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SARS-CoV2 Nsp3 protein triggers cell death and exacerbates amyloid β42-mediated neurodegeneration

Neural Regeneration Research 2024年第6期19卷 1385-1392页

作者： Aditi Singh Anuradha Venkatakrishnan Chimata Prajakta Deshpande Soumya Bajpai Anjali Sangeeth Mrigendra Rajput Amit Singh Department of Biology University of Dayton Premedical Program University of Dayton center for Tissue Regeneration and Engineering at Dayton (TREND) University of Dayton The Integrative Science and Engineering center University of Dayton center for Genomic Advocacy (TCGA) Indiana State University

Infection caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV2) virus, responsible for the coronavirus disease 2019(COVID-19) pandemic, induces symptoms including increased inflammatory response, severe acute respiratory syndrome(SARS), cognitive dysfunction like brain fog, and cardiovascular defects. Long-term effects of SARS-CoV2 COVID-19 syndrome referred to as post-COVID-19 syndrome on age-related progressive neurodegenerative disorders such as Alzheimer’s disease remain understudied. Using the targeted misexpression of individual SARS-CoV2 proteins in the retinal neurons of the Drosophila melanogaster eye, we found that misexpression of nonstructural protein 3(Nsp3), a papain-like protease, ablates the eye and generates dark necrotic spots. Targeted misexpression of Nsp3 in the eye triggers reactive oxygen species production and leads to apoptosis as shown by cell death reporters, terminal deoxynucleotidyl transferase(TdT) dUTP Nick-end labeling(TUNEL) assay, and dihydroethidium staining. Furthermore, Nsp3 misexpression activates both apoptosis and autophagy mechanism(s) to regulate tissue homeostasis. Transient expression of SARS-CoV2 Nsp3 in murine neuroblastoma, Neuro-2a cells, significantly reduced the metabolic activity of these cells and triggers cell death. Misexpression of SARS-CoV2 Nsp3 in an Alzheimer’s disease transgenic fly eye model(glass multiple repeats [GMR]>amyloid β42) further enhances the neurodegenerative rough eye phenotype due to increased cell death. These findings suggest that SARS-CoV2 utilizes Nsp3 protein to potentiate cell death response in a neurodegenerative disease background that has high pre-existing levels of neuroinflammation and cell death.

关键词： Alzheimer’s disease apoptosis autophagy COVID-19 Drosophila necrosis Neuro-2a cells neurodegeneration post COVID-19 syndrome SARS-CoV2

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Higher-order topology induced by structural buckling

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National Science Review 2022年第8期9卷 55-61页

作者： Huaqing Huang Feng Liu School of Physics Peking University Collaborative Innovation center of Quantum Matter center for High Energy Physics Peking University Department of Materials Science and Engineering University of Utah

Higher-order topological insulator(HOTI) states, such as two-dimension(2D) HOTI featured with topologically protected corner modes at the intersection of two gapped crystalline boundaries, have attracted much recent interest. However, the physical mechanism underlying the formation of HOTI states is not fully understood, which has hindered our fundamental understanding and discovery of HOTI materials. Here we propose a mechanistic approach to induce higher-order topological phases via structural buckling of 2D topological crystalline insulators(TCIs). While in-plane mirror symmetry is broken by structural buckling, which destroys the TCI state, the combination of mirror and rotation symmetry is preserved in the buckled system, which gives rise to the HOTI state. We demonstrate that this approach is generally applicable to various 2D lattices with different symmetries and buckling patterns, opening a horizon of possible materials to realize 2D HOTIs. The HOTIs so generated are also shown to be robust against buckling height fluctuation and in-plane displacement. A concrete example is given for the buckledβ-Sb monolayer from first-principles calculations. Our finding not only enriches our fundamental understanding of higher-order topology, but also opens a new route to discovering HOTI materials.

关键词： higher-order topological insulators structural buckling rotation-reflection symmetry buckled honeycomb antimony monolayer

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The impact of chemotherapy-naïve open radical cystectomy delay and perioperative transfusion on the recurrence-free survival: A perioperative parameters-based nomogram

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Asian Journal of Urology 2024年第2期11卷 294-303页

作者： Ahmed M.Harraz Ahmed Elkarta Mohamed H.Zahran Ahmed Mosbah Atallah A.Shaaban Hassan Abol-Enein Urology and Nephrology center Mansoura UniversityEgypt

Objective: To develop and internally validate a nomogram to predict recurrence-free survival (RFS) including the time to radical cystectomy (RC) and perioperative blood transfusion (PBT) as potential predictors.Methods: Patients who underwent open RC and ileal conduit between January 1996 to December 2016 were split into developing (n=948) and validating (n=237) cohorts. The time to radical cystectomy (TTC) was defined as the interval between the onset of symptoms and RC. The regression coefficients of the independent predictors obtained by Cox regression were used to construct the nomogram. Discrimination, validation, and clinical usefulness in the validation cohort were assessed by the area under the curve, the calibration plot, and decision curve analysis.Results: In the developing dataset, the 1-, 5-, and 10-year RFS were 83.0%, 47.2%, and 44.4%, respectively. On multivariate analysis, independent predictors were TTC (hazards ratio [HR] 1.07, 95% confidence interval [CI] 1.05-1.08, p<0.001), PBT (one unit: HR 1.40, 95% CI 1.03-1.90, p=0.03;two or more units: HR 1.72, 95% CI 1.29-2.29, p<0.001), bilateral hydronephrosis (HR 1.54, 95% CI 1.21-1.97, p<0.001), squamous cell carcinoma (HR 0.60, 95% CI 0.45-0.81, p=0.001), pT3-T4 (HR 1.77, 95% CI 1.41-2.22, p<0.001), lymph node status (HR 1.53, 95% CI 1.21-1.95, p<0.001), and lymphovascular invasion (HR 1.28, 95% CI 1.01-1.62, p=0.044). The areas under the curve in the validation dataset were 79.3%, 69.6%, and 76.2%, for 1-, 5-, and 10-year RFS, respectively. Calibration plots showed considerable correspondence between predicted and actual survival probabilities. The decision curve analysis revealed a better net benefit of the nomogram.Conclusion: A nomogram with good discrimination, validation, and clinical utility was constructed utilizing TTC and PBT in addition to standard pathological criteria.

关键词： Radicalcystectomy Blood transfusion Time to radical cystectomy Survival Nomogram

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Blood-brain barrier pathology in cerebral small vessel disease

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Neural Regeneration Research 2024年第6期19卷 1233-1240页

作者： Ruxue Jia Gemma Solé-Guardia Amanda J.Kiliaan Department of Medical Imaging Anatomy Radboud University Medical Center Donders Institute for Brain Cognition & Behavior Center for Medical Neuroscience Preclinical Imaging Center PRIME Radboud Alzheimer Center

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly. Although at first it was considered innocuous, small vessel disease is nowadays regarded as one of the major vascular causes of dementia. Radiological signs of small vessel disease include small subcortical infarcts, white matter magnetic resonance imaging hyperintensities, lacunes, enlarged perivascular spaces, cerebral microbleeds, and brain atrophy; however, great heterogeneity in clinical symptoms is observed in small vessel disease patients. The pathophysiology of these lesions has been linked to multiple processes, such as hypoperfusion, defective cerebrovascular reactivity, and blood-brain barrier dysfunction. Notably, studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease. Therefore, the purpose of this review is to provide a new foundation in the study of small vessel disease pathology. First, we discuss the main structural domains and functions of the blood-brain barrier. Secondly, we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease. Finally, we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

关键词： blood-brain barrier dysfunction cerebral blood flow cerebral hypoperfusion endothelial dysfunction hypertension inflammation magnetic resonance imaging neurovascular unit oxidative stress small vessel disease tight junctions transcytosis

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Pediatric endocrinopathies related to COVID‑19:an update

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World Journal of Pediatrics 2023年第9期19卷 823-834页

作者： Elmira Haji Esmaeli Memar Reihaneh Mohsenipour Seyedeh Taravat Sadrosadat Parastoo Rostami Pediatric center of Excellence Tehran University of Medical SciencesTehranIran Growth and Development Research center Children’s Medical CenterTehran University of Medical SciencesTehranIran Universal Scientific Education and Research Network(USERN) TehranIran Children’s Medical center Pediatric Center of ExcellenceTehran University of Medical SciencesTehranIran Growth and Development Research center Department of Endocrinology and MetabolismPediatric Center of ExcellenceChildren’s Medical CenterTehran University of Medical SciencesTehranIran

Background Coronavirus disease 2019(COVID-19)is a disease caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the seventh coronavirus to be linked to human disease.The SARS-CoV-2 virus may have several pathophysiologic interactions with endocrine systems,resulting in disruptions in glucose metabolism,hypothalamus and pituitary function,adrenal function,and mineral metabolism.An increasing amount of evidence demonstrates both the influence of underlying endocrine abnormalities on the outcome of COVID-19 and the effect of the SARS-CoV-2 virus on endocrine systems.However,a systematic examination of the link to pediatric endocrine diseases has been missing.Data sources The purpose of this review is to discuss the impact of SARS-CoV-2 infection on endocrine systems and to summarize the available knowledge on COVID-19 consequences in children with underlying endocrine abnormalities.For this purpose,a literature search was conducted in EMBASE,and data that were discussed about the effects of COVID-19 on endocrine systems were used in the current study.Results Treatment suggestions were provided for endocrinopathies associated with SARS-CoV-2 infection.Conclusions With the global outbreak of COVID-19,it is critical for pediatric endocrinologists to understand how SARSCoV-2 interacts with the endocrine system and the therapeutic concerns for children with underlying problems who develop COVID-19.While children and adults share certain risk factors for SARS-CoV-2 infection sequelae,it is becoming obvious that pediatric responses are different and that adult study results cannot be generalized.While pediatric research gives some insight,it also shows the need for more study in this area.

关键词： Coronavirus disease 2019(COVID-19) Endocrine Infection Pediatrics

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Targeting O-GlcNAcylation in ischemic stroke

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Neural Regeneration Research 2022年第11期17卷 2427-2428页

作者： Xuan Li Wei Yang center for Perioperative Organ Protection Department of AnesthesiologyDuke University Medical Center

Ischemic stroke is a common and often devastating disease that prima rily affects the elderly.Treatment currently consists predominantly of acute thrombolysis and/or thrombectomy to restore blood flow.This reperfusion therapy,however,is only accessible to a small fraction of stroke patients,and even among these patients,many still suffer lifelong neurologic deficits.Thus,new stroke therapeutics are urgently needed to improve the quality of life for stroke patients.

关键词： acute patients stroke

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Uncoupling protein 2 deficiency of non-cancerous tissues inhibits the progression of pancreatic cancer in mice

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Hepatobiliary & Pancreatic Diseases International 2023年第2期22卷 190-199页

作者： Denis Revskij Jakob Runst Camilla Umstätter Luise Ehlers Sarah Rohde Dietmar Zechner Manuela Bastian Brigitte Müller-Hilke Georg Fuellen Larissa Henze Hugo Murua Escobar Christian Junghanss Axel Kowald Uwe Walter Rüdiger Köhling Olaf Wolkenhauer Robert Jaster Department of Medicine Ⅱ Division of GastroenterologyRostock University Medical CenterRostockGermany Rudolf-Zenker-Institute of Experimental Surgery Rostock University Medical CenterRostockGermany Institute of Clinical Chemistry and Laboratory Medicine Rostock University Medical CenterRostockGermany Facility for Cell Sorting and Cell Analysis and Institute of Immunology Rostock University Medical CenterRostockGermany Institute for Biostatistics and Informatics in Medicine and Ageing Research Rostock University Medical CenterRostockGermany Department of Medicine Clinic ⅢHematologyOncologyPalliative MedicineRostock University Medical CenterRostockGermany Department of Neurology Rostock University Medical CenterRostockGermany Oscar LangendorffInstitute of Physiology Rostock University Medical CenterRostockGermany Department of Systems Biology and Bioinformatics University of RostockRostockGermany

Background: Pancreatic ductal adenocarcinoma(PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown. Methods: We took advantage of a model of accelerated aging, uncoupling protein 2-deficient( Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically transplanted Ucp2 wild-type(WT) PDAC cells(cell lines Panc02 and 6606PDA) in vivo and to study strain-dependent differences of the PDAC microenvironment. Results: Measurements of tumor weights and quantification of proliferating cells indicated a significant growth advantage of Panc02 and 6606PDA cells in WT mice compared to Ucp2 KO mice. In tumors in the knockout strain, higher levels of interferon-γ m RNA despite similar numbers of tumor-infiltrating T cells were observed. 6606PDA cells triggered a stronger stromal reaction in Ucp2 KO mice than in WT animals. Accordingly, pancreatic stellate cells from Ucp2 KO mice proliferated at a higher rate than cells of the WT strain when they were incubated with conditioned media from PDAC cells. Conclusions: Ucp2 modulates PDAC microenvironment in a way that favors tumor progression and implicates an altered stromal response as one of the underlying mechanisms.

关键词： Pancreatic cancer Orthotopic model Uncoupling protein 2 Fibrosis

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结直肠癌、基质和正常结肠黏膜显微解剖区域N-糖组的显著多样性

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Engineering 2023年第7期26卷 32-43,I0002页

作者： Di Wang Katarina Madunic Tao Zhang Guinevere S.M.Lageveen-Kammeijer Manfred Wuhrer center for Proteomics and Metabolomics Leiden University Medical CenterLeiden 2300 RCNetherlands Copenhagen center for Glycomics Department of Cellular and Molecular MedicineUniversity of CopenhagenCopenhagen 2200Denmark

Aberrant glycosylation is considered to be a hallmark of colorectal cancer(CRC),as demonstrated by various studies.While the N-glycosylation of cell lines and serum has been widely examined,the analysis of cancer-associated N-glycans from tissues has been hampered by the heterogeneity of tumors and the complexity of N-glycan structures.To overcome these obstacles,we present a study using laser capture microdissection that makes it possible to largely deconvolute distinct N-glycomic signatures originating from different regions of heterogeneous tissues including cancerous,stromal,and healthy mucosa cells.N-glycan alditols were analyzed by means of porous graphitized carbon liquid chromatographyelectrospray ionization tandem mass spectrometry,enabling the differentiation and structural characterization of isomeric species.In total,116 N-glycans were identified that showed profound differences in expression among cancer,stroma,and normal mucosa.In comparison with healthy mucosa,the cancer cells showed an increase in a2-6 sialylation and monoantennary N-glycans,as well as a decrease in bisected N-glycans.Moreover,specific sialylated and(sialyl-)LewisA/X antigen-carrying N-glycans were exclusively expressed in cancers.In comparison with cancer,the stroma showed lower levels of oligomannosidic and monoantennary N-glycans,LewisA/X epitopes,and sulfation,as well as increased expression of(core-)fucosylation and a2-3 sialylation.Our study reveals the distinct N-glycomic profiles of different cell types in CRC and control tissues,proving the necessity of their separate analysis for the discovery of cancer-associated glycans.

关键词： Colorectal cancer Tumor Porous graphitized carbon liquid chromatography mass spectrometry N-glycomics Antibody response

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On the complexity of computing Markov perfect equilibrium in general-sum stochastic games

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National Science Review 2023年第1期10卷 288-301页

作者： Xiaotie Deng Ningyuan Li David Mguni Jun Wang Yaodong Yang center on Frontiers of Computing Studies School of Computer Science Peking University center for Multi-Agent Research Institute for AI Peking University Huawei UK Computer Science University College London

Similar to the role of Markov decision processes in reinforcement learning,Markov games(also called stochastic games) lay down the foundation for the study of multi-agent reinforcement learning and se quential agent interactions.We introduce approximate Markov perfect equilibrium as a solution to the computational problem of finite-state sto chastic games repeated in the infinite horizon and prove its PPAD-completeness.This solution concept preserves the Markov perfect property and opens up the possibility for the success of multi-agent reinforcement learning algorithms on static two-player games to be extended to multi-agent dynamic games,expanding the reign of the PPAD-complete class.

关键词： Markov game multi-agent reinforcement learning Markov perfect equilibrium PPAD-completeness stochastic game

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A quantitative study of airway ultrasound in predicting difficult laryngoscopy:A prospective study

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Chinese Journal of Traumatology 2023年第6期26卷 351-356页

作者： Lin Ning Xing Zhu Hong-Chao Li Shi-Jie Zhou Qi-Wei Zhang Hong-Yu Zou Qing-Xiang Mao Hong Yan Department of Anaesthesiology Army Medical Center of PLADaping Hospital of Army Medical UniversityChongqingChina Laboratory of Anaesthesia center Army Medical Center of PLADaping Hospital of Army Medical UniversityChongqingChina Anaesthesia center Army Medical Center of PLADaping Hospital of Army Medical UniversityChongqingChina

Purpose:As common clinical screening tests cannot effectively predict a difficult airway,and unanticipated difficult laryngoscopy remains a challenge for physicians.We herein used ultrasound to develop some point-of-care predictors for difficult laryngoscopy.Methods:This prospective observational study included 502 patients who underwent laryngoscopy and a detailed sonographic assessment.Patients under 18 years old,or with maxillofacial deformities or fractures,limited mouth opening,limited neck movement or history of neck surgery were excluded from the study.Laryngoscopic views of all patients were scored and grouping using the modified Cormack-Lehane(CL)scoring system.The measurements acquired comprised tongue width,the longitudinal cross-sectional area of the tongue,tongue volume,the mandible-hyoid bone distance,the hyoid boneglottis distance,the mandible-hyoid bone-glottis angle,the skin-thyrohyoid membrane distance,the glottis-superior edge of the thyroid cartilage distance(DGTC),the skin-hyoid bone distance,and the epiglottis midway-skin distance.ANOVA and Chi-square were used to compare differences between groups.Logistic regression was used to identify risk factors for difficult laryngoscopy and it was visualized by receiver operating characteristic curves and nomogram.R version 3.6.3 and SPSS version 26.0 were used for statistical analyses.Results:Difficult laryngoscopy was indicated in 49 patients(CL grade III-IV)and easy laryngoscopy in 453 patients(CL grade I-II).The ultrasound-measured mandible-hyoid bone-glottis angle and DGTC significantly differed between the 2 groups(p<0.001).Difficult laryngoscopy was predicted by an area under the curve(AUC)of 0.930 with a threshold mandible-hyoid bone-glottis angle of 125.5and by an AUC of 0.722 with a threshold DGTC of 1.22 cm.The longitudinal cross-sectional area of the tongue,tongue width,tongue volume,the mandible-hyoid distance,and the hyoid-glottis distance did not significantly differ between the groups.Conclusion:Difficult laryngoscopy may be anticipa

关键词： Airway management Intubation Ultrasonography Airway Difficult laryngoscopy

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