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DNA-delivered monoclonal antibodies targeting the p53 R175H mutant epitope inhibit tumor development in mice

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Genes & Diseases 2024年第4期11卷 368-380页

作者： Dafei Chai Xu Wang Praveen Neeli Shan Zhou Xingfang Yu Kanaga Sabapathy Yong Li Department of Medicine Section of Epidemiology and Population SciencesDan L Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTX 77030USA Division of Cellular&molecular Research Humphrey Oei Institute of Cancer ResearchNational Cancer Centre SingaporeSingapore 168583Singapore

tThe tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense ***,there are currently no approved targeted therapies or immunotherapies against mutant ***,we characterized and inves-tigated a monoclonal antibody(mAb)that recognizes the mutant p53-R175H for its affinity,specificity,and activity against tumor cells in *** then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic *** results showed that the anti-R175H mAb specifically bound to the p53-R175H an-tigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells,with no cross-reactivity with wild-type *** cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular *** made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 *** vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in *** administration of the anti-R175H BsAb plasmid showed no therapeutic effects,yet potent anti-tumor activity was observed in combination with the anti-PD-1 *** results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.

关键词： BsAb Cytotoxicity mAb Mutant p53 PD-1 R175H

Stereoselective recognition of morphine enantiomers by μ-opioid receptor

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National Science Review 2024年第3期11卷 183-191页

作者： Yibo Wang Van A.Ngo Xiaohui Wang Laboratory of Chemical Biology Changchun Institute of Applied ChemistryChinese Academy of Sciences Advanced Computing for Life Sciences and Engineering Group Science Engagement Section National Center for Computational Sciences Oak Ridge National Lab School of Applied Chemistry and Engineering University of Science and Technology of China Beijing National Laboratory for molecular Sciences

Stereospecific recognition of chiral molecules plays a crucial role in biological systems. The μ-opioid receptor（MOR） exhibits binding affinity towards（-）-morphine, a well-established gold standard in pain management, while it shows minimal binding affinity for the（+）-morphine enantiomer, resulting in a lack of analgesic activity. Understanding how MOR stereoselectively recognizes morphine enantiomers has remained a puzzle in neuroscience and pharmacology for over half-a-century due to the lack of direct observation techniques. To unravel this mystery, we constructed the binding and unbinding processes of morphine enantiomers with MOR via molecular dynamics simulations to investigate the thermodynamics and kinetics governing MOR's stereoselective recognition of morphine enantiomers. Our findings reveal that the binding of（-）-morphine stabilizes MOR in its activated state, exhibiting a deep energy well and a prolonged residence time. In contrast,（+）-morphine fails to sustain the activation state of ***, the results suggest that specific residues, namely D1142.50and D1473.32, are deprotonated in the active state of MOR bound to（-）-morphine. This work highlights that the selectivity in molecular recognition goes beyond binding affinities, extending into the realm of residence time.

关键词： stereoselective recognition thermodynamics and kinetics residence time morphine enantiomers μ-opioid receptor

Anoctamin 4 defines glucose-inhibited neurons in the ventromedial hypothalamus

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Neural Regeneration Research 2024年第6期19卷 1177-1178页

作者： Longlong Tu Yanlin He Yong Xu Children's Nutrition Research Center Department of Pediatrics Baylor College of Medicine Department of molecular and Cellular Biology Section of Endocrinology Diabetes and Metabolism Department of Medicine Baylor College of Medicine Brain Glycemic and Metabolism Control Department Pennington Biomedical Research Center Louisiana State University

Glucose is the primary fuel source of the brain,and therefore glucose levels need to be tightly regulated and maintained within a small physiological ***,the body necessitates a stable supply of energy mainly provided by glucose for various bodily *** or low blood glucose levels would impair the physiological functions of various organs of the *** high blood glucose(i.e.,

关键词： HYPOGLYCEMIA

Role of pituitary adenylate cyclase-activating polypeptide in peripheral nerve regeneration:a cellular and molecular perspective

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Neural Regeneration Research 2024年第7期19卷 1429-1430页

作者： Grazia Maugeri Velia D’Agata section of Anatomy Histology and Movement SciencesDepartment of Biomedical and Biotechnological SciencesUniversity of CataniaCataniaItaly

Neuro regeneration is a very complex phenomenon characterized by the generation of new neurons and synapses,involving connections between adjacent cells and axonal *** supplies additional longterm resources to replace... 详细信息

关键词： replace functional regeneration

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Recurrent evolution of seaweed body plan complexity among photosynthetic eukaryotes

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molecular Plant 2024年第7期17卷 999-1001页

作者： Elisa S.Goldbecker Iker Irisarri Jan de Vries Department of Applied Bioinformatics Institute for Microbiology and GeneticsUniversity of GottingenGoldschmidtstr.137077 GottingenGermany section Phylogenomics Center for Molecular Biodiversity ResearchLeibniz Institute for the Analysis of Biodiversity Change(LIB)Museum of Nature HamburgMartin-Luther-King-Platz 320146 HamburgGermany Department of Applied Bioinformatics Campus Institute Data Science(CIDAS)University of GottingenGoldschmidtstr.137077 GottingenGermany Department of Applied Bioinformatics Gottingen Center for Molecular Biosciences(GZMB)University of GottingenGoldschmidtstr.137077 GottingenGermany

The evolutionary origin of multicellularity is an age-old question in biological *** studies have delved into the evolutionary processes that led to the evolution of multicellular life forms from unicellular *** beauty and the challenge about this topic are that evolution has brought forth various forms of multicellular life,multiple times independently,scattered across the evolutionary tree of *** to the challenge,multicellular organisms exist in a diversity of forms and complexities,and the mechanisms by which multicellularity emerged are also likely different between animals,algae,or fungi(Niklas and Newman,2020).Recently,Nelson et al.(2024)presented a large-scale comparative genomics study focused on particularly intricate multicellular organisms:macroalgae(seaweeds),which emerged independently in three distinct eukaryotic lineages-green algae(Chlorophyta),red algae(Rhodophyta),and brown algae(Phaeophyceae).

关键词： algae seaweed evolution

RNA modifications in the progression of liver diseases: from fatty liver to cancer

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Science China Life Sciences 2024年

作者： Simiao Li Wajahat Z Mehal Xinshou Ouyang Yale University School of Medicine section of Digestive Diseases Department of Internal Medicine

Non-alcoholic fatty liver disease (NAFLD) has emerged as a prominent global health concern associated with high risk of metabolic syndrome, and has impacted a substantial segment of the population. The disease spectrum ranges from simple fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma (HCC) and is increasingly becoming a prevalent indication for liver transplantation. The existing therapeutic options for NAFLD, NASH, and HCC are limited, underscoring the urgent need for innovative treatment strategies. Insights into gene expression, particularly RNA modifications such as N6methyladenosine (m6A), hold promising avenues for interventions. These modifications play integral roles in RNA metabolism and cellular functions, encompassing the entire NAFLD-NASH-HCC progression. This review will encompass recent insights on diverse RNA modifications, including m6A, pseudouridine (Ψ), N1-methyladenosine (m1A), and 5-methylcytidine (m5C) across various RNA species. It will uncover their significance in crucial aspects such as steatosis, inflammation, fibrosis, and tumorigenesis. Furthermore, prospective research directions and therapeutic implications will be explored, advancing our comprehensive understanding of the intricate interconnected nature of these pathological conditions.

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Genomic Mosaicism of the Brain:Origin,Impact,and Utility

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Neuroscience Bulletin 2024年第6期40卷 759-776页

作者： Jared H.Graham Johannes C.M.Schlachetzki Xiaoxu Yang Martin W.Breuss Department of Pediatrics Section of Clinical Genetics and MetabolismUniversity of Colorado School of MedicineAurora80045-2581COUSA Department of Cellular and molecular Medicine University of California San DiegoLa Jolla92093-0021San DiegoCAUSA Department of Neurosciences University of California San DiegoLa Jolla92093-0021San DiegoCAUSA Rady Children’s Institute for Genomic Medicine San Diego92123CAUSA

Genomic mosaicism describes the phenomenon where some but not all cells within a tissue harbor unique genetic ***,research focused on the impact of genomic mosaicism on clinical phenotype—motivated by its involvement in cancers and overgrowth *** recently,we increasingly shifted towards the plethora of neutral mosaic variants that can act as recorders of cellular lineage and environmental ***,we summarize the current state of the field of genomic mosaicism research with a special emphasis on our current understanding of this phenomenon in brain development and *** the field of genomic mosaicism has a rich history,technological advances in the last decade have changed our approaches and greatly improved our *** will provide current definitions and an overview of contemporary detection approaches for genomic ***,we will discuss the impact and utility of genomic mosaicism.

关键词： Genomics Brain development Brain homeostasis Genomic mosaicism

Decoding human brain functions: Multi-modal, multi-scale insights

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The Innovation 2024年第1期5卷 17-18页

作者： Camilla T.Erichsen Deying Li Lingzhong Fan Sino-Danish Center University of Chinese Academy of SciencesBeijing 100190China Brainnetome Center Institute of AutomationChinese Academy of SciencesBeijing 100190China Core Centre for molecular Morphology Section for Stereology and MicroscopyDepartment of Clinical MedicineAarhus University8200 Aarhus NDenmark School of Health and Life Sciences University of Health and Rehabilitation SciencesQingdao 266000China

Unraveling the intricate relationship between the structure and function of the human brain remains a central and unresolved question in *** considerations impose significant constraints on invasive techniques in human neuroscience ***,knowledge about human brain function often relies on animal models to provide valuable discoveries and ***,caution is warranted,as findings from animal studies may not always be directly translatable to humans,especially when investigating higher cognitive functions.

关键词： functions insight modal

Theoretical investigation of electron-impact ionization of W8+ion

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Chinese Physics B 2024年第3期33卷 341-349页

作者：张世平张芳军张登红丁晓彬蒋军颉录有马玉龙李麦娟 Marek Sikorski 董晨钟 Key Laboratory of Atomic and molecular Physics & Functional Materials of Gansu Province College of Physics and Electronic EngineeringNorthwest Normal UniversityLanzhou 730070China

The electron-impact single ionization cross section for W8+ion has been calculated using flexible atomic code,employing the level-to-level distorted-wave *** calculations takes into account contributions form both direct ionization(DI)and excitation autoionization(EA).However,the theoretical predictions,based solely on the ground state,tends to underestimate the experimental *** discrepancy can be mitigated by incorporation contributions from excited *** extended the theoretical analysis,including the contributions from the long-lived metastable states with lifetimes exceeding 1.5×10-5 *** employed two statistical models to predict the fraction of ground state ions in the parent ion *** a 79%fraction of parent ions in ground configuration,the experiment measurements align with the *** we derived the theoretical cross-section for the ground state as correlated plasma rate coefficients,and compared it with existing *** the uncertainty in our calculations,our results are still acceptable.

关键词： tungsten ions electron-impact ionization cross section

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