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1.
J Glob Health ; 14: 04163, 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39148475

RESUMO

Background: The relationship between sarcopenia and frailty among middle-aged and elder adults remains unclear. This study conducted a cross-sectional and longitudinal analysis to investigate the association of sarcopenia and frailty in the middle-aged and elder Chinese population. Methods: Our data were drawn from the China Health and Retirement Longitudinal Study. Sarcopenia status was assessed according to the Asian Working Group for Sarcopenia 2019 criteria and categorised into: no sarcopenia, possible sarcopenia, sarcopenia, and severe sarcopenia. A 38-item deficit-accumulation frailty index was constructed to assess frailty trajectories at each visit. Generalised linear regression models were performed to analyse the cross-sectional associations between sarcopenia and frailty index. The Group-based trajectory modelling was adopted to identify potential frailty trajectories, and we then examined the associations of sarcopenia and frailty trajectories using logistic regression analysis. Results: A total of 13 218 participants were enrolled in the cross-sectional analysis and 4200 individuals were included in the longitudinal study. The cross-sectional study found that possible sarcopenia (regression coefficient (ß) = 0.76; 95% confidence interval (CI) = 0.64-0.87, P < 0.001), sarcopenia (ß = 0.56; 95% CI = 0.37-0.75, P < 0.001) and severe sarcopenia (ß = 1.35; 95% CI = 0.97-1.73, P < 0.001) were significantly associated with higher frailty index. The longitudinal study indicated that participants with possible sarcopenia (odds ratio (OR) = 2.46; 95% CI = 1.77-3.42, P < 0.001), sarcopenia (OR = 1.87; 95% CI = 1.27-2.74, P < 0.001) and severe sarcopenia (OR = 6.57; 95% CI = 3.14-13.77, P < 0.001) had a higher risk of accelerated progression of frailty compared to those with no sarcopenia. Conclusions: Possible sarcopenia, sarcopenia, and severe sarcopenia were associated with higher levels of frailty and accelerated progression of frailty. Therefore, clinical medical professionals should pay more attention to frailty status in individuals who have possible sarcopenia and sarcopenia.


Assuntos
Fragilidade , Sarcopenia , Humanos , Estudos Longitudinais , Sarcopenia/epidemiologia , Masculino , Feminino , China/epidemiologia , Idoso , Estudos Transversais , Fragilidade/epidemiologia , Pessoa de Meia-Idade , Idoso Fragilizado/estatística & dados numéricos , Idoso de 80 Anos ou mais , Aposentadoria/estatística & dados numéricos , Avaliação Geriátrica
2.
Eur Spine J ; 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39103616

RESUMO

BACKGROUND: Osteoporotic vertebral compression fracture (OVCF) is a common consequence of osteoporosis and can significantly impact the quality of life for affected individuals. Despite treatment options such as vertebroplasty and kyphoplasty, many patients continue to experience residual back pain (RBP) even after the fracture has healed. The incidence of RBP after OVCF treatment varies among studies, and there is a need for further research to understand the risk factors associated with RBP. METHODS: A systematic review and meta-analysis were conducted following the PRISMA guidelines. Electronic databases were searched, and relevant studies were selected based on inclusion and exclusion criteria. Data extraction and quality assessment were performed independently by two authors. Statistical analysis included single-proportion meta-analyses and pooling of odds ratios (OR) using the inverse-variance method, to calculate the overall incidences of RBP and cement leakage and identify risk factors associated with RBP. RESULTS: A total of 19 studies were included in the analysis. The overall incidences of RBP and cement leakage were found to be 16% and 18%, respectively. Several risk factors were identified, including gender, bone mineral density, depression, baseline visual analog scale (VAS) score, intravertebral vacuum cleft, number of fractured segments, cement distribution, history of vertebral fracture, thoracolumbar fascial injury, and fracture non-union. CONCLUSIONS: This study provides potential value within the scope of the incidence and risk factors of RBP following treatment of OVCFs. The identified risk factors can help clinicians identify high-risk patients and tailor appropriate interventions. Future research should focus on standardizing the definition of RBP and patient selection criteria to improve the accuracy of estimates and facilitate better management strategies for OVCF patients.

3.
iScience ; 27(8): 110434, 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39108714

RESUMO

Ovarian cancer is a highly lethal gynecological malignancy, emphasizing the need for effective treatment strategies. This study investigated the synergistic effects of quercetin and paclitaxel on ovarian cancer. Using SKOV3 and A2780 cell lines, we found that the combined treatment significantly enhanced cell apoptosis and inhibited invasion and migration compared to individual treatments. Then, we identified 32 common targets between quercetin/paclitaxel and ovarian cancer, with 29 genes showing differential expression between normal ovarian tissue and ovarian tumor tissue. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that quercetin and paclitaxel modulated cancer-related pathways in ovarian cancer treatment. Mechanistic analysis further discovered that the synergistic effect was mediated by downregulating ERBB2 and BIRC5 and upregulating CASP3 expression. This study provides strong evidence that quercetin enhances the effectiveness of paclitaxel in treating ovarian cancer.

4.
Mon Not R Astron Soc ; 533(2): 1426-1441, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39176180

RESUMO

In the context of upcoming large-scale surveys like Euclid, the necessity for the automation of strong lens detection is essential. While existing machine learning pipelines heavily rely on the classification probability (P), this study intends to address the importance of integrating additional metrics, such as Information Content (IC) and the number of pixels above the segmentation threshold ([Formula: see text]), to alleviate the false positive rate in unbalanced data-sets. In this work, we introduce a segmentation algorithm (U-Net) as a supplementary step in the established strong gravitational lens identification pipeline (Denselens), which primarily utilizes [Formula: see text] and [Formula: see text] parameters for the detection and ranking. The results demonstrate that the inclusion of segmentation enables significant reduction of false positives by approximately 25 per cent in the final sample extracted from DenseLens, without compromising the identification of strong lenses. The main objective of this study is to automate the strong lens detection process by integrating these three metrics. To achieve this, a decision tree-based selection process is introduced, applied to the Kilo Degree Survey (KiDS) data. This process involves rank-ordering based on classification scores ([Formula: see text]), filtering based on Information Content ([Formula: see text]), and segmentation score ([Formula: see text]). Additionally, the study presents 14 newly discovered strong lensing candidates identified by the U-Denselens network using the KiDS DR4 data.

5.
Front Physiol ; 15: 1424931, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39189027

RESUMO

Introduction: Digital twins of patients are virtual models that can create a digital patient replica to test clinical interventions in silico without exposing real patients to risk. With the increasing availability of electronic health records and sensor-derived patient data, digital twins offer significant potential for applications in the healthcare sector. Methods: This article presents a scalable full-stack architecture for a patient simulation application driven by graph-based models. This patient simulation application enables medical practitioners and trainees to simulate the trajectory of critically ill patients with sepsis. Directed acyclic graphs are utilized to model the complex underlying causal pathways that focus on the physiological interactions and medication effects relevant to the first 6 h of critical illness. To realize the sepsis patient simulation at scale, we propose an application architecture with three core components, a cross-platform frontend application that clinicians and trainees use to run the simulation, a simulation engine hosted in the cloud on a serverless function that performs all of the computations, and a graph database that hosts the graph model utilized by the simulation engine to determine the progression of each simulation. Results: A short case study is presented to demonstrate the viability of the proposed simulation architecture. Discussion: The proposed patient simulation application could help train future generations of healthcare professionals and could be used to facilitate clinicians' bedside decision-making.

6.
Chin J Integr Med ; 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39190272

RESUMO

Benign prostatic hyperplasia (BPH) is one of the most common diseases in elderly men, the incidence of which gradually increases with age and leads to lower urinary tract symptoms (LUTS), which seriously affects the quality of life of patients. Chinese herbal medicines (CHMs) are widely used for the treatment of BPH in China and some other countries. To explore the molecular mechanisms of CHMs for BPH, we conducted a review based on peer-reviewed English-language publications in PubMed and Web of Science databases from inception to December 31, 2023. This article primarily reviewed 32 papers on the use of CHMs and its active compounds in the treatment of BPH, covering animal and cell experiments, and identified relevant mechanisms of action. The results suggest that the mechanisms of action of CHMs in treating BPH may involve the regulation of sex hormones, downregulation of cell growth factors, anti-inflammatory and antioxidative effects, inhibition of cell proliferation, and promotion of apoptosis. CHMs also exhibit α-blocker-like effects, with the potential to relax urethral smooth muscle and alleviate LUTS. Additionally, we also reviewed 4 clinical trials and meta-analyses of CHMs for the treatment of BPH patients, which provided initial evidence of the safety and effectiveness of CHMs treatment. CHMs treatment for BPH shows advantages as a multi-component, multi-target, and multi-pathway therapy, which can mitigate the severity of the disease, improve LUTS, and may become a reliable treatment option in the future.

7.
Angew Chem Int Ed Engl ; : e202403432, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39023052

RESUMO

In the pursuit of next-generation ultrahigh-energy-density Li-O2 batteries, it is imperative to develop an electrolyte with stability against the strong oxidation environments. N,N-dimethylacetamide (DMA) is a recognized solvent known for its robust resistance to the highly reactive reduced oxygen species, yet its application in Li-O2 batteries has been constrained due to its poor compatibility with the Li metal anode. In this study, a rationally selected hydrofluoroether diluent, methyl nonafluorobutyl ether (M3), has been introduced into the DMA-based electrolyte to construct a localized high concentration electrolyte. The stable -CH3 and C-F bonds within the M3 structure could not only augment the fundamental properties of the electrolyte but also fortify its resilience against attacks from O2- and 1O2. Additionally, the strong electron-withdrawing groups (-F) presented in the M3 diluent could facilitate coordination with the electron-donating groups (-CH3) in the DMA solvent. This intermolecular interaction promotes more alignment of Li+-anions with a small amount of M3 addition, leading to the construction of an anion-derived inorganic-rich SEI that enhances the stability of the Li anode. As a result, the Li-O2 batteries with the DMA/M3 electrolyte exhibit superior cycling performance at both 30 °C (359th) and -10 °C (120th).

8.
Cell Commun Signal ; 22(1): 364, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39014433

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide, characterized by persistent respiratory symptoms and airflow limitation. The involvement of C-C motif chemokine ligand 2 (CCL2) in COPD pathogenesis, particularly in macrophage regulation and activation, is poorly understood despite its recognized role in chronic inflammation. Our study aims to elucidate the regulatory role and molecular mechanisms of CCL2 in the pathogenesis of COPD, providing new insights for therapeutic strategies. METHODS: This study focused on the CCL2-CCR2 signaling pathway, exploring its role in COPD pathogenesis using both Ccl2 knockout (KO) mice and pharmacological inhibitors. To dissect the underlying mechanisms, we employed various in vitro and in vivo methods to analyze the secretion patterns and pathogenic effects of CCL2 and its downstream molecular signaling through the CCL2-CCR2 axis. RESULTS: Elevated Ccl2 expression was confirmed in the lungs of COPD mice and was associated with enhanced recruitment and activation of macrophages. Deletion of Ccl2 in knockout mice, as well as treatment with a Ccr2 inhibitor, resulted in protection against CS- and LPS-induced alveolar injury and airway remodeling. Mechanistically, CCL2 was predominantly secreted by bronchial epithelial cells in a process dependent on STAT1 phosphorylation and acted through the CCR2 receptor on macrophages. This interaction activated the PI3K-AKT signaling pathway, which was pivotal for macrophage activation and the secretion of inflammatory cytokines, further influencing the progression of COPD. CONCLUSIONS: The study highlighted the crucial role of CCL2 in mediating inflammatory responses and remodeling in COPD. It enhanced our understanding of COPD's molecular mechanisms, particularly how CCL2's interaction with the CCR2 activates critical signaling pathways. Targeting the CCL2-CCR2 axis emerged as a promising strategy to alleviate COPD pathology.


Assuntos
Quimiocina CCL2 , Macrófagos , Camundongos Knockout , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Doença Pulmonar Obstrutiva Crônica , Receptores CCR2 , Transdução de Sinais , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Animais , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Receptores CCR2/metabolismo , Receptores CCR2/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Humanos , Camundongos Endogâmicos C57BL , Masculino
10.
Acta Diabetol ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38954041

RESUMO

BACKGROUND: This study investigates the therapeutic mechanisms of Cai's Herbal Tea in Type 1 Diabetes Mellitus (T1DM) mice, focusing on its effects on mitochondrial change and autophagy via the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway. METHODS: The composition of Cai's Herbal Tea was analyzed by Ultra-High Performance Liquid Chromatography-Quadrupole Time of Flight Mass Spectrometry (UHPLC-Q/TOF-MS). C57BL/6 mice and Min6 pancreatic beta cells were divided into control, diabetic mellitus (DM)/high glucose (HG), and treatment groups (low, medium, and high doses of Cai's Tea, and Metformin). Key physiological parameters, pancreatic islet health, Min6 cell morphology, viability, and insulin (INS) secretion were assessed. Small Interfering RNA-AMPK (si-AMPK) was utilized to confirm the pathway involvement. RESULTS: Cai's Herbal Tea improved body weight, pancreatic islet pathological injury, and INS secretion whereas reduced total triglycerides, fasting blood sugar, and Interferon gamma (INF-γ) in T1DM mice, particularly at higher doses. In Min6 cells, Cai's Tea mitigated HG-induced damage and proinflammatory response, enhancing cell viability and INS secretion. Notably, it reduced swelling and improved cristae structure in treated groups of mitochondria and promoted autophagy via the AMPK-mTOR pathway, evidenced by increased LC3II/LC3I and P-AMPK/AMPK ratios, and decreased P-mTOR/mTOR and P62 expressions in pancreatic islet ß-cells. Furthermore, these effects were converted by si-AMPK interference. CONCLUSION: Cai's Herbal Tea exhibits significant therapeutic efficacy in T1DM mice by improving mitochondrial health and inducing autophagy through the AMPK-mTOR pathway in pancreatic islet ß-cells. These findings highlight its potential as a therapeutic approach for T1DM management.

11.
Mar Environ Res ; 200: 106639, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38991430

RESUMO

Ophiuroids, as an important group of echinoderms, are widely distributed in marine benthic habitats. Previous studies have identified two primary feeding types of ophiuroids in the Yellow Sea, including carnivorous (Ophiura sarsii vadicola and Stegophiura sladeni) and suspension feeders (Ophiopholis mirabilis). Despite their ecological role in the benthic food webs, little is known about their accumulation of trace metal elements (TMEs). In this study, the content of TMEs (Pb, As, Cd, Hg, Cr, Cu, Zn), methylmercury (MeHg) and δ15N value of three ophiuroids species from the North Yellow Sea were determined. Our results showed that the contents of some TMEs (As, Cd, Cr, Cu and Zn) and MeHg were significantly different in three species of ophiuroid (p < 0.05). There were significant correlations between the accumulations of trace metal elements (Pb, Cd and Zn) and the δ15N value of the ophiuroids (p < 0.05). Additionally, As and Zn exhibited opposite correlations in ophiuroid with two feeding types, which may be related to their host species and different feeding habits. This study provided fundamental data for understanding the distribution of trace metal elements in echinoderms.


Assuntos
Equinodermos , Monitoramento Ambiental , Oligoelementos , Poluentes Químicos da Água , Animais , Equinodermos/metabolismo , Oligoelementos/análise , Poluentes Químicos da Água/análise , Cadeia Alimentar , Metais/análise , China
12.
J Hazard Mater ; 476: 135147, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39029189

RESUMO

Mangrove forests, a critical coastal ecosystem, face numerous anthropogenic threats, particularly from aquaculture activities. Despite the acknowledged significance of viruses in local and global biogeochemical cycles, there is limited knowledge regarding the community structure, genomic diversity, and ecological roles of viruses in mangrove forests ecosystems, especially regarding their responses to aquaculture. In this study, we identified 17,755 viral operational taxonomic units (vOTUs) from nine sediments viromes across three distinct ecological regions of the mangrove forests ecosystem: mangrove, bare flat, and aquaculture regions. Viral assemblages varied among three regions, and the pathogenic viruses associated with marine animals, such as the white spot syndrome virus (WSSV) from Nimaviridae, were identified in this study. The relative abundance of Nimaviridae in the bare flat region was higher than in other regions. Furthermore, viruses in distinct mangrove forests sediments regions have adapted to their environments by adopting distinct survival strategies and encoding various auxiliary metabolic genes involved in carbon metabolism and antibiotic resistance. These adaptations may have profound impacts on biogeochemical cycles. This study provides the first insights into the effects of vegetation cover and aquaculture on the community structure and ecological roles of viruses in mangrove forests sediments. These findings are crucial for understanding the risks posed by anthropogenic threats to mangrove forests ecosystems and informing effective management strategies.


Assuntos
Aquicultura , Sedimentos Geológicos , Vírus , Sedimentos Geológicos/virologia , Vírus/genética , Áreas Alagadas , Animais , Viroma , Ecossistema
13.
Gut Microbes ; 16(1): 2377576, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39068517

RESUMO

The global incidence and prevalence of inflammatory bowel disease (IBD) are gradually increasing. A high-fat diet (HFD) is known to disrupt intestinal homeostasis and aggravate IBD, yet the underlying mechanisms remain largely undefined. Here, a positive correlation between dietary fat intake and disease severity in both IBD patients and murine colitis models is observed. A HFD induces a significant decrease in indole-3-acetic acid (IAA) and leads to intestinal barrier damage. Furthermore, IAA supplementation enhances intestinal mucin sulfation and effectively alleviates colitis. Mechanistically, IAA upregulates key molecules involved in mucin sulfation, including 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (Papss2) and solute carrier family 35 member B3 (Slc35b3), the synthesis enzyme and the transferase of 3'-phosphoadenosine-5'-phosphosulfate (PAPS), via the aryl hydrocarbon receptor (AHR). More importantly, AHR can directly bind to the transcription start site of Papss2. Oral administration of Lactobacillus reuteri, which can produce IAA, contributes to protecting against colitis and promoting mucin sulfation, while the modified L. reuteri strain lacking the iaaM gene (LactobacillusΔiaaM) and the ability to produce IAA fail to exhibit such effects. Overall, IAA enhances intestinal mucin sulfation through the AHR-Papss2-Slc35b3 pathway, contributing to the protection of intestinal homfeostasis.


A HFD can lead to the development of colitis by disrupting tryptophan metabolism in the gut microbiome and lowering levels of IAA. Supplementation with IAA has been shown to alleviate colitis in mice and improve intestinal barrier function. It is believed that IAA may activate the AHR to upregulate the expression of Papss2 and Slc35b3, promoting sulfation modification of mucins and protecting the intestinal barrier. HFD, high-fat diet; AHR, aryl hydrocarbon receptor; IAA, indole-3-acetic acid; Papss2, 3'-phosphoadenosine 5'-phosphosulfate synthase 2; Slc35b3, solute carrier family 35 member B3.


Assuntos
Microbioma Gastrointestinal , Homeostase , Ácidos Indolacéticos , Mucosa Intestinal , Mucinas , Animais , Humanos , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Mucinas/metabolismo , Ácidos Indolacéticos/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos Endogâmicos C57BL , Colite/microbiologia , Colite/metabolismo , Colite/induzido quimicamente , Limosilactobacillus reuteri/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Masculino , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Modelos Animais de Doenças
14.
RSC Adv ; 14(32): 23559, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39071476

RESUMO

[This corrects the article DOI: 10.1039/C9RA03713F.].

15.
Healthcare (Basel) ; 12(13)2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38998845

RESUMO

Advancements in information technology have facilitated the emergence of mHealth apps as crucial tools for health management and chronic disease prevention. This research work focuses on mHealth apps for the management of diabetes by patients on their own. Given that China has the highest number of diabetes patients in the world, with 141 million people and a prevalence rate of 12.8% (mentioned in the Global Overview of Diabetes), the development of a usability research methodology to assess and validate the user-friendliness of apps is necessary. This study describes a usability evaluation model that combines task analysis methods and eye movement data. A blood glucose recording application was designed to be evaluated. The evaluation was designed based on the model, and the feasibility of the model was demonstrated by comparing the usability of the blood glucose logging application before and after a prototype modification based on the improvement suggestions derived from the evaluation. Tests showed that an improvement plan based on error logs and post-task questionnaires for task analysis improves interaction usability by about 24%, in addition to an improvement plan based on eye movement data analysis for hotspot movement acceleration that improves information access usability by about 15%. The results demonstrate that this study presents a usability evaluation model for mHealth apps that enables the effective evaluation of the usability of mHealth apps.

16.
ISA Trans ; 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38987043

RESUMO

Prediction of Remaining Useful Life (RUL) for Rolling Element Bearings (REB) has attracted widespread attention from academia and industry. However, there are still several bottlenecks, including the effective utilization of multi-sensor data, the interpretability of prediction models, and the prediction across the entire life cycle, which limit prediction accuracy. In view of that, we propose a knowledge-based explainable life-cycle RUL prediction framework. First, considering the feature fusion of fast-changing signals, the Pearson correlation coefficient matrix and feature transformation objective function are incorporated to an Improved Graph Convolutional Autoencoder. Furthermore, to integrate the multi-source signals, a Cascaded Multi-head Self-attention Autoencoder with Characteristic Guidance is proposed to construct health indicators. Then, the whole life cycle of REB is divided into different stages based on the Continuous Gradient Recognition with Outlier Detection. With the development of Measurement-based Correction Life Formula and Bidirectional Recursive Gated Dual Attention Unit, accurate life-cycle RUL prediction is achieved. Data from self-designed test rig and PHM 2012 Prognostic challenge datasets are analyzed with the proposed framework and five existing prediction models. Compared with the strongest prediction model among the five, the proposed framework demonstrates significant improvements. For the data from self-designed test rig, there is a 1.66 % enhancement in Corrected Cumulative Relative Accuracy (CCRA) and a 49.00 % improvement in Coefficient of Determination (R2). For the PHM 2012 datasets, there is a 4.04 % increase in CCRA and a 120.72 % boost in R2.

17.
Chembiochem ; : e202400355, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39058554

RESUMO

Cellular senescence has emerged as a potential therapeutic target for aging and a wide range of age-related disorders. Despite the encouraging therapeutic impact of senolytic agents on improving lifespan and the outcomes of pharmacological intervention, the senolytic induced side effects pose barriers to clinical application. There is a pressing need for selective ablation of senescent cells (SnCs). The design of senolytic prodrugs has been demonstrated as a promising approach to addressing these issues. These prodrugs are generally designed via modification of senolytics with a cleavable galactose moiety to respond to the senescent biomarker - senescence-associated ß-galactosidase (SA-ß-gal) to restore their therapeutic effects. In this Concept, we summarize the developments by categorizing these prodrugs into two classes: 1) galactose-modified senolytic prodrugs, in which sensing unit galactose is either directly conjugated to the drug or via a self-immolative linker and 2) bioorthogonal activation of senolytic prodrugs. In the bioorthogonal prodrug design, galactose is incorporated into dihydrotetrazine to sense SA-ß-gal for click activation. Notably, in addition to repurposed chemotherapeutics and small molecule inhibitors, PROTACs and photodynamic therapy have been introduced as new senolytics in the prodrug design. It is expected that the senolytic prodrugs would facilitate translating small-molecule senolytics into clinical use.

18.
Am J Med Genet A ; : e63828, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39058251

RESUMO

Autosomal recessive spinocerebellar ataxias (SCARs) are a heterogeneous group of neurodegenerative disorders. VPS13D gene is currently the only gene associated with autosomal recessive spinocerebellar ataxia type 4 (SCAR4), also known as VPS13D dyskinesia. SCAR4 is a rare inherited disease, with only 34 reported cases reported worldwide. In this study, we reported three independent SCAR4 cases with adolescent onsets caused by five novel variants of the VPS13D gene. Each patient carried one frameshift and one missense variant: Patient 1 with c.10474del and c.9734C > A (p.Leu3492Tyrfs*43 and p.Thr3245Asn), Patient 2 with c.6094_6107delGTTCTCTTGATCCC and c.9734C > A (p.Val2032Argfs*7 and p.Thr3245Asn), and Patient 3 with c.11954_11963del and c.9833 T > G (p.Phe3985Serfs*10 and p.Ile3278Ser). Two of the three patients shared nystagmus with an identical variant c.9734C > A. Magnetic resonance imaging indicated thoracic spinal atrophy in all three patients and corpus callosum atrophy in one patient, along with other typical manifestations of white matter degradation, cerebral atrophy, and cerebellar atrophy. These findings expanded the genetic, clinical, and neuroimaging spectrum of SCAR4, and provided new insights into the genetic counseling, molecular mechanisms, and differential diagnosis of the disease.

19.
Bioact Mater ; 40: 261-274, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38973991

RESUMO

Artificial skin involves multidisciplinary efforts, including materials science, biology, medicine, and tissue engineering. Recent studies have aimed at creating skins that are multifunctional, intelligent, and capable of regenerating tissue. In this work, we present a specialized 3D printing ink composed of polyurethane and bioactive glass (PU-BG) and prepare dual-function skin patch by microfluidic-regulated 3D bioprinting (MRBP) technique. The MRBP endows the skin patch with a highly controlled microstructure and superior strength. Besides, an asymmetric tri-layer is further constructed, which promotes cell attachment and growth through a dual transport mechanism based on hydrogen bonds and gradient structure from hydrophilic to superhydrophilic. More importantly, by combining the features of biomedical skin with electronic skin (e-skin), we achieved a biomedical and electronic dual-function skin patch. In vivo experiments have shown that this skin patch can enhance hemostasis, resist bacterial growth, stimulate the regeneration of blood vessels, and accelerate the healing process. Meanwhile, it also mimics the sensory functions of natural skin to realize signal detection, where the sensitivity reached up to 5.87 kPa-1, as well as cyclic stability (over 500 cycles), a wide detection range of 0-150 kPa, high pressure resolution of 0.1 % under the pressure of 100 kPa. This work offers a versatile and effective method for creating dual-function skin patches and provide new insights into wound healing and tissue repair, which have significant implications for clinical applications.

20.
Sci Total Environ ; 947: 174384, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-38964389

RESUMO

The characteristics of lake dissolved organic matter (DOM) pool and lake ecosystem interact, and studying the responses between sediment DOM characteristics and lake ecosystem changes may shed light on the inherent connection between ecosystem evolution and carbon biogeochemical cycles. Lakes in cold and arid regions are sensitive to changes and accumulate large amounts of carbon as DOM, which may provide a window into more explicit relationships between ecosystem evolution and changes in sediment DOM characteristics in time dimension. However, considerable blind spots exist in the responses between the sediment DOM and ecosystem evolution on time scale and the underlying mechanisms. In this study, multiple approaches were combined to investigate the relationship between the variation trend of sediment DOM characteristics and the evolution of fragile lake ecosystems across three different lake ecosystems in cold and arid regions of China. A strong positive relationship between sediment DOM stabilities, especially humification, and ecosystem degradation was found, consistent for the three lakes. Ultra-high-resolution mass spectrometry and structural equation modeling revealed that the changes of ecosystems affected sediment DOM stability through direct pathways (0.24), such as the contents of terrestrial DOM in lake DOM pool, and indirect pathways, including algae-mediated (0.43) and salinity-mediated pathways (0.22), which all increased the contents of refractory DOM in the lake DOM pool and sediments. Based on the fact that DOM stability changes could act on the ecosystem in turn, a possible positive feedback mechanism between ecosystem degradation and increased DOM stability was further inferred. These results suggested that the continuous increased stability of sediment DOM in may implies ecosystem degradation of lakes in the cold and arid regions. This study provides a new perspective for recognizing ecosystem evolution through sediment DOM and improves the understanding of the interaction of lake ecosystem evolution and the biogeochemical cycle of DOM.

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