23 results on '"Denghong Zhang"'
Search Results
2. Implantable cardiac monitor and leadless pacemaker in the management of syncope due to intermittent high-degree atrioventricular block: a case report
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Nian Tang, Xiaoxiao Chen, Denghong Zhang, and Hongfei Li
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Implantable ECG event monitor ,Leadless atrioventricular synchronous pacemaker micra AV ,High atrioventricular block ,Surgery ,RD1-811 ,Anesthesiology ,RD78.3-87.3 - Abstract
Abstract Background Lead dislodgements, tricuspid valve failure, and wound infections are prominent issues addressed by leadless pacemakers (LPM). These devises have emerged as viable alternatives to conventional transvenous pacemakers. LPMs offer minimized complications and effective pacing, particularly beneficial for elderly patients with a low body mass index (BMI) who are at heightened infection of risk. The Micra AV leadless pacemaker was released in the US in 2020, featuring a VDD pacing mode akin to conventional pacemakers. It senses atrial activity to pace ventricular beats while maintaining the natural atrioventricular activation sequence. Micra AV achieves atrioventricular synchronization through mechanical sensing principles. Ongoing research aims to assess its efficacy, implantation feasibility, and clinical safety. Case presentation An 83-year-old man with a history of syncope was the focus of this case study. An implantable cardiac monitor (ICM) recorded occasional high-degree atrioventricular block in the patient. Subsequently, the Micra AV was implanted via the left femoral vein, and its settings were adjusted in accordance with data obtained from the ICM. No significant issues regarding pacing threshold or impedance were found during the follow-up examinations post-surgery. Importantly, the patient experienced a noticeable reduction in symptoms compared to before the implantation. Discussion This case underscores the significance of ICM monitoring in elucidating cardiac events leading to syncope and guiding appropriate treatment. It also highlights the successful outcomes and reliable implantation of the Micra AV for managing high-degree atrioventricular block. This study contributes to the growing body of evidence supporting the adoption of leadless pacemakers as a viable option for patients requiring cardiac pacing, particularly those vulnerable to complications associated with traditional pacemakers. It provides real-world evidence of Micra AV’s efficacy and safety, further validating its role in clinical practice.
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- 2024
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3. Beneficial effects of upgrading to His-Purkinje system pacing in patients with pacing-induced cardiomyopathy: a systematic review and meta-analysis
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Nian Tang, Xiaoxiao Chen, Hongfei Li, and Denghong Zhang
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His-purkinje system packing ,Left bundle branch pacing ,Pacing-induced cardiomyopathy ,Systematic review ,Meta-analysis ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Background The purpose of this study was to evaluate the effectiveness of His-Purkinje system pacing (HPSP) in the management of patients with pace-induced cardiomyopathy (PICM). Methods PubMed, Embase, Web of Science, and the Cochrane Library were searched comprehensively to collect related studies published from the inception of databases to June 1, 2022. R 4.04 software, including the Metafor package, matrix package, and the Meta package, was utilized to conduct the singe-arm meta-analysis. The methodology index for non-randomized studies (MINORS) was used to assess the methodological quality of the included studies. Results A total of seven studies were included, involving 164 PICM patients. The meta-analysis showed that HPSP ameliorated the left ventricular ejection fraction (LVEF) by 13.41% (95% CI [11.21–15.61]), improved the New York Heart Association (NYHA) classification by 1.02 (95% CI [−1.41 to −0.63]), and shortened the QRS duration (QRSd) by 60.85 ms (95% CI [−63.94 to −57.75]), resulting in improved cardiac functions in PICM patients. Besides, HPSP reversed the ventricular remodeling, with a 32.46 ml (95% CI [−53.18 to −11.75]) decrease in left ventricular end systolic volume (LVESV) and a 5.93 mm (95% CI [−7.68 to −4.19]) decrease in left ventricular end-diastolic dimension (LVEDD). HPSP also showed stable electrical parameters of pacemakers, with a 0.07 V (95% CI [0.01–0.13]) increase in pacing threshold, a 0.02 mV (95% CI [−0.85 to 0.90]) increase in sensed R-wave amplitude, and a 31.12 Ω reduction in impedance (95% CI [−69.62 to 7.39]). Compared with LBBP, HBP improved LVEF by 13.28% (95% CI [−11.64 to 14.92]) vs 14.43% (95% CI [−13.01 to 15.85]), ameliorated NHYA classification by 1.18 (95% CI [−1.97 to −0.39]) vs 0.95 (95% CI [−1.33 to −0.58]), shortened QRSd by 63.16 ms (95% CI [−67.00 to −59.32]) vs 57.98 ms (95% CI [−62.52 to −53.25]), and decreased LVEDD by 4.12 mm (95% CI [−5.79 to −2.45]) vs 6.26 mm (95% CI [−62.52 to −53.25]). The electrical parameters of the pacemaker were stable in both groups. Conclusions This meta-analysis showed that HPSP could significantly improve cardiac function, promote reverse remodeling, and provide stable electrical parameters of pacemakers for PICM patients.
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- 2023
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4. Collisional-radiative modeling for the EUV spectrum of W40+-W42+ions
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Lirong Lei, Xiaobin Ding, Cunqiang Wu, Denghong Zhang, Ling Zhang, Fengling Zhang, Ke Yao, Yang Yang, Yunqing Fu, and Chenzhong Dong
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collisional-radiative model ,tungsten ions ,plasma spectrum ,Science ,Physics ,QC1-999 - Abstract
The wavelengths and transition rates of W ^40+ -W ^42+ ions within the range of 40–140 Å, have been calculated using the Flexible Atomic Code of the Dirac-Fock-Slater method with a central potential. We investigated the charge state distribution of W ^38+ -W ^45+ ions at different temperatures by constructing an appropriate rate equation and demonstrate the importance of the dielectronic recombination process. Additionally, we simulated the emission spectra of W ^40+ -W ^42+ ions in a Tokamak plasma environment using collisional-radiative modeling. Our findings demonstrate strong agreement with experimental results and other related theoretical investigations. Finally, we propose certain pairs of transition lines as diagnostic tools for plasma temperature and density, leveraging the correlation between line intensity ratio and electron temperature and density.
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- 2024
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5. Oral iron supplementation in patients with heart failure: a systematic review and meta‐analysis
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Zhiping Song, Mingyang Tang, Gang Tang, Guoqi Fu, Dengke Ou, Fengyou Yao, Xingzhi Hou, and Denghong Zhang
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Heart failure ,Oral iron ,Iron deficiency ,Anaemia ,Efficacy ,Safety ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Aims This review aimed to assess whether oral iron supplementation in a chronic heart failure (HF) population with iron deficiency (ID) or mild anaemia is safe and effective according to evidence‐based medicine. Methods We retrieved 1803 records from the PubMed, Embase, and the Cochrane Library databases from 1 January 1991 to 15 September 2021. The clinical outcome of oral iron supplementation for ID anaemia in patients with HF was the primary endpoint. The primary safety measures included adverse events and all‐cause mortality, and efficacy measures included transferrin saturation (Tsat), ferritin levels, and the 6‐min walk test (6MWT). The rate ratio (RR) was used to pool the efficacy measures. Results Five randomized controlled trials that compared oral iron treatment for patients with the placebo group and included a combined total of 590 participants were analysed. No significant difference was found in all‐cause death between oral iron treatment and placebo groups (RR = 0.77; 95% confidence intervals (CI), 0.46–1.29, Z = 0.98; P = 0.33). However, adverse events were not significantly higher in the iron treatment group (RR = 0.83; 95% CI, 0.60–1.16, Z = 1.07; P = 0.28). In addition, ferritin levels and Tsat were slightly increased after iron complex administration in patients with HF but were not statistically significant (ferritin: mean difference [MD] = 2.70, 95% CI, –2.41 to 7.81, Z = 1.04; P = 0.30; Tsat: MD = 27.42, 95% CI, –4.93 to 59.78, Z = 1.66; P = 0.10). No significant difference was found in exercise capacity, as indicated by the 6MWT results (MD = 59.60, 95% CI, –17.89 to 137.08, Z = 1.51; P = 0.13). We also analysed two non‐randomized controlled trials with follow‐up results showing that oral iron supplementation increased serum iron levels (MD = 28.87, 95% CI, 1.62–56.12, Z = 2.08; P = 0.04). Conclusions Based on the current findings, oral iron supplementation can increase serum iron levels in patients with HF and ID or mild anaemia but does not improve Tsat and 6MWT. In addition, oral iron supplementation is relatively safe.
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- 2022
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6. Comparative proteomics of three Chinese potato cultivars to improve understanding of potato molecular response to late blight disease
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Chunfang Xiao, Mengling Huang, Jianhua Gao, Zhen Wang, Denghong Zhang, Yuanxue Zhang, Lei Yan, Xiao Yu, Bo Li, and Yanfen Shen
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Comparative proteomics ,Potato cultivars ,Phytophthora infestans ,Late blight disease ,Hypersensitive response ,Susceptible ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Late blight disease (LBD) caused by the pathogen Phytophthora infestans (PI), is the most devastating disease limiting potato (Solanum tuberosum) production globally. Currently, this disease pathogen is re-emerging and appearing in new areas at a very high intensity. A better understanding of the natural defense mechanisms against PI in different potato cultivars especially at the protein level is still lacking. Therefore, to elucidate potato proteome response to PI, we investigated changes in the proteome and leaf morphology of three potato cultivars, namely; Favorita (FA), Mira (MA), and E-malingshu N0.14 (E14) infected with PI by using the iTRAQ-based quantitative proteomics analysis. Results A total of 3306 proteins were found in the three potato genotypes, and 2044 proteins were quantified. Cluster analysis revealed MA and E14 clustered together separately from FA. The protein profile and related functions revealed that the cultivars shared a typical hypersensitive response to PI, including induction of elicitors, oxidative burst, and suppression of photosynthesis in the potato leaves. Meanwhile, MA and E14 deployed additional specific response mechanism different from FA, involving high induction of protease inhibitors, serine/threonine kinases, terpenoid, hormone signaling, and transport, which contributed to MA tolerance of LBD. Furthermore, inductions of pathogenesis-related proteins, LRR receptor-like kinases, mitogen-activated protein kinase, WRKY transcription factors, jasmonic acid, and phenolic compounds mediate E14 resistance against LBD. These proteins were confirmed at the transcription level by a quantitative polymerase chain reaction and at the translation level by western-blot. Conclusions We found several proteins that were differentially abundant among the cultivars, that includes common and cultivar specific proteins which highlighted similarities and significant differences between FA, MA, and E14 in terms of their defense response to PI. Here the specific accumulation of mitogen-activated protein kinase, Serine/threonine kinases, WRKY transcription played a positive role in E14 immunity against PI. The candidate proteins identified reported in this study will form the basis of future studies and may improve our understanding of the molecular mechanisms of late blight disease resistance in potato.
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- 2020
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7. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
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Tiantian Guo, Denghong Zhang, Yuzhe Zeng, Timothy Y. Huang, Huaxi Xu, and Yingjun Zhao
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Alzheimer’s disease ,Aβ ,Tau ,Microglia ,Astrocyte ,Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. Herein, we review recent progress with respect to Aβ- and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aβ-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. Although we have gained much towards understanding various aspects underlying this devastating neurodegenerative disorder, greater commitment towards research in molecular mechanism, diagnostics and treatment will be needed in future AD research.
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- 2020
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8. Correction: Wang et al. Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation. Molecules 2018, 23, 391
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Yiding Wang, Jing Zhang, Denghong Zhang, Huixiang Xiao, Shengwei Xiong, and Chunhong Huang
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n/a ,Organic chemistry ,QD241-441 - Abstract
The authors would like to correct an error in the original publication [...]
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- 2022
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9. Quantitative Proteomics of Potato Leaves Infected with Phytophthora infestans Provides Insights into Coordinated and Altered Protein Expression during Early and Late Disease Stages
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Chunfang Xiao, Jianhua Gao, Yuanxue Zhang, Zhen Wang, Denghong Zhang, Qiaoling Chen, Xingzhi Ye, Yi Xu, Guocai Yang, Lei Yan, Qun Cheng, Jiaji Chen, and Yanfen Shen
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late blight disease ,potato proteomics ,Phytophthora infestans ,Sarpo Mira ,early and late disease stages ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
In order to get a better understanding of protein association during Solanum tuberosum (cv. Sarpo Mira)–Phytophthora infestans incompatible interaction, we investigated the proteome dynamics of cv. Sarpo Mira, after foliar application of zoospore suspension from P. infestans isolate, at three key time-points: zero hours post inoculation (hpi) (Control), 48 hpi (EI), and 120 hpi (LI); divided into early and late disease stages by the tandem mass tagging (TMT) method. A total of 1229 differentially-expressed proteins (DEPs) were identified in cv. Sarpo Mira in a pairwise comparison of the two disease stages, including commonly shared DEPs, specific DEPs in early and late disease stages, respectively. Over 80% of the changes in protein abundance were up-regulated in the early stages of infection, whereas more DEPs (61%) were down-regulated in the later disease stage. Expression patterns, functional category, and enrichment tests highlighted significant coordination and enrichment of cell wall-associated defense response proteins during the early stage of infection. The late stage was characterized by a cellular protein modification process, membrane protein complex formation, and cell death induction. These results, together with phenotypic observations, provide further insight into the molecular mechanism of P. infestans resistance in potatos.
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- 2019
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10. Inactivation of Venom PLA2 Alleviates Myonecrosis and Facilitates Muscle Regeneration in Envenomed Mice: A Time Course Observation
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Huixiang Xiao, Haoran Li, Denghong Zhang, Yuanyuan Li, Shimin Sun, and Chunhong Huang
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varespladib ,muscle regeneration ,Deinagkistrodon acutus ,fibrosis ,Organic chemistry ,QD241-441 - Abstract
Snake venom is a complex cocktail of toxins which induces a series of clinical and pathophysiological manifestations in victims, including severe local tissue damage and systemic alterations. Deinagkistrodon acutus (D. acutus) ranks among the “big four” life-threatening venomous species in China, whose venom possesses strong myotoxicity and hematotoxicity that often lead to permanent disability or muscle atrophy. Varespladib, an inhibitor of mammalian phospholipase A2 (PLA2), has been recently reproposed as an effective antidote against snakebite envenomation. The present study aimed at evaluating the protective role of varespladib on muscle regeneration in envenomed mice. Mice were grouped and subjected to inoculation with D. acutus venom or a mixture of venom and varespladib or control vehicle in the gastrocnemius muscle. Local injuries including hemorrhage, myonecrosis, ulceration, and systemic damages including general dysfunction, visceral failure, and inflammatory responses were observed at 1, 3, 7, 14, and 21 days. The results indicated that most of the muscle myonecrosis and hemorrhage were alleviated by varespladib. Besides, the pretreated mice recovered rapidly with lesser atrophy and muscle fibrosis. In conclusion, the findings of the present study suggested that varespladib is an effective antidote that could neutralize D. acutus venom and allow for earlier and improved rehabilitation outcome.
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- 2018
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11. Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation
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Yiding Wang, Jing Zhang, Denghong Zhang, Huixiang Xiao, Shengwei Xiong, and Chunhong Huang
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antivenom ,myotoxicity ,phospholipase A2 ,varespladib ,Organic chemistry ,QD241-441 - Abstract
Phospholipase A2s (PLA2) is a major component of snake venom with diverse pathologic toxicities and, therefore, a potential target for antivenom therapy. Varespladib was initially designed as an inhibitor of mammal PLA2s, and was recently repurposed to a broad-spectrum inhibitor of PLA2 in snake venom. To evaluate the protective abilities of varespladib to hemorrhage, myonecrosis, and systemic toxicities that are inflicted by different crude snake venoms, subcutaneous ecchymosis, muscle damage, and biochemical variation in serum enzymes derived from the envenomed mice were determined, respectively. Varespladib treatment showed a significant inhibitory effect to snake venom PLA2, which was estimated by IC50 in vitro and ED50 in vivo. In animal models, the severely hemorrhagic toxicity of D. acutus and A. halys venom was almost fully inhibited after administration of varespladib. Moreover, signs of edema in gastrocnemius muscle were remarkably attenuated by administration of varespladib, with a reduced loss of myonecrosis and desmin. Serum levels of creatine kinase, lactate dehydrogenase isoenzyme 1, aspartate transaminase, and alanine transaminase were down-regulated after treatment with varespladib, which indicated the protection to viscera injury. In conclusion, varespladib may be a potential first-line drug candidate in snakebite envenomation first aid or clinical therapy.
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- 2018
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12. A Case of Löffler Endocarditis Complicated with Listeria Sepsis
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Fengyou, Yao, Shilan, Liu, Qian, Yu, Luyong, Huang, Denghong, Zhang, Yong, Li, Mingjian, Lang, and Jingjing, Hu
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Endocarditis ,Listeria ,Sepsis ,Humans ,Endocarditis, Bacterial - Published
- 2022
13. Downregulating PTBP1 fails to convert astrocytes into hippocampal neurons and to alleviate symptoms in Alzheimer’s mouse models
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Tiantian Guo, Xinjia Pan, Guangtong Jiang, Denghong Zhang, Jinghui Qi, Lin Shao, Zhanxiang Wang, Huaxi Xu, and Yingjun Zhao
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nervous system ,General Neuroscience ,Research Articles - Abstract
Conversion of astroglia into functional neurons has been considered a promising therapeutic strategy for neurodegenerative diseases. Recent studies reported that downregulation of the RNA binding protein, polypyrimidine tract-binding protein 1 (PTBP1), converts astrocytes into neurons in situ in multiple mouse brain regions, consequently improving pathologic phenotypes associated with Parkinson's disease, RGC loss, and aging. Here, we demonstrate that PTBP1 downregulation using an astrocyte-specific AAV-mediated shRNA system fails to convert hippocampal astrocytes into neurons in both male and female wild-type (WT) and β-amyloid (5×FAD) and tau (PS19) Alzheimer's disease (AD) mouse models and fails to reverse synaptic/cognitive deficits and AD-associated pathology in male mice. Similarly, PTBP1 downregulation cannot convert astrocytes into neurons in the striatum and substantia nigra in both male and female WT mice. Together, our study suggests that cell fate conversion strategy for neurodegenerative disease therapy through manipulating one single gene, such as PTBP1, warrants more rigorous scrutiny. SIGNIFICANCE STATEMENT Our results do not support some of the recent extraordinary and revolutionary claims that resident astrocytes can be directly and efficiently converted into neurons. Our study is critical for the field of neural regeneration and degeneration. In addition, our study is financially important because it may prevent other researchers/organizations from wasting a vast amount of time and resources on relevant investigations.
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- 2022
14. Real optical imaging simulation of laser-produced aluminum plasmas
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Siqi He, Qi Min, Maogen Su, Haidong Lu, Yanhong Wu, Shiquan Cao, Duixiong Sun, Denghong Zhang, and Chenzhong Dong
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Atomic and Molecular Physics, and Optics - Abstract
We developed a post-processing optical imaging model based on two-dimensional axisymmetric radiation hydrodynamics. Simulation and program benchmarks were performed using laser-produced Al plasma optical images obtained via transient imaging. The emission profiles of a laser-produced Al plasma plume in air at atmospheric pressure were reproduced, and the influence of plasma state parameters on radiation characteristics were clarified. In this model, the radiation transport equation is solved on the real optical path, which is mainly used to study the radiation of luminescent particles during plasma expansion. The model outputs consist of the electron temperature, particle density, charge distribution, absorption coefficient, and corresponding spatio-temporal evolution of the optical radiation profile. The model helps with understanding element detection and quantitative analysis of laser-induced breakdown spectroscopy.
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- 2023
15. Treatment of atrial fibrillation with third-degree atrioventricular block by pacing His bundle and left bundle branch
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Denghong Zhang and Xiaoming Huang
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Bundle of His ,left bundle branch pacing ,medicine.medical_specialty ,Cardiac pacing ,medicine.medical_treatment ,Cardiac resynchronization therapy ,third degree atrioventricular block ,Cardiac Resynchronization Therapy ,03 medical and health sciences ,0302 clinical medicine ,His bundle pacing ,Internal medicine ,Atrial Fibrillation ,Left bundle branch ,medicine ,Humans ,Clinical Case Report ,030212 general & internal medicine ,Atrioventricular Block ,Aged ,business.industry ,Third-degree atrioventricular block ,Atrial fibrillation ,General Medicine ,medicine.disease ,030220 oncology & carcinogenesis ,Bundle ,Heart failure ,Cardiology ,Female ,business ,Atrioventricular block ,Research Article - Abstract
Introduction: Substantial advances in cardiac pacing technology have been developed in the past decades. However, efforts to improve pacing technology to achieve physiological electrical activity, such as with cardiac resynchronization therapy, are underway. Permanent His bundle pacing, which directly stimulates the His-Purkinje network and electrically activates both ventricles, simulates physiological electric activity in the heart, and has been considered an ideal pacing strategy to treat arrhythmias. For patients with atrial fibrillation complicated by third-degree atrioventricular block (AVB), permanent His bundle pacing is a better option than conventional right ventricular apical or septal pacing, the latter of which may be associated with risks, such as heart failure. However, His bundle pacing exhibits some shortcomings, including elevated pacing threshold, dislocation, and abnormal sensing. Case presentation: A 69-year-old female patient who had atrial fibrillation (AF) complicated by third-degree AVB and who was treated with permanent His bundle pacing combined with left bundle branch pacing. Diagnosis: AF complicated by third-degree AVB. Interventions: We used the left bundle branch as a backup pacing site to overcome any shortcomings related to permanent His bundle pacing. Outcomes: The patient recovered well without any events. Conclusion: We selected His bundle pacing as the primary pacing, but also used left bundle branch pacing as a backup approach. If His bundle pacing results in an increased sensing threshold, pacing threshold changes, or dislocations, left bundle branch pacing can compensate for dysfunction of permanent deficiencies in His bundle pacing, preserving physiological pacing.
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- 2020
16. Effects of electron correlation and the Breit interaction on one- and two-electron one-photon transitions in double K hole states of He-like ions (10 ≤ Z ≤ 47)*
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Chenzhong Dong, Deyang Yu, Mingxin Cao, Xiaobin Ding, Denghong Zhang, Cunqiang Wu, Yingli Xue, and Mingwu Zhang
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Physics ,Photon ,Electronic correlation ,Atomic Physics (physics.atom-ph) ,Computer Science::Information Retrieval ,FOS: Physical sciences ,General Physics and Astronomy ,Electron ,Atomic physics ,Physics - Atomic Physics ,Ion - Abstract
The x-ray energies and transition rates associated with single and double electron radiative transitions from the double K hole state $2s2p$ to the $1s2s$ and $1s^{2}$ configurations of 11 He-like ions ($10\!\leq\!Z\!\leq\!47$) are evaluated using the fully relativistic multi-configuration Dirac-Fock method. An appropriate electron correlation model is constructed with the aid of the active space method, which allows the electron correlation effects to be studied efficiently. The contributions of electron correlation and the Breit interaction to the transition properties are analyzed in detail. It is found that the two-electron one-photon (TEOP) transition is correlation sensitive. The Breit interaction and electron correlation both contribute significantly to the radiative transition properties of the double K hole state of He-like ions. Good agreement between the present calculation and previous work is achieved. The calculated data will be helpful to future investigations on double K hole decay processes of He-like ions., 9 pages, 2 figures and 4 tables
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- 2020
17. Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation
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Jing Zhang, Huixiang Xiao, Denghong Zhang, Chunhong Huang, Yiding Wang, and Shengwei Xiong
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0301 basic medicine ,Indoles ,Antivenom ,Ecchymosis ,Pharmaceutical Science ,Snake Bites ,Venom ,Pharmacology ,Acetates ,Analytical Chemistry ,chemistry.chemical_compound ,Mice ,Drug Discovery ,Medicine ,Edema ,Creatine Kinase ,biology ,Antivenins ,Alanine Transaminase ,Keto Acids ,Isoenzymes ,Chemistry (miscellaneous) ,Snake venom ,Molecular Medicine ,Female ,antivenom ,myotoxicity ,phospholipase A2 ,varespladib ,Phospholipase A2 Inhibitors ,Myotoxin ,Aspartate transaminase ,complex mixtures ,Article ,lcsh:QD241-441 ,03 medical and health sciences ,lcsh:Organic chemistry ,Crotalid Venoms ,Animals ,Aspartate Aminotransferases ,Physical and Theoretical Chemistry ,Envenomation ,Muscle, Skeletal ,L-Lactate Dehydrogenase ,business.industry ,Organic Chemistry ,Phospholipases A2 ,030104 developmental biology ,chemistry ,Alanine transaminase ,biology.protein ,Varespladib ,business ,Crotalinae - Abstract
Phospholipase A2s (PLA2) is a major component of snake venom with diverse pathologic toxicities and, therefore, a potential target for antivenom therapy. Varespladib was initially designed as an inhibitor of mammal PLA2s, and was recently repurposed to a broad-spectrum inhibitor of PLA2 in snake venom. To evaluate the protective abilities of varespladib to hemorrhage, myonecrosis, and systemic toxicities that are inflicted by different crude snake venoms, subcutaneous ecchymosis, muscle damage, and biochemical variation in serum enzymes derived from the envenomed mice were determined, respectively. Varespladib treatment showed a significant inhibitory effect to snake venom PLA2, which was estimated by IC50 in vitro and ED50 in vivo. In animal models, the severely hemorrhagic toxicity of D. acutus and A. halys venom was almost fully inhibited after administration of varespladib. Moreover, signs of edema in gastrocnemius muscle were remarkably attenuated by administration of varespladib, with a reduced loss of myonecrosis and desmin. Serum levels of creatine kinase, lactate dehydrogenase isoenzyme 1, aspartate transaminase, and alanine transaminase were down-regulated after treatment with varespladib, which indicated the protection to viscera injury. In conclusion, varespladib may be a potential first-line drug candidate in snakebite envenomation first aid or clinical therapy.
- Published
- 2018
18. Genome-Wide Identification of Early-Firing Human Replication Origins by Optical Replication Mapping
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David M. Gilbert, Saki Chan, Zhiping Weng, Alex Hastie, Denghong Zhang, Chun-Long Chen, Weitao Wang, Nicholas Rhind, Kyle N. Klein, and Tyler M. Borrman
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Genetics ,0303 health sciences ,Replication timing ,DNA replication ,Genomics ,Biology ,Origin of replication ,Genome ,Replication (computing) ,03 medical and health sciences ,0302 clinical medicine ,Evolutionary biology ,Replication Initiation ,030220 oncology & carcinogenesis ,ORC1 ,030304 developmental biology - Abstract
The timing of DNA replication is largely regulated by the location and timing of replication origin firing. Therefore, much effort has been invested in identifying and analyzing human replication origins. However, the heterogeneous nature of eukaryotic replication kinetics and the low efficiency of individual origins in metazoans has made mapping the location and timing of replication initiation in human cells difficult. We have mapped early-firing origins in HeLa cells using Optical Replication Mapping, a high-throughput single-molecule approach based on Bionano Genomics genomic mapping technology. The single-molecule nature and 290-fold coverage of our dataset allowed us to identify origins that fire with as little as 1% efficiency. We find sites of human replication initiation in early S phase are not confined to well-defined efficient replication origins, but are instead distributed across broad initiation zones consisting of many inefficient origins. These early-firing initiation zones co-localize with initiation zones inferred from Okazaki-fragment-mapping analysis and are enriched in ORC1 binding sites. Although most early-firing origins fire in early-replication regions of the genome, a significant number fire in late-replicating regions, suggesting that the major difference between origins in early and late replicating regions is their probability of firing in early S-phase, as opposed to qualitative differences in their firing-time distributions. This observation is consistent with stochastic models of origin timing regulation, which explain the regulation of replication timing in yeast.
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- 2017
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19. IκB kinase ε and TANK-binding kinase 1 activate AKT by direct phosphorylation
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Bin Zhao, Xiaoduo Xie, Kun-Liang Guan, Denghong Zhang, Cun-Yu Wang, Gianluigi Condorelli, Ming You, and Min Kan Lu
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Multidisciplinary ,TANK-binding kinase 1 ,Akt/PKB signaling pathway ,I-Kappa-B Kinase ,Phosphorylation ,Biology ,Protein kinase A ,Protein kinase B ,mTORC2 ,PI3K/AKT/mTOR pathway ,Cell biology - Abstract
AKT activation requires phosphorylation of the activation loop (T308) by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and the hydrophobic motif (S473) by the mammalian target of rapamycin complex 2 (mTORC2). We recently observed that phosphorylation of the AKT hydrophobic motif was dramatically elevated, rather than decreased, in mTOR knockout heart tissues, indicating the existence of other kinase(s) contributing to AKT phosphorylation. Here we show that the atypical IκB kinase ε and TANK-binding kinase 1 (IKKε/TBK1) phosphorylate AKT on both the hydrophobic motif and the activation loop in a manner dependent on PI3K signaling. This dual phosphorylation results in a robust AKT activation in vitro. Consistently, we found that growth factors can induce AKT (S473) phosphorylation in Rictor −/− cells, and this effect is insensitive to mTOR inhibitor Torin1. In IKKε/TBK1 double-knockout cells, AKT activation by growth factors is compromised. We also observed that TBK1 expression is elevated in the mTOR knockout heart tissues, and that TBK1 is required for Ras-induced mouse embryonic fibroblast transformation. Our observations suggest a physiological function of IKKε/TBK1 in AKT regulation and a possible mechanism of IKKε/TBK1 in oncogenesis by activating AKT.
- Published
- 2011
20. MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice
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Denghong, Zhang, Riccardo, Contu, Michael V G, Latronico, Jianlin, Zhang, Jian Ling, Zhang, Roberto, Rizzi, Daniele, Catalucci, Shigeki, Miyamoto, Katherine, Huang, Marcello, Ceci, Yusu, Gu, Nancy D, Dalton, Kirk L, Peterson, Kun-Liang, Guan, Joan Heller, Brown, Ju, Chen, Nahum, Sonenberg, and Gianluigi, Condorelli
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Cardiomyopathy, Dilated ,Male ,Cardiac function curve ,medicine.medical_specialty ,Cell Survival ,Apoptosis ,Cardiomegaly ,Cell Cycle Proteins ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,Mice ,Clinical investigation ,Internal medicine ,Eukaryotic initiation factor ,Animals ,Myocyte ,Medicine ,Initiation factor ,Myocytes, Cardiac ,Eukaryotic Initiation Factors ,Phosphorylation ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,Pressure overload ,biology ,business.industry ,Cell growth ,Myocardium ,TOR Serine-Threonine Kinases ,Autophagy ,Proteins ,Heart ,General Medicine ,Phosphoproteins ,Cell biology ,Mice, Inbred C57BL ,Endocrinology ,Multiprotein Complexes ,Cardiology ,biology.protein ,Female ,Carrier Proteins ,Corrigendum ,business ,Transcription Factors ,Research Article - Abstract
Mechanistic target of rapamycin (MTOR) plays a critical role in the regulation of cell growth and in the response to energy state changes. Drugs inhibiting MTOR are increasingly used in antineoplastic therapies. Myocardial MTOR activity changes during hypertrophy and heart failure (HF). However, whether MTOR exerts a positive or a negative effect on myocardial function remains to be fully elucidated. Here, we show that ablation of Mtor in the adult mouse myocardium results in a fatal, dilated cardiomyopathy that is characterized by apoptosis, autophagy, altered mitochondrial structure, and accumulation of eukaryotic translation initiation factor 4E–binding protein 1 (4E-BP1). 4E-BP1 is an MTOR-containing multiprotein complex-1 (MTORC1) substrate that inhibits translation initiation. When subjected to pressure overload, Mtor-ablated mice demonstrated an impaired hypertrophic response and accelerated HF progression. When the gene encoding 4E-BP1 was ablated together with Mtor, marked improvements were observed in apoptosis, heart function, and survival. Our results demonstrate a role for the MTORC1 signaling network in the myocardial response to stress. In particular, they highlight the role of 4E-BP1 in regulating cardiomyocyte viability and in HF. Because the effects of reduced MTOR activity were mediated through increased 4E-BP1 inhibitory activity, blunting this mechanism may represent a novel therapeutic strategy for improving cardiac function in clinical HF.
- Published
- 2010
21. Abstract 203: Protein Synthesis Inhibitors 4E-BPs Regulate Cardiac Function
- Author
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Denghong Zhang, Riccardo Contu, Michael Latronico, Kirk Peterson, Ju Chen, and Gianluigi Condorelli
- Subjects
Physiology ,Cardiology and Cardiovascular Medicine - Abstract
Rationale: mTOR regulates cardiac functionality and hypertrophy. We have shown that cardiac-specific deletion of mTOR induces fatal dilated cardiomyopathy. This model of heart failure is characterized biochemically by accumulation of the mTOR substrate 4E-BP1, which inhibits protein synthesis through the regulation of translation initiation. Deletion of the 4E-BP1 gene, Eif4ebp1, in mTOR-KO mice significantly, albeit partially, improved cardiac function and survival. Objective: To investigate the role of the 4E-BP family in the heart by determining whether absence of its members improves cardiac function in different models of heart failure. Methods and Results: In the absence of Eif4ebp1, cardiac expression of the 4E-BP2 homolog increases strikingly. Deletion of Eif4ebp2 along with Eif4ebp1 (4E-BP1/4E-BP2-dKO mice) abrogated the negative effects of the loss of mTOR on cardiac function, and led to a further significant improvement in survival rate. Moreover, when 4E-BP1/4E-BP2-dKO mice where subjected to pressure-overload stress, cardiac function and survival were significantly improved compared with similarly treated control mice. The hypertrophic response to pressure overload in these mice was not affected by the absence of 4E-BPs. Conclusions: Our data indicate that 4E-BPs are responsible for an important part of mTOR effects on cardiac function, further strengthening the concept that the regulation of mRNA translation profoundly affects cardiac inotropism under stress.
- Published
- 2012
22. IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation
- Author
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Xiaoduo, Xie, Denghong, Zhang, Bin, Zhao, Min-Kan, Lu, Ming, You, Gianluigi, Condorelli, Cun-Yu, Wang, and Kun-Liang, Guan
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Mice, Knockout ,Myocardium ,Amino Acid Motifs ,Mutation, Missense ,Fibroblasts ,Protein Serine-Threonine Kinases ,Biological Sciences ,I-kappa B Kinase ,Enzyme Activation ,Mice ,Cell Transformation, Neoplastic ,HEK293 Cells ,Rapamycin-Insensitive Companion of mTOR Protein ,Amino Acid Substitution ,Trans-Activators ,Animals ,Humans ,Naphthyridines ,Phosphorylation ,Carrier Proteins ,Proto-Oncogene Proteins c-akt ,HeLa Cells ,Transcription Factors - Abstract
AKT activation requires phosphorylation of the activation loop (T308) by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and the hydrophobic motif (S473) by the mammalian target of rapamycin complex 2 (mTORC2). We recently observed that phosphorylation of the AKT hydrophobic motif was dramatically elevated, rather than decreased, in mTOR knockout heart tissues, indicating the existence of other kinase(s) contributing to AKT phosphorylation. Here we show that the atypical IκB kinase ε and TANK-binding kinase 1 (IKKε/TBK1) phosphorylate AKT on both the hydrophobic motif and the activation loop in a manner dependent on PI3K signaling. This dual phosphorylation results in a robust AKT activation in vitro. Consistently, we found that growth factors can induce AKT (S473) phosphorylation in Rictor(-/-) cells, and this effect is insensitive to mTOR inhibitor Torin1. In IKKε/TBK1 double-knockout cells, AKT activation by growth factors is compromised. We also observed that TBK1 expression is elevated in the mTOR knockout heart tissues, and that TBK1 is required for Ras-induced mouse embryonic fibroblast transformation. Our observations suggest a physiological function of IKKε/TBK1 in AKT regulation and a possible mechanism of IKKε/TBK1 in oncogenesis by activating AKT.
- Published
- 2011
23. 1KB kinase ϵ and TANK-binding kinase 1 activate AKT by direct phosphorylation.
- Author
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Xiaoduo Xie, Denghong Zhang, Bin Zhao, Min-Kan Lu, Ming You, Condorelli, Gianluigi, Cun-Yu Wang, and Kun-Liang Guan
- Subjects
- *
PROTEIN kinases , *PHOSPHORYLATION , *RAPAMYCIN , *CARCINOGENESIS , *CANCER treatment - Abstract
AKT activation requires phosphorylation of the activation loop (T308) by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and the hydrophobic motif (S473) by the mammalian target of rapamycin complex 2 (mTORC2). We recently observed that phosphorylation of the AKT hydrophobic motif was dramatically elevated, rather than decreased, in mTOR knockout heart tissues, indicating the existence of other kinase(s) contributing to AKT phosphorylation. Here we show that the atypical IκB kinase ϵ and TANK-binding kinase 1 (IKKϵ/TBK1) phosphorylate AKT on both the hydrophobic motif and the activation loop in a manner dependent on PI3K signaling. This dual phosphorylation results in a robust AKT activation in vitro. Consistently, we found that growth factors can induce AKT (S473) phosphorylation in Rictor-/- cells, and this effect is insensitive to mTOR inhibitor Torini. In IKKϵ/TBK1 double-knock-out cells, AKT activation by growth factors is compromised. We also observed that TBK1 expression is elevated in the mTOR knockout heart tissues, and that TBK1 is required for Ras-induced mouse embryonic fibroblast transformation. Our observations suggest a physiological function of IKKϵ/TBK1 in AKT regulation and a possible mechanism of IKKϵ/TBK1 in oncogenesis by activating AKT. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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