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Base-flipping dynamics from an intrahelical to an extrahelical state exerted by thymine DNA glycosylase during DNA repair process

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Base-flipping dynamics from an intrahelical to an extrahelic...

Distribution of per-and polyfluoroalkyl substances in blood,serum,and urine of patients with liver cancer and associations with liver function biomarkers

中国生物化学与分子生物学会2019年全国学术会议暨学会...

作者： lin-tai da Jin Yu Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Center for Systems Biomedicine Shanghai JiaoTong University Beijing Computational Science Research Center

Thymine DNA glycosylase(TDG) is a DNA repair enzyme that excises a variety of mismatched or damaged nucleotides(nt), e.g., dU, dT, 5 fC, and 5 caC. TDG is shown to play essential roles in maintaining genome integrity and correctly programming epigenetic modifications through DNA demethylation. After locating the lesion sites, TDG employs a base-flipping strategy to recognize the damaged nucleobases, thereby the interrogated nt is extruded from the DNA helical stack and binds into the TDG active site. The dynamic mechanism of the base-flipping process at an atomistic level, however, remains elusive and challenging to be probed by current experimental techniques. Here, we employed the Markov State Model(MSM) constructed from extensive all-atom molecular dynamics(MD) simulations to reveal the base-flipping mechanism in the presence of TDG at tens of microsecond timescales. We capture several critical intermediate states of the mispaired dT nt during its extrusion process and identify several key TDG residues that are directly involved in the inter-state transitions. Moreover, our studies reveal the atomistic-level details of how TDG participates in sculpturing the DNA backbone and penetrates into the DNA minor groove. Notably, our comparative simulations of the naked and TDG-bound DNA systems indicate that the key intercalated residue Arg275 is critical to stabilize the partially flipped nt by forming a cation-π interaction, most likely via an active recognition scenario. The subsequent base eversion process is shown to be actively promoted by TDG. Finally, we extended our studies to three additional TDG substrates(dU, 5 fC, and 5 caC) to evaluate the substituent effects of various chemical modifications of the pyrimidine rings on the base-flipping dynamics.

关键词： DNA repair molecular dynamics simulations Markov state model

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Journal of Environmental Sciences 2024年第5期139卷 418-427页

作者： Cao dai lin Peng Yanjie Li Zhendong Li da Chen Fei Wang Nan lin Department of Hepatobiliary Surgery The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630China School of Environment Guangdong Key Laboratory of Environmental Pollution and HealthJinan UniversityGuangzhou 510632China State Key Laboratory of Environmental and Biological Analysis Department of ChemistryHong Kong Baptist UniversityHong Kong 999077China South China Institute of Environmental Sciences MEEGuangzhou 510655China

Studies have shown that per-and polyfluoroalkyl substances(PFASs)may be hepatotoxic in animals or humans.However,data on clinical epidemiology are very limited.In this study,21PFASs were determined in patients with liver diseases,with the highest median concentrations detected in the serum sample(26.7 ng/mL),followed by blood(10.7 ng/mL)and urine(5.02 ng/mL).Higher total PFAS concentrations were found in hepatocellular carcinoma(HCC)patients compared to non-HCC patients,with significant discrepancies in serum and blood samples.Besides,significant correlations were also found among PFAS concentrations and age,gender,body mass index(BMI),and liver function biomarkers levels.For example,PFAS concentrations are significantly higher in males than in females;Several serum PFASs concentrations increase with age and BMI,while the serum perfluorohexane sulfonic acid(PFHxS)concentrations are negatively correlated with age.In addition,multiple regression models adjusted for age,gender and BMI found that increased serum perfluorobutane sulfonic acid(PFBS),perfluoroheptane sulfonic acid(PFHpS)and perfluorohexylphosphonic acid(PFHxPA)conentrations are correlated with elevated alkaline phosphatase(ALP),aspartate aminotransferase(AST),and alpha-fetoprotein(AFP)(plinical hepatotoxicity of PFAS.

关键词： Per-and polyfluoroalkyl substances(PFASs) Liver cancer Serum Blood Urine Liver function biomarkers

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Meibomian glands segmentation in infrared images with limited annotation

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International Journal of Ophthalmology(English edition) 2024年第3期17卷 401-407页

作者： Jia-Wen lin ling-Jie lin Feng Lu tai-Chen Lai Jing Zou lin-ling Guo Zhi-Ming lin Li Li College of Computer and data Science Fuzhou UniversityFuzhou 350108Fujian ProvinceChina Fujian Provincial Key Laboratory of Networking Computing and Intelligent Information Processing Fuzhou UniversityFuzhou 350108Fujian ProvinceChina Shengli Clinical Medical College of Fujian Medical University Fuzhou 350001Fujian ProvinceChina Department of Ophthalmology Fujian Provincial Hospital South BranchFujian Provincial HospitalFuzhou 350001Fujian ProvinceChina

●AIM:To investigate a pioneering framework for the segmentation of meibomian glands(MGs),using limited annotations to reduce the workload on ophthalmologists and enhance the efficiency of clinical diagnosis.●METHODS:Totally 203 infrared meibomian images from 138 patients with dry eye disease,accompanied by corresponding annotations,were gathered for the study.A rectified scribble-supervised gland segmentation(RSSGS)model,incorporating temporal ensemble prediction,uncertainty estimation,and a transformation equivariance constraint,was introduced to address constraints imposed by limited supervision information inherent in scribble annotations.The viability and efficacy of the proposed model were assessed based on accuracy,intersection over union(IoU),and dice coefficient.●RESULTS:Using manual labels as the gold standard,RSSGS demonstrated outcomes with an accuracy of 93.54%,a dice coefficient of 78.02%,and an IoU of 64.18%.Notably,these performance metrics exceed the current weakly supervised state-of-the-art methods by 0.76%,2.06%,and 2.69%,respectively.Furthermore,despite achieving a substantial 80%reduction in annotation costs,it only lags behind fully annotated methods by 0.72%,1.51%,and 2.04%.●CONCLUSION:An innovative automatic segmentation model is developed for MGs in infrared eyelid images,using scribble annotation for training.This model maintains an exceptionally high level of segmentation accuracy while substantially reducing training costs.It holds substantial utility for calculating clinical parameters,thereby greatly enhancing the diagnostic efficiency of ophthalmologists in evaluating meibomian gland dysfunction.

关键词： infrared meibomian glands images meibomian gland dysfunction meibomian glands segmentation weak supervision scribbled annotation

Integrability and solutions of a nonsymmetric discrete Korteweg-de Vries equation

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Communications in Theoretical Physics 2024年第2期76卷 45-50页

作者： Maebel Mesfun da-jun Zhang Song-lin Zhao Department of Mathematics Shanghai UniversityShanghai 200444China Newtouch Center for Mathematics of Shanghai University Shanghai 200444China Department of Applied Mathematics Zhejiang University of TechnologyHangzhou 310023China

In this paper,we present Lax pairs and solutions for a nonsymmetric lattice equation,which is a torqued version of the lattice potential Korteweg-de Vries equation.This nonsymmetric equation is special in the sense that it contains only one spacing parameter but consists of two consistent cubes with other integrable lattice equations.Using such a multidimensionally consistent property we are able to derive its two Lax pairs and also construct solutions using B?cklund transformations.

关键词： discrete Korteweg-de Vries equation nonsymmetric multi-dimensional consistency Backlund transformation solution

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Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance

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中华医学杂志(英文版) 2024年第7期137卷 859-870页

作者： Wang Xianlong Zhao Chuan lin Jincheng Liu Hongxing Zeng Qiuhong Chen Huadong Wang Ye Xu dapeng Chen Wen Xu Moping Zhang En lin da lin Zhixiong Sanbo Brain Hospital Capital Medical University Beijing 100093 Department of Bioinformatics School of Medical Technology and Engineering Key Laboratory of Medical Bioinformatics Key Laboratory of Ministry of Education for Gastrointestinal Cancer Fujian Medical University Fuzhou Fujian 350122 China Department of Neurosurgery

Background: Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies.Methods: Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively.Results: Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/β-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox,P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group (P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB (P = 0.01).Conclusions: ACP comprises three molecular subtypes with disti

关键词： Craniopharyngioma Central nervous system tumor Precision medicine beta Catenin Proto-Oncogene Proteins B-raf

Regulatory Role of One Critical Catalytic Loop of Polypeptide N-Acetyl-Galactosaminyltransferase-2 in Substrate Binding and Catalysis during Mucin-Type O-Glycosylation

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Regulatory Role of One Critical Catalytic Loop of Polypeptid...

Intra-thyroid esophageal duplication cyst:A case report

2020年糖科学青年科技论坛

作者： Jiaqi Tian Feng Liu Zhijue Xu Jingjing Shi Tao Liang Yan Zhang lin-tai da Key Laboratory of Systems Biomedicine （Ministry of Education） Shanghai Center for Systems BiomedicineShanghai Jiao Tong University

One of the dominant post-translational modifications in mammals is mucin-type（GalNAc-type）O-glycosylation initiated by polypeptide N-acetyl-galactosaminyltransferases（ppGalNAc-Ts）,which is closely associated with many physiological and pathological conditions.An atomic-level understanding of the structural dynamics of one critical catalytic loop in ppGalNAc-Ts from an open to a closed state upon substrate binding,however,is still elusive.Here,by constructing a Markov state model based on extensive all-atom molecular dynamics（MD） simulations with an aggregated simulation time of ～20 μs,we reveal,at atomistic resolution,the key metastable states of the catalytic loop in ppGalNAc-T2 during its closing/opening dynamics after donor substrate（UDP-GalNAc） binding [1].The overall catalytic-loop closing motion is estimated to take place at a timescale of ～tens of μs,with the rate-limiting transition caused by some critical structural rearrangements within the catalytic loop region,coupled with the desolvation process.We find that the presence of UDP-GalNAc facilitates the formation of a stable interaction network with several non-loop residues（i.e.,L204,V330,H145,and W331）,which in turn promotes the loop closing.Moreover,the functional roles of several critical active-site residues were further evaluated through combining site-directed mutagenesis,high-performance liquid chromatography,MS/MS,and mutant MD simulations.It is intriguing to observe that the UDP-GalNAc binding and the following catalysis can tolerate all the tested loop-residue substitutions,some can even profoundly enhance the enzyme efficacy（i.e.,H365 A and F377 A）.More importantly,the catalytic loop is found to play a decisive role in regulating the glycosylation-site preferences.Our work provides the structural basis for the key regulatory factors that dictate the substrate loading and following catalysis during mucin-type O-glycosylation.

关键词： ppGalNAc-T2 Closing/opening dynamics Molecular dynamics simulations Markov state model

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World Journal of Clinical Cases 2024年第13期12卷 2231-2236页

作者： Hong-Guo lin Ming Liu Xue-Yang Huang da-Sheng Liu Department of Vascular Thyroid Surgery The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510006Guangdong ProvinceChina

BACKGROUND Esophageal cysts are relatively rare in clinical practice,with most of the literature comprising case reports.Esophageal cysts protruding into the thyroid gland are easily misdiagnosed as thyroid tumors.No such cases have been reported so far.CASE SUMMARY This article reports the case of a 31-year-old adult male diagnosed with thyroid nodules before admission.The patient underwent left thyroidectomy and isthmusectomy.During the surgery,esophageal cysts were identified in the esophageal muscle and thyroid glands.The pathology results confirmed a nodular goiter combined with esophageal cysts.Postoperatively,the patient developed a neck infection and underwent another operation and broad-spectrum antibiotic treatment for recovery.CONCLUSION We report the first clinical case of an esophageal cyst located within the thyroid gland that was successfully treated surgically.Esophageal cyst located within the thyroid gland cause difficulties in diagnosis.In the present study,the contents of the esophageal cysts were calcified foci,and a small amount of fluid mixture,which were easily misdiagnosed as thyroid nodules and misled the surgical methods.

关键词： Esophageal cysts Thyroid Diagnosed Surgery Case report

Associations between remnant cholesterol levels and mortality in patients with diabetes

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World Journal of Diabetes 2024年第4期15卷 712-723页

作者： Deng Pan lin Xu Li-Xiao Zhang da-Zhuo Shi Ming Guo Department of Cardiovascular Xiyuan Hospital of China Academy of Chinese Medical SciencesBeijing 100091China Graduate School Beijing University of Chinese MedicineBeijing 100020China National Clinical Research Center for Chinese Medicine Cardiology Xiyuan Hospital of China Academy of Chinese Medical SciencesBeijing 100091China Gynecological Department of Traditional Chinese Medicine China-Japan Friendship HospitalBeijing 100020China

BACKGROUND Dyslipidemia is frequently present in patients with diabetes.The associations of remnant cholesterol and mortality remains unclear in patients with diabetes.AIM To explore the associations of remnant cholesterol with all-cause and cardiovas-cular mortality in patients with diabetes.METHODS This prospective cohort study included 4740 patients with diabetes who par-ticipated in the National Health and Nutrition Examination Survey from 1999 through 2018.Remnant cholesterol was used as the exposure variable,and all-cause and cardiovascular mortality were considered outcome events.Outcome data were obtained from the National Death Index,and all participants were followed from the interview date until death or December 31,2019.Multivariate proportional Cox regression models were used to explore the associations between exposure and outcomes,in which remnant cholesterol was modeled as both a categorical and a continuous variable.Restricted cubic splines(RCSs)were calculated to assess the nonlinearity of associations.Subgroup(stratified by sex,age,body mass index,and duration of diabetes)and a series of sensitivity analyses were performed to evaluate the robustness of the associations.RESULTS During a median follow-up duration of 83 months,1370 all-cause deaths and 389 cardiovascular deaths were documented.Patients with remnant cholesterol levels in the third quartile had a reduced risk of all-cause mortality[hazard ratio(HR)95%confidence interval(CI):0.66(0.52-0.85)];however,when remnant cholesterol was modeled as a continuous variable,it was associated with increased risks of all-cause[HR(95%CI):1.12(1.02-1.21)per SD]and cardiovascular[HR(95%CI):1.16(1.01-1.32),per SD]mortality.The RCS demonstrated nonlinear associations of remnant cholesterol with all-cause and cardiovascular mortality.Subgroup and sensitivity analyses did not reveal significant differences from the above results.CONCLUSION In patients with diabetes,higher remnant cholesterol was associated with increased risks of all-cause and cardiovascul

关键词： Diabetes Remnant cholesterol Mortality Cardiovascular National Health and Nutrition Examination Survey

Millisecond dynamics of colloidal suspension studied by X-ray photon correlation spectroscopy at the Shanghai Synchrotron Radiation Facility

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Nuclear Science and Techniques 2024年第1期35卷 1-9页

作者： Chen-Hui Cui Zi-Mu Zhou lin-Feng Wei Song-lin Li Feng Tian Xiu-Hong Li Zhi Guo Yi-Hui Xu Huai-Dong Jiang Ren-Zhong tai Shanghai Synchrotron Radiation Facility Shanghai Advanced Research InstituteChinese Academy of SciencesShanghai 201204China School of Physical Science and Technology ShanghaiTech UniversityShanghai 201210China Shanghai Institute of Applied Physics Chinese Academy of SciencesShanghai 201800China University of Chinese Academy of Sciences Chinese Academy of SciencesBeijing 100049China Center for Transformative Science ShanghaiTech UniversityShanghai 201210China

X-ray photon correlation spectroscopy(XPCS)has emerged as a powerful tool for probing the nanoscale dynamics of soft condensed matter and strongly correlated materials owing to its high spatial resolution and penetration capabilities.This technique requires high brilliance and beam coherence,which are not directly available at modern synchrotron beamlines in China.To facilitate future XPCS experiments,we modified the optical setup of the newly commissioned BL10U1 USAXS beamline at the Shanghai Synchrotron Radiation Facility(SSRF).Subsequently,we performed XPCS measurements on silica suspensions in glycerol,which were opaque owing to their high concentrations.Images were collected using a high frame rate area detector.A comprehensive analysis was performed,yielding correlation functions and several key dynamic parameters.All the results were consistent with the theory of Brownian motion and demonstrated the feasibility of XPCS at SSRF.Finally,by carefully optimizing the setup and analyzing the algorithms,we achieved a time resolution of 2 ms,which enabled the characterization of millisecond dynamics in opaque systems.

关键词： XPCS SSRF Silica suspension Glycerol Brownian motion Millisecond dynamics

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