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New aspects of a small GTPase RAB35 in brain development and function

Neural Regeneration Research 2025年第7期20卷 1971-1980页

作者： Ikuko Maejima Ken Sato Laboratory of molecular Traffic Institute for Molecular and Cellular RegulationGunma UniversityMaebashiJapan

In eukaryotic cells,organelles in the secretory,lysosomal,and endocytic pathways actively exchange biological materials with each other through intracellular membrane trafficking,which is the process of transporting the cargo of proteins,lipids,and other molecules to appropriate compartments via transport vesicles or *** processes are strictly regulated by various small GTPases such as the RAS-like in rat brain(RAB)protein family,which is the largest subfamily of the RAS *** of membrane trafficking affects tissue homeostasis and leads to a wide range of diseases,including neurological disorders and neurodegenerative ***,it is important to understand the physiological and pathological roles of RAB proteins in brain ***35,a member of the RAB family,is an evolutionarily conserved protein in metazoans.A wide range of studies using cultured mammalian cells and model organisms have revealed that RAB35 mediates various processes such as cytokinesis,endocytic recycling,actin bundling,and cell ***35 is also involved in neurite outgrowth and turnover of synaptic *** generated brain-specific Rab35 knockout mice to study the physiological roles of RAB35 in brain development and *** mice exhibited defects in anxiety-related behaviors and spatial ***,RAB35 is required for the precise positioning of pyramidal neurons during hippocampal development,and thereby for normal hippocampal *** contrast,layer formation in the cerebral cortex occurred superficially,even in the absence of RAB35,suggesting a predominant role for RAB35 in hippocampal development rather than in cerebral cortex *** studies have suggested an association between RAB35 and neurodegenerative diseases,including Parkinson's disease and Alzheimer's *** this review,we provide an overview of the current understanding of subcellular functions of *** also provide insights into the phys

关键词： endocytosis endosomes hippocampal development neurodegenerative diseases RAB35

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Targeting RAF dimers in RAS mutant tumors:From biology to clinic

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1895-1923页

作者： Huanhuan Yin Qiulin Tang Hongwei Xia Feng Bi division of Abdominal Cancer Department of Medical OncologyCancer Center and Laboratory of Molecular Targeted Therapy in OncologyWest China HospitalSichuan UniversityChengdu 610041China

RAS mutations occur in approximately 30%of tumors worldwide and have a poor prognosis due to limited *** targeting of KRAS G12C has achieved significant success in recent years,but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations.A highly promising approach is to target the MAPK pathway downstream of RAS,with a particular focus on RAF ***-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a ***,their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF *** address the issue of RAF dimerization,type II RAF inhibitors have emerged as leading *** clinical studies have shown the initial effectiveness of these agents against RAS mutant ***,type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant *** review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations,as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.

关键词： RAS mutations RAF dimerization RAF inhibitors Cancer therapy Drug resistance

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Heat Shock Factor A1s are required for phytochrome-interacting factor 4-mediated thermomorphogenesis in Arabidopsis

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Journal of Integrative Plant Biology 2024年第1期66卷 20-35页

作者： Bingjie Li Shimeng Jiang Liang Gao Wenhui Wang Haozheng Luo Yining Dong Zhihua Gao Shuzhi Zheng Xinye Liu Wenqiang Tang Key Laboratory of molecular and cellular Biology of Ministry of Education Hebei Research Center of the Basic Discipline of Cell BiologyHebei Collaboration Innovation Center for Cell SignalingHebei Key Laboratory of Molecular and Cellular BiologyCollege of Life SciencesHebei Normal UniversityShijiazhuang 050024China School of Information Technology Hebei University of Economics and BusinessShijiazhuang 050061China

Thermomorphogenesis and the heat shock(HS)response are distinct thermal responses in plants that are regulated by PHYTOCHROME-INTERACTING FACTOR 4(PIF4)and HEAT SHOCK FACTOR A1s(HSFA1s),*** is known about whether these responses are interconnected and whether they are activated by similar *** analysis of transcriptome dynamics in response to warm temperature(28℃)treatment revealed that 30 min of exposure activated the expression of a subset of HSFA1 target genes in Arabidopsis ***,a loss-of-function HSFA1 quadruple mutant(hsfa1-cq)was insensitive to warm temperature-induced hypocotyl *** hsfa1-cq plants grown at 28℃,the protein and transcript levels of PIF4 were greatly reduced,and the circadian rhythm of many thermomorphogenesis-related genes(including PIF4)was ***,the nuclear localization of HSFA1s and the binding of HSFA1d to the PIF4 promoter increased following warm temperature exposure,whereas PIF4 overexpression in hsfa1-cq partially rescued the altered warm temperature-induced hypocotyl growth of the *** together,these results suggest that HSFA1s are required for PIF4 accumulation at a warm temperature,and they establish a central role for HSFA1s in regulating both thermomorphogenesis and HS responses in Arabidopsis.

关键词： HSFA1 PIF4 thermomorphogenesis

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The dual role of striatal interneurons: circuit modulation and trophic support for the basal ganglia

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Neural Regeneration Research 2024年第6期19卷 1277-1283页

作者： Elliot Wegman Marlena Wosiski-Kuhn Yu Luo Department of molecular and cellular Biosciences University of Cincinnati 2. Department of Emergency Medicine at the School of Medicine University of Cincinnati Neuroscience Graduate Program University of Cincinnati

Striatal interneurons play a key role in modulating striatal-dependent behaviors, including motor activity and reward and emotional processing. Interneurons not only provide modulation to the basal ganglia circuitry under homeostasis but are also involved in changes to plasticity and adaptation during disease conditions such as Parkinson’s or Huntington’s disease. This review aims to summarize recent findings regarding the role of striatal cholinergic and GABAergic interneurons in providing circuit modulation to the basal ganglia in both homeostatic and disease conditions. In addition to direct circuit modulation, striatal interneurons have also been shown to provide trophic support to maintain neuron populations in adulthood. We discuss this interesting and novel role of striatal interneurons, with a focus on the maintenance of adult dopaminergic neurons from interneuronderived sonic-hedgehog.

关键词： cholinergic dopamine GABAergic interneuron levodopa-induced dyskinesia parvalbumin sonic hedgehog striatum trophic factor

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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

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Transcriptomic and pathological profiling of a new congenic mouse model with Lepr mutation:Evaluating susceptibility to the development of obesity and NAFLD

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Genes & Diseases 2024年第3期11卷 34-38页

作者： MJ Mahesh Kumar Shailendra Arindkar Masum Saini Perumal Nagarajan National Institute of Immunology New Delhi 100067India Center for cellular and molecular Biology Hyderabad 500007India Regional Center for Biotechnology Faridabad 121001India

Non-alcoholic fatty liver disease(NAFLD)and type 2 diabetes mellitus(T2DM)are two disease conditions for which obesity is a risk factor.^(1)Due to the close relationship between the three pathologies,researchers frequently use the same mouse models to identify the underlying processes of obesity,NAFLD,and *** instance,leptin(Lep)-null(ob/ob)and leptin receptor(Lepr)-deficient(db/db)mice spontaneously develop NAFLD and show different phenotypes of extreme obesity and diabetes,respectively.

关键词： obesity NAFLD Lep

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Multiplexed fluorescence and scatter detection with single cell resolution using on-chip fiber optics for droplet microfluidic applications

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Microsystems & Nanoengineering 2024年第2期10卷 207-218页

作者： Preksha Gupta Ambili Mohan Apurv Mishra Atindra Nair Neeladri Chowdhury Dhanush Balekai Kavyashree Rai Anil Prabhakar Taslimarif Saiyed Discovery Innovation Accelerator Centre for Cellular and Molecular PlatformsBellary RoadBengaluru560065KarnatakaIndia Department of Electrical Engineering Indian Institute of Technology MadrasChennai600036Tamil NaduIndia

Droplet microfluidics has emerged as a critical component of several high-throughput single-cell analysis techniques in biomedical research and *** significant progress in the development of individual assays,multiparametric optical sensing of droplets and their encapsulated contents has been *** current approaches,most commonly involving microscopy-based high-speed imaging of droplets,are technically complex and require expensive instrumentation,limiting their widespread *** address these limitations,we developed the OptiDrop platform;this platform is a novel optofluidic setup that leverages the principles of flow *** platform enables on-chip detection of the scatter and multiple fluorescence signals from the microfluidic droplets and their contents using optical *** highly customizable on-chip optical fiber-based signal detection system enables simplified,miniaturized,low-cost,multiparametric sensing of optical signals with high sensitivity and single-cell resolution within each *** demonstrate the ability of the OptiDrop platform,we conducted a differential expression analysis of the major histocompatibility complex(MHC)protein in response to IFNγ*** results showed the platform’s ability to sensitively detect cell surface biomarkers using fluorescently labeled ***,the OptiDrop platform combines the versatility of flow cytometry with the power of droplet microfluidics to provide wide-ranging,scalable optical sensing solutions for research and diagnostics.

关键词： scatter enable resolution

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Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor?

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Neural Regeneration Research 2024年第1期19卷 29-34页

作者： Marta Zagrebelsky Martin Korte division of cellular Neurobiology Zoological InstituteTU BraunschweigBraunschweigGermany Helmholtz Centre for Infection Research AG NINDBraunschweigGermany

Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological *** has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the *** to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological *** r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic ***,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side *** re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational *** the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist *** this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological ***,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist *** benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal ***,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin recepto

关键词： Alzheimer's disease brain-derived neurotrophic factor depression Parkinson's disease tropomyosin receptor kinase B receptor

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Orientation Bias of Self-Assembled Alkanes and Their Derivatives Under Dynamic Lateral Nanoconfinement Conditions

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CCS Chemistry 2024年第4期6卷 1024-1033页

作者： Conditions Lihua Yu Yuanzhi Xia Tianze Hu Brent Daelemans Steven De Feyter Department of Chemistry Division of Molecular Imaging and PhotonicsKU LeuvenB-3001 Leuven

Self-assembled molecular networks(SAMNs)formed on crystalline solid substrates result from the spontaneous arrangement of individual molecules into structured *** interaction between molecules and the substrate leads to a nonrandom orientation of SAMNs with respect to the substrate’s *** the case of graphite,the sixfold rotational symmetry of the substrate results in an equivalent rotational degeneracy in the orientation of *** this study,we explored how nanoconfinement,that is,the restriction of SAMN formation to nanometersized areas,known as nanocorrals,could impact and potentially alleviate the orientational degeneracy of SAMNs,with emphasis on the influence of molecule symmetry,size,and intermolecular *** this end,we investigated the orientation distribution of n-alkanes and functionalized alkanes within nanocorrals,which were fabricated using scanning tunneling microscopy lithography(nanoshaving).We observed lifting of orientational degeneracy for long alkanes,contrary to shorter alkanes,which did not exhibit this orientation ***,functionalized alkanes with hydrogen bonding groups demonstrated preferential alignment regardless of length,highlighting the significance of stabilizing intermolecular interactions in the alignment *** study discussed the underlying principles of the molecular packing process and shed light on the complexity of molecular self-assembly in nanoconfined spaces.

关键词： self-assembly confinement condition nanocorral orientation bias scanning tunneling microscopy

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AtVQ25 promotes salicylic acid-related leaf senescence by fine-tuning the self-repression of AtWRKY53

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Journal of Integrative Plant Biology 2024年第6期66卷 1126-1147页

作者： Qi Tan Mingming Zhao Jingwei Gao Ke Li Mengwei Zhang Yunjia Li Zeting Liu Yujia Song Xiaoyue Lu Zhengge Zhu Rongcheng Lin Pengcheng Yin Chunjiang Zhou Geng Wang Ministry of Education Key Laboratory of molecular and cellular Biology Hebei Research Center of the Basic Discipline of Cell BiologyHebei Collaboration Innovation Center for Cell Signaling and Environmental AdaptationHebei Key Laboratory of Molecular and Cellular BiologyCollege of Life SciencesHebei Normal UniversityShijiazhuang 050024China College of Chemical Engineering Shijiazhuang UniversityShijiazhuang 050035China Institute of Botany Chinese Academy of SciencesBeijing 100093China

Most mechanistic details of chronologically ordered regulation of leaf senescence are *** networks centered on AtWRKY53 are crucial for orchestrating and integrating various senescence-related ***,AtWRKY53binds to its own promoter and represses transcription of AtWRKY53,but the biological significance and mechanism underlying this selfrepression remain *** this study,we identified the VQ motif-containing protein AtVQ25as a cooperator of *** expression level of AtVQ25 peaked at mature stage and was specifically repressed after the onset of leaf ***25-overexpressing plants and atvq25 mutants displayed precocious and delayed leaf senescence,***,we identified AtWRKY53 as an interacting partner of *** determined that interaction between AtVQ25 and AtWRKY53 prevented AtWRKY53from binding to W-box elements on the AtWRKY53promoter and thus counteracted the selfrepression of *** addition,our RNA-sequencing data revealed that the AtVQ25-AtWRKY53 module is related to the salicylic acid(SA)*** leaf senescence and SA-induced leaf senescence in AtVQ25-overexpressing lines were inhibited by an SA pathway mutant,atsid2,and Nah G transgenic plants;AtVQ25-overexpressing/atwrky53 plants were also insensitive to SA-induced leaf ***,we demonstrated that AtVQ25 directly attenuates the self-repression of AtWRKY53 during the onset of leaf senescence,which is substantially helpful for understanding the timing of leaf senescence onset modulated by AtWRKY53.

关键词： AtWRKY53 leaf senescence salicylic acid transcriptional regulation VQ motif-containing proteins

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