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1.
Adv Sci (Weinh) ; : e2405077, 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38959393

RESUMEN

Energy and environmental issues have increasingly garnered significant attention for sustainable development. Flexible and shape-stable phase change materials display great potential in regulation of environmental temperature for energy saving and human comfort. Here, inspired by the water absorption behavior of salt-tolerant animals and plants in salinity environment and the Hofmeister theory, highly stable phase change salogels (PCSGs) are fabricated through in situ polymerization of hydrophilic monomers in molten salt hydrates, which can serve multiple functions including thermal management patches, smart windows, and ice blocking coatings. The gelation principles of the polymer in high ion concentration solution are explored through the density functional theory simulation and verified the feasibility of four types of salt hydrates. The high concentration chaotropic ions strongly interacted with polymer chains and promoted the gelation at low polymer concentrations which derive highly-stable and ultra-moisturizing PCSGs with high latent heat (> 200 J g-1). The synergistic adhesion and transparency switching abilities accompanied with phase transition enable their smart thermal management. The study resolves the melting leakage and thermal cycling stability of salt hydrates, and open an avenue to fabricate flexible PCM of low cost, high latent heat, and long-term durability for energy-saving, ice-blocking, and thermal management.

2.
Microb Pathog ; 194: 106829, 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39084310

RESUMEN

Goose astroviruses (GAstVs) are important pathogens which can cause gout in goslings leading to huge economic losses for the goose farming industry in China. In 2023, an infectious disease characterized by visceral gout broke out in commercial goose farms in Guangxi and Guangdong provinces of China. In this study, two GAstV strains of GXNN and GDCS were successfully isolated from these two disease-ridden goose farms. The complete genomic lengths of these two strains were 7166 bp, and phylogenetic analysis showed that they were both GAstV-2 subtypes. The 3-dimensional structures of the capsid protein were predicted and six characteristic mutation sites at amino acid positions 60, 61, 228, 229, 456 and 523 were found within the strong antigenic regions. A recombination event occurred at 6833-7070 nt between the GAstV TZ03 and Turkey astrovirus CA/00 and this was detected in both the GXNN and GDCS strains. Another recombinant event occurred at 63-2747 nt between the GAstV XT1 and GAstV SDPY and this was detected in the GDCS strain. When 1-day-old goslings were infected with the novel GXNN and GDCS strains, they showed severe visceral gout. This was accompanied by enlarged spleens, liver hemorrhages and urate deposits in the kidneys and ureters and their blood urea nitrogen levels were significantly elevated. The mortality rates of the GXNN- and GDCS-infected groups were pathogenically high at 80 % and 60 %, respectively. These results will promote our understanding of the evolution and epidemic potential of GAstVs in China.

3.
Nat Commun ; 15(1): 6357, 2024 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-39069555

RESUMEN

DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.


Asunto(s)
5-Metilcitosina , Envejecimiento , Cerebelo , Metilación de ADN , Hígado , Animales , Envejecimiento/genética , Envejecimiento/metabolismo , 5-Metilcitosina/metabolismo , 5-Metilcitosina/análogos & derivados , Hígado/metabolismo , Ratones , Humanos , Cerebelo/metabolismo , Ratones Endogámicos C57BL , Longevidad/genética , Masculino , Empalme Alternativo , Transcripción Genética , Femenino , Regulación de la Expresión Génica
4.
Front Biosci (Landmark Ed) ; 29(5): 201, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38812314

RESUMEN

BACKGROUND: Ibrutinib could increase the risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL) patients. However, the precise mechanism underlying ibrutinib-induced AF remains incompletely elucidated. METHODS: We investigated the proportion of ibrutinib-treated CLL patients with new-onset AF. Optical mapping was conducted to reveal the proarrhythmic effect of ibrutinib on HL-1 cells. Fluorescence staining and western blot were used to compare connexins 43 and 40 expression in ibrutinib-treated and control groups. To identify autophagy phenotypes, we used western blot to detect autophagy-related proteins, transmission electron microscopy to picture autophagosomes, and transfected mCherry-GFP-LC3 virus to label autophagosomes and lysosomes. Hydroxychloroquine as an autophagy inhibitor was administered to rescue ibrutinib-induced Cx43 and Cx40 degradation. RESULTS: About 2.67% of patients developed atrial arrhythmias after ibrutinib administration. HL-1 cells treated with ibrutinib exhibited diminished conduction velocity and a higher incidence of reentry-like arrhythmias compared to controls. Cx43 and Cx40 expression reduced along with autophagy markers increased in HL-1 cells treated with ibrutinib. Inhibiting autophagy upregulated Cx43 and Cx40. CONCLUSIONS: The off-target effect of ibrutinib on the PI3K-AKT-mTOR signaling pathway caused connexin degradation and atrial arrhythmia via promoting autophagy. CLINICAL TRIAL REGISTRATION: ChiCTR2100046062, https://clin.larvol.com/trial-detail/ChiCTR2100046062.


Asunto(s)
Adenina , Fibrilación Atrial , Autofagia , Conexina 43 , Conexinas , Fosfatidilinositol 3-Quinasas , Piperidinas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Adenina/análogos & derivados , Adenina/farmacología , Adenina/efectos adversos , Serina-Treonina Quinasas TOR/metabolismo , Autofagia/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piperidinas/farmacología , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Conexina 43/metabolismo , Conexina 43/genética , Femenino , Fibrilación Atrial/metabolismo , Fibrilación Atrial/inducido químicamente , Conexinas/metabolismo , Conexinas/genética , Masculino , Anciano , Persona de Mediana Edad , Proteína alfa-5 de Unión Comunicante , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/inducido químicamente
5.
Aging (Albany NY) ; 16(8): 6717-6730, 2024 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-38637019

RESUMEN

Evaporation of sweat on the skin surface is the major mechanism for dissipating heat in humans. The secretory capacity of sweat glands (SWGs) declines during aging, leading to heat intolerance in the elderly, but the mechanisms responsible for this decline are poorly understood. We investigated the molecular changes accompanying SWG aging in mice, where sweat tests confirmed a significant reduction of active SWGs in old mice relative to young mice. We first identified SWG-enriched mRNAs by comparing the skin transcriptome of Eda mutant Tabby male mice, which lack SWGs, with that of wild-type control mice by RNA-sequencing analysis. This comparison revealed 171 mRNAs enriched in SWGs, including 47 mRNAs encoding 'core secretory' proteins such as transcription factors, ion channels, ion transporters, and trans-synaptic signaling proteins. Among these, 28 SWG-enriched mRNAs showed significantly altered abundance in the aged male footpad skin, and 11 of them, including Foxa1, Best2, Chrm3, and Foxc1 mRNAs, were found in the 'core secretory' category. Consistent with the changes in mRNA expression levels, immunohistology revealed that higher numbers of secretory cells from old SWGs express the transcription factor FOXC1, the protein product of Foxc1 mRNA. In sum, our study identified mRNAs enriched in SWGs, including those that encode core secretory proteins, and altered abundance of these mRNAs and proteins with aging in mouse SWGs.


Asunto(s)
Envejecimiento , Glándulas Sudoríparas , Animales , Glándulas Sudoríparas/metabolismo , Ratones , Envejecimiento/genética , Envejecimiento/metabolismo , Masculino , ARN Mensajero/metabolismo , ARN Mensajero/genética , Transcriptoma
6.
Int J Med Sci ; 21(5): 965-977, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38616996

RESUMEN

Cardiac hypertrophy is the most prevalent compensatory heart disease that ultimately leads to spontaneous heart failure. Mounting evidence suggests that microRNAs (miRs) and endogenous hydrogen sulfide (H2S) play a crucial role in the regulation of cardiac hypertrophy. In this study, we aimed to investigate whether inhibition of miR-27a could protect against cardiac hypertrophy by modulating H2S signaling. We established a model of cardiac hypertrophy by obtaining hypertrophic tissue from mice subjected to transverse aortic constriction (TAC) and from cells treated with angiotensin-II. Molecular alterations in the myocardium were quantified using quantitative real time PCR (qRT-PCR), Western blotting, and ELISA. Morphological changes were characterized by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Functional myocardial changes were assessed using echocardiography. Our results demonstrated that miR-27a levels were elevated, while H2S levels were reduced in TAC mice and myocardial hypertrophy. Further luciferase and target scan assays confirmed that cystathionine-γ-lyase (CSE) was a direct target of miR-27a and was negatively regulated by it. Notably, enhancement of H2S expression in the heart was observed in mice injected with recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-27a and in cells transfected with a miR-27a inhibitor during cardiac hypertrophy. However, this effect was abolished by co-transfection with CSE siRNA and the miR-27a inhibitor. Conversely, injecting rAAV9-miR-27a yielded opposite results. Interestingly, our findings demonstrated that glucagon-like peptide-1 (GLP-1) agonists could mitigate myocardial damage by down-regulating miR-27a and up-regulating CSE. In summary, our study suggests that inhibition of miR-27a holds therapeutic promise for the treatment of cardiac hypertrophy by increasing H2S levels. Furthermore, our findings unveil a novel mechanism of GLP-1 agonists involving the miR-27a/H2S pathway in the management of cardiac hypertrophy.


Asunto(s)
Estenosis de la Válvula Aórtica , Insuficiencia Cardíaca , MicroARNs , Animales , Ratones , Cardiomegalia/genética , Péptido 1 Similar al Glucagón , MicroARNs/genética , Cistationina gamma-Liasa
7.
ACS Nano ; 18(14): 10216-10229, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38436241

RESUMEN

Substantial advancements have been achieved in the realm of cardiac tissue repair utilizing functional hydrogel materials. Additionally, drug-loaded hydrogels have emerged as a research hotspot for modulating adverse microenvironments and preventing left ventricular remodeling after myocardial infarction (MI), thereby fostering improved reparative outcomes. In this study, diacrylated Pluronic F127 micelles were used as macro-cross-linkers for the hydrogel, and the hydrophobic drug α-tocopherol (α-TOH) was loaded. Through the in situ synthesis of polydopamine (PDA) and the incorporation of conductive components, an injectable and highly compliant antioxidant/conductive composite FPDA hydrogel was constructed. The hydrogel exhibited exceptional stretchability, high toughness, good conductivity, cell affinity, and tissue adhesion. In a rabbit model, the material was surgically implanted onto the myocardial tissue, subsequent to the ligation of the left anterior descending coronary artery. Four weeks postimplantation, there was discernible functional recovery, manifesting as augmented fractional shortening and ejection fraction, alongside reduced infarcted areas. The findings of this investigation underscore the substantial utility of FPDA hydrogels given their proactive capacity to modulate the post-MI infarct microenvironment and thereby enhance the therapeutic outcomes of myocardial infarction.


Asunto(s)
Hidrogeles , Infarto del Miocardio , Animales , Conejos , Hidrogeles/uso terapéutico , alfa-Tocoferol/uso terapéutico , Infarto del Miocardio/terapia , Miocardio , Remodelación Ventricular
8.
Heart Rhythm ; 21(7): 1001-1007, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38365127

RESUMEN

BACKGROUND: Female sex has long been recognized to present a higher risk of stroke and atrial fibrillation (AF) recurrence after circumferential pulmonary vein isolation (CPVI) than in males. However, the underlying mechanisms and benefits of additional low-voltage area (LVA) modification in women remain unknown. OBJECTIVE: The purpose of this study was to investigate differences in atrial substrate and efficacy of additive LVA ablation between sex subgroups. METHODS: Patients with paroxysmal atrial fibrillation (PAF) aged 65-80 years were randomly assigned to either CPVI plus LVA modification (STABLE-SR) group or CPVI alone group. The primary outcome was freedom from atrial arrhythmias after a single ablation procedure. RESULTS: Of 414 patients included in STABLE-SR-III, 204 (49.3%) were women (mean age 70.5 ± 4.7 years). Women demonstrated significantly higher LVA prevalence (51.5% vs 32.9%; P <.001) and LVA burden (6.5% vs 2.9%; P <.001) than men. In the STABLE-SR group, additional LVA ablation was associated with a 63% reduction in recurrence for women compared with the CPVI alone group (10.8% vs 29.4%; adjusted hazard ratio 0.37; 95% confidence interval 0.18-0.75; P for interaction = .040). However, this finding was not observed in men (18.7% vs 18.5%). In the female subgroup, both group 1 (CPVI + LVA modification) and group 3 (CPVI alone in females without LVA) had similar clinical outcomes, which were much better than in Group 2 (CPVI alone in women with LVA) (90% vs 83.8% vs 63.6%; P = .003). CONCLUSION: In older patients with PAF, women demonstrated more advanced atrial substrate, including higher prevalence and burden of LVA compared with men. Women may receive greater benefit from additional LVA modification than men.


Asunto(s)
Fibrilación Atrial , Ablación por Catéter , Atrios Cardíacos , Venas Pulmonares , Humanos , Femenino , Anciano , Fibrilación Atrial/cirugía , Fibrilación Atrial/epidemiología , Fibrilación Atrial/fisiopatología , Masculino , Ablación por Catéter/métodos , Atrios Cardíacos/fisiopatología , Prevalencia , Venas Pulmonares/cirugía , Factores Sexuales , Anciano de 80 o más Años , Cicatriz/etiología , Cicatriz/epidemiología , Recurrencia , Resultado del Tratamiento , Estudios de Seguimiento
9.
IEEE J Biomed Health Inform ; 28(5): 3090-3101, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38319782

RESUMEN

Survival analysis is employed to analyze the time before the event of interest occurs, which is broadly applied in many fields. The existence of censored data with incomplete supervision information about survival outcomes is one key challenge in survival analysis tasks. Although some progress has been made on this issue recently, the present methods generally treat the instances as separate ones while ignoring their potential correlations, thus rendering unsatisfactory performance. In this study, we propose a novel Deep Survival Analysis model with latent Clustering and Contrastive learning (DSACC). Specifically, we jointly optimize representation learning, latent clustering and survival prediction in a unified framework. In this way, the clusters distribution structure in latent representation space is revealed, and meanwhile the structure of the clusters is well incorporated to improve the ability of survival prediction. Besides, by virtue of the learned clusters, we further propose a contrastive loss function, where the uncensored data in each cluster are set as anchors, and the censored data are treated as positive/negative sample pairs according to whether they belong to the same cluster or not. This design enables the censored data to make full use of the supervision information of the uncensored samples. Through extensive experiments on four popular clinical datasets, we demonstrate that our proposed DSACC achieves advanced performance in terms of both C-index (0.6722, 0.6793, 0.6350, and 0.7943) and Integrated Brier Score (IBS) (0.1616, 0.1826, 0.2028, and 0.1120).


Asunto(s)
Aprendizaje Profundo , Análisis de Clases Latentes , Análisis de Supervivencia , Femenino , Humanos , Masculino , Factores de Edad , Presión Sanguínea , Temperatura Corporal , Comorbilidad , Creatina/sangre , Conjuntos de Datos como Asunto , Demencia , Diabetes Mellitus , Frecuencia Cardíaca , Recuento de Leucocitos , Neoplasias , Grupos Raciales , Frecuencia Respiratoria , Sodio/sangre , Temperatura
10.
ACS Nano ; 18(10): 7532-7545, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38412072

RESUMEN

Ti3C2Tx MXene often suffers from poor lithium storage behaviors due to its electrochemically unfavorable OH terminations. Herein, we propose molecular-level interfacial chemistry regulation of Ti3C2Tx MXene with phytic acid (PA) to directly activate its OH terminations. Through constructing hydrogen bonds (H-bonds) between oxygen atoms of PA and OH terminations on Ti3C2Tx surface, interfacial charge distribution of Ti3C2Tx has been effectively regulated, thereby enabling sufficient ion-storage sites and expediting ion transport kinetics for high-performance energy storage. The results show that Li ions preferably bind to H-bond acceptors (oxygen atoms from PA), and the flexibility of H-bonds therefore renders their interactions with adsorbed Li ions chemically "tunable", thus alleviating undesirable localized geometric changes of the OH terminations. Meanwhile the H-bond-induced microscopic dipoles can act as directional Li-ion pumps to expedite ion diffusion kinetics with lower energy barrier. As a result, the as-designed Ti3C2Tx/PA achieves a 2.4-fold capacity enhancement compared with pristine Ti3C2Tx (even beyond theoretical capacity), superior long-term cyclability (220.0 mAh g-1 after 2000 cycles at 2.0 A g-1), and broad temperature adaptability (-20 to 50 °C). This work offers a promising interface engineering strategy to regulate microenvironments of inherent terminations for breaking through the energy storage performance of MXenes.

11.
Transl Res ; 267: 54-66, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38199433

RESUMEN

Atrial cardiomyopathy (ACM) forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. However, generating stable animal models that accurately replicate the entire progression of atrial lesions, particularly the onset of AF, presents significant challenges. In the present study, we found that the isoform of CRE-binding protein modulator (CREM-IbΔC-X), which is involved in the regulation of cardiac development and atrial rhythm, was highly expressed in atrial biopsies from patients with AF. Building upon this finding, we employed CRISPR/Cas9 technology to create a mouse model with cardiac-specific overexpression of CREM-IbΔC-X (referred to as CS-CREM mice). This animal model effectively illustrated the development of ACM through electrophysiological and structural remodelings over time. Proteomics and Chip-qPCR analysis of atrial samples revealed significant upregulation of cell-matrix adhesion and extracellular matrix structural components, alongside significant downregulation of genes related to atrial functions in the CS-CREM mice. Furthermore, the corresponding responses to anti-arrhythmia drugs, i.e., amiodarone and propafenone, suggested that CS-CREM mice could serve as an ideal in vivo model for drug testing. Our study introduced a novel ACM model with spontaneous AF by cardiac-specifically overexpressing CREM-IbΔC-X in mice, providing valuable insights into the mechanisms and therapeutic targets of ACM.


Asunto(s)
Fibrilación Atrial , Cardiomiopatías , Ratones , Humanos , Animales , Sistemas CRISPR-Cas/genética , Ratones Transgénicos , Atrios Cardíacos/patología , Cardiomiopatías/genética , Modulador del Elemento de Respuesta al AMP Cíclico/genética , Modulador del Elemento de Respuesta al AMP Cíclico/metabolismo
12.
ACS Nano ; 18(2): 1702-1713, 2024 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-38165231

RESUMEN

Implantable neuroelectronic interfaces have gained significant importance in long-term brain-computer interfacing and neuroscience therapy. However, due to the mechanical and geometrical mismatches between the electrode-nerve interfaces, personalized and compatible neural interfaces remain serious issues for peripheral neuromodulation. This study introduces the stretchable and flexible electronics class as a self-rolled neural interface for neurological diagnosis and modulation. These stretchable electronics are made from liquid metal-polymer conductors with a high resolution of 30 µm using microfluidic printing technology. They exhibit high conformability and stretchability (over 600% strain) during body movements and have good biocompatibility during long-term implantation (over 8 weeks). These stretchable electronics offer real-time monitoring of epileptiform activities with excellent conformability to soft brain tissue. The study also develops self-rolled microfluidic electrodes that tightly wind the deforming nerves with minimal constraint (160 µm in diameter). The in vivo signal recording of the vagus and sciatic nerve demonstrates the potential of self-rolled cuff electrodes for sciatic and vagus neural modulation by recording action potential and reducing heart rate. The findings of this study suggest that the robust, easy-to-use self-rolled microfluidic electrodes may provide useful tools for compatible neuroelectronics and neural modulation.


Asunto(s)
Microfluídica , Nervio Ciático , Electrodos , Electrónica , Encéfalo
13.
J Anim Sci Biotechnol ; 15(1): 4, 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38238856

RESUMEN

BACKGROUND: The benefits of combining benzoic acid and essential oils (BAO) to mitigate intestinal impairment during the weaning process have been well established, while the detailed underlying mechanism has not been fully elucidated. Previous research has primarily focused on the reparative effects of BAO on intestinal injury, while neglecting its potential in enhancing intestinal stress resistance. METHODS: In this study, we investigated the pre-protective effect of BAO against LPS-induced stress using a modified experimental procedure. Piglets were pre-supplemented with BAO for 14 d, followed by a challenge with LPS or saline to collect blood and intestinal samples. RESULTS: Our findings demonstrated that BAO supplementation led to significant improvements in piglets' final weight, average daily gain, and feed intake/body gain ratio. Additionally, BAO supplementation positively influenced the composition of intestinal microbiota, increasing beneficial Actinobacteriota and Alloprevotella while reducing harmful Desulfobacterota, Prevotella and Oscillospira. Furthermore, BAO supplementation effectively mitigated oxidative disturbances and inflammatory responses induced by acute LPS challenge. This was evidenced by elevated levels of T-AOC, SOD, and GSH, as well as decreased levels of MDA, TNF-α, and IL-6 in the plasma. Moreover, piglets subjected to LPS challenge and pre-supplemented with BAO exhibited significant improvements in intestinal morphological structure and enhanced integrity, as indicated by restored expression levels of Occludin and Claudin-1 compared to the non-supplemented counterparts. Further analysis revealed that BAO supplementation enhanced the jejunal antioxidative capacity by increasing GSH-Px levels and decreasing MDA levels under the LPS challenge and stimulated the activation of the Nrf2 signaling pathway. Additionally, the reduction of TLR4/NF-κB/MAPK signaling pathways activation and proinflammatory factor were also observed in the jejunal of those piglets fed with BAO. CONCLUSIONS: In summary, our study demonstrates that pre-supplementation of BAO enhances the anti-stress capacity of weaned piglets by improving intestinal microbiota composition, reinforcing the intestinal barrier, and enhancing antioxidative and anti-inflammatory capabilities. These effects are closely associated with the activation of Nrf2 and TLR4/NF-κB/MAPK signaling pathways.

14.
Acta Pharmacol Sin ; 45(1): 76-86, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37670136

RESUMEN

Mechanosensitive cation channels such as Piezo1 and Piezo2 are activated by mechanical force like a starched wall of the aorta while blood pressure (BP) rising, which helps to elucidate the underlying mechanism of mechanotransduction of baroreceptor endings. In this study we investigated how Piezo1 channel activation-mediated gender- and afferent-specific BP regulation in rats. We established high-fat diet and fructose drink-induced hypertension model rats (HFD-HTN) and deoxycorticosterone (DOCA)-sensitive hypertension model rats. We showed that the expression levels of Piezo1 and Piezo2 were significantly up-regulated in left ventricle of HFD and DOCA hypertensive rats, whereas the down-regulation of Piezo1 was likely to be compensated by Piezo2 up-regulation in the aorta. Likewise, down-regulated Piezo1 was observed in the nodose ganglion (NG), while up-regulated Piezo2 was found in the nucleus tractus solitarius (NTS), which might synergistically reduce the excitatory neurotransmitter release from the presynaptic membrane. Notably, microinjection of Yoda1 (0.025-2.5 mg/ml) into the NG concentration-dependently reduced BP in both hypertensive rat models as well as in control rats with similar EC50; the effect of Yoda1 was abolished by microinjection of a Piezo1 antagonist GsMTx4 (1.0 µM). Functional analysis in an in vitro aortic arch preparation showed that instantaneous firing frequency of single Ah-fiber of aortic depressor nerve was dramatically increased by Yoda1 (0.03-1.0 µM) and blocked by GsMTx4 (1.0 µM). Moreover, spontaneous synaptic currents recorded from identified 2nd-order Ah-type baroreceptive neurons in the NTS was also facilitated over 100% by Yoda1 (1.0 µM) and completely blocked by GsMTx4 (3.0 µM). These results demonstrate that Piezo1 expressed on Ah-type baroreceptor and baroreceptive neurons in the NG and NTS plays a key role in a sexual-dimorphic BP regulation under physiological and hypertensive condition through facilitation of baroreflex afferent neurotransmission, which is presumably collaborated by Piezo2 expression at different level of baroreflex afferent pathway via compensatory and synergistic mechanisms.


Asunto(s)
Acetato de Desoxicorticosterona , Hipertensión , Ratas , Animales , Barorreflejo , Presión Sanguínea , Mecanotransducción Celular/fisiología , Acetato de Desoxicorticosterona/farmacología , Transmisión Sináptica
15.
J Thromb Haemost ; 22(4): 1167-1178, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38103736

RESUMEN

BACKGROUND: Primary immune thrombocytopenia (ITP) in children is typically self-limiting; however, 20% to 30% of patients may experience prolonged thrombocytopenia lasting over a year. The challenge is predicting chronicity to ensure personalized treatment approaches. OBJECTIVES: To address this issue, we developed and internally validated 4 machine learning (ML) models using demographic and immunologic characteristics to predict the likelihood of chronicity. METHODS: The present study was conducted at Beijing Children's Hospital from June 2018 to December 2021, aiming to develop predictive models for determining the chronicity of pediatric ITP. Four ML models, based on a logistic regression classifier, random forest classifier, eXtreme Gradient Boosting (XGBoost), and support vector machine, were employed. These models used a set of 16 variables, including 14 immunologic and 2 demographic predictors. The performance evaluation criteria included prediction accuracy, precision, recall, F1 score, and area under the receiver operating characteristic curve (AUROC). RESULTS: Data were collected from 662 patients who were randomly assigned to either a training dataset or a testing dataset using a random number generator. Among them, 26.5% had chronic disease. All models performed well, with AUROC values ranging from 0.81 to 0.84, and XGBoost was selected for its highest AUROC score and interpretability in constructing the predictive model. Age, T helper 17, T helper 17-to-regulatory T cell ratio, T helper 1, and double-negative T cells were identified as significant predictors by the XGBoost algorithm. CONCLUSION: We developed a precise predictive model for chronicity in pediatric ITP using ML during the initial phase. The XGBoost model achieved high predictive accuracy by using individual patient clinical parameters and demonstrated commendable interpretability.


Asunto(s)
Púrpura Trombocitopénica Idiopática , Trombocitopenia , Niño , Humanos , Algoritmos , Área Bajo la Curva , Aprendizaje Automático , Púrpura Trombocitopénica Idiopática/diagnóstico , Trombocitopenia/diagnóstico
16.
Thromb Res ; 232: 43-53, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37931538

RESUMEN

BACKGROUND: Physical activity is a crucial part of an active lifestyle for haemophiliac children. However, the fear of bleeds has been identified as barriers to participating physical activity for haemophiliac children even with prophylaxis. Lack of evidence and metrics driven by data is key problem. OBJECTIVES: We aim to develop machine learning models based on clinical data with multiple potential factors considered to predict risk of physical activity bleeding for haemophilia children with prophylaxis. METHODS: From this cohort study, we collected information on 98 haemophiliac children with adequate prophylaxis (trough FVIII:C level > 1 %). The involved potential predictor variables include demographic information, treatment information, physical activity, joint evaluation, and pharmacokinetic parameters, etc. We applied CoxPH, Random Survival Forests (RSF) and DeepSurv to construct prediction models for the risk of bleeding during physical activities. All three survival analysis models were internally and externally validated. RESULTS: A total of 98 patients were enrolled in this study. Their median age was 7.9 (5.5, 10.2) years. The CoxPH, RSF and DeepSurv models' discriminative and calibration abilities were all high, and the RSF model had the best performance (Internal validation: C-index, 0.7648 ± 0.0139; Brier Score, 0.1098 ± 0.0015; External validation: C-index, 0.7260 ± 0.0154; Brier Score, 0.0930 ± 0.0018). The prediction curves demonstrated that the developed RSF model can distinguish the risks well between bleeding and non-bleeding patients, as well as patients with different levels of physical activity. Meanwhile, the feature importance analysis confirmed that physical activity bleeding was deduced by comprehensive effects of various factors, and the importance of different factors on bleeding outcome is discrepant. CONCLUSIONS: This study revealed from the mechanism that it is necessary to incorporate multiple factors to accurately predict physical activity related bleeding risk. In clinical practice, the designed machine learning models can provide guidance for children with haemophilia A to positively participate in physical activity.


Asunto(s)
Hemofilia A , Masculino , Niño , Humanos , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Estudios de Cohortes , Pueblos del Este de Asia , Hemorragia/etiología , Ejercicio Físico , Aprendizaje Automático
17.
Angew Chem Int Ed Engl ; 62(52): e202314019, 2023 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-37926680

RESUMEN

The key to type 1 copper (T1Cu) function lies in the fine tuning of the CuII/I reduction potential (E°'T1Cu ) to match those of its redox partners, enabling efficient electron transfer in a wide range of biological systems. While the secondary coordination sphere (SCS) effects have been used to tune E°'T1Cu in azurin over a wide range, these principles are yet to be generalized to other T1Cu-containing proteins to tune catalytic properties. To this end, we have examined the effects of Y229F, V290N and S292F mutations around the T1Cu of small laccase (SLAC) from Streptomyces coelicolor to match the high E°'T1Cu of fungal laccases. Using ultraviolet-visible absorption and electron paramagnetic resonance spectroscopies, together with X-ray crystallography and redox titrations, we have probed the influence of SCS mutations on the T1Cu and corresponding E°'T1Cu . While minimal and small E°'T1Cu increases are observed in Y229F- and S292F-SLAC, the V290N mutant exhibits a major E°'T1Cu increase. Moreover, the influence of these mutations on E°'T1Cu is additive, culminating in a triple mutant Y229F/V290N/S292F-SLAC with the highest E°'T1Cu of 556 mV vs. SHE reported to date. Further activity assays indicate that all mutants retain oxygen reduction reaction activity, and display improved catalytic efficiencies (kcat /KM ) relative to WT-SLAC.


Asunto(s)
Lacasa , Streptomyces coelicolor , Cobre/química , Lacasa/metabolismo , Mutación , Oxidación-Reducción , Streptomyces coelicolor/genética , Streptomyces coelicolor/metabolismo
18.
J Agric Food Chem ; 71(49): 19592-19609, 2023 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-38018895

RESUMEN

The exacerbation of the greenhouse effect has made heat stress (HS) an important risk factor for the occurrence of intrauterine growth restriction (IUGR). The experiment aims to uncover the effects of maternal HS on IUGR and its mechanisms. The results showed that HS leads to decreased maternal and fetal birth weights, accompanied by increased serum oxidative stress and cortisol levels. Moreover, HS inflicted significant damage to both the intestinal and placental barriers, altering maternal gut microbiota and increasing intestinal LPS levels. As a result, LPS levels increased in maternal serum, placenta, and fetus. Furthermore, HS damaged the intestinal structure, intensifying inflammation and disrupting the redox balance. The placenta exposed to HS exhibited changes in the placental structure along with disrupted angiogenesis and decreased levels of nutritional transporters. Additionally, the leakage of LPS triggered placental JNK and ERK phosphorylation, ultimately inducing severe placental inflammation and oxidative stress. This study suggests that LPS translocation from the maternal intestine to the fetus, due to a disrupted gut microbiota balance and compromised intestinal and placental barrier integrity, may be the primary cause of HS-induced IUGR. Furthermore, increased LPS leakage leads to placental inflammation, redox imbalance, and impaired nutrient transport, further restricting fetal growth.


Asunto(s)
Retardo del Crecimiento Fetal , Placenta , Humanos , Embarazo , Ratones , Femenino , Animales , Retardo del Crecimiento Fetal/etiología , Lipopolisacáridos/efectos adversos , Feto , Intestinos , Inflamación/inducido químicamente
20.
Am J Cancer Res ; 13(9): 4057-4072, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37818062

RESUMEN

Osteosarcoma (OS) is the most frequent primary bone cancer, which is mainly suffered by children and young adults. While the current surgical treatment combined with chemotherapy is effective for the early stage of OS, advanced OS preferentially metastasizes to the lung and is difficult to treat. Here, we examined the efficacy of ten anti-OS peptide candidates from a trypsin-digested conditioned medium that was derived from the secretome of induced tumor-suppressing cells (iTSCs). Using OS cell lines, the antitumor capabilities of the peptide candidates were evaluated by assaying the alterations in metabolic activities, proliferation, motility, and invasion of OS cells. Among ten candidates, peptide P05 (ADDGRPFPQVIK), a fragment of aldolase A (ALDOA), presented the most potent OS-suppressing capabilities. Its efficacy was additive with standard-of-care chemotherapeutic agents such as cisplatin and doxorubicin, and it downregulated oncoproteins such as epidermal growth factor receptor (EGFR), Snail, and Src in OS cells. Interestingly, P05 did not present inhibitory effects on non-OS skeletal cells such as mesenchymal stem cells and osteoblast cells. Collectively, this study demonstrated that iTSC-derived secretomes may provide a source for identifying anticancer peptides, and P05 may warrant further evaluations for the treatment of OS.

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