGï¼ in the Loess Plateau ï¼LPï¼ and exploring the relationship between its spatial and temporal distribution and the influencing factors were important references for the development of regional recycling as well as the formulation of ecological protection policies. Based on the data of climate, human activities, and SOCD in the surface ï¼0-20 cmï¼ and deep ï¼0-100 cmï¼ soil before and after GFG in the LP from 2001 to 2020, we investigated the changes in SOCD at different spatial and temporal scales by using the methods of trend analysis, the kriging method, and variance partitioning analysis. The results showed thatï¼ â Before and after the GFG, the surface SOCS of the whole region increased by 8 338.7×104 tï¼ the deep SOCS increased by 1 160.02×104 t. â¡ In each bioclimatic subregion, the whole-region average SOCD of â ï¼Semi-Humid Forest Regionï¼, â ¡ ï¼Semi-Humid Semi-Arid Forest and Grassland Regionï¼, and â ¢ ï¼Semi-Arid Typical Grassland Regionï¼ showed a significant increasing trend, with a decreasing trend in â £ ï¼arid semi-arid desert grassland areaï¼ and â ¤ ï¼arid desert areaï¼. ⢠The average surface SOCS increase in different ecosystems was ranked as followsï¼ cropland > grassland > woodland > shrubs > bare land and sparse vegetation. The deep soil increase was ranked as followsï¼ grassland > cropland > woodland > shrubs > bare land and sparse vegetation. ⣠Climate factors were the most important driving factors for changes in SOCDï¼ the annual average temperature and precipitation were significantly positively correlated with changes in SOCD. The results of the study could provide data support for regional ecological management and land use policy formulation to promote high quality development of the ecological environment in the LP.
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Carbono , Cambio Climático , Suelo , Suelo/química , China , Carbono/análisis , Compuestos Orgánicos/análisis , Conservación de los Recursos Naturales , Actividades Humanas , Bosques , Ecosistema , Monitoreo del Ambiente/métodos , Altitud , Pradera , Secuestro de Carbono , Humanos , Productos Agrícolas/crecimiento & desarrolloRESUMEN
RATIONALE: Warthin tumor (WT) is the second most common benign tumor in salivary gland. It has a slow growth rate and most frequently occurs in the parotid gland. Most patients present with an incidental finding of a painless mass inferior/anterior to the ear. Besides the epithelial component of the tumor, WT is characteristically associated with lymphoid stroma that is considered benign. While there have been a few reports of malignant transformation of the lymphoid components in WT, cases of WT concomitant with mantle cell lymphoma (MCL) are extremely rare. To the best of our knowledge, two cases have been described in the English literature. Herein, we report a case of WT concomitant with MCL in a 70-year-old female patient, and emphasize the importance of careful examination of lymphoid stroma in WT so that concurrent lymphoma is not missed. PATIENT CONCERNS: A 70-year-old Chinese woman with a 40-year history of cigarette smoking presented with a one year history of a right submaxillary mass with recent enlargement. DIAGNOSIS: Cervical ultrasound (US) and computed tomography (CT) scans of the neck revealed a well-circumscribed mass in the right parotid with a maximum diameter of 3.1 cm. Surgical resection of the mass was performed. Histopathological examination revealed a characteristic double-layer of neoplastic epithelium with prominent lymphoid stroma, suggesting WT. In addition, morphology and immunohistochemistry studies confirmed the coexistence of MCL. Thereafter, the final diagnosis of this case was WT concomitant with MCL. INTERVENTIONS: The patient was staged as stage I after clinical assessment. Due to the slow growth of parotid lesions, close observation was decided with periodic clinical and radiological monitoring. OUTCOMES: Currently, the patient demonstrates a stable disease by clinical evaluation. LESSONS: To the best of our knowledge, reported cases of WT concomitant with MCL are very rare. This case highlights the importance of a comprehensive assessment of the lymphoid stroma of WT to avoid missed diagnosis of a lymphoma component in a collision tumor.
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Adenolinfoma , Linfoma de Células del Manto , Neoplasias de la Parótida , Humanos , Linfoma de Células del Manto/patología , Linfoma de Células del Manto/complicaciones , Linfoma de Células del Manto/diagnóstico , Femenino , Anciano , Adenolinfoma/patología , Adenolinfoma/complicaciones , Adenolinfoma/cirugía , Neoplasias de la Parótida/patología , Neoplasias de la Parótida/complicaciones , Glándula Parótida/patología , Glándula Parótida/diagnóstico por imagen , Glándula Parótida/cirugíaRESUMEN
Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3-7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12-22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion.
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Linfocitos T CD8-positivos , Hepatitis B Crónica , Hígado , Animales , Humanos , Masculino , Ratones , Linfocitos T CD8-positivos/enzimología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Modulador del Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Hepatocitos/inmunología , Hepatocitos/virología , Hígado/inmunología , Hígado/virología , Fosforilación , Transducción de Señal , Activación de LinfocitosRESUMEN
A series of C-3 arylated huperzine A (HPA) derivatives (1-30) were designed and synthesized in good yields via palladium-catalyzed Suzuki cross-coupling reaction. Cholinesterase inhibitory and neuroprotective activities of all 30 derivatives were evaluated. Cholinesterase inhibition results revealed that derivatives 2 and 15 exhibited dual inhibitory activity against both acetylcholinesterase (AChE inhibition: 2, IC50 = 1.205 ± 0.395 µM; 15, IC50 = 0.225 ± 0.062 µM) and butyrylcholinesterase (BChE inhibition: 2, IC50 = 8.598 ± 3.605 µM; 15, IC50 = 4.013 ± 0.068 µM), a feature not observed in huperzine A. Molecular docking results indicated that the introduction of aryl groups enhanced the affinity of the derivatives for the acyl-binding pocket of BChE, thereby limiting the hydrolysis of acetyl choline. However, these derivatives exhibited poor performance in cytotoxicity and neuroprotection assays.
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Alcaloides , Enfermedad de Alzheimer , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Simulación del Acoplamiento Molecular , Fármacos Neuroprotectores , Sesquiterpenos , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Sesquiterpenos/farmacología , Sesquiterpenos/síntesis química , Sesquiterpenos/química , Alcaloides/farmacología , Alcaloides/síntesis química , Alcaloides/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Butirilcolinesterasa/metabolismo , Estructura Molecular , Enfermedad de Alzheimer/tratamiento farmacológico , Acetilcolinesterasa/metabolismo , Animales , Humanos , Relación Estructura-Actividad , Diseño de FármacosRESUMEN
Women who undergo cesarean delivery have reported experiencing mood distress related to the surgery and postoperative pain. Heart rate variability biofeedback (HRVB) training is known to have positive effects on mental health, but its effects on women undergoing cesarean delivery have not yet been determined. This study evaluated the effects of an HRVB training intervention on stress, anxiety, and depression in women undergoing cesarean delivery. We hypothesized that 10 sessions of HRVB training could cumulatively improve emotion regulation in participants. This study was designed as a double-blinded randomized controlled trial involving a total of 86 enrolled women who were then divided into two groups: intervention and control. During their hospitalization, the intervention group underwent HRVB training daily, while both groups received standard perinatal care. Heart rate variability (HRV) was assessed using root mean square of successive differences (RMSSD), standard deviation of normal-to-normal intervals (SDNN), high-frequency power (HF) and low-frequency power (LF). HRV parameters, stress, anxiety, and depression were evaluated at baseline and on the fifth day after childbirth. Intention-to-treat (ITT) analyses examined change over time between groups. Although no significant effects were found for the RMSSD and HF, a significant increase was observed in SDNN (F = 13.43, p = < 0.001, Æ2 = 0.14), and LF at post-assessment (F = 4.26, p = .04, Æ2 = 0.05) compared to the control group. Except for the depression variable, stress (F = 6.11, p = .02, Æ2 = 0.07) and anxiety (F = 8.78, p = .004, Æ2 = 0.10) significantly decreased compared to the control group on the fifth postpartum day. Furthermore, post-hoc analysis showed that HRVB was more effective in decreasing mild to severe depressive symptoms (F = 7.60, p = .001, Æ2 = 0.27). The intervention program successfully decreased self-perceived stress and anxiety in the postpartum period and relieved symptoms in more severely depressed participants. Our findings suggest that this program is suitable and beneficial for application in women during the early postpartum period following cesarean delivery.
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Functional brain networks have preserved architectures in rest and task; nevertheless, previous work consistently demonstrated task-related brain functional reorganization. Efficient rest-to-task functional network reconfiguration is associated with better cognition in young adults. However, aging and cognitive load effects, as well as contributions of intra- and internetwork reconfiguration, remain unclear. We assessed age-related and load-dependent effects on global and network-specific functional reconfiguration between rest and a spatial working memory (SWM) task in young and older adults, then investigated associations between functional reconfiguration and SWM across loads and age groups. Overall, global and network-level functional reconfiguration between rest and task increased with age and load. Importantly, more efficient functional reconfiguration associated with better performance across age groups. However, older adults relied more on internetwork reconfiguration of higher cognitive and task-relevant networks. These reflect the consistent importance of efficient network updating despite recruitment of additional functional networks to offset reduction in neural resources and a change in brain functional topology in older adults. Our findings generalize the association between efficient functional reconfiguration and cognition to aging and demonstrate distinct brain functional reconfiguration patterns associated with SWM in aging, highlighting the importance of combining rest and task measures to study aging cognition.
Brain networks identified by functional connectivity (FC) have preserved architectures from rest to task and across task demands. Higher similarity, implying more efficient network reconfiguration, was associated with better cognition and task performance in young adults. To examine how it may be influenced by aging, we compared whole-brain and network-level FC similarities between resting-state and spatial working memory fMRI in young and older adults. At whole-brain level and higher order cognitive networks, older adults evidenced less efficient network reconfiguration from rest to task than young adults. Importantly, more efficient reconfiguration was associated with better accuracy. This relationship relied more on internetwork connections in older adults. Despite reduced neural resources compared to young, maintaining efficient network updating still contributes to better cognition at older age.
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BACKGROUND: Positron emission tomography (PET) has been investigated for its ability to reconstruct proton-induced positron activity distributions in proton therapy. This technique holds potential for range verification in clinical practice. Recently, deep learning-based dose estimation from positron activity distributions shows promise for in vivo proton dose monitoring and guided proton therapy. PURPOSE: This study evaluates the effectiveness of three classical neural network models, recurrent neural network (RNN), U-Net, and Transformer, for proton dose estimating. It also investigates the characteristics of these models, providing valuable insights for selecting the appropriate model in clinical practice. METHODS: Proton dose calculations for spot beams were simulated using Geant4. Computed tomography (CT) images from four head cases were utilized, with three for training neural networks and the remaining one for testing. The neural networks were trained with one-dimensional (1D) positron activity distributions as inputs and generated 1D dose distributions as outputs. The impact of the number of training samples on the networks was examined, and their dose prediction performance in both homogeneous brain and heterogeneous nasopharynx sites was evaluated. Additionally, the effect of positron activity distribution uncertainty on dose prediction performance was investigated. To quantitatively evaluate the models, mean relative error (MRE) and absolute range error (ARE) were used as evaluation metrics. RESULTS: The U-Net exhibited a notable advantage in range verification with a smaller number of training samples, achieving approximately 75% of AREs below 0.5 mm using only 500 training samples. The networks performed better in the homogeneous brain site compared to the heterogeneous nasopharyngeal site. In the homogeneous brain site, all networks exhibited small AREs, with approximately 90% of the AREs below 0.5 mm. The Transformer exhibited the best overall dose distribution prediction, with approximately 92% of MREs below 3%. In the heterogeneous nasopharyngeal site, all networks demonstrated acceptable AREs, with approximately 88% of AREs below 3 mm. The Transformer maintained the best overall dose distribution prediction, with approximately 85% of MREs below 5%. The performance of all three networks in dose prediction declined as the uncertainty of positron activity distribution increased, and the Transformer consistently outperformed the other networks in all cases. CONCLUSIONS: Both the U-Net and the Transformer have certain advantages in the proton dose estimation task. The U-Net proves well suited for range verification with a small training sample size, while the Transformer outperforms others at dose-guided proton therapy.
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Motivation: Single-cell RNA sequencing (scRNA-seq) has become a valuable tool for studying cellular heterogeneity. However, the analysis of scRNA-seq data is challenging because of inherent noise and technical variability. Existing methods often struggle to simultaneously explore heterogeneity across cells, handle dropout events, and account for batch effects. These drawbacks call for a robust and comprehensive method that can address these challenges and provide accurate insights into heterogeneity at the single-cell level. Results: In this study, we introduce scVIC, an algorithm designed to account for variational inference, while simultaneously handling biological heterogeneity and batch effects at the single-cell level. scVIC explicitly models both biological heterogeneity and technical variability to learn cellular heterogeneity in a manner free from dropout events and the bias of batch effects. By leveraging variational inference, we provide a robust framework for inferring the parameters of scVIC. To test the performance of scVIC, we employed both simulated and biological scRNA-seq datasets, either including, or not, batch effects. scVIC was found to outperform other approaches because of its superior clustering ability and circumvention of the batch effects problem. Availability and implementation: The code of scVIC and replication for this study are available at https://github.com/HiBearME/scVIC/tree/v1.0.
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PURPOSE: The polarization of macrophages with the resulting inflammatory response play a crucial part in tissue and organ damage due to inflammatory. Study has proved Lian Hua Qing Wen capsules (LHQW) can reduce activation of inflammatory response and damage of tissue derived from the inflammatory reactions. However, the mechanism of LHQW regulates the macrophage-induced inflammatory response is unclear. Therefore, we investigated the mechanism of LHQW regulated the inflammatory response of M1 macrophages by cellular experiments and computer simulations. METHODS: This study has analysed the targets and mechanisms of macrophage regulating inflammatory response at gene and protein levels through bioinformatics. The monomeric components of LHQW were analyzed by High Performance Liquid Chromatography (HPLC). We established the in vitro cell model by M1 macrophages (Induction of THP-1 cells into M1 macrophages). RT-qPCR and immunofluorescence were used to detect changes in gene and protein levels of key targets after LHQW treatment. Computer simulations were utilized to verify the binding stability of monomeric components and protein targets. RESULTS: Macrophages had 140,690 gene targets, inflammatory response had 12,192 gene targets, intersection gene targets were 11,772. Key monomeric components (including: Pinocembrin, Fargesone-A, Nodakenin and Bowdichione) of LHQW were screened by HPLC. The results of cellular experiments indicated that LHQW could significantly reduce the mRNA expression of CCR5, CSF2, IFNG and TNF, thereby alleviating the inflammatory response caused by M1 macrophage. The computer simulations further validated the binding stability and conformation of key monomeric components and key protein targets, and IFNG/Nodakenin was able to form the most stable binding conformation for its action. CONCLUSION: In this study, the mechanism of LHQW inhibits the polarization of macrophages and the resulting inflammatory response was investigated by computer simulations and cellular experiments. We found that LHQW may not only reduce cell damage and death by acting on TNF and CCR5, but also inhibit the immune recognition process and inflammatory response by regulating CSF2 and IFNG to prevent polarization of macrophages. Therefore, these results suggested that LHQW may act through multiple targets to inhibit the polarization of macrophages and the resulting inflammatory response.
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Simulación por Computador , Medicamentos Herbarios Chinos , Macrófagos , Humanos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Inflamación , Antiinflamatorios/farmacología , Células THP-1 , Biología Computacional , Cromatografía Líquida de Alta PresiónRESUMEN
Mutations in the tyrosine phosphatase Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) are associated with a variety of human diseases. Most mutations in SHP2 increase its basal catalytic activity by disrupting autoinhibitory interactions between its phosphatase domain and N-terminal SH2 (phosphotyrosine recognition) domain. By contrast, some disease-associated mutations located in the ligand-binding pockets of the N- or C-terminal SH2 domains do not increase basal activity and likely exert their pathogenicity through alternative mechanisms. We lack a molecular understanding of how these SH2 mutations impact SHP2 structure, activity, and signaling. Here, we characterize five SHP2 SH2 domain ligand-binding pocket mutants through a combination of high-throughput biochemical screens, biophysical and biochemical measurements, and molecular dynamics simulations. We show that while some of these mutations alter binding affinity to phosphorylation sites, the T42A mutation in the N-SH2 domain is unique in that it also substantially alters ligand-binding specificity, despite being 8 to 10 Å from the specificity-determining region of the SH2 domain. This mutation exerts its effect on sequence specificity by remodeling the phosphotyrosine-binding pocket, altering the mode of engagement of both the phosphotyrosine and surrounding residues on the ligand. The functional consequence of this altered specificity is that the T42A mutant has biased sensitivity toward a subset of activating ligands and enhances downstream signaling. Our study highlights an example of a nuanced mechanism of action for a disease-associated mutation, characterized by a change in protein-protein interaction specificity that alters enzyme activation.
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Simulación de Dinámica Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Dominios Homologos src , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/química , Humanos , Dominios Homologos src/genética , Unión Proteica , Mutación , Fosforilación , Sitios de Unión/genética , Fosfotirosina/metabolismo , LigandosRESUMEN
With the increasing incidence of kidney diseases, there is an urgent need to develop therapeutic strategies to combat post-injury fibrosis. Immune cells, including platelets, play a pivotal role in this repair process, primarily through their released cytokines. However, the specific role of platelets in kidney injury and subsequent repair remains underexplored. Here, the detrimental role of platelets in renal recovery following ischemia/reperfusion injury and its contribution to acute kidney injury to chronic kidney disease transition is aimed to investigated. In this study, it is shown that depleting platelets accelerates injury resolution and significantly reduces fibrosis. Employing advanced single-cell and spatial transcriptomic techniques, macrophages as the primary mediators modulated by platelet signals is identified. A novel subset of macrophages, termed "cycling M2", which exhibit an M2 phenotype combined with enhanced proliferative activity is uncovered. This subset emerges in the injured kidney during the resolution phase and is modulated by platelet-derived thrombospondin 1 (THBS1) signaling, acquiring profibrotic characteristics. Conversely, targeted inhibition of THBS1 markedly downregulates the cycling M2 macrophage, thereby mitigating fibrotic progression. Overall, this findings highlight the adverse role of platelet THBS1-boosted cycling M2 macrophages in renal injury repair and suggest platelet THBS1 as a promising therapeutic target for alleviating inflammation and kidney fibrosis.
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Plaquetas , Fibrosis , Macrófagos , Transcriptoma , Macrófagos/metabolismo , Animales , Fibrosis/metabolismo , Ratones , Plaquetas/metabolismo , Transcriptoma/genética , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Análisis de la Célula Individual/métodos , Daño por Reperfusión/metabolismo , Daño por Reperfusión/genética , Riñón/metabolismo , Riñón/patologíaRESUMEN
OBJECTIVE: We aimed to examine biventricular remodeling and function after Ebstein anomaly (EbA) surgical correction using echocardiographic techniques, particularly, the relations between the biventricular changes and the EbA types. METHODS: From April 2015 to August 2022, 110 patients with EbA were included in this retrospective study based on the Carpentier classification. Echocardiography assessments during the preoperative, early, and mid-term postoperative periods were performed. RESULTS: The 54 patients with types A and B EbA were included in group 1, whereas the 56 patients with types C and D were in group 2. Seventy-eight patients underwent surgical correction of EbA. The median age at operation was 8.8 years. During the mid-term follow-up, only 9.1% of the patients had moderate or severe tricuspid regurgitation. Right ventricular (RV) systolic function worsened in group 2 at discharge (fractional area change: 27.6 ± 11.2 vs. 35.4 ± 11.5 [baseline], P < 0.05; global longitudinal strain: -10.8 ± 4.4 vs. -17.9 ± 4.7 [baseline], P = 0.0001). RV function slowly recovered at a mean of 12 months of follow-up. Regarding left ventricular (LV) and RV systolic function, no statistical difference was found between before and after surgery in group 1. CONCLUSION: A high success rate of surgical correction of EbA, with an encouraging durability of the valve, was noted. Biventricular systolic function was maintained fairly in most patients with types A and B postoperatively. A late increase in RV systolic function after an initial reduction and unchanged LV systolic function were observed in the patients with types C and D postoperatively.
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Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.
[Box: see text].
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Acetilcolinesterasa , Enfermedad de Alzheimer , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Fármacos Neuroprotectores , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Relación Estructura-Actividad , Piperidinas/química , Piperidinas/farmacología , Piperidinas/síntesis química , Estructura Molecular , Línea Celular Tumoral , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/antagonistas & inhibidores , IndolesRESUMEN
OBJECTIVE: Employing whole-exome sequencing (WES) technology to investigate the etiology of infantile epileptic spasm syndrome (IESS), and determining whether different etiologies exhibit phenotypic variations, while elucidating the potential associated factors, might improve short-term responses to first-line treatment. METHODS: We retrospectively evaluated patients with IESS admitted for treatment between January 2018 and June 2023. Clinical phenotypic differences among etiological classifications and clinical manifestations were analyzed. Variable selection using the best subset method was performed, followed by logistic regression analysis to identify the factors influencing treatment response. RESULTS: A total of 577 patients were included; 412 completed trio-WES. Magnetic resonance imaging abnormalities were detected in 387 patients (67.1%). Patients with etiology as structural abnormalities were likelier to have non-spasms at the initial seizure onset. A total of 532 patients completed the first-line treatment; 273 patients received it for the first time at our hospital (initial response rates: 30.1% and 42.1%, respectively). The response group had a lower proportion of early-onset seizures (≤3 months) than the no-response group (11.3% vs. 23.7%, p < 0.01 and 11.3% vs. 21.5%, p = 0.03, respectively). Logistic regression analysis indicated that earlier initiation of first-line treatment was associated with a higher likelihood of an initial response. However, the etiological classification did not have a significant impact on the initial response. INTERPRETATION: IESS patients with structural abnormalities are more likely to present with non-spasm seizures at initial onset. Early initiation of first-line treatment is crucial; however, initial responses may be less favorable when seizures occur in early infancy.
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Anticonvulsivantes , Espasmos Infantiles , Humanos , Masculino , Femenino , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/etiología , Lactante , Estudios Retrospectivos , Anticonvulsivantes/farmacología , Anticonvulsivantes/administración & dosificación , Preescolar , Secuenciación del Exoma , Niño , Imagen por Resonancia MagnéticaRESUMEN
Muscle damage can occur due to excessive, high-intensity, or inappropriate exercise. It is crucial for athletes and sports enthusiasts to have access to ways that expedite their recovery and alleviate discomfort. Our previous clinical trial demonstrated the anti-inflammatory and muscle damage-ameliorating properties of Lacticaseibacillus paracasei PS23 (PS23), prompting us to further explore the role of this probiotic in muscle damage recovery. This post-hoc analysis of a randomized controlled study investigated potential mediators between the intake of PS23 and the prevention of strength loss after muscle damage. We recruited 105 students from a sports university who had participated in the previously published clinical trial. These participants were randomly allocated to three groups, receiving capsuled live PS23 (L-PS23), heat-treated PS23 (HT-PS23), or a placebo over a period of six weeks. Baseline and endpoint measurements were taken for the levels of circulating ghrelin and other blood markers, stress, mood, quality of life, and the fecal microbiota. A significant increase in ghrelin levels was recorded in the L-PS23 group compared to the other groups. Additionally, both L-PS23 and HT-PS23 interventions led to positive shifts in the gut microbiota composition, particularly in elevated Lacticaseibacillus, Blautia, and Lactobacillus populations. The abundance of these bacteria was positively correlated with exercise performance and inversely correlated with inflammatory markers. In conclusion, dietary supplementation with PS23 may enhance exercise performance and influence muscle damage by increasing ghrelin levels and modulating the gut microbiota composition. Further clarification of the possible mechanisms and clinical implications is required.