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To investigate the changes in neuronal lipid droplet (LD) accumulation and lipid metabolism after acute spinal cord injury (SCI), we established a rat model of compressive SCI. Oil Red O staining, BODIPY 493/503 staining, and 4-hydroxynonenal immunofluorescence staining were performed to determine overall LD accumulation, neuronal LD accumulation, and lipid peroxidation. Lipidomics was conducted to identify the lipid components in the local SCI microenvironment. We focused on the expression and regulation of perilipin 2 (PLIN2) and knocked down PLIN2 in vivo by intrathecal injection of adeno-associated virus 9-synapsin-short-hairpin RNA-PLIN2 (AAV9-SYN-shPlin2). Motor function was assessed using the Basso-Beattie-Bresnahan score. Proteins that interacted with PLIN2 were screened by immunoprecipitation (IP) and qualitative shotgun proteomics, and confirmed by co-IP. A ubiquitination assay was performed to validate whether ubiquitination was involved in PLIN2 degradation. Oil Red O staining indicated that LDs steadily accumulated after SCI. Fluorescent staining indicated the accumulation of LDs in neurons with increased lipid peroxidation. Lipidomics revealed significant changes in lipid components after SCI. PLIN2 expression significantly increased following SCI, and knockdown of PLIN2 using AAV9-SYN-Plin2 reduced neuronal LD accumulation. This intervention improved the neuronal survival and motor function of injured rats. IP and qualitative shotgun proteomics identified tripartite motif-containing protein 21 (TRIM21) as a direct binding protein of PLIN2, and this interaction was confirmed by co-IP in vitro and immunofluorescence staining in vivo. By manipulating TRIM21 expression, we found it was negatively correlated with PLIN2 expression. In conclusion, PLIN2 is involved in neuronal LD accumulation following SCI. TRIM21 mediated the ubiquitination and degradation of PLIN2 in neurons. Inhibition of PLIN2 enhanced the recovery of motor function after SCI.
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STUDY DESIGN: Preclinical experimental study. OBJECTIVE: To develop an intraoperative ultrasound-assisted imaging device, which could be placed at the surgical site through an endoscopic working channel and which could help surgeon recognition of different tissue types during endoscopic spinal surgery (ESS). SUMMARY OF BACKGROUND DATA: ESS remains a challenging task for spinal surgeons. Great proficiency and experience are needed to perform procedures such as intervertebral discectomy and neural decompression within a narrow channel. The limited surgical view poses a risk of damaging important structures, such as nerve roots. METHODS: We constructed a spinal endoscopic ultrasound system, using a 4-mm custom ultrasound probe, which can be easily inserted through the ESS working channel, allowing up to 10 mm depth detection. This system was applied to ovine lumbar spine samples to obtain ultrasound images. Subsequently, we proposed a two-stage classification algorithm, based on a pretrained DenseNet architecture for automated tissue recognition. The recognition algorithm was evaluated using accuracy and consistency. RESULTS: The probe can be easily used in the ESS working channel and produce clear and characteristic ultrasound images. We collected 367 images for training and testing of the recognition algorithm, including images of the spinal cord, nucleus pulposus, adipose tissue, bone, annulus fibrosus and nerve roots. The algorithm achieved over 90% accuracy in recognizing all types of tissues with a Kappa value of 0.875. The recognition times were under 0.1 s using the current configuration. CONCLUSION: Our system was able to be used in existing ESS working channels and clearly identified at-risk spinal structures in vitro. The pretrained algorithms could identify six intraspinal tissue types accurately and quickly. The concept and innovative application of intraoperative ultrasound in ESS may shorten the learning curve of ESS and improve surgical efficiency and safety.
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RATIONALE AND OBJECTIVES: This study aimed to investigate the prognostic value of preoperative CT scan-derived myocardial biomarkers in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). MATERIALS AND METHODS: In April 2024, three databases (PubMed, Web of Science and Embase) were searched to identify studies. A random-effects model for meta-analysis was conducted to calculate pooled hazard ratios (HR) and 95% confidence intervals (CI) to assess the prognostic value. The I2 statistic was used to assess heterogeneity. Meta-regression analysis was conducted to appraise which variables yielded a significant impact on the HR of included biomarkers. RESULTS: 11 studies were identified, of which six studies involved 678 patients reporting extracellular volume fraction (ECV), one study involved 300 patients reporting ECV and left ventricular global longitudinal strain (LVGLS), three studies involved 868 patients reporting LVGLS and one study involved 376 patients reporting LVGLS and peak left atrial longitudinal strain (PALS). The endpoints included all-cause mortality, major adverse cardiovascular events (MACE) and a composite outcome of the previous two. The meta-analysis revealed that ECV, whether considered as a dichotomous variable (pooled HR: 3.87, 95% CI: 2.63-5.70, I2 = 0%), or as a continuous variable (pooled HR: 1.12, 95% CI: 1.05-1.19, I2 = 66%), and LVGLS, whether considered as a dichotomous variable (pooled HR: 1.70, 95% CI: 1.30-2.22, I2 = 0%) or a continuous variable (pooled HR: 1.07, 95% CI: 1.04-1.10, I2 = 0%) were all significant predictors for outcomes in patients with severe AS after TAVR. Age, sex, follow-up time and mean pressure gradient had a significant impact on the model of ECV (continuous). CONCLUSION: The higher CT-derived ECV and impaired LVGLS are able to predict worse outcomes in patients with severe AS who have undergone TAVR.
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Cardiac magnetic resonance imaging (CMR) is the gold standard for cardiac function assessment and plays a crucial role in diagnosing cardiovascular disease (CVD). However, its widespread application has been limited by the heavy resource burden of CMR interpretation. Here, to address this challenge, we developed and validated computerized CMR interpretation for screening and diagnosis of 11 types of CVD in 9,719 patients. We propose a two-stage paradigm consisting of noninvasive cine-based CVD screening followed by cine and late gadolinium enhancement-based diagnosis. The screening and diagnostic models achieved high performance (area under the curve of 0.988 ± 0.3% and 0.991 ± 0.0%, respectively) in both internal and external datasets. Furthermore, the diagnostic model outperformed cardiologists in diagnosing pulmonary arterial hypertension, demonstrating the ability of artificial intelligence-enabled CMR to detect previously unidentified CMR features. This proof-of-concept study holds the potential to substantially advance the efficiency and scalability of CMR interpretation, thereby improving CVD screening and diagnosis.
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Inteligência Artificial , Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética/métodos , Imagem Cinética por Ressonância Magnética/métodos , Programas de Rastreamento/métodos , Idoso , AdultoRESUMO
BACKGROUND: Early diagnosis of acute gallstone pancreatitis severity (GSP) is challenging in clinical practice. We aimed to investigate the efficacy of CT features and radiomics for the early prediction of acute GSP severity. METHODS: We retrospectively recruited GSP patients who underwent CT imaging within 48 h of admission from tertiary referral centre. Radiomics and CT features were extracted from CT scans. The clinical and CT features were selected by the random forest algorithm to develop the ML GSP model for the identification of severity of GSP (mild or severe), and its predictive efficacy was compared with radiomics model. The predictive performance was assessed by the area under operating characteristic curve. Calibration curve and decision curve analysis were performed to demonstrate the classification performance and clinical efficacy. Furthermore, we built a web-based open access GSP severity calculator. The study was registered with ClinicalTrials.gov (NCT05498961). RESULTS: A total of 301 patients were enrolled. They were randomly assigned into the training (n = 210) and validation (n = 91) cohorts at a ratio of 7:3. The random forest algorithm identified the level of calcium ions, WBC count, urea level, combined cholecystitis, gallbladder wall thickening, gallstones, and hydrothorax as the seven predictive factors for severity of GSP. In the validation cohort, the areas under the curve for the radiomics model and ML GSP model were 0.841 (0.757-0.926) and 0.914 (0.851-0.978), respectively. The calibration plot shows that the ML GSP model has good consistency between the prediction probability and the observation probability. Decision curve analysis showed that the ML GSP model had high clinical utility. CONCLUSIONS: We built the ML GSP model based on clinical and CT image features and distributed it as a free web-based calculator. Our results indicated that the ML GSP model is useful for predicting the severity of GSP.
ML GSP model based on machine learning has good severity discrimination in both training and validation cohorts (0.916 (0.8720.958), 0.914 (0.8510.978), respectively).We built an online user-friendly platform for the ML GSP model to help clinicians better identify the severity of GSP.
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Cálculos Biliares , Aprendizado de Máquina , Pancreatite , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Humanos , Pancreatite/diagnóstico por imagem , Pancreatite/diagnóstico , Feminino , Cálculos Biliares/diagnóstico por imagem , Cálculos Biliares/complicações , Masculino , Tomografia Computadorizada por Raios X/métodos , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Idoso , Doença Aguda , Valor Preditivo dos Testes , Diagnóstico Precoce , Algoritmos , Curva ROCRESUMO
Lithium-sulfur (Li-S) batteries are highly considered as next-generation energy storage techniques. Weakly solvating electrolyte with low lithium polysulfide (LiPS) solvating power promises Li anode protection and improved cycling stability. However, the cathodic LiPS kinetics is inevitably deteriorated, resulting in severe cathodic polarization and limited energy density. Herein, the LiPS kinetic degradation mechanism in weakly solvating electrolytes is disclosed to construct high-energy-density Li-S batteries. Activation polarization instead of concentration or ohmic polarization is identified as the dominant kinetic limitation, which originates from higher charge-transfer activation energy and a changed rate-determining step. To solve the kinetic issue, a titanium nitride (TiN) electrocatalyst is introduced and corresponding Li-S batteries exhibit reduced polarization, prolonged cycling lifespan, and high actual energy density of 381 Wh kg-1 in 2.5 Ah-level pouch cells. This work clarifies the LiPS reaction mechanism in protective weakly solvating electrolytes and highlights the electrocatalytic regulation strategy toward high-energy-density and long-cycling Li-S batteries.
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Pseudoaneurysm is a rare but lethal complication of acute myocardial infarction. In this study, we present a unique case of a patient with left ventricular free wall rupture detected by cardiac magnetic resonance more than 1 year after a percutaneous transluminal coronary intervention.
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INTRODUCTION: Phosphatidylinositol 3-kinases (PI3Ks) overexpression can elicit cellular homeostatic dysregulation, which further contributes to tumorigenesis, with PI3Kα emerging as the most prevalent mutant isoform kinase among PI3Ks. Therefore, selective inhibitors targeting PI3Kα have attracted considerable interest in recent years. Molecular hybridization, with the advantage of simplified pharmacokinetics and drug-drug interactions, emerged as one of the important avenues for discovering potential drugs. OBJECTIVES: This study aimed to construct PI3Kα inhibitors by hybridization and investigate their antitumor activity and mechanism. METHODS: 26 quinazoline-2-indolinone derivatives were obtained by molecular hybridization, and their structure-activity relationship was analyzed by MTT, in vitro kinase activity and molecular docking. The biological evaluation of compound 8 was performed by transwell, flow cytometry, laser scanning confocal microscopy, Western blot, CTESA and immunohistochemistry. RESULTS: Here, we employed molecular hybridization methods to construct a series of quinazoline-2-indolinone derivatives as PI3Kα selective inhibitors. Encouragingly, representative compound 8 exhibited a PI3Kα enzymatic IC50 value of 9.11 nM and 10.41/16.99/37.53-fold relative to the biochemical selectivity for PI3Kß/γ/δ, respectively. Moreover, compound 8 effectively suppressed the viability of B16, HCT116, MCF-7, H22, PC-3, and A549 cells (IC50 values: 0.2 µM â¼ 0.98 µM), and dramatically inhibited the proliferation and migration of NSCLC cells, as well as induced mitochondrial apoptosis through the PI3K/Akt/mTOR pathway. Importantly, compound 8 demonstrated potent in vivo anti-tumor activity in non-small cell lung cancer mouse models without visible toxicity. CONCLUSIONS: This study presented a new avenue for the development of PI3Kα inhibitors and provided a solid foundation for novel QHIDs as potential future therapies for the treatment of NSCLC.
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The cycle life of high-energy-density lithium-sulfur (Li-S) batteries is severely plagued by the incessant parasitic reactions between Li metal anodes and reactive Li polysulfides (LiPSs). Encapsulating Li-polysulfide electrolyte (EPSE) emerges as an effective electrolyte design to mitigate the parasitic reactions kinetically. Nevertheless, the rate performance of Li-S batteries with EPSE is synchronously suppressed. Herein, the sacrifice in rate performance by EPSE is circumvented while mitigating parasitic reactions by employing hexyl methyl ether (HME) as a co-solvent. The specific capacity of Li-S batteries with HME-based EPSE is nearly not decreased at 0.1â C compared with conventional ether electrolytes. With an ultrathin Li metal anode (50â µm) and a high-areal-loading sulfur cathode (4.4â mgS cm-2 ), a longer cycle life of 113â cycles was achieved in HME-based EPSE compared with that of 65â cycles in conventional ether electrolytes at 0.1â C. Furthermore, both high energy density of 387â Wh kg-1 and stable cycle life of 27â cycles were achieved in a Li-S pouch cell (2.7â Ah). This work inspires the feasibility of regulating the solvation structure of LiPSs in EPSE for Li-S batteries with balanced performance.
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Current pharmaceutical research is energetically excavating the pharmacotherapeutic role of herb-derived ingredients in multiple malignancies' targeting. Luteolin is one of the major phytochemical components that exist in various traditional Chinese medicine or medical herbs. Mounting evidence reveals that this phytoconstituent endows prominent therapeutic actions on diverse malignancies, with the underlying mechanisms, combined medication strategy, and pharmacokinetics elusive. Additionally, the clinical trial and pharmaceutical investigation of luteolin remain to be systematically delineated. The present review aimed to comprehensively summarize the updated information with regard to the anticancer mechanism, combined medication strategies, pharmacokinetics, clinical trials, and pharmaceutical researches of luteolin. The survey corroborates that luteolin executes multiple anticancer effects mainly by dampening proliferation and invasion, spurring apoptosis, intercepting cell cycle, regulating autophagy and immune, inhibiting inflammatory response, inducing ferroptosis, and pyroptosis, as well as epigenetic modification, and so on. Luteolin can be applied in combination with numerous clinical anticarcinogens and natural ingredients to synergistically enhance the therapeutic efficacy of malignancies while reducing adverse reactions. For pharmacokinetics, luteolin has an unfavorable oral bioavailability, it mainly persists in plasma as glucuronides and sulfate-conjugates after being metabolized, and is regarded as potent inhibitors of OATP1B1 and OATP2B1, which may be messed with the pharmacokinetic interactions of miscellaneous bioactive substances in vivo. Besides, pharmaceutical innovation of luteolin with leading-edge drug delivery systems such as host-guest complexes, nanoparticles, liposomes, nanoemulsion, microspheres, and hydrogels are beneficial to the exploitation of luteolin-based products. Moreover, some registered clinical trials on luteolin are being carried out, yet clinical research on anticancer effects should be continuously promoted.
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Flavonas , Neoplasias , Humanos , Luteolina/farmacologia , Luteolina/uso terapêutico , Preparações Farmacêuticas , Flavonas/farmacologia , Flavonas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Disponibilidade BiológicaRESUMO
Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity, damaging the neurons. However, how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear. Herein, we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury. We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice. Lipid droplet accumulation could be induced by myelin debris in HT22 cells. Myelin debris degradation by phospholipase led to massive free fatty acid production, which increased lipid droplet synthesis, ß-oxidation, and oxidative phosphorylation. Excessive oxidative phosphorylation increased reactive oxygen species generation, which led to increased lipid peroxidation and HT22 cell apoptosis. Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway, thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells. Motor function, lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury. The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.
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Minimally invasive surgery is widely used for spine surgery, however the commonly used optical endoscopes cannot identity tissues under surface. In this study, a forward-oriented ultrasound endoscopic system was proposed to detect and identity different types of tissues for surgical approaches. A total of 150 ultrasound image data were collected from 6 types of intervertebral disc tissue using a custom-developed endoscopic probe. The gray-level co-occurrence matrix (GLCM) properties including energy (angular second moment, ASM), contrast, entropy, and homogeneity (inverse difference moment, IDM) were calculated on the acquired ultrasound images, and the single-parameter and combined parameter were applied for tissue classification. The classification accuracies of fibrous ring, nerve roots and bone were 100%, and the overall accuracy for all tissues was 73.33%. The results indicated that the combined parameter method provided more accurate classification output. It demonstrated that the proposed endoscopic ultrasonography system had the potential of identifying different tissues under surface during the endoscopic spine surgery.Clinical Relevance-This study establishes that the forward-oriented ultrasound endoscopic system was feasible to identify different types of tissues under surface during the endoscopic spine surgery.
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Deslocamento do Disco Intervertebral , Disco Intervertebral , Humanos , Estudos de Viabilidade , Disco Intervertebral/diagnóstico por imagem , Disco Intervertebral/cirurgia , Ultrassonografia/métodos , Endoscopia/métodosRESUMO
BACKGROUND AND PURPOSE: Neoadjuvant chemotherapy (NACT) has become an essential component of the comprehensive treatment of cervical squamous cell carcinoma (CSCC). However, not all patients respond to chemotherapy due to individual differences in sensitivity and tolerance to chemotherapy drugs. Therefore, accurately predicting the sensitivity of CSCC patients to NACT was vital for individual chemotherapy. This study aims to construct a machine learning radiomics model based on magnetic resonance imaging (MRI) to assess its efficacy in predicting NACT susceptibility among CSCC patients. METHODS: This study included 234 patients with CSCC from two hospitals, who were divided into a training set (n = 180), a testing set (n = 20), and an external validation set (n = 34). Manual radiomic features were extracted from transverse section MRI images, and feature selection was performed using the recursive feature elimination (RFE) method. A prediction model was then generated using three machine learning algorithms, namely logistic regression, random forest, and support vector machines (SVM), for predicting NACT susceptibility. The model's performance was assessed based on the area under the receiver operating characteristic curve (AUC), accuracy, and sensitivity. RESULTS: The SVM approach achieves the highest scores on both the testing set and the external validation set. In the testing set and external validation set, the AUC of the model was 0.88 and 0.764, and the accuracy was 0.90 and 0.853, the sensitivity was 0.93 and 0.962, respectively. CONCLUSIONS: Machine learning radiomics models based on MRI images have achieved satisfactory performance in predicting the sensitivity of NACT in CSCC patients with high accuracy and robustness, which has great significance for the treatment and personalized medicine of CSCC patients.
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Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , Humanos , Feminino , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/tratamento farmacológico , Terapia Neoadjuvante , Imageamento por Ressonância Magnética , Aprendizado de Máquina , Estudos RetrospectivosRESUMO
Lithium-sulfur (Li-S) batteries are promising due to ultrahigh theoretical energy density. However, their cycling lifespan is crucially affected by the electrode kinetics of lithium polysulfides. Herein, the polysulfide solvation structure is correlated with polysulfide electrode kinetics towards long-cycling Li-S batteries. The solvation structure derived from strong solvating power electrolyte induces fast anode kinetics and rapid anode failure, while that derived from weak solvating power electrolyte causes sluggish cathode kinetics and rapid capacity loss. By contrast, the solvation structure derived from medium solvating power electrolyte balances cathode and anode kinetics and improves the cycling performance of Li-S batteries. Li-S coin cells with ultra-thin Li anodes and high-S-loading cathodes deliver 146 cycles and a 338â Wh kg-1 pouch cell undergoes stable 30 cycles. This work clarifies the relationship between polysulfide solvation structure and electrode kinetics and inspires rational electrolyte design for long-cycling Li-S batteries.
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Lithium-sulfur (Li-S) batteries afford great promise on achieving practical high energy density beyond lithium-ion batteries. Lean-electrolyte conditions constitute the prerequisite for achieving high-energy-density Li-S batteries but inevitably deteriorates battery performances, especially the sulfur cathode kinetics. Herein, the polarizations of the sulfur cathode are systematically decoupled to identify the key kinetic limiting factor in lean-electrolyte Li-S batteries. Concretely, an electrochemical impedance spectroscopy combined galvanostatic intermittent titration technique method is developed to decouple the cathodic polarizations into activation, concentration, and ohmic parts. Therein, activation polarization during lithium sulfide nucleation emerges as the dominant polarization as the electrolyte-to-sulfur ratio (E/S ratio) decreases, and the sluggish interfacial charge transfer kinetics is identified as the main reason for degraded cell performances under lean-electrolyte conditions. Accordingly, a lithium bis(fluorosulfonyl)imide electrolyte is proposed to decrease activation polarization, and Li-S batteries adopting this electrolyte provide a discharge capacity of 985 mAh g-1 under a low E/S ratio of 4 µL mg-1 at 0.2 C. This work identifies the key kinetic limiting factor of lean-electrolyte Li-S batteries and provides guidance on designing rational promotion strategies to achieve advanced Li-S batteries.
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In this paper, we investigate the problem of a dynamic event-triggered robust controller design for flexible robotic arm systems with continuous-time phase-type semi-Markov jump process. In particular, the change in moment of inertia is first considered in the flexible robotic arm system, which is necessary for ensuring the security and stability control of special robots employed under special circumstances, such as surgical robots and assisted-living robots which have strict lightweight requirements. To handle this problem, a semi-Markov chain is conducted to model this process. Furthermore, the dynamic event-triggered scheme is used to solve the problem of limited bandwidth in the network transmission environment, while considering the impact of DoS attacks. With regard to the challenging circumstances and negative elements previously mentioned, the adequate criteria for the existence of the resilient H∞ controller are obtained using the Lyapunov function approach, and the controller gains, Lyapunov parameters and event-triggered parameters are co-designed. Finally, the effectiveness of the designed controller is demonstrated via numerical simulation using the LMI toolbox in MATLAB.
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Procedimentos Cirúrgicos Robóticos , Cadeias de Markov , Simulação por ComputadorRESUMO
Practical lithium-sulfur (Li-S) batteries are severely plagued by the instability of solid electrolyte interphase (SEI) formed in routine ether electrolytes. Herein, an electrolyte with 1,3,5-trioxane (TO) and 1,2-dimethoxyethane (DME) as co-solvents is proposed to construct a high-mechanical-stability SEI by enriching organic components in Li-S batteries. The high-mechanical-stability SEI works compatibly in Li-S batteries. TO with high polymerization capability can preferentially decompose and form organic-rich SEI, strengthening mechanical stability of SEI, which mitigates crack and regeneration of SEI and reduces the consumption rate of active Li, Li polysulfides, and electrolytes. Meanwhile, DME ensures high specific capacity of S cathodes. Accordingly, the lifespan of Li-S batteries increases from 75â cycles in routine ether electrolyte to 216â cycles in TO-based electrolyte. Furthermore, a 417â Wh kg-1 Li-S pouch cell undergoes 20â cycles. This work provides an emerging electrolyte design for practical Li-S batteries.
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BACKGROUND: Danon disease is characterized by the failure of lysosomal biogenesis, maturation, and function due to a deficiency of lysosomal membrane structural protein (LAMP2). METHODS: The current report describes a female patient with a sudden syncope and hypertrophic cardiomyopathy phenotype. We identified the pathogenic mutations in patients by whole-exon sequencing, followed by a series of molecular biology and genetic approaches to identify and functional analysis of the mutations. RESULTS: Suggestive findings by cardiac magnetic resonance (CMR), electrocardiogram (ECG), and laboratory examination suggested Danon disease which was confirmed by genetic testing. The patient carried a novel de novo mutation, LAMP2 c.2T>C located at the initiation codon. The quantitative polymerase chain reaction (qPCR) and Western blot (WB) analysis of peripheral blood leukocytes from the patients revealed evidence of LAMP2 haploinsufficiency. Labeling of the new initiation codon predicted by the software with green fluorescent protein followed by fluorescence microscopy and Western blotting showed that the first ATG downstream from the original initiation codon became the new translational initiation codon. The three-dimensional structure of the mutated protein predicted by alphafold2 revealed that it consisted of only six amino acids and failed to form a functional polypeptide or protein. Overexpression of the mutated LAMP2 c.2T>C showed a loss of function of the protein, as assessed by the dual-fluorescence autophagy indicator system. The mutation was confirmed to be null, AR experiments and sequencing results confirmed that 28% of the mutant X chromosome remained active. CONCLUSION: We propose possible mechanisms of mutations associated with haploinsufficiency of LAMP2: (1) The inactivation X chromosome carrying the mutation was not significantly skewed. However, it decreased in the mRNA level and the expression ratio of the mutant transcripts; (2) The identified mutation is null, and the active mutant transcript fails to translate into the normal LAMP2 proteins. The presence of haploinsufficiency in LAMP2 and the X chromosome inactivation pattern were crucial factors contributing to the early onset of Danon disease in this female patient.
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Cardiomiopatia Hipertrófica , Doença de Depósito de Glicogênio Tipo IIb , Humanos , Feminino , Doença de Depósito de Glicogênio Tipo IIb/patologia , Códon de Iniciação , Mutação de Sentido Incorreto , Cardiomiopatia Hipertrófica/genética , Mutação , Proteína 2 de Membrana Associada ao Lisossomo/genéticaRESUMO
Lithium-sulfur (Li-S) batteries are regarded as promising high-energy-density energy storage devices. However, the cycling stability of Li-S batteries is restricted by the parasitic reactions between Li metal anodes and soluble lithium polysulfides (LiPSs). Encapsulating LiPS electrolyte (EPSE) can efficiently suppress the parasitic reactions but inevitably sacrifices the cathode sulfur redox kinetics. To address the above dilemma, a redox comediation strategy for EPSE is proposed to realize high-energy-density and long-cycling Li-S batteries. Concretely, dimethyl diselenide (DMDSe) is employed as an efficient redox comediator to facilitate the sulfur redox kinetics in Li-S batteries with EPSE. DMDSe enhances the liquid-liquid and liquid-solid conversion kinetics of LiPS in EPSE while maintains the ability to alleviate the anode parasitic reactions from LiPSs. Consequently, a Li-S pouch cell with a high energy density of 359â Wh kg-1 at cell level and stable 37â cycles is realized. This work provides an effective redox comediation strategy for EPSE to simultaneously achieve high energy density and long cycling stability in Li-S batteries and inspires rational integration of multi-strategies for practical working batteries.
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Purpose: Dysfunction of endothelium is associated with multiple pathological vascular diseases. However, how to regulate reendothelialization after vascular injury is not well defined. This study aims to determine whether and how Paeonol controls reendothelialization following artery injury. Methods: The endothelium of murine carotid artery was denuded by catheter guide wires injury. H&E staining and IF staining were performed to determine whether Paeonol is critical for reendothelialization. BRDU Incorporation Assay, Boyden Chamber Migration Assay, Tube Formation Assay, and Spheroid Sprouting Assay were used to investigate whether Paeonol is involved in regulating proliferation and migration of endothelial cells. The underlying mechanism of how Paeonol regulates reendothelialization was determined by Molecular docking simulation and CO-IP Assay. Results: Paeonol treatment significantly inhibits neointima formation in carotid artery ligation model by promoting proliferation and migration of endothelial cells. Mechanistically, Paeonol enhances c-Myc expression, consequently interacts with VEGFR2 results in activating VEGF signaling pathway, and eventually promotes reendothelialization after vascular injury. Conclusion: Our data demonstrated that Paeonol plays a critical role in regulating vascular reendothelialization, which may be therapeutically used for treatment of pathological vascular diseases.