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SARS-CoV-2 ORF10 hijacking ubiquitination machinery reveals potential unique drug targeting sites

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4164-4173页

作者： Kaixiang Zhu Lili Song Linyue Wang Lei Hua Ziyu Luo Tongyun Wang Bo qin Shuofeng yuan Xiaopan Gao Wenyi Mi Sheng Cui NHC Key Laboratory of Systems Biology of Pathogens National Institute of Pathogen BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Key Laboratory of Pathogen Infection Prevention and Control(Peking Union Medical College) Ministry of EducationBeijing 100730China The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease(Ministry of Education)Tianjin Medical University General HospitalDepartment of ImmunologyTianjin Medical UniversityTianjin 300070China Medical School Yan’an UniversityShaanxi ProvinceYan’an 716000China State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SARChina department of Microbiology Li Ka ShingFaculty of Medicinethe University of Hong KongPokfulamHong Kong SARChina

Viruses often manipulate ubiquitination pathways to facilitate their replication and ***2ZYG11B known as the substrate receptor of cullin-2 RING E3 ligase,is bound by SARS-CoV-2 ORF10 to increase its E3 ligase activity,leading to degradation of IFT46,a protein component of the intraflagellar transport(IFT)complex *** results in dysfunctional cilia,which explains certain symptoms that are specific to ***,the precise molecular mechanism of how ORF10 recognizes CUL2ZYG11B remains ***,we determined the crystal structure of CUL2ZYG11B complexed with the N-terminal extension(NTE)of SARS-CoV-2 ORF10(2.9 A°).The structure reveals that the ORF10 N-terminal heptapeptide(NTH)mimics the Gly/N-degron to bind *** studies identified key residues within ORF10 that are key players in its interaction with CUL2ZYG11B both in ITC assay and in vivo *** addition,we prove that enhancement of CUL2ZYG11B activity for IFT46 degradation by which ORF10-mediated correlates with the binding affinity between ORF10 and ***,we used a Global Protein Stability system to show that the NTH of ORF10 mimics the Gly/N-degron motif,thereby binding competitively to CUL2ZYG11B and inhibiting the degradation of target substrates bearing the Gly/N-degron ***,this study sheds light on how SARS-CoV-2 ORF10 exploits the ubiquitination machinery for proteasomal degradation,and offers valuable insights for optimizing PROTAC-based drug design based on NTH CUL2ZYG11B interaction,while pinpointing a promising target for the development of treatments for COVID-19.

关键词： SARS-CoV-2 ORF10 Crystal structure cullin-2 RING E3 ligase Drug design

A Communication Theory Perspective on Prompting Engineering Methods for Large Language Models

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Journal of Computer Science & Technology 2024年第4期39卷 984-1004页

作者： yuan-Feng Song yuan-qin He Xue-Fang Zhao Han-Lin Gu Di Jiang Hai-Jun Yang Li-Xin Fan AI Group WeBank Co.LtdShenzhen 518000China

The springing up of large language models(LLMs)has shifted the community from single-task-orientated natural language processing(NLP)research to a holistic end-to-end multi-task learning *** this line of research endeavors in the area,LLM-based prompting methods have attracted much attention,partially due to the technological advantages brought by prompt engineering(PE)as well as the underlying NLP principles disclosed by various prompting *** supervised learning usually requires training a model based on labeled data and then making *** contrast,PE methods directly use the powerful capabilities of existing LLMs(e.g.,GPT-3 and GPT-4)via composing appropriate prompts,especially under few-shot or zero-shot *** the abundance of studies related to the prompting and the ever-evolving nature of this field,this article aims to 1)illustrate a novel perspective to review existing PE methods within the well-established communication theory framework,2)facilitate a better/deeper understanding of developing trends of existing PE methods used in three typical tasks,and 3)shed light on promising research directions for future PE methods.

关键词： prompting method large language model communication theory

Structure,ligands,and roles of GPR126/ADGRG6 in the development and diseases

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Genes & Diseases 2024年第1期11卷 294-305页

作者： Qi Li Anran Huo Mengqi Li Jiali Wang Qiao Yin Lumiao Chen Xin Chu yuan qin Yuwan Qi Yang Li Hengxiang Cui Qifei Cong Institute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases Soochow UniversitySuzhouJiangsu215123China department of Neurology and Clinical Research Center of Neurological Disease The Second Affliated Hospital of Soochow UniversitySuzhouJiangsu 215004China department of Nephrology The Second Affiliated Hospital of Soochow UniversitySuzhouJiangsu 215004China department of Emergency Center The Second Affiliated Hospital of Nantong UniversityNantongJiangsu226001China department of Neurology Huzhou Central HospitalThe Affiliated Huzhou HospitalZhejiang University School of MedicineHuzhouZhejiang 313000China Institute of Neuroscience State Key Laboratory of NeuroscienceCAS Center for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesShanghai 200031China Shanghai Key Laboratory of Psychotic Disorders Shanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghai 200030China

Adhesion G protein-coupled receptors(aGPCRs)are the second largest diverse group within the GPCR superfamily,which play critical roles in many physiological and patho-logical processes through cell-cell and cell-extracellular matrix *** adhesion GPCR Adgrg6,also known as GPR126,is one of the better-characterized ***126 was previously found to have critical developmental roles in Schwann cell maturation and its mediated myelination in the peripheral nervous system in both zebrafish and *** studies have extended our understanding of GPR126-mediated roles during develop-ment and in human *** this review,we highlighted these recent advances in GPR126 in expression profile,molecular structure,ligand-receptor interactions,and associated physiological and pathological functions in development and diseases.

关键词： Adhesion G protein-coupled receptor Function GPR126/Adgrg6 Ligand Structure

Semicrystalline Unfused Polymer Donors with Backbone Halogenation toward Cost-Effective Organic Solar Cells

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Chinese Journal of Chemistry 2024年第7期42卷 752-759页

作者： Yuxin Kong Shijie Ju Hongmei qin Min Hun Jee Simeng Xia Jiaqi Ren Chao Gao Jianyu yuan Wenyan Su Han Young Woo Yuxiang Li School of Materials Science and Engineering Xi'an University of Science and TechnologyXianShaanxi 710054China department of Chemistry Korea UniversitySeoul 02841Republic of Korea Xi'an Key Laboratory of Liquid Crystal and Organic Photovoltaic Materials State Key Laboratory of Fluorine&Nitrogen ChemicalsXi'an Modern Chemistry Research InstituteXi'anShaanxi 710065China Jiangsu Key Laboratory for Carbon-Based Functional Materials&devices Institute of Functional Nano&Soft Materials(FUNSOM)Soochow University199 Ren'ai RoadSuzhouJiangsu 215123China

developing novel unfused building blocks with simple synthesis and low cost is essential to advance and enrich cost-effective poly-mer donors;however,it remains a challenge due to the lack of efficient molecular ***,a class of low-cost and fully unfused polymer donors with precisely regulated backbone planarity via halogenation was designed and synthesized,namely PDTBTBz-2H,PDTBTBz-2F,and *** polymer donors possess a four-step synthesis route with over 80%yield from cheap raw chemicals comparable to existing low-cost polymer donors,such as *** from the planar backbone via in-corporating the F…S non-covalent interactions,PDTBTBz-2F exhibits more robust J-type aggregation in solution and a long-ranged molecular stacking in film relative to PDTBTBz-2H and ***,the systematical study of PDTBTBz-based organic so-lar cells(OSCs)reveals the close relationship between optimized molecular self-assembly and charge separation/transport regarding backbone halogenation when paired with the non-fullerene acceptor(Y6-BO-4F).As a result,the photovoltaic devices based on semicrystalline PDTBTBz-2F achieved a promising power conversion efficiency(PCE)of 12.37%.Our work highlighted the influence of backbone halogenation on the molecular self-assembly properties and a potential unfused backbone motif for further developing cost-effective OSCs.

关键词： Low-cost Polymer donors Backbone halogenation Molecular self-assembly Organic solar cells

Nitro-oleic acid ameliorates erectile dysfunction in a streptozotocin-induced rat model of diabetes by inhibiting oxidative stress and apoptosis and activating the NO/cGMP pathway

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Asian Journal of Andrology 2024年第1期26卷 57-66页

作者： Chang-Bo Zhao Wei-Bo Chen Wen-Zhen Wang Fang-Xin Gong Cui-qin Fan Ye Li Tian Lan Wen-Jing Wang Ming-Zhen yuan department of Urology Shandong Provincial HospitalShandong UniversityJinan 250012China department of Andrology Liaocheng People's HospitalShandong UniversityLiaocheng 252000China department of Urology The Second Hospital of Shandong UniversityJinan 250012China department of Physiology School of Basic Medical SciencesShandong UniversityJinan 250012China

The major vascular complications associated with diabetes make the management of diabetic mellitus erectile dysfunction(DMED)a challenging *** factors contributing to DMED include oxidative stress,nitric oxide(NO)/cyclic guanosine monophosphate(cGMP)pathway activation,and apoptosis,while nitro-oleic acid(NO,-OA)has been shown to be beneficial in treating these aspects of this ***,herein,investigated the effects and possible mechanisms of NO,-OA on erectile function as assessed in a streptozotocin-induced rat model of *** results revealed that the erectile function of DMED rats was significantly impaired compared with that of the control ***,in response to 4 weeks of NO,-OA treatment,there was an improvement in erectile *** expression of oxidative stress-related indicators was significantly increased and the NO/cGMP pathway was impaired in the DMED *** expression of proapoptotic factors was increased,while that of antiapoptotic factors was decreased in the DMED ***,the cell morphology in the cavernous tissue of the DMED group also changed ***,-OA treatment significantly reversed all these changes observed in the DMED *** conclusion,NO,-OA treatment partially improved erectile function in DMED rats through mechanisms that included inhibition of oxidative stress,activation of the NO/cGMP pathway,and a reduction in apoptosis.

关键词： apoptosis diabetic mellitus erectile dysfunction nitro-oleic acid NO/cGMP pathway oxidative stress

Evolution of template-assisted two-dimensional porphyrin chiral grating structure by directed self-assembly using chiral second harmonic generation microscopy

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Chinese Chemical Letters 2024年第10期35卷 196-200页

作者： Changhui Yu Peng Shang Huihui Hu Yuening Zhang Xujin qin Linyu Han Caihe Liu Xiaohan Liu Minghua Liu yuan Guo Zhen Zhang Beijing National Laboratory for Molecular Sciences State Key Laboratory of Molecular Reaction Dynamics Institute of Chemistry Chinese Academy of Sciences University of Chinese Academy of Sciences Beijing National Laboratory for Molecular Science CAS Key Laboratory of Colloid Interface and Chemical Thermodynamics Institute of Chemistry Chinese Academy of Sciences

Directed self-assembly has been used to create micro-nano scale patterns, including chiral periodic structures of organic molecules, for potential applications in optics, photonics, metamaterials, and medical and sensing technologies. This study presents a straightforward approach for fabricating large-scale chiral grating porphyrin assemblies through template-assisted techniques. The solution of tetrakis(4-sulfonatophenyl)porphyrin(TPPS) was induced by chiral amino acids(L/D-arginine and L/D-serine) to selfassemble into highly ordered chiral grating structures with the assistance of sodium dodecyl sulfate(SDS).The structures show precise line widths(5.5 μm) and gaps(18 μm). Using in situ optical microscopy and second harmonic generation(SHG) microscopy, the chiral characteristics and dynamic evolution of the template-assisted self-assembly are investigated. It is found that the chirality of amino acids induced TPPS self-assembled into chiral structures and the liquid contraction interface significantly enhanced the chirality of the assemblies. This study is significant for understanding the mechanism of chiral evolution and designing novel micro-nano materials with predetermined chiral properties.

关键词： Chiral assembly Chiral evolution Micro-nano structure Porphyrin Second harmonic generation microscopy Template-assisted self-assembly

Human immunodeficiency virus-associated dementia complex with positive 14-3-3 protein in cerebrospinal fluid:A case report

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World Journal of Clinical Cases 2024年第12期12卷 2065-2073页

作者： Yun-Sen He Xiao-Hong qin Min Feng qin-Jiang Huang Meng-Jun Zhang Li-Li Guo Ming-Bin Bao Ye Tao Hong-yuan Dai Bo Wu department of Neurosurgery Sichuan Lansheng Brain Hospital&Shanghai Lansheng Brain Hospital Investment Co.Ltd.Chengdu 610036Sichuan ProvinceChina department of Psychiatry Sichuan Provincial Center for Mental HealthChengdu 610072Sichuan ProvinceChina department of Geriatrics Municipal People’s Hospital in LuzhouLuzhou 646000Sichuan ProvinceChina department of Neurosurgery Wenjiang District People’s Hospital of ChengduChengdu 611100Sichuan ProvinceChina department of Neurosurgery Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of China ChengduChengdu 610072Sichuan ProvinceChina department of Neurology Sichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengdu 610072Sichuan ProvinceChina

BACKGROUND Human immunodeficiency virus(HIV)-associated dementia(HAD)is a subcortical form of dementia characterized by memory deficits and psychomotor ***,HAD often presents with symptoms similar to those of Creutzfeldt-Jakob disease(CJD),particularly in patients with acquired immune deficiency syndrome(AIDS).CASE SUMMARY We report the case of a 54-year-old male who exhibited cognitive dysfunction and secondary behavioral changes following HIV infection and suspected prion *** patient was diagnosed with HIV during hospitalization and his cerebrospinal fluid tested positive for 14-3-3 *** electroencephalogram showed a borderline-abnormal periodic triphasic wave ***-enhanced magnetic resonance imaging revealed moderate encephalatrophy and ***,symptomatic treatment and administration of amantadine were pursued for presumed CJD,but the patient’s condition continued to *** contrast,the patient’s condition improved following anti-HIV *** individual is also the only patient with this prognosis to have survived over 4 ***,the diagnosis was revised to *** In the diagnostic process of rapidly progressive dementia,it is crucial to rule out as many potential causes as possible and to consider an autopsy to diminish diagnostic *** 14-3-3 protein should not be regarded as the definitive marker for *** laboratory screening for infectious diseases is essential to enhance diagnostic precision,especially in AIDS patients with potential ***,a trial of diagnostic treatment may be considered when additional testing is not feasible.

关键词： HIV-associated dementia Cognitive dysfunction Creutzfeld-Jakob disease Rapidly progressive dementia Case report

An Innovative Finite Element Geometric Modeling of Single-Layer Multi-Bead WAAMed Part

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Computer Modeling in Engineering & Sciences 2024年第3期138卷 2383-2401页

作者： Xiangman Zhou Jingping qin Zichuan Fu Min Wang Youlu yuan Junjian Fu Haiou Zhang Seyed Reza Elmi Hosseini College of Mechanical and Power Engineering China Three Gorges UniversityYichang443002China School of Mechanical Science and Engineering Huazhong University of Science and TechnologyWuhan430074China School of Metallurgy and Materials Engineering Iran University of Science and TechnologyNarmakIran

Finite element (FE) coupled thermal-mechanical analysis is widely used to predict the deformation and residualstress of wire arc additive manufacturing (WAAM) parts. In this study, an innovative single-layermulti-bead profilegeometric modeling method through the isosceles trapezoid function is proposed to build the FE model of theWAAMprocess. Firstly, a straight-line model for overlapping beads based on the parabola function was establishedto calculate the optimal center distance. Then, the isosceles trapezoid-based profile was employed to replace theparabola profiles of the parabola-based overlapping model to establish an innovative isosceles trapezoid-basedmulti-bead overlapping geometric model. The rationality of the isosceles trapezoid-based overlapping model wasconfirmed by comparing the geometric deviation and the heat dissipation performance index of the two overlappingmodels. In addition, the FE-coupled thermal-mechanical analysis, as well as a comparative experiment of thesingle-layer eight-bead deposition process show that the simulation results of the above two models agree with theexperimental results. At the same time, the proposed isosceles trapezoid-based overlappingmodels are all straightlineprofiles, which can be divided into high-quality FE elements. It can improve the modeling efficiency andshorten the simulation calculation time. The innovative modeling method proposed in this study can provide anefficient and high-precision geometricmodelingmethod forWAAMpart FE coupled thermal-mechanical analysis.

关键词： WAAM FE coupled thermal-mechanical analysis the isosceles trapezoid-based model residual stress

Extended survival with metastatic pancreatic cancer under fruquintinib treatment after failed chemotherapy:Two case reports

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World Journal of Clinical Cases 2024年第7期12卷 1296-1304页

作者： Dan Wu Qiong Wang Shuai Yan Xia Sun Ya qin Ming yuan Nan-Yao Wang Xian-Ting Huang department of Oncology Jiangyin People's HospitalWuxi 214400Jiangsu ProvinceChina

BACKGROUND Pancreatic cancer is a highly malignant *** decades of treatment progress,the current five-year survival rate for patients is still less than 10%.For later-line treatment,the treatment options are even more ***-angiogenic drugs can improve progression-free survival in patients with advanced pancreatic *** data show that fruquintinib might improve the prognosis of advanced pancreatic cancer by targeting angiogenesis and lymphopoiesis,improving the abnormal vascular structure,and modulating the tumour immune *** SUMMARY We present two cases of third-line fruquintinib monotherapy that brought an extraprolonged progress-free survival(PFS)of 10 *** 1 took adjuvant gemcitabine-based and first-line nab-paclitaxel-based chemotherapy and then used local radiotherapy combined with programmed cell death 1 receptor(PD-1).Each line lasted approximately 7 ***,the patient took third-line fruquintinib,which was followed by stable disease for 10 months,during which no additional adverse effect was *** patient later refused to take fruquintinib due to difficulty urinating and lower abdominal pain after the coronavirus disease 2019(COVID-19)*** patient died in February *** 2 also took two prior lines of chemotherapy and then local radiotherapy combined with *** confirmed disease progression,the patient experienced a continuous partial response after using fruquintinib monotherapy in the third *** the patient had COVID-19 in december 2022,fruquintinib was *** patient died in January 2023 due to disease *** Both cases achieved a PFS benefit from later-line single-agent fruquintinib *** its better safety profile,fruquintinib may be worth exploring and studying in more depth as a later-line treatment for pancreatic cancer patients.

关键词： Pancreatic cancer Anti-vascular endothelial growth factor receptor Fruquintinib Case report