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1.
Front Psychiatry ; 15: 1428028, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39119078

RESUMEN

Background: Post-stroke depression (PSD) is a prevalent psychiatric disorder affecting about one-third of stroke survivors, significantly hindering recovery and quality of life. PSD also imposes a substantial burden on caregivers and healthcare systems. Aromatherapy has shown promise in alleviating depression, anxiety, and sleep disorders. This pilot randomized controlled trial aims to assess the feasibility and preliminary efficacy of mixed herb aromatherapy in treating PSD. Feasibility outcomes encompass recruitment, intervention adherence, assessment completion and safety assessment. Secondary outcomes include evaluations of depression, anxiety, cognitive function, sleep quality, quality of life, and brain function using EEG and fNIRS. Methods: This single-blind pilot randomized controlled trial will be conducted at the Second Rehabilitation Hospital of Shanghai, enrolling ninety-nine post-stroke patients with PSD. Participants will be randomized into three groups: a Non-Active Control Group receiving standardized rehabilitation therapy, a CBT Group receiving conventional rehabilitation with bi-weekly CBT sessions, and an Aromatherapy Group receiving conventional rehabilitation with daily aromatic inhalation sessions. Interventions will last for four weeks, with efficacy assessed at baseline, post-intervention, and one month post-intervention. Rating scales will be used to measure changes in depression, sleep quality, cognitive function, and quality of life. EEG and fNIRS will specifically be used to measure changes in cerebral cortex activity and their correlations with depression. Feasibility will be evaluated through recruitment, intervention adherence, assessment completion and safety assessment. Discussion: This pilot study highlights the potential of mixed herb aromatherapy inhalation for treating PSD, addressing limitations of CBT by promoting self-management. While demonstrating feasibility through recruitment, adherence, assessment completion and safety assessment, the study also acknowledges limitations such as unequal intervention times, the lack of physical function data. And the use of culturally relevant plant powders may enhance compliance but limits generalizability. Despite these constraints, the study provides valuable preliminary data and insights into the mechanisms of aromatherapy, encouraging further research and development of effective PSD treatments.

2.
J Clin Transl Hepatol ; 12(8): 713-725, 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-39130624

RESUMEN

Background and Aims: Hepatocellular carcinoma (HCC) is a highly aggressive tumor with limited treatment options and high mortality. Senecavirus A (SVA) has shown potential in selectively targeting tumors while sparing healthy tissues. This study aimed to investigate the effects of SVA on HCC cells in vitro and in vivo and to elucidate its mechanisms of action. Methods: The cell counting kit-8 assay and colony formation assay were conducted to examine cell proliferation. Flow cytometry and nuclear staining were employed to analyze cell cycle distribution and apoptosis occurrence. A subcutaneous tumor xenograft HCC mouse model was created in vivo using HepG2 cells, and Ki67 expression in the tumor tissues was assessed. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay and hematoxylin and eosin staining were employed to evaluate HCC apoptosis and the toxicity of SVA on mouse organs. Results: In vitro, SVA effectively suppressed the growth of tumor cells by inducing apoptosis and cell cycle arrest. However, it did not have a notable effect on normal hepatocytes (MIHA cells). In an in vivo setting, SVA effectively suppressed the growth of HCC in a mouse model. SVA treatment resulted in a significant decrease in Ki67 expression and an increase in apoptosis of tumor cells. No notable histopathological alterations were observed in the organs of mice during SVA administration. Conclusions: SVA inhibits the growth of HCC cells by inducing cell cycle arrest and apoptosis. It does not cause any noticeable toxicity to vital organs.

3.
Plant Direct ; 8(7): e624, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39076347

RESUMEN

Cytoplasmic projections (CPs) formed by the generative and sperm cells link the male gametes with the vegetative cell (VC) nucleus, which are required to build the male germ unit (MGU) assemblage in the angiosperm pollen grain. As molecular and genetic controls underlying CP development and formation of the MGU are unknown, it was hypothesized that physical association between germ cells and the VC nucleus might be lost in germ unit malformed (gum) mutants or in those which either block generative cell (GC) division or that additionally prevent gamete differentiation. In vivo, analysis of marked cellular components demonstrated a linkage of sperm cells (SCs) and the VC nucleus in gum mutant alleles despite their increased physical separation. Similarly, for several independent classes of bicellular pollen mutants, undivided GCs were associated with the VC nucleus like GCs in wild-type pollen. We conclude that the early formation of GC CPs to establish the MGU is regulated independently of DUO1-DAZ1 and DUO3 transcription factors as well as cyclin-dependent kinase function (CDKA;1). As the absence of cytoplasmic protrusion was expected in the gum mutants in Arabidopsis, early histological studies reported temporal disappearance of cytoplasmic protrusion in several organisms. Our findings demonstrated the striking importance of live imaging to verify the broad conservation of the persistent MGU contact in all the angiosperms and its important role in successful double fertilization.

4.
Hepatol Commun ; 8(8)2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39023343

RESUMEN

BACKGROUND: When massive necrosis occurs in acute liver failure (ALF), rapid expansion of HSCs called liver progenitor cells (LPCs) in a process called ductular reaction is required for survival. The underlying mechanisms governing this process are not entirely known to date. In ALF, high levels of retinoic acid (RA), a molecule known for its pleiotropic roles in embryonic development, are secreted by activated HSCs. We hypothesized that RA plays a key role in ductular reaction during ALF. METHODS: RNAseq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPCs. Functional assays were performed in HepaRG cells treated with atRA or cocultured with LX-2 cells and in the liver tissue of patients suffering from ALF. RESULTS: Under ALF conditions, activated HSCs secreted RA, inducing RARα nuclear translocation in LPCs. RNAseq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-ß-Catenin pathway, enhanced stemness genes (SOX9, AFP, and others), increased energy storage, and elevated the expression of ATP-binding cassette transporters in a RARα nuclear translocation-dependent manner. Further, atRA treatment-induced pathways were confirmed in a coculture system of HepaRG with LX-2 cells. Patients suffering from ALF who displayed RARα nuclear translocation in the LPCs had significantly better MELD scores than those without. CONCLUSIONS: During ALF, RA secreted by activated HSCs promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.


Asunto(s)
Fallo Hepático Agudo , Células Madre , Tretinoina , Humanos , Tretinoina/farmacología , Células Madre/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Hígado/efectos de los fármacos , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Técnicas de Cocultivo , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo
5.
Cancer Imaging ; 24(1): 86, 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38965552

RESUMEN

PURPOSE: To develop a radiomics-based model using [68Ga]Ga-PSMA PET/CT to predict postoperative adverse pathology (AP) in patients with biopsy Gleason Grade Group (GGG) 1-2 prostate cancer (PCa), assisting in the selection of patients for active surveillance (AS). METHODS: A total of 75 men with biopsy GGG 1-2 PCa who underwent radical prostatectomy (RP) were enrolled. The patients were randomly divided into a training group (70%) and a testing group (30%). Radiomics features of entire prostate were extracted from the [68Ga]Ga-PSMA PET scans and selected using the minimum redundancy maximum relevance algorithm and the least absolute shrinkage and selection operator regression model. Logistic regression analyses were conducted to construct the prediction models. Receiver operating characteristic (ROC) curve, decision curve analysis (DCA), and calibration curve were employed to evaluate the diagnostic value, clinical utility, and predictive accuracy of the models, respectively. RESULTS: Among the 75 patients, 30 had AP confirmed by RP. The clinical model showed an area under the curve (AUC) of 0.821 (0.695-0.947) in the training set and 0.795 (0.603-0.987) in the testing set. The radiomics model achieved AUC values of 0.830 (0.720-0.941) in the training set and 0.829 (0.624-1.000) in the testing set. The combined model, which incorporated the Radiomics score (Radscore) and free prostate-specific antigen (FPSA)/total prostate-specific antigen (TPSA), demonstrated higher diagnostic efficacy than both the clinical and radiomics models, with AUC values of 0.875 (0.780-0.970) in the training set and 0.872 (0.678-1.000) in the testing set. DCA showed that the net benefits of the combined model and radiomics model exceeded those of the clinical model. CONCLUSION: The combined model shows potential in stratifying men with biopsy GGG 1-2 PCa based on the presence of AP at final pathology and outperforms models based solely on clinical or radiomics features. It may be expected to aid urologists in better selecting suitable patients for AS.


Asunto(s)
Isótopos de Galio , Radioisótopos de Galio , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Persona de Mediana Edad , Anciano , Prostatectomía/métodos , Biopsia/métodos , Clasificación del Tumor , Oligopéptidos , Radiofármacos , Espera Vigilante/métodos , Ácido Edético/análogos & derivados , Estudios Retrospectivos , Radiómica
6.
Int J Endocrinol ; 2024: 5588104, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39040973

RESUMEN

Introduction: The correlation between potassium and nonalcoholic fatty liver disease (NAFLD) is currently still poorly understood. We conducted this study to explore the correlation between dietary potassium intake and NAFLD, as well as advanced hepatic fibrosis (AHF). The study also sought to identify any potential interactions. Methods: The data employed in this study were obtained from the National Health and Nutrition Examination Survey (NHANES) program, encompassing a period from 2007 to 2018. Employing the multiple logistic regression analysis, we evaluated the association of dietary potassium intake with NAFLD and AHF. Subsequently, stratification analysis, based on demographic variables, was constructed so as to assess the stability of the results. In addition, potential interaction effects were assessed by interaction tests. Results: A total of 9443 participants were included in the analysis. The mean age of the participants was 50.4 years, and their daily mean dietary potassium and vitamin C intake was 2556.49 mg and 82.93 mg, respectively. Following comprehensive statistical analyses, the findings indicated a negative correlation between dietary potassium intake and both NAFLD and AHF. Participants in Q4 group with dietary potassium intake exhibited a 31% and 42% reduction in the odds of developing NAFLD and AHF, respectively, in comparison to Q1 group. An interaction effect of dietary vitamin C intake was observed in the association between dietary potassium intake and NAFLD. The results imply that high dietary vitamin C intake augment the inverse relationship between dietary potassium intake and NAFLD. Conclusion: Dietary potassium intake was found to have an inverse association with the odds of both NAFLD and AHF. The association between dietary potassium intake and NAFLD was amplified by the presence of vitamin C in the diet.

7.
Am J Cardiol ; 225: 37-40, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-38866354

RESUMEN

Cardiac sympathetic denervation (CSD) is a surgical procedure increasingly used for managing ventricular arrhythmia refractory to conventional medical therapy. Long-term outcomes of CSD in patients with systolic heart failure has not been well studied. This observational study aimed to evaluate the medical co-morbidities and outcomes of patients with systolic heart failure who underwent CSD performed as treatment for ventricular arrhythmia refractory to conventional therapy. A retrospective analysis in adult patients with ventricular arrhythmia and systolic heart failure who underwent unilateral or bilateral CSD at a single center was performed. Unadjusted Kaplan-Meier survival curves were constructed to evaluate survival after CSD. Between June 1, 2011 and March 31, 2021, 32 adult patients (age 62 ± 11.6 years, 88% male, left ventricular ejection fraction 22% ± 8.2%) with systolic heart failure underwent unilateral left (n = 4), unilateral right (n = 1), or bilateral CSD (n = 27). Mean survival after CSD was 613 ± 745 days, and the mean time from CSD to death was 291 ± 447 days. The cumulative probability of survival 1 year after CSD was 61.4%. In this single-center observational study, CSD performed for refractory ventricular arrhythmia showed favorable survival in patients with systolic heart failure. In conclusion, this study lays the groundwork for a more in-depth analysis of the potential survival benefits of CSD in this patient group.


Asunto(s)
Insuficiencia Cardíaca Sistólica , Simpatectomía , Humanos , Masculino , Femenino , Persona de Mediana Edad , Insuficiencia Cardíaca Sistólica/cirugía , Insuficiencia Cardíaca Sistólica/fisiopatología , Simpatectomía/métodos , Estudios Retrospectivos , Anciano , Resultado del Tratamiento , Taquicardia Ventricular/cirugía , Taquicardia Ventricular/fisiopatología , Tasa de Supervivencia/tendencias , Volumen Sistólico/fisiología , Estudios de Seguimiento
8.
Int J Mol Sci ; 25(12)2024 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-38928338

RESUMEN

The flavonoids in citrus fruits are crucial physiological regulators and natural bioactive products of high pharmaceutical value. Melatonin is a pleiotropic hormone that can regulate plant morphogenesis and stress resistance and alter the accumulation of flavonoids in these processes. However, the direct effect of melatonin on citrus flavonoids remains unclear. In this study, nontargeted metabolomics and transcriptomics were utilized to reveal how exogenous melatonin affects flavonoid biosynthesis in "Bingtangcheng" citrus fruits. The melatonin treatment at 0.1 mmol L-1 significantly increased the contents of seven polymethoxylated flavones (PMFs) and up-regulated a series of flavonoid pathway genes, including 4CL (4-coumaroyl CoA ligase), FNS (flavone synthase), and FHs (flavonoid hydroxylases). Meanwhile, CHS (chalcone synthase) was down-regulated, causing a decrease in the content of most flavonoid glycosides. Pearson correlation analysis obtained 21 transcription factors co-expressed with differentially accumulated flavonoids, among which the AP2/EREBP members were the most numerous. Additionally, circadian rhythm and photosynthesis pathways were enriched in the DEG (differentially expressed gene) analysis, suggesting that melatonin might also mediate changes in the flavonoid biosynthesis pathway by affecting the fruit's circadian rhythm. These results provide valuable information for further exploration of the molecular mechanisms through which melatonin regulates citrus fruit metabolism.


Asunto(s)
Citrus , Flavonoides , Frutas , Regulación de la Expresión Génica de las Plantas , Melatonina , Metabolómica , Citrus/metabolismo , Citrus/efectos de los fármacos , Citrus/genética , Melatonina/farmacología , Melatonina/metabolismo , Flavonoides/metabolismo , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Frutas/metabolismo , Frutas/efectos de los fármacos , Frutas/genética , Metabolómica/métodos , Perfilación de la Expresión Génica , Transcriptoma , Metaboloma/efectos de los fármacos , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética
9.
Front Pharmacol ; 15: 1379251, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38846094

RESUMEN

Objectives: To investigate the risk of atrial fibrillation (AF) with sodium-glucose cotransporter-2 inhibitors (SGLT2is) compared to dipeptidyl peptidase-4 inhibitor (DPP4i) use in older US adults and across diverse subgroups. Methods: We conducted a retrospective cohort analysis using claims data from 15% random samples of Medicare fee-for-service beneficiaries. Patients were adults with type 2 diabetes (T2D), no preexisting AF, and were newly initiated on SGLT2i or DPP4i. The outcome was the first incident AF. Inverse probability treatment weighting (IPTW) was used to balance the baseline covariates between the treatment groups including sociodemographics, comorbidities, and co-medications. Cox regression models were used to assess the effect of SGLT2i compared to DPP4i on incident AF. Results: Of the 97,436 eligible individuals (mean age 71.2 ± 9.8 years, 54.6% women), 1.01% (n = 983) had incident AF over a median follow-up of 361 days. The adjusted incidence rate was 8.39 (95% CI: 6.67-9.99) and 11.70 (95% CI: 10.9-12.55) per 1,000 person-years in the SGLT2i and DPP4i groups, respectively. SGLT2is were associated with a significantly lower risk of incident AF (HR 0.73; 95% CI, 0.57 to 0.91; p = 0.01) than DPP4is. The risk reduction of incident AF was significant in non-Hispanic White individuals and subgroups with existing atherosclerotic cardiovascular diseases and chronic kidney disease. Conclusion: Compared to the use of DPP4i, that of SGLT2i was associated with a lower risk of AF in patients with T2D. Our findings contribute to the real-world evidence regarding the effectiveness of SGLT2i in preventing AF and support a tailored therapeutic approach to optimize treatment selection based on individual characteristics.

10.
CRISPR J ; 7(3): 156-167, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38922054

RESUMEN

CRISPR-Cas technology is a widely utilized gene-editing tool that involves gRNA-guided sequence recognition and Cas nuclease-mediated cleavage. The design and evaluation of gRNA are essential for enhancing CRISPR/Cas editing efficiency. Various assays such as single-strand annealing, in vitro cleavage, and T7 endonuclease I (T7EI) are commonly used to assess gRNA-mediated Cas protein cleavage activity. In this study, a firefly luciferase and Renilla luciferase co-expressed and a cleavage-based single-plasmid dual-luciferase surrogate reporter was built to evaluate the gRNA-mediated Cas12a cleavage efficiency. The cleavage activities of CRISPR-Cas12a can be quantitatively determined by the recovery degree of firefly luciferase activity. The cleavage efficiency of CRISPR-Cas12a can be quantitatively measured by the recovery of firefly luciferase activity. By using this system, the cleavage efficiency of CRISPR-Cas12a on hepatitis B virus (HBV)/D expression plasmid was evaluated, revealing a negative correlation between gRNA cleavage efficiency and HBV gene expression measured using an enzyme-linked immunosorbent assay. This simple, efficient, and quantifiable system only requires the dual-luciferase vector and CRISPR-Cas12a vector, making it a valuable tool for selecting effective gRNAs for gene editing.


Asunto(s)
Proteínas Asociadas a CRISPR , Sistemas CRISPR-Cas , Edición Génica , Genes Reporteros , Luciferasas , Plásmidos , ARN Guía de Sistemas CRISPR-Cas , Edición Génica/métodos , ARN Guía de Sistemas CRISPR-Cas/genética , Plásmidos/genética , Humanos , Luciferasas/genética , Luciferasas/metabolismo , Proteínas Asociadas a CRISPR/genética , Proteínas Asociadas a CRISPR/metabolismo , Virus de la Hepatitis B/genética , Endodesoxirribonucleasas/metabolismo , Endodesoxirribonucleasas/genética , Luciferasas de Luciérnaga/genética , Luciferasas de Luciérnaga/metabolismo , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo
11.
Front Neurol ; 15: 1357777, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38737352

RESUMEN

Background: Parkinson's disease (PD) is a common neurodegenerative disorder that affects motor and non-motor functions, significantly reducing patients' quality of life. No effective drug-based treatments are known to solve this problem. Non-drug therapies such as Yijinjing exercise have shown potential in improving cognitive and motor functions in PD patients. However, solid evidence must still be provided to support their clinical efficacy. This study aims to evaluate the clinical efficacy of Yijinjing exercise interventions in PD patients and explore the underlying mechanisms between the cognitive and motor functions in PD. Methods: This is a single-center randomized controlled trial in which 96 eligible PD patients will be randomly assigned to receive either Yijinjing exercise group or brisk walking group or control group in a ratio of 1:1:1. Interventions (Yijinjing exercise or brisk walking training, 40 min per session) will be provided in 3 sessions per week (Monday, Wednesday, Friday) for 12 weeks, with a total of 36 sessions. After the treatment, there will be a 1-month follow-up period. The primary outcomes will be measured using the Montreal Cognitive Assessment (MoCA) and the Unified Parkinson's Disease Rating Scale motor section (UPDRS-III). Secondary outcomes include balance function, executive function, walking function, sleep quality, and quality of life. Additionally, the prefrontal cerebral and sensorimotor cortex blood oxygen signal level will be collected to explore the underlying mechanisms. All outcomes will be assessed at baseline, at the end of 12 weeks of treatment and after an additional 1-month follow-up period. Discussion: The results of the study protocol will provide high-quality evidence for the potential of intervention measures based on the Yijinjing exercise to improve the cognitive and activity levels of Parkinson's disease patients. We envision the Yijinjing exercise as a non-pharmacological family activity that can provide a new and more effective method for the treatment of Parkinson's disease patients or those at risk. Clinical trial registration: This study was approved by the Ethics Committee of the Second Rehabilitation Hospital of Shanghai (2020-05-01). The trial has been registered in the China Clinical Trials Registry (ChiCTR2200055636).

12.
J Med Virol ; 96(5): e29659, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38747016

RESUMEN

Hepatitis B virus (HBV) infection is a major global health burden with 820 000 deaths per year. In our previous study, we found that the knockdown of autophagy-related protein 5 (ATG5) significantly upregulated the interferon-stimulated genes (ISGs) expression to exert the anti-HCV effect. However, the regulation of ATG5 on HBV replication and its underlying mechanism remains unclear. In this study, we screened the altered expression of type I interferon (IFN-I) pathway genes using RT² Profiler™ PCR array following ATG5 knock-down and we found the bone marrow stromal cell antigen 2 (BST2) expression was significantly increased. We then verified the upregulation of BST2 by ATG5 knockdown using RT-qPCR and found that the knockdown of ATG5 activated the Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway. ATG5 knockdown or BST2 overexpression decreased Hepatitis B core Antigen (HBcAg) protein, HBV DNA levels in cells and supernatants of HepAD38 and HBV-infected NTCP-HepG2. Knockdown of BST2 abrogated the anti-HBV effect of ATG5 knockdown. Furthermore, we found that ATG5 interacted with BST2, and further formed a ternary complex together with HBV-X (HBx). In conclusion, our finding indicates that ATG5 promotes HBV replication through decreasing BST2 expression and interacting with it directly to antagonize its antiviral function.


Asunto(s)
Antígenos CD , Proteína 5 Relacionada con la Autofagia , Antígeno 2 del Estroma de la Médula Ósea , Proteínas Ligadas a GPI , Virus de la Hepatitis B , Replicación Viral , Humanos , Antígenos CD/genética , Antígenos CD/metabolismo , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Técnicas de Silenciamiento del Gen , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/genética , Células Hep G2 , Hepatitis B/virología , Hepatitis B/genética , Virus de la Hepatitis B/fisiología , Virus de la Hepatitis B/genética , Interacciones Huésped-Patógeno , Transducción de Señal , Antígeno 2 del Estroma de la Médula Ósea/metabolismo
13.
Int J Biol Sci ; 20(7): 2640-2657, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38725843

RESUMEN

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Proteína HMGA1a , Inhibidores mTOR , Proteína Proto-Oncogénica c-ets-1 , Proteína 1A de Unión a Tacrolimus , Animales , Humanos , Ratones , Línea Celular Tumoral , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Proteína HMGA1a/metabolismo , Proteína HMGA1a/genética , Ratones Desnudos , Inhibidores mTOR/farmacología , Inhibidores mTOR/uso terapéutico , Proteína Proto-Oncogénica c-ets-1/metabolismo , Proteína Proto-Oncogénica c-ets-1/genética , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Sirolimus/uso terapéutico , Proteína 1A de Unión a Tacrolimus/metabolismo , Proteína 1A de Unión a Tacrolimus/genética , Serina-Treonina Quinasas TOR/metabolismo
14.
IEEE Trans Cybern ; 54(7): 4204-4215, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38687666

RESUMEN

This article investigates the problem of dynamic memory event-triggered (DMET) fixed-time tracking control within time-varying asymmetric constraints for nonaffine nonstrict-feedback uncertain nonlinear systems with unmodeled dynamics and unknown disturbances. The existing dynamic event-triggered control methods cannot handle the nonlinear systems with unmodeled dynamics and nonaffine inputs, which greatly limits the applicability of the strategy. To this end, a novel DMET adaptive fuzzy fixed-time control protocol is constructed based on the idea of command filtered backstepping, in which a new dynamic signal function is established to deal with the unmodeled dynamics and an improved DMET mechanism (DMETM) is designed to solve the problem of nonaffine inputs. It is proved that the newly DMET control strategy ensures the tracking error converges to an arbitrarily small compact set in a fixed time and all the signals of the closed-loop systems are bounded. The effectiveness of the proposed approach is demonstrated by two simulation examples.

15.
Artículo en Inglés | MEDLINE | ID: mdl-38604834

RESUMEN

BACKGROUND: Patients with dementia are at increased risk for adverse events following valvular surgery. Outcomes after mitral transcatheter edge-to-edge repair (TEER) for mitral regurgitation in this vulnerable population are not well understood. METHODS: We queried the National Inpatient Sample database for all hospitalizations for mitral TEER between 2016 and 2019. Patients with a validated diagnosis code for dementia were identified by ICD-10 codes and compared to a matched cohort of non-dementia patients using multivariable regression analysis. The primary outcome was in-hospital mortality. Secondary outcomes were hospital length of stay, discharge to nursing facility, total hospital charges, and in-hospital adverse events. RESULTS: 24,550 hospitalizations for mitral TEER were identified, including 880 patients (3.6 %) with dementia. Dementia was associated with higher in-hospital mortality (OR 4.31, 95 % CI 2.65 to 6.99, p < 0.001), prolonged length of hospital stay (OR 1.33, 95 % CI 1.12 to 1.57, p 0.001), higher discharge rate to nursing facility (OR 2.71, 95 % CI 2.13-3.44, p < 0.001), and higher rate of in-hospital adverse events including delirium (OR 5.88, 95 % CI 4.06 to 8.52, p < 0.001) and acute stroke (OR 8.87, 95 % CI 5.01 to 15.70, p < 0.001). CONCLUSIONS: Dementia is associated with worse post-procedural outcomes after mitral TEER. Further investigation is needed to elucidate mechanisms of poor clinical outcomes and guide shared decision-making in this vulnerable population.

16.
Mikrochim Acta ; 191(5): 271, 2024 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-38632191

RESUMEN

Pathogen infections including Shigella flexneri have posed a significant threat to human health for numerous years. Although culturing and qPCR were the gold standards for pathogen detection, time-consuming and instrument-dependent restrict their application in rapid diagnosis and economically less-developed regions. Thus, it is urgently needed to develop rapid, simple, sensitive, accurate, and low-cost detection methods for pathogen detection. In this study, an immunomagnetic beads-recombinase polymerase amplification-CRISPR/Cas12a (IMB-RPA-CRISPR/Cas12a) method was built based on a cascaded signal amplification strategy for ultra-specific, ultra-sensitive, and visual detection of S. flexneri in the laboratory. Firstly, S. flexneri was specifically captured and enriched by IMB (Shigella antibody-coated magnetic beads), and the genomic DNA was released and used as the template in the RPA reaction. Then, the RPA products were mixed with the pre-loaded CRISPR/Cas12a for fluorescence visualization. The results were observed by naked eyes under LED blue light, with a sensitivity of 5 CFU/mL in a time of 70 min. With no specialized equipment or complicated technical requirements, the IMB-RPA-CRISPR/Cas12a diagnostic method can be used for visual, rapid, and simple detection of S. flexneri and can be easily adapted to monitoring other pathogens.


Asunto(s)
Anticuerpos , Shigella flexneri , Humanos , Luz Azul , Fluorescencia , Recombinasas
17.
J Med Virol ; 96(4): e29624, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38647075

RESUMEN

Respiratory infections pose a serious threat to global public health, underscoring the urgent need for rapid, accurate, and large-scale diagnostic tools. In recent years, the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated) system, combined with isothermal amplification methods, has seen widespread application in nucleic acid testing (NAT). However, achieving a single-tube reaction system containing all necessary components is challenging due to the competitive effects between recombinase polymerase amplification (RPA) and CRISPR/Cas reagents. Furthermore, to enable precision medicine, distinguishing between bacterial and viral infections is essential. Here, we have developed a novel NAT method, termed one-pot-RPA-CRISPR/Cas12a, which combines RPA with CRISPR molecular diagnostic technology, enabling simultaneous detection of 12 common respiratory pathogens, including six bacteria and six viruses. RPA and CRISPR/Cas12a reactions are separated by paraffin, providing an independent platform for RPA reactions to generate sufficient target products before being mixed with the CRISPR/Cas12a system. Results can be visually observed under LED blue light. The sensitivity of the one-pot-RPA-CRISPR/Cas12a method is 2.5 × 100 copies/µL plasmids, with no cross-reaction with other bacteria or viruses. Additionally, the clinical utility was evaluated by testing clinical isolates of bacteria and virus throat swab samples, demonstrating favorable performance. Thus, our one-pot-RPA-CRISPR/Cas12a method shows immense potential for accurate and large-scale detection of 12 common respiratory pathogens in point-of-care testing.


Asunto(s)
Bacterias , Sistemas CRISPR-Cas , Técnicas de Diagnóstico Molecular , Infecciones del Sistema Respiratorio , Virus , Bacterias/genética , Bacterias/aislamiento & purificación , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/microbiología , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificación de Ácido Nucleico/métodos , Recombinasas/genética , Recombinasas/metabolismo , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/virología , Infecciones del Sistema Respiratorio/microbiología , Sensibilidad y Especificidad , Virosis/diagnóstico , Virus/genética , Virus/aislamiento & purificación
18.
Lab Chip ; 24(9): 2454-2467, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38644805

RESUMEN

Safe, accurate, and reliable analysis of urinary biomarkers is clinically important for early detection and monitoring of the progression of chronic kidney disease (CKD), as it has become one of the world's most prevalent non-communicable diseases. However, current technologies for measuring urinary biomarkers are either time-consuming and limited to well-equipped hospitals or lack the necessary sensitivity for quantitative analysis and post a health risk to frontline practitioners. Here we report a robust paper-based dual functional biosensor, which is integrated with the clinical urine sampling vial, for the simultaneous and quantitative analysis of pH and glucose in urine. The pH sensor was fabricated by electrochemically depositing IrOx onto a paper substrate using optimised parameters, which enabled an ultrahigh sensitivity of 71.58 mV pH-1. Glucose oxidase (GOx) was used in combination with an electrochemically deposited Prussian blue layer for the detection of glucose, and its performance was enhanced by gold nanoparticles (AuNPs), chitosan, and graphite composites, achieving a sensitivity of 1.5 µA mM-1. This dual function biosensor was validated using clinical urine samples, where a correlation coefficient of 0.96 for pH and 0.98 for glucose detection was achieved with commercial methods as references. More importantly, the urine sampling vial was kept sealed throughout the sample-to-result process, which minimised the health risk to frontline practitioners and simplified the diagnostic procedures. This diagnostic platform, therefore, holds high promise as a rapid, accurate, safe, and user-friendly point-of-care (POC) technology for the analysis of urinary biomarkers in frontline clinical settings.


Asunto(s)
Técnicas Biosensibles , Papel , Sistemas de Atención de Punto , Humanos , Concentración de Iones de Hidrógeno , Oro/química , Glucosa/análisis , Urinálisis/instrumentación , Glucosa Oxidasa/química , Glucosa Oxidasa/metabolismo , Técnicas Electroquímicas , Nanopartículas del Metal/química , Grafito/química , Biomarcadores/orina
19.
Materials (Basel) ; 17(5)2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38473509

RESUMEN

It is highly attractive to develop a photoelectrochemical (PEC) sensing platform based on a non-noble-metal nano array architecture. In this paper, a PEC hydrogen peroxide (H2O2) biosensor based on Ni/WS2/WC heterostructures was synthesized by a facile hydrothermal synthesis method and melamine carbonization process. The morphology, structural and composition and light absorption properties of the Ni/WS2/WC catalyst were investigated by scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and UV-visible spectrophotometer. The average size of the Ni/WS2/WC nanosheets was about 200 nm. Additionally, the electrochemical properties toward H2O2 were studied using an electrochemical workstation. Benefiting from the Ni and C atoms, the optimized Ni/WS2/WC catalyst showed superior H2O2 sensing performance and a large photocurrent response. It was found that the detection sensitivity of the Ni/WS2/WC catalyst was 25.7 µA/cm2/mM, and the detection limit was 0.3 mmol/L in the linear range of 1-10 mM. Simultaneously, the synthesized Ni/WS2/WC electrode displayed excellent electrocatalytic properties in hydrogen evolution reaction (HER), with a relatively small overpotential of 126 mV at 10 mA/cm2 in 0.5 M H2SO4. This novel Ni/WS2/WC electrode may provide new insights into preparing other efficient hybrid photoelectrodes for PEC applications.

20.
Nat Commun ; 15(1): 2163, 2024 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-38461299

RESUMEN

Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2ß as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2ß rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2ß controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2ß binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2ß-targeted inhibitor, Z36-MP5, which reduces Mi-2ß ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.


Asunto(s)
ADN Helicasas , Proteína Potenciadora del Homólogo Zeste 2 , Evasión Inmune , Melanoma , Animales , Humanos , Ratones , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Evasión Inmune/genética , Melanoma/tratamiento farmacológico , Metilación , ADN Helicasas/genética , ADN Helicasas/metabolismo
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