RESUMEN
Porcine reproductive and respiratory syndrome virus (PRRSV) has become widespread in China particularly the highly pathogenic porcine reproductive and respiratory syndromes (HP-PRRSV), NADC30, and NADC34 strains, and has posed a threat to the swine industry for over 20 years. To monitor genetic variation in PRRSV-2 GP3 strains in China, we analyzed 618 strains isolated between 1996 to 2023 and constructed phylogenetic trees. Additionally, 60 selected strains were used to analyze nucleotide and amino acid homology. PRRSV GP3 gene exhibited nucleotide identity ranging from 78.2% to 100.0% and amino acid similarity ranging from 74.9% to 99.6%. The GP3 gene in the 60 selected strains consisted of 254 amino acids, and amino acid mutations in the strains primarily occurred in B-cell epitopes, T-cell epitopes, and highly variable regions. The glycosylation sites of the strains used for amino acid sequence comparisons remained unaltered, except for the N29 site in the GD20220303-2022 strain. PRRSV-2 strains in China belong to lineages 1, 3, 5, and 8. Recombination analysis detected two recombination events, involving lineages 1 and 8. In conclusion, this study investigated multiple strains of the PRRSV-2 GP3 gene to explore the prevalence and genetic diversity of the GP3 gene in China from a gene family perspective. The results of the analyses provide a basis for clinical prevention strategies and vaccine development.
RESUMEN
In this study, a deep learning method combining knowledge graph and diffusion Transformer has been proposed for cucumber disease detection. By incorporating the diffusion attention mechanism and diffusion loss function, the research aims to enhance the model's ability to recognize complex agricultural disease features and to address the issue of sample imbalance efficiently. Experimental results demonstrate that the proposed method outperforms existing deep learning models in cucumber disease detection tasks. Specifically, the method achieved a precision of 93%, a recall of 89%, an accuracy of 92%, and a mean average precision (mAP) of 91%, with a frame rate of 57 frames per second (FPS). Additionally, the study successfully implemented model lightweighting, enabling effective operation on mobile devices, which supports rapid on-site diagnosis of cucumber diseases. The research not only optimizes the performance of cucumber disease detection, but also opens new possibilities for the application of deep learning in the field of agricultural disease detection.
RESUMEN
Prosocial motives such as social equality and efficiency are key to altruistic behaviors. However, predicting the range of altruistic behaviors in varying contexts and individuals proves challenging if we limit ourselves to one or two motives. Here we demonstrate the numerous, interdependent motives in altruistic behaviors and the possibility to disentangle them through behavioral experimental data and computational modeling. In one laboratory experiment (N = 157) and one preregistered online replication (N = 1,258), across 100 different situations, we found that both third-party punishment and third-party helping behaviors (that is, an unaffected individual punishes the transgressor or helps the victim) aligned best with a model of seven socioeconomic motives, referred to as a motive cocktail. For instance, the inequality discounting motives imply that individuals, when confronted with costly interventions, behave as if the inequality between others barely exists. The motive cocktail model also provides a unified explanation for the differences in intervention willingness between second parties (victims) and third parties, and between punishment and helping.
RESUMEN
Since its advent in 2011, black titanium oxide (B-TiOx) has garnered significant attention due to its exceptional optical characteristics, notably its enhanced absorption spectrum ranging from 200 to 2000 nm, in stark contrast to its unmodified counterpart. The escalating urgency to address global climate change has spurred intensified research into this material for sustainable hydrogen production through thermal, photocatalytic, electrocatalytic, or hybrid water-splitting techniques. The rapid advancements in this dynamic field necessitate a comprehensive update. In this review, we endeavor to provide a detailed examination and forward-looking insights into the captivating attributes, synthesis methods, modifications, and characterizations of B-TiOx, as well as a nuanced understanding of its physicochemical properties. We place particular emphasis on the potential integration of B-TiOx into solar and electrochemical energy systems, highlighting its applications in green hydrogen generation, CO2 reduction, and supercapacitor technology, among others. Recent breakthroughs in the structure-property relationship of B-TiOx and its applications, grounded in both theoretical and empirical studies, are underscored. Additionally, we will address the challenges of scaling up B-TiOx production, its long-term stability, and economic viability to align with ambitious future objectives.
RESUMEN
Objective: This study aims to investigate the potential functions of miR-19a-3p in HCC. Method: We collected serum samples to analyze miR-19a-3p expression. We utilized CCK8 and Transwell assays to access miR-19a-3p's influence on HCC cells malignancy. We used dual-luciferase reporter and western blotting to validate the impact of p53/miR-19 on miR-19/SOX4. Results: The results demonstrated that miR-19a-3p was highly expressed in pre-operative serum samples and HCC cells, which can promote cell proliferation, migration and invasion in HCC under in vitro conditions. Additionally, there was a p53 binding site on the upstream of miR-19a-3p, which was inhibited by p53. SOX4 was the direct gene targeted by miR-19a-3p. The imbalance of p53-miR-19-SOX4 loop was one reason for the progress of HCC. Conclusion: Our findings validate the mechanisms of miR-19a-3p and highlight its potential as a therapeutic target in HCC.
RESUMEN
In today's globalized agricultural system, information leakage of agricultural biological risk factors can lead to business risks and public panic, jeopardizing corporate reputation. To solve the above problems, this study constructs a blockchain network for agricultural product biological risk traceability based on agricultural product biological risk factor data to achieve traceability of biological risk traceability data of agricultural product supply chain to meet the sustainability challenges. To guarantee the secure and flexible sharing of agricultural product biological risk privacy information and limit the scope of privacy information dissemination, the blockchain-based proxy re-encryption access control method (BBPR-AC) is designed. Aiming at the problems of proxy re-encryption technology, such as the third-party agent being prone to evil, the authorization judgment being cumbersome, and the authorization process not automated, we design the proxy re-encryption access control mechanism based on the traceability of agricultural products' biological risk factors. Designing an attribute-based access control (ABAC) mechanism based on the traceability blockchain for agricultural products involves defining the attributes of each link in the agricultural supply chain, formulating policies, and evaluating and executing these policies, deployed in the blockchain system in the form of smart contracts. This approach achieves decentralization of authorization and automation of authority judgment. By analyzing the data characteristics within the agricultural product supply chain to avoid the malicious behavior of third-party agents, the decentralized blockchain system acts as a trusted third-party agent, and the proxy re-encryption is combined with symmetric encryption to improve the encryption efficiency. This ensures a efficient encryption process, making the system safe, transparent, and efficient. Finally, a prototype blockchain system for traceability of agricultural biological risk factors is built based on Hyperledger Fabric to verify this research method's reliability, security, and efficiency. The experimental results show that this research scheme's initial encryption, re-encryption, and decryption sessions exhibit lower computational overheads than traditional encryption methods. When the number of policies and the number of requests in the access control session is 100, the policy query latency is less than 400 ms, the request-response latency is slightly more than 360ms, and the data uploading throughput is 48.7 tx/s. The data query throughput is 81.8 tx/s, the system performance consumption is low and can meet the biological risk privacy protection needs of the agricultural supply chain. The BBPR-AC method proposed in this study provides ideas for achieving refined traceability management in the agricultural supply chain and promoting digital transformation in the agricultural industry.
Asunto(s)
Agricultura , Cadena de Bloques , Seguridad Computacional , Agricultura/métodos , Humanos , Privacidad , Factores de Riesgo , Difusión de la Información/métodosRESUMEN
Common arterial grafts used in coronary artery bypass grafting include internal thoracic artery (ITA), radial artery (RA) and right gastroepiploic artery (RGA) grafts; of these, the ITA has the best clinical outcome. Here, by analyzing the single-cell transcriptome of different arterial grafts, we suggest optimization strategies for the RA and RGA based on the ITA as a reference. Compared with the ITA, the RA had more lipid-handling-related CD36+ endothelial cells. Vascular smooth muscle cells from the RGA were more susceptible to spasm, followed by those from the RA; comparison with the ITA suggested that potassium channel openers may counteract vasospasm. Fibroblasts from the RA and RGA highly expressed GDF10 and CREB5, respectively; both GDF10 and CREB5 are associated with extracellular matrix deposition. Cell-cell communication analysis revealed high levels of macrophage migration inhibitory factor signaling in the RA. Administration of macrophage migration inhibitory factor inhibitor to mice with partial carotid artery ligation blocked neointimal hyperplasia induced by disturbed flow. Modulation of identified targets may have protective effects on arterial grafts.
Asunto(s)
Arterias Mamarias , Animales , Humanos , Arterias Mamarias/trasplante , Arterias Mamarias/metabolismo , Análisis de la Célula Individual , Arteria Radial/trasplante , Arteria Radial/metabolismo , Arteria Gastroepiploica/metabolismo , Arteria Gastroepiploica/trasplante , Miocitos del Músculo Liso/metabolismo , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/citología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Neointima/patología , Neointima/metabolismo , Puente de Arteria Coronaria/métodos , Comunicación Celular , Fibroblastos/metabolismo , Células Endoteliales/metabolismo , Ratones , Transducción de Señal , Transcriptoma , Vasoconstricción/efectos de los fármacos , Células Cultivadas , Hiperplasia/metabolismo , Hiperplasia/patología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismoRESUMEN
BACKGROUND: Lumbar degenerative disease (LDD) is one of the main causes of low back pain in the elderly. Surgical treatment usually involves decompression surgery and fusion techniques; however, standard fusion surgery in elderly patients is associated with a higher rate of complications, hospital length of stay, and readmission. Although minimally invasive surgery can reduce risk and shorten hospital stays, it still cannot eliminate the inherent complications of fusion or internal fixation, especially in frail patients. Therefore, it is necessary to find a surgical technology that can not only reduce the risk of operation but also effectively reduce the inherent complications of fusion or internal fixation. The purpose of this study was to evaluate the clinical efficacy and feasibility of percutaneous cement discoplasty for the treatment of LDDs. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The search strategy was conducted in PubMed, Web of Science, MEDLINE, Google Scholar, China National Knowledge Infrastructure, China Biology Medicine Disc, and Medical Knowledge Network Citation Database. The quality of the included study was assessed by the Methodological Index for Non-Randomized Studies (MINORS) score. The risk of bias (RoB) about the included study was assessed by the Non-Randomized Studies of Interventions (ROBINS-I) tool. The main results were summarized and analyzed in RevMan 5.4. RESULTS: Finally, we included 10 articles and collected a total of 359 patients, including 171 males (47.63%) and 180 females (52.37%), with an average age of 73.09â ±â 2.74 years. The Methodological Index for Non-Randomized Studies (MINORS) tool was used to assess the articles included in this study, the methodological quality score of 10 retrospective studies varied from 7 to 11. The RoB was assessed using the ROBINS-I tool. Critical RoB was found in 4/10 articles, high RoB was found in 5/10 articles, and intermediate RoB was found in 1/10 articles. The study found that the Visual Analog Scale scores at 1 day (mean difference [MD]: 3.48; 95% confidence interval [CI]: 3.04, 3.93; I2â =â 0%), 3 to 6 months (MD: 4.05; 95% CI: 3.53, 4.56; I2â =â 65%), and 12 to 24 months (MD: 4.00; 95% CI: 3.53, 4.47; I2â =â 45%) after operation were significantly different from those before operation. Meanwhile, the Oswestry Disability Index at 1 day (MD: 42.67; 95% CI: 36.78, 48.57; I2â =â 76%), 3 to 6 months (MD: 42.64; 95% CI: 34.44, 50.83; I2â =â 91%), and 12 to 24 months (MD: 49.22; 95% CI: 42.23, 56.22; I2â =â 83 %) after operation were still significantly different from those before operation. The results with high heterogeneity (I2>50%) were analyzed by sensitivity analysis and subgroup analysis. The results still have significant statistical differences. CONCLUSION: Studies have shown that percutaneous cement discoplasty is a potential intervention for the treatment of LDDs, which can effectively relieve pain and improve dysfunction.
Asunto(s)
Degeneración del Disco Intervertebral , Vértebras Lumbares , Humanos , Degeneración del Disco Intervertebral/cirugía , Vértebras Lumbares/cirugía , Cementos para Huesos/uso terapéutico , Cementoplastia/métodos , Anciano , Femenino , Masculino , Resultado del TratamientoRESUMEN
Current medical therapies for treating acute myeloid leukemia (AML) remain unmet, and AML patients may benefit from targeted immunotherapy approaches that focus on specific tumor antigens. GRP78, which is upregulated in various malignant tumors such as AML, is partially expressed as cell surface GRP78 (csGRP78) on the cell membrane, making it an ideal target for redirecting T cells, including T-cell engagers. However, considering the conventional approach of using two scFv segments to construct a bispecific T-cell engager (BiTE), we have undertaken the development of a novel BiTE that utilizes a cyclic peptide ligand to specifically target csGRP78, which we refer to as GRP78-CD3/BiTE. We studied the effects of GRP78-CD3/BiTE on treatments for AML in vitro and in vivo and assessed the pharmacokinetics of this engager. Our findings demonstrated that GRP78-CD3/BiTE could not only effectively mediate the cytotoxicity of T cells against csGRP78-expressing AML cells but also specifically eliminate primary AML tumor cells in vitro. Furthermore, GRP78-CD3/BiTE exhibited a longer half-life despite having a lower molecular weight than CD19-CD3/BiTE. In a xenograft mouse model of AML, treatment with GRP78-CD3/BiTE prolonged the survival time of the mice. Our findings demonstrate that GRP78-CD3/BiTE is effective and selective for eliminating csGRP78-expressing AML cells and suggest that this approach to targeted immunotherapy could lead to effective new treatments for AML.
Asunto(s)
Anticuerpos Biespecíficos , Chaperón BiP del Retículo Endoplásmico , Leucemia Mieloide Aguda , Linfocitos T , Humanos , Animales , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/tratamiento farmacológico , Ratones , Linfocitos T/inmunología , Linfocitos T/metabolismo , Anticuerpos Biespecíficos/inmunología , Anticuerpos Biespecíficos/farmacología , Complejo CD3/inmunología , Proteínas de Choque Térmico/inmunología , Proteínas de Choque Térmico/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Ligandos , Femenino , Ratones SCID , Inmunoterapia/métodos , Ratones Endogámicos NODRESUMEN
Incorporating sulfur atoms into photosensitizers (PSs) has been well-established to populate triplet states and increase singlet oxygen (1O2) production when exposed to light. In this work, we found that progressive thiolation of porphyrin ß-periphery does promote intersystem crossing (ISC) between triplets and singlets, as seen in the excited state dynamics in dichloromethane or PS nanoparticles in water. However, in the latter case, more sulfur substitution deactivates 1O2 photosensitization, in contrast to the expected trend observed in dichloromethane. This observation was further supported by photocytotoxicity studies, where 1O2 photosensitization was switched off in living cells and multicellular spheroids despite being switched on in in vivo mice models. To understand the inconsistency, we performed molecular dynamics simulation and time-dependent density functional theory calculations to investigate possible aggregation and related excited states. We found that the extent of thiolation could regulate molecular packing inside nanoparticles, which gradually lowers the energy levels of triplet states even lower than that of 1O2 and, in turn, alters their energy dissipation pathways. Therefore, this study provides new insights into the design of metal-free PSs and sheds light on the excited state dynamics in aqueous media beyond the molecular level.
RESUMEN
Evaluating toxicity and decoding the underlying mechanisms of active compounds are crucial for drug development. In this study, we present an innovative, integrated approach that combines air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI), time-of-flight secondary ion mass spectrometry (ToF-SIMS), and spatial metabolomics to comprehensively investigate the nephrotoxicity and underlying mechanisms of nitidine chloride (NC), a promising anti-tumor drug candidate. Our quantitive AFADESI-MSI analysis unveiled the region specific of accumulation of NC in the kidney, particularly within the inner cortex (IC) region, following single and repeated dose of NC. High spatial resolution ToF-SIMS analysis further allowed us to precisely map the localization of NC within the renal tubule. Employing spatial metabolomics based on AFADESI-MSI, we identified over 70 discriminating endogenous metabolites associated with chronic NC exposure. These findings suggest the renal tubule as the primary target of NC toxicity and implicate renal transporters (organic cation transporters, multidrug and toxin extrusion, and organic cation transporter 2 (OCT2)), metabolic enzymes (protein arginine N-methyltransferase (PRMT) and nitric oxide synthase), mitochondria, oxidative stress, and inflammation in NC-induced nephrotoxicity. This study offers novel insights into NC-induced renal damage, representing a crucial step towards devising strategies to mitigate renal damage caused by this compound.
RESUMEN
BACKGROUND: Radiotherapy is one of the main treatments for cervical cancer. Long-term complications of radiation exposure include the emergence of secondary tumors. This is a retrospective study based on an American population. We discuss the optimal treatment modality for patients with radiation-induced secondary uterine malignancy based on the Surveillance, Epidemiology, and End Results database. METHODS: The study included patients with a definitive pathological diagnosis of cervical cancer who were diagnosed with a uterine malignant tumor ≥ 1 year later. Patients in whom cervical cancer was not the first tumor or patients with missing data were excluded. Univariate and multivariate analyses were performed using the COX regression model to screen independent prognostic factors affecting overall survival. Kaplan-Meier survival curves were analyzed using the R software package. RESULTS: We screened 142 patients with a secondary uterine malignancy after cervical cancer treatment, 115 patients with a secondary uterine malignancy after radiotherapy, and 27 patients with a secondary uterine malignancy who did not receive radiotherapy. The average latency period for developing a secondary tumor was 8 years, and 57.04% of the patients had a second tumor at ≥ 60 years of age. In patients with a secondary uterine malignancy after radiotherapy, surgery improved the prognosis [hazard ratio (HR), 0.374; 95% confidence interval (CI), 0.229-0.612], whereas radiotherapy and chemotherapy did not reduce the risk of death. In the subgroup analysis, the surgery plus chemotherapy group had a significantly better survival prognosis than the other groups (HR, 0.251; 95% CI, 0.122-0.515). CONCLUSIONS: The results suggest that the treatment modality in patients with secondary uterine malignancy after radiotherapy for cervical cancer has a significant impact on survival. The survival outcomes of patients receiving surgery combined with chemotherapy are superior to those of patients receiving other treatments.
Asunto(s)
Programa de VERF , Neoplasias del Cuello Uterino , Neoplasias Uterinas , Humanos , Femenino , Neoplasias del Cuello Uterino/radioterapia , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Uterinas/radioterapia , Anciano , Adulto , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Inducidas por Radiación/etiología , Pronóstico , Estimación de Kaplan-Meier , Modelos de Riesgos Proporcionales , Estados Unidos/epidemiologíaRESUMEN
Chemotherapy is an important factor leading to male infertility. It is crucial to discover safe and effective treatments to prevent male reproductive injury caused by chemotherapy. The Ganoderma lucidum polysaccharide peptide (GLPP) has multiple pharmacological activities. The purpose of this study was to determine whether GLPP could protect the male sperm production from chemotherapeutic injury using a mouse model, with testicular damage induced by cyclophosphamide (CP). CP (50 mg/kg/day) was injected intraperitoneally into male ICR mice gavaged with different doses of GLPP at certain spermatogenic stages. The experimental results showed that GLPP alleviated the CP-induced reduction in reproductive organ coefficients and sperm parameters and reduced the morphological damage of testicular tissues in a dose-dependent manner. GLPP significantly improved the reproductive index, sperm-related parameters, sex hormone levels, and histological testis architecture at different spermatogenic stages. Furthermore, GLPP significantly increased superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), Nrf2, and HO-1, and decreased malondialdehyde (MDA) and Keap-1 in the testicular tissue, indicating reduced oxidative stress. In addition, GLPP limited CP-induced apoptosis via a reduction in Bax expression and increase in Bcl-2 expression. This study suggests that GLPP plays a protective role in spermatogenesis by reducing chemotherapeutic injury and might be developed into drug for male patients receiving chemotherapy.
RESUMEN
PURPOSE: This study aims to explore the correlation between PET and CMR in integrated [68Ga]Ga-FAPI-04 PET/CMR multimodal imaging and its value in the diagnosis and risk assessment of hypertrophic cardiomyopathy (HCM). METHODS: This study included 20 HCM patients and 11 age- and gender-matched controls. PET analysis evaluated left ventricular (LV) [68Ga]Ga-FAPI-04 uptake, including SUVmax, TBR, cardiac fibroblast activity (CFA) and volume (CFV), and total SUV of the 16 segments. CMR tissue characterization parameters included cardiac function, myocardial thickness, late gadolinium enhancement (LGE), relaxation time, extracellular volume (ECV), and peak strain parameters. The 5-year sudden cardiac death (SCD) risk score and the 2-year and 5-year atrial fibrillation (AF) risk scores were calculated for each patient. The study analyzed differences between HCM patients and controls, the correlation between [68Ga]Ga-FAPI-04 PET and concurrent CMR imaging results, and the predictive value of PET/CMR. RESULT: The FAPI uptake, myocardial mass, myocardial thickness, and T1/T2 mapping values were significantly higher in HCM patients compared to controls. Twenty HCM patients and their 320 myocardial segments were discussed. Increased [68Ga]Ga-FAPI-04 uptake in the left ventricular wall was observed in 95% (19/20) of the patients, covering 48.8% (156/320) of the segments. On concurrent CMR, 80% (16/20) of the patients showed LGE, including 95 (29.7%) segments. The FAPI(+)LGE(+) segments exhibited the highest myocardial PET uptake, greatest thickness, longest T1/T2 native values, largest ECV value and the greatest loss of myocardial strain capacity (P < 0.05). There was a significant correlation between FAPI uptake and CMR parameters (P < 0.05). Higher [68Ga]Ga-FAPI-04 uptake showed a positive correlation with SCD and AF risk scores (P < 0.05). The number of LGE(+) segments, mapping parameters, and ECV values in CMR also had prognostic significance. Combining PET with CMR aided in further risk stratification of HCM. CONCLUSION: [68Ga]Ga-FAPI-04 PET/CMR multimodal imaging has potential value in the detection of damaged myocardial lesions and risk assessment of HCM patients. [68Ga]Ga-FAPI-04 PET can detect more affected myocardium compared to CMR, and segments with abnormalities in both PET and CMR show more severe myocardial damage.
RESUMEN
Covalent polymer chains are known to undergo mechanochemical events when subjected to mechanical forces. Such force-coupled reactions, like C-C bond scission in homopolymers, typically occur in a non-selective manner but with a higher probability at the mid-chain. In contrast, block copolymers (BCPs), composed of two or more chemically distinct chains linked by covalent bonds, have recently been shown to exhibit significantly different mechanochemical reactivities and selectivities. These differences may be attributable to the atypical conformations adopted by their chains, compared to the regular random coil. Beyond individual molecules, when BCPs self-assemble into ordered aggregates in solution, the non-covalent interactions between the chains lead to meaningful acceleration in the activation of embedded force-sensitive motifs. Furthermore, the microphase segregation of BCPs in bulk creates periodically dispersed polydomains, locking the blocks in specific conformations which have also been shown to affect their mechanochemical reactivity, with different morphologies influencing reactivity to varying extents. This review summarizes the studies of mechanochemistry in BCPs over the past two decades, from the molecular level to assemblies, and up to bulk materials.
RESUMEN
Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa , Isquemia Encefálica , Sustancia Blanca , Animales , Masculino , Ratones , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Isquemia Encefálica/metabolismo , Enfermedad Crónica , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/patología , Sustancia Blanca/metabolismoRESUMEN
BACKGROUND: Acute respiratory distress syndrome (ARDS) after cardiac surgery is a severe respiratory complication with high mortality and morbidity. Traditional clinical approaches may lead to under recognition of this heterogeneous syndrome, potentially resulting in diagnosis delay. This study aims to develop and external validate seven machine learning (ML) models, trained on electronic health records data, for predicting ARDS after cardiac surgery. METHODS: This multicenter, observational cohort study included patients who underwent cardiac surgery in the training and testing cohorts (data from Nanjing First Hospital), as well as those patients who had cardiac surgery in a validation cohort (data from Shanghai General Hospital). The number of important features was determined using the sliding windows sequential forward feature selection method (SWSFS). We developed a set of tree-based ML models, including Decision Tree, GBDT, AdaBoost, XGBoost, LightGBM, Random Forest, and Deep Forest. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and Brier score. The SHapley Additive exPlanation (SHAP) techinque was employed to interpret the ML model. Furthermore, a comparison was made between the ML models and traditional scoring systems. ARDS is defined according to the Berlin definition. RESULTS: A total of 1996 patients who had cardiac surgery were included in the study. The top five important features identified by the SWSFS were chronic obstructive pulmonary disease, preoperative albumin, central venous pressure_T4, cardiopulmonary bypass time, and left ventricular ejection fraction. Among the seven ML models, Deep Forest demonstrated the best performance, with an AUC of 0.882 and a Brier score of 0.809 in the validation cohort. Notably, the SHAP values effectively illustrated the contribution of the 13 features attributed to the model output and the individual feature's effect on model prediction. In addition, the ensemble ML models demonstrated better performance than the other six traditional scoring systems. CONCLUSIONS: Our study identified 13 important features and provided multiple ML models to enhance the risk stratification for ARDS after cardiac surgery. Using these predictors and ML models might provide a basis for early diagnostic and preventive strategies in the perioperative management of ARDS patients.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Aprendizaje Automático , Síndrome de Dificultad Respiratoria , Humanos , Síndrome de Dificultad Respiratoria/etiología , Masculino , Femenino , Persona de Mediana Edad , Estudios de Cohortes , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Anciano , Curva ROC , Área Bajo la CurvaRESUMEN
Fungi from the plant rhizosphere microbiome are considered an important source of bioactive novel natural compounds. In this study, three new sesquiterpenes, penisterpenoids A-C (1-3), and three new viridin derivatives, peniviridiols A-C (4-6), along with twenty one known compounds (7-27), were isolated from the rhizosphere fungus Penicillium sp. SMU0102 of medicinal plant Bupleurum chinense DC. Their structures were elucidated by extensive spectroscopic analysis. The absolute configurations of compounds 1-6 were determined by experimental and calculated ECD spectra, DP4 + probability analysis, modified Mosher's method, and X-ray crystallography. All new compounds were screened for their cytotoxic and lipid-lowering activities in vitro. Among them, compound 1 (20 µM) remarkably alleviated lipid accumulation both in FFA-induced LO2 cells and TAA-induced zebrafish NAFLD models. Furthermore, compound 1 enhanced ATP production and mitochondrial membrane potential (MMP), suppressed reactive oxygen species (ROS) formation, restored mitochondrial structure, and induced autophagosome formation. Moreover, compound 1 significantly upregulated the expression of representative proteins for the mitochondrial homeostasis, including OPA1, DRP1, MFF, and Fis1, as well as mitophagy representative proteins PINK1, Parkin, and P62. Further mechanistic investigations indicated that compound 1 primarily alleviated lipid accumulation through selective activation of the PINK1/Parkin mitophagy signaling pathway.
Asunto(s)
Relación Dosis-Respuesta a Droga , Mitofagia , Enfermedad del Hígado Graso no Alcohólico , Penicillium , Proteínas Quinasas , Sesquiterpenos , Ubiquitina-Proteína Ligasas , Pez Cebra , Penicillium/química , Mitofagia/efectos de los fármacos , Sesquiterpenos/farmacología , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Animales , Estructura Molecular , Humanos , Proteínas Quinasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.
Asunto(s)
Antígenos CD19 , Inmunoterapia Adoptiva , Miositis , Receptores Quiméricos de Antígenos , Esclerodermia Sistémica , Humanos , Antígenos CD19/inmunología , Antígenos CD19/metabolismo , Miositis/terapia , Miositis/inmunología , Esclerodermia Sistémica/terapia , Esclerodermia Sistémica/inmunología , Inmunoterapia Adoptiva/métodos , Femenino , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Masculino , Persona de Mediana Edad , Adulto , Linfocitos T/inmunología , Linfocitos T/metabolismo , Trasplante HomólogoRESUMEN
The IKZF1 gene encodes a transcription factor that belongs to the family of zinc-finger DNA-binding proteins associated with chromatin remodeling. The protein product, IKAROS, had been proved to regulate lymphopoiesis. Subsequent mouse model studies have further confirmed its regulating role in lymphopoiesis as well as in hematopoiesis; besides, it associates with immune function, certain immune disorders like common variable immunodeficiency and dysgammaglobulinemia have been proved to be associated with germline IKZF1 mutations. Dysfunction of IKAROS also bears paramount significance in leukemic transformation and alterations of IKZF1 gene predicts a poor prognosis in hematological malignancies. As an independent prognostic marker, IKZF1 has been incorporated in the risk stratification of BCP-ALL and stratification-guided therapy has also been generated. In this review, we provide a concise and comprehensive overview on the multifaceted roles of IKZF1 gene.