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Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.
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Complejo CD3 , Activación de Linfocitos , Linfocitos T , Escape del Tumor , Microambiente Tumoral , Animales , Complejo CD3/metabolismo , Complejo CD3/inmunología , Humanos , Ratones , Linfocitos T/inmunología , Linfocitos T/metabolismo , Microambiente Tumoral/inmunología , Perros , Neoplasias/inmunología , Línea Celular Tumoral , Femenino , Unión Proteica , Proteína Tirosina Quinasa ZAP-70/metabolismo , Anticuerpos Neutralizantes/inmunología , Ratones Endogámicos C57BLRESUMEN
TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Intriguingly, cancer-associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC catch bonds. Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes. Our findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCR-pMHC catch bonds but also have implications for T cell-based immunotherapy.
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Inmunidad Adaptativa , Antígeno HLA-A2/inmunología , Mecanotransducción Celular , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Células HEK293 , Antígeno HLA-A2/química , Antígeno HLA-A2/genética , Antígeno HLA-A2/metabolismo , Humanos , Hibridomas , Ratones Endogámicos C57BL , Ratones Transgénicos , Simulación de Dinámica Molecular , Mutación , Unión Proteica , Conformación Proteica , Receptores de Antígenos de Linfocitos T/química , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Imagen Individual de Molécula/métodos , Relación Estructura-Actividad , Linfocitos T/metabolismoRESUMEN
Stimulatory immune receptor NKG2D binds diverse ligands to elicit differential anti-tumor and anti-virus immune responses. Two conflicting degeneracy recognition models based on static crystal structures and in-solution binding affinities have been considered for almost two decades. Whether and how NKG2D recognizes and discriminates diverse ligands still remain unclear. Using live-cell-based single-molecule biomechanical assay, we characterized the in situ binding kinetics of NKG2D interacting with different ligands in the absence or presence of mechanical force. We found that mechanical force application selectively prolonged NKG2D interaction lifetimes with the ligands MICA and MICB, but not with ULBPs, and that force-strengthened binding is much more pronounced for MICA than for other ligands. We also integrated steered molecular dynamics simulations and mutagenesis to reveal force-induced rotational conformational changes of MICA, involving formation of additional hydrogen bonds on its binding interface with NKG2D, impeding MICA dissociation under force. We further provided a kinetic triggering model to reveal that force-dependent affinity determines NKG2D ligand discrimination and its downstream NK cell activation. Together, our results demonstrate that NKG2D has a discrimination power to recognize different ligands, which depends on selective mechanical force-induced ligand conformational changes.
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Subfamilia K de Receptores Similares a Lectina de Células NK/química , Sitios de Unión , Células Cultivadas , Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Células K562 , Ligandos , Fenómenos Mecánicos , Simulación de Dinámica Molecular , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Unión Proteica , Imagen Individual de MoléculaRESUMEN
BACKGROUND: A main obstacle in current valvular heart disease research is the lack of high-quality homogeneous functional heart valve cells. Human induced pluripotent stem cells (hiPSCs)-derived heart valve cells may help with this dilemma. However, there are no well-established protocols to induce hiPSCs to differentiate into functional heart valve cells, and the networks that mediate the differentiation have not been fully elucidated. METHODS: To generate heart valve cells from hiPSCs, we sequentially activated the Wnt, BMP4, VEGF (vascular endothelial growth factor), and NFATc1 signaling pathways using CHIR-99021, BMP4, VEGF-165, and forskolin, respectively. The transcriptional and functional similarity of hiPSC-derived heart valve cells compared with primary heart valve cells were characterized. Longitudinal single-cell RNA sequencing was used to uncover the trajectory, switch genes, pathways, and transcription factors of the differentiation. RESULTS: An efficient protocol was developed to induce hiPSCs to differentiate into functional hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells. After 6-day differentiation and CD144 magnetic bead sorting, ≈70% CD144+ cells and 30% CD144- cells were obtained. On the basis of single-cell RNA sequencing data, the CD144+ cells and CD144- cells were found to be highly similar to primary heart valve endothelial cells and primary heart valve interstitial cells in gene expression profile. Furthermore, CD144+ cells had the typical function of primary heart valve endothelial cells, including tube formation, uptake of low-density lipoprotein, generation of endothelial nitric oxide synthase, and response to shear stress. Meanwhile, CD144- cells could secret collagen and matrix metalloproteinases, and differentiate into osteogenic or adipogenic lineages like primary heart valve interstitial cells. Therefore, we identified CD144+ cells and CD144- cells as hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells, respectively. Using single-cell RNA sequencing analysis, we demonstrated that the trajectory of heart valve cell differentiation was consistent with embryonic valve development. We identified the main switch genes (NOTCH1, HEY1, and MEF2C), signaling pathways (TGF-ß, Wnt, and NOTCH), and transcription factors (MSX1, SP5, and MECOM) that mediated the differentiation. Finally, we found that hiPSC-derived valve interstitial-like cells might derive from hiPSC-derived valve endothelial-like cells undergoing endocardial-mesenchymal transition. CONCLUSIONS: In summary, this is the first study to report an efficient strategy to generate functional hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells from hiPSCs, as well as to elucidate the differentiation trajectory and transcriptional dynamics of hiPSCs differentiated into heart valve cells.
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Diferenciación Celular , Válvulas Cardíacas , Células Madre Pluripotentes Inducidas , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Válvulas Cardíacas/citología , Válvulas Cardíacas/metabolismo , Células Cultivadas , Células Endoteliales/metabolismo , Células Endoteliales/citología , Transducción de SeñalRESUMEN
Intense inflammatory response impairs bone marrow mesenchymal stem cell (BMSC)-mediated bone regeneration, with transforming growth factor (TGF)-ß1 being the most highly expressed cytokine. However, how to find effective and safe means to improve bone formation impaired by excessive TGF-ß1 remains unclear. In this study, we found that the expression of orphan nuclear receptor Nr4a1, an endogenous repressor of TGF-ß1, was suppressed directly by TGF-ß1-induced Smad3 and indirectly by Hdac4, respectively. Importantly, Nr4a1 overexpression promoted BMSC osteogenesis and reversed TGF-ß1-mediated osteogenic inhibition and pro-fibrotic effects. Transcriptomic and histologic analyses confirmed that upregulation of Nr4a1 increased the transcription of Wnt family member 4 (Wnt4) and activated Wnt pathway. Mechanistically, Nr4a1 bound to the promoter of Wnt4 and regulated its expression, thereby enhancing the osteogenic capacity of BMSCs. Moreover, treatment with Nr4a1 gene therapy or Nr4a1 agonist Csn-B could promote ectopic bone formation, defect repair, and fracture healing. Finally, we demonstrated the correlation of NR4A1 with osteogenesis and the activation of the WNT4/ß-catenin pathway in human BMSCs and fracture samples. Taken together, these findings uncover the critical role of Nr4a1 in bone formation and alleviation of inflammation-induced bone regeneration disorders, and suggest that Nr4a1 has the potential to be a therapeutic target for accelerating bone healing.
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Regeneración Ósea , Inflamación , Células Madre Mesenquimatosas , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Osteogénesis , Proteína Wnt4 , Células Madre Mesenquimatosas/metabolismo , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Osteogénesis/genética , Regeneración Ósea/genética , Animales , Ratones , Proteína Wnt4/metabolismo , Proteína Wnt4/genética , Humanos , Inflamación/genética , Inflamación/metabolismo , Regulación de la Expresión Génica , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Vía de Señalización Wnt , Masculino , Transcripción Genética , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Modelos Animales de EnfermedadRESUMEN
BACKGROUND AND AIMS: Valve interstitial cells (VICs) undergo a transition to intermediate state cells before ultimately transforming into the osteogenic cell population, which is a pivotal cellular process in calcific aortic valve disease (CAVD). Herein, this study successfully delineated the stages of VIC osteogenic transformation and elucidated a novel key regulatory role of lumican (LUM) in this process. METHODS: Single-cell RNA-sequencing (scRNA-seq) from nine human aortic valves was used to characterize the pathological switch process and identify key regulatory factors. The in vitro, ex vivo, in vivo, and double knockout mice were constructed to further unravel the calcification-promoting effect of LUM. Moreover, the multi-omic approaches were employed to analyse the molecular mechanism of LUM in CAVD. RESULTS: ScRNA-seq successfully delineated the process of VIC pathological transformation and highlighted the significance of LUM as a novel molecule in this process. The pro-calcification role of LUM is confirmed on the in vitro, ex vivo, in vivo level, and ApoE-/-//LUM-/- double knockout mice. The LUM induces osteogenesis in VICs via activation of inflammatory pathways and augmentation of cellular glycolysis, resulting in the accumulation of lactate. Subsequent investigation has unveiled a novel LUM driving histone modification, lactylation, which plays a role in facilitating valve calcification. More importantly, this study has identified two specific sites of histone lactylation, namely, H3K14la and H3K9la, which have been found to facilitate the process of calcification. The confirmation of these modification sites' association with the expression of calcific genes Runx2 and BMP2 has been achieved through ChIP-PCR analysis. CONCLUSIONS: The study presents novel findings, being the first to establish the involvement of lumican in mediating H3 histone lactylation, thus facilitating the development of aortic valve calcification. Consequently, lumican would be a promising therapeutic target for intervention in the treatment of CAVD.
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Neuritin, also known as candidate plasticity gene 15 (CPG15), was first identified as one of the activity-dependent gene products in the brain. Previous studies have been reported that Neuritin induces neuritogenesis, neurite arborization, neurite outgrowth and synapse formation, which are involved in the development and functions of the central nervous system. However, the role of Neuritin in peripheral nerve injury is still unknown. Given the importance and necessity of Schwann cell dedifferentiation response to peripheral nerve injury, we aim to investigate the molecular mechanism of Neuritin steering Schwann cell dedifferentiation during Wallerian degeneration (WD) in injured peripheral nerve. Herein, using the explants of sciatic nerve, an ex vivo model of nerve degeneration, we provided evidences indicating that Neuritin vividly accelerates Schwann cell dedifferentiation. Moreover, we found that Neuritin promotes Schwann cell demyelination as well as axonal degeneration, phagocytosis, secretion capacity. In summary, we first described Neuritin acts as a positive regulator for Schwann cell dedifferentiation and WD after peripheral nerve injury.
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Desdiferenciación Celular , Neuropéptidos , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Células de Schwann , Nervio Ciático , Transducción de Señal , Serina-Treonina Quinasas TOR , Degeneración Walleriana , Células de Schwann/metabolismo , Células de Schwann/patología , Degeneración Walleriana/metabolismo , Degeneración Walleriana/patología , Animales , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neuropéptidos/metabolismo , Neuropéptidos/genética , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Nervio Ciático/patología , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/genética , Ratas , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/patología , Ratas Sprague-Dawley , Axones/metabolismo , Axones/patología , Masculino , Fagocitosis , RatonesRESUMEN
Phase change material (PCM) can provide a battery system with a buffer platform to respond to thermal failure problems. However, current PCMs through compositing inorganics still suffer from insufficient thermal-transport behavior and safety reliability against external force. Herein, a best-of-both-worlds method is reported to allow the PCM out of this predicament. It is conducted by combining a traditional PCM (i.e., paraffin wax/boron nitride) with a spirally weaved polyethylene fiber fabric, just like the traditional PCM is wearing functional underwear. On the one hand, the spirally continuous thermal pathways of polyethylene fibers in the fabric collaborate with the boron nitride network in the PCM, enhancing the through-plane and in-plane thermal conductivity to 10.05 and 7.92 W m-1 K, respectively. On the other, strong polyethylene fibers allow the PCM to withstand a high puncture strength of 47.13 N and tensile strength of 18.45 MPa although above the phase transition temperature. After this typical PCM packs a triple Li-ion battery system, the battery can be promised reliable safety management against both thermal and mechanical abuse. An obvious temperature drop of >10 °C is observed in the battery electrode during the cycling charging and discharging process.
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The microphenotype plays a key role in bridging the gap between the genotype and the complex macro phenotype. In this article, we review the advances in data acquisition and the intelligent analysis of plant microphenotyping and present applications of microphenotyping in plant science over the past two decades. We then point out several challenges in this field and suggest that cross-scale image acquisition strategies, powerful artificial intelligence algorithms, advanced genetic analysis, and computational phenotyping need to be established and performed to better understand interactions among genotype, environment, and management. Microphenotyping has entered the era of Microphenotyping 3.0 and will largely advance functional genomics and plant science.
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Inteligencia Artificial , Genómica , Fenotipo , Genómica/métodos , Genotipo , Plantas/genéticaRESUMEN
Most nonoxide catalysts based on transition metal elements will inevitably change their primitive phases under anodic oxidation conditions in alkaline media. Establishing a relationship between the bulk phase and surface evolution is imperative to reveal the intrinsic catalytic active sites. In this work, it is demonstrated that the introduction of Fe facilitates the phase transition of orthorhombic CoSe2 into its cubic counterpart and then accelerates the Co-Fe hydroxide layer generation on the surface during electrocatalytic oxygen evolution reaction (OER). As a result, the Fe-doped cubic CoSe2 catalyst exhibits a significantly enhanced activity with a considerable overpotential decrease of 79.9 and 66.9 mV to deliver 10 mA·cm-2 accompanied by a Tafel slope of 48.0 mV·dec-1 toward OER when compared to orthorhombic CoSe2 and Fe-doped orthorhombic CoSe2, respectively. Density functional theory (DFT) calculations reveal that the introduction of Fe on the surface hydroxide layers will tune electron density around Co atoms and raise the d-band center. These findings will provide deep insights into the surface reconstitution of the OER electrocatalysts based on transition metal elements.
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Background: In the early postoperative stage after heart transplantation, there is a lack of predictive tools to guide postoperative management. Whether the vasoactive-inotropic score (VIS) can aid this prediction is not well illustrated. Methods: In total, 325 adult patients who underwent heart transplantation at our center between January 2015 and December 2018 were included. The maximum VIS (VISmax) within 24 h postoperatively was calculated. The Kaplan-Meier method was used for survival analysis. A logistic regression model was established to determine independent risk factors and to develop a nomogram for a composite severe adverse outcome combining early mortality and morbidity. Results: VISmax was significantly associated with extensive early outcomes such as early death, renal injury, cardiac reoperation and mechanical circulatory support in a grade-dependent manner, and also predicted 90-day and 1-year survival (p < 0.05). A VIS-based nomogram for the severe adverse outcome was developed that included VISmax, preoperative advanced heart failure treatment, hemoglobin and serum creatinine. The nomogram was well calibrated (Hosmer-Lemeshow p = 0.424) with moderate to strong discrimination (C-index = 0.745) and good clinical utility. Conclusion: VISmax is a valuable prognostic index in heart transplantation. In the early post-transplant stage, this VIS-based nomogram can easily aid intensive care clinicians in inferring recipient status and guiding postoperative management.
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Trasplante de Corazón , Nomogramas , Humanos , Trasplante de Corazón/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/diagnóstico , Insuficiencia Cardíaca/cirugía , Factores de Riesgo , Cuidados Posoperatorios/métodos , Estimación de Kaplan-Meier , Anciano , PronósticoRESUMEN
Tissue engineered heart valves (TEHVs) demonstrates the potential for tissue growth and remodel, offering particular benefit for pediatric patients. A significant challenge in designing functional TEHV lies in replicating the anisotropic mechanical properties of native valve leaflets. To establish a biomimetic TEHV model, we employed melt-electrowriting (MEW) technology to fabricate an anisotropic PCL scaffold. By integrating the anisotropic MEW-PCL scaffold with bioactive hydrogels (GelMA/ChsMA), we successfully crafted an elastic scaffold with tunable mechanical properties closely mirroring the structure and mechanical characteristics of natural heart valves. This scaffold not only supports the growth of valvular interstitial cells (VICs) within a 3D culture but also fosters the remodeling of extracellular matrix of VICs. The in vitro experiments demonstrated that the introduction of ChsMA improved the hemocompatibility and endothelialization of TEHV scaffold. The in vivo experiments revealed that, compared to their non-hydrogel counterparts, the PCL-GelMA/ChsMA scaffold, when implanted into SD rats, significantly suppressed immune reactions and calcification. In comparison with the PCL scaffold, the PCL-GelMA/ChsMA scaffold exhibited higher bioactivity and superior biocompatibility. The amalgamation of MEW technology and biomimetic design approaches provides a new paradigm for manufacturing scaffolds with highly controllable microstructures, biocompatibility, and anisotropic mechanical properties required for the fabrication of TEHVs.
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Válvulas Cardíacas , Hidrogeles , Ratas Sprague-Dawley , Ingeniería de Tejidos , Andamios del Tejido , Ingeniería de Tejidos/métodos , Animales , Andamios del Tejido/química , Anisotropía , Ratas , Hidrogeles/química , Materiales Biocompatibles/química , Prótesis Valvulares Cardíacas , Poliésteres/química , Células Cultivadas , Humanos , Matriz Extracelular/química , MasculinoRESUMEN
BACKGROUND: Cancer subtype classification is helpful for personalized cancer treatment. Although, some approaches have been developed to classifying caner subtype based on high dimensional gene expression data, it is difficult to obtain satisfactory classification results. Meanwhile, some cancers have been well studied and classified to some subtypes, which are adopt by most researchers. Hence, this priori knowledge is significant for further identifying new meaningful subtypes. RESULTS: In this paper, we present a combined parallel random forest and autoencoder approach for cancer subtype identification based on high dimensional gene expression data, ForestSubtype. ForestSubtype first adopts the parallel RF and the priori knowledge of cancer subtype to train a module and extract significant candidate features. Second, ForestSubtype uses a random forest as the base module and ten parallel random forests to compute each feature weight and rank them separately. Then, the intersection of the features with the larger weights output by the ten parallel random forests is taken as our subsequent candidate features. Third, ForestSubtype uses an autoencoder to condenses the selected features into a two-dimensional data. Fourth, ForestSubtype utilizes k-means++ to obtain new cancer subtype identification results. In this paper, the breast cancer gene expression data obtained from The Cancer Genome Atlas are used for training and validation, and an independent breast cancer dataset from the Molecular Taxonomy of Breast Cancer International Consortium is used for testing. Additionally, we use two other cancer datasets for validating the generalizability of ForestSubtype. ForestSubtype outperforms the other two methods in terms of the distribution of clusters, internal and external metric results. The open-source code is available at https://github.com/lffyd/ForestSubtype . CONCLUSIONS: Our work shows that the combination of high-dimensional gene expression data and parallel random forests and autoencoder, guided by a priori knowledge, can identify new subtypes more effectively than existing methods of cancer subtype classification.
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Neoplasias de la Mama , Bosques Aleatorios , Humanos , Femenino , Genómica , Programas InformáticosRESUMEN
BACKGROUND: The cholinergic anti-inflammatory pathway (CAP) has been widely studied to modulate the immune response. Current stimulating strategies are invasive or imprecise. Noninvasive low-intensity pulsed ultrasound (LIPUS) has become increasingly appreciated for targeted neuronal modulation. However, its mechanisms and physiological role on myocarditis remain poorly defined. METHODS: The mouse model of experimental autoimmune myocarditis was established. Low-intensity pulsed ultrasound was targeted at the spleen to stimulate the spleen nerve. Under different ultrasound parameters, histological tests and molecular biology were performed to observe inflammatory lesions and changes in immune cell subsets in the spleen and heart. In addition, we evaluated the dependence of the spleen nerve and cholinergic anti-inflammatory pathway of low-intensity pulsed ultrasound in treating autoimmune myocarditis in mice through different control groups. RESULTS: The echocardiography and flow cytometry of splenic or heart infiltrating immune cells revealed that splenic ultrasound could alleviate the immune response, regulate the proportion and function of CD4+ Treg and macrophages by activating cholinergic anti-inflammatory pathway, and finally reduce heart inflammatory injury and improve cardiac remodeling, which is as effective as an acetylcholine receptor agonists GTS-21. Transcriptome sequencing showed significant differential expressed genes due to ultrasound modulation. CONCLUSIONS: It is worth noting that the ultrasound therapeutic efficacy depends greatly on acoustic pressure and exposure duration, and the effective targeting organ was the spleen but not the heart. This study provides novel insight into the therapeutic potentials of LIPUS, which are essential for its future application.
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Miocarditis , Animales , Ratones , Miocarditis/terapia , Miocarditis/patología , Bazo/patología , Ultrasonografía , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Vitamin D deficiency is common among the population, but its relationship with mortality of postmenopausal females is unclear. The aim of this study is to explore the association between serum 25-Hydroxyvitamin D (25(OH)D) and all-cause and cause-specific mortality among postmenopausal women in the United States. METHODS: 6812 participants of postmenopausal females from the National Health and Nutrition Examination Survey (2001-2018) were included in this study. The mortality status of the follow-up was ascertained by linkage to National Death Index (NDI) records through 31 December 2019. We used cox proportional hazards models to estimate the association of serum 25(OH)D concentrations and mortality of postmenopausal females. RESULTS: The mean level of serum 25(OH)D was 72.57 ± 29.93 nmol/L, and 65.34% had insufficient vitamin D. In postmenopausal females, low serum 25(OH)D concentrations were significantly associated with higher levels of glycohemoglobin, glucose, and lower levels of HDL. During follow-up, 1448 all-cause deaths occurred, including 393 cardiovascular disease (CVD)-related deaths and 263 cancer deaths. After multivariate adjustment, higher serum 25(OH)D levels were significantly related with lower all-cause and CVD mortality. In addition, serum 25(OH)D presented a L-shaped relationship with all-cause mortality, while appeared a U-shaped with CVD mortality, and the cut-off value is 73.89 nmol/L and 46.75 nmol/L respectively. CONCLUSIONS: Low serum 25(OH)D levels are associated with the higher risk of all-cause and CVD mortality in postmenopausal females. These findings provide new ideas and targets for the health management of postmenopausal women.
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Enfermedades Cardiovasculares , Posmenopausia , Femenino , Humanos , Encuestas Nutricionales , Causas de Muerte , Vitamina DRESUMEN
Salt stress is a major limiting factor that severely affects the survival and growth of crops. It is important to understand the salt stress tolerance ability of Brassica napus and explore the underlying related genetic resources. We used a high-throughput phenotyping platform to quantify 2111 image-based traits (i-traits) of a natural population under three different salt stress conditions and an intervarietal substitution line (ISL) population under nine different stress conditions to monitor and evaluate the salt stress tolerance of B. napus over time. We finally identified 928 high-quality i-traits associated with the salt stress tolerance of B. napus. Moreover, we mapped the salt stress-related loci in the natural population via a genome-wide association study and performed a linkage analysis associated with the ISL population, respectively. These results revealed 234 candidate genes associated with salt stress response, and two novel candidate genes, BnCKX5 and BnERF3, were experimentally verified to regulate the salt stress tolerance of B. napus. This study demonstrates the feasibility of using high-throughput phenotyping-based quantitative trait loci mapping to accurately and comprehensively quantify i-traits associated with B. napus. The mapped loci could be used for genomics-assisted breeding to genetically improve the salt stress tolerance of B. napus.
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Brassica napus , Sitios de Carácter Cuantitativo , Sitios de Carácter Cuantitativo/genética , Brassica napus/fisiología , Mapeo Cromosómico/métodos , Estudio de Asociación del Genoma Completo , Tolerancia a la Sal/genéticaRESUMEN
Spontaneous imbibition has garnered increasing attention as an attractive mechanism for developing tight reservoirs. Despite valuable insights from previous experiments, there remains a lack of understanding regarding the imbibition process within multiscale nanopore-fracture networks. In this work, we devised an innovative multiscale model incorporating over 105 nanochannels and integrating a microfracture network to explore the complex imbibition behavior in tight formations. Additionally, fracture-free nanomatrix models with low permeability were developed for comparative discussions. The results show that the Lucas-Washburn equation remains valid at the tremendous fracture-free nanopore networks under the confinement of 500 nm, with a relative deviation of ±6%. The nanomatrix's heterogeneity hinders the imbibition rate, resulting in a reduction of 4.6 to 10.8% in the imbibition slope. The viscosity plays a dominant role in the change of imbibition slope as temperature varies. Our experiments also found that the interactions between the nanomatrix and bulk fracture complicate the imbibition process. A single wetting front no longer applies in the nanomatrix-fracture networks. Differing fracture/microchannel connectivity leads to disparities in macroscopic patterns, saturation rates, and flow directions. The spatial arrangement of fractures significantly impacts the imbibition time. Overall, this work based on nanofluidic techniques systematically explores the effects of matrix heterogeneity, temperature, and fractures on the imbibition process. The real-time in situ visualization of fluid distribution in multiscale matrix-fracture systems has been achieved, which offers theoretical guidance for practical engineering applications.
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BACKGROUND: Heart transplantation is the definitive therapy for patients with end-stage heart failure. Antecedent studies reported that a substantial proportion of heart transplant recipients developed postoperative cognitive impairment in the long term. However, no studies have explored the association between postoperative cognitive impairment and survival after heart transplantation. METHODS: The data of 43 adult patients who underwent heart transplantation were consecutively enrolled and assessed using the MMSE and MoCA neuropsychological tests. Kaplan-Meier curves and Cox proportional hazards models were used for survival analyses. Primary component analysis was performed to integrate MoCA subtests into the "Attention factor," "Naming factor," and "Orientation factor." RESULTS: About 30% of the patients were diagnosed with short-term postoperative cognitive impairment. The impairment group was older and had lower baseline cognitive performances, larger LV diameter, worse MMSE decline and higher ratio of significant MoCA decline. Postoperative cognitive impairment was significantly associated with worse survival (P = .028). Multivariate Cox analyses showed that higher postoperative MoCA score was significantly associated with lower mid-term post-transplant mortality (HR = .744 [.584, .949], P = .017), in which "Attention factor" contributed to this association most (HR = .345 [.123, .970], P = .044) rather than "Naming factor" or "Orientation factor." Notably, preoperative cognitive impairment was closely related with postoperative cognitive impairment and also indicated the worse post-transplant survival (P = .015). CONCLUSION: Postoperative as well as preoperative cognitive impairments were associated with a worse mid-term survival after heart transplantation, indicating that neuropsychological assessments before and after heart transplantation should be routinely performed for heart transplant recipients for better risk stratification.
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Insuficiencia Cardíaca , Trasplante de Corazón , Complicaciones Cognitivas Postoperatorias , Complicaciones Cognitivas Postoperatorias/diagnóstico , Complicaciones Cognitivas Postoperatorias/etiología , Complicaciones Cognitivas Postoperatorias/mortalidad , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/mortalidad , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/cirugía , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/mortalidad , Pruebas Neuropsicológicas , Cuidados Preoperatorios , Medición de Riesgo , Persona de Mediana Edad , Humanos , Masculino , Femenino , AdultoRESUMEN
BACKGROUND: Fasting blood glucose (FBG) variability, an emerging marker of glycemic control, has been shown to be related to the risk of cardiovascular events and all-cause mortality in subjects with or without diabetes. However, whether FBG variability is independently associated with a higher all-cause mortality in heart transplant recipients remains unknown. METHODS: We performed a retrospective cohort study including 373 adult recipients who survived for at least 1 year after heart transplantation with a functioning graft and measured FBG more than three times within first year after transplantation. Multivariable adjusted Cox regression analyses were performed to assess the association between FBG variability and all-cause mortality. RESULTS: Patients were categorized into three groups according to the coefficient of variation of FBG level: ≤7.0%, 7.0%-13.5%, and >13.5%. During a median follow-up of 44.4 months (interquartile range [IQR], 22.6-63.3 months), 31 (8.3%) participants died. In univariate analyses, FBG variability was associated with an increased all-cause mortality (hazard ratio [HR]: 3.00, 95% confidence interval [CI]: 1.67, 5.38; p < .001). This association remained materially unchanged in the multivariable model adjusted for components of demographics, cardiovascular history and lifestyle, hospital information, immunosuppressive therapy, and post-transplant renal function (HR: 2.75, 95% CI: 1.43, 5.28; p = .004). CONCLUSIONS: After heart transplantation, high FBG variability is strongly and independently associated with an increased risk of all-cause mortality. Our findings suggest that FBG variability is a novel risk factor and prognostic marker for heart transplantation recipients in outpatient clinic.
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Diabetes Mellitus , Trasplante de Corazón , Adulto , Humanos , Glucemia , Estudios Retrospectivos , Factores de Riesgo , Trasplante de Corazón/efectos adversos , Ayuno , Receptores de TrasplantesRESUMEN
BACKGROUND: The objective of this study was to develop and validate a nomogram for the individualized prediction of adverse events in patients with Stanford type A aortic dissection (TAAD) undergoing hybrid total aortic arch repair. METHODS: From April 2019 to April 2022, we conducted a comprehensive review of the medical records of Stanford type A aortic dissection patients who underwent hybrid total aortic arch repair surgery at our hospital. Patients were separated into two groups based on whether or not a composite adverse event occurred following surgery. Using univariate and multivariate analyses of logistic regression, the prediction model was created. Construct risk prediction models utilizing nomograms and evaluate their precision, discrimination, and clinical utility. RESULTS: Age, platelets, serum blood urea nitrogen, and ascending aortic diameter were the variables included in the nomogram by univariate and multivariate analysis. The risk model performed well in internal validation, with an area under the curve (AUC) of 0.829. The calibration curve demonstrated good agreement between predicted and actual probabilities (Hosmer-Lemeshow test, P = 0.22). Clinical decision analysis curves demonstrate predictive nomograms' clinical utility. CONCLUSION: This study created and validated a nomogram for predicting the risk of composite endpoint events in TAAD patients undergoing hybrid total aortic arch repair. The nomogram can help determine the severity of a patient's condition and provide a more personalized diagnosis and treatment.