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

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 mutant.However,there are currently no approved targeted therapies or immunotherapies against mutant p53.Here,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 vitro.We then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic effects.Our 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 p53.In cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular cytotoxicity.We made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 alleles.In vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in mice.The 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 antibody.These 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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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 diagnostics.Despite significant progress in the development of individual assays,multiparametric optical sensing of droplets and their encapsulated contents has been challenging.The current approaches,most commonly involving microscopy-based high-speed imaging of droplets,are technically complex and require expensive instrumentation,limiting their widespread adoption.To address these limitations,we developed the OptiDrop platform;this platform is a novel optofluidic setup that leverages the principles of flow cytometry.Our platform enables on-chip detection of the scatter and multiple fluorescence signals from the microfluidic droplets and their contents using optical fibers.The 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 droplet.To demonstrate the ability of the OptiDrop platform,we conducted a differential expression analysis of the major histocompatibility complex(MHC)protein in response to IFNγstimulation.Our results showed the platform’s ability to sensitively detect cell surface biomarkers using fluorescently labeled antibodies.Thus,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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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),respectively.Little is known about whether these responses are interconnected and whether they are activated by similar mechanisms.An 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 thaliana.Meanwhile,a loss-of-function HSFA1 quadruple mutant(hsfa1-cq)was insensitive to warm temperature-induced hypocotyl growth.In 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 disturbed.Additionally,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 mutant.Taken 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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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 Adaptation Hebei Key Laboratory of Molecular and Cellular Biology College of Life Sciences Hebei Normal University College of Chemical Engineering Shijiazhuang University Institute of Botany Chinese Academy of Sciences

Most mechanistic details of chronologically ordered regulation of leaf senescence are unknown.Regulatory networks centered on AtWRKY53 are crucial for orchestrating and integrating various senescence-related signals. Notably, AtWRKY53binds to its own promoter and represses transcription of AtWRKY53, but the biological significance and mechanism underlying this selfrepression remain unclear. In this study, we identified the VQ motif-containing protein AtVQ25as a cooperator of AtWRKY53. The expression level of AtVQ25 peaked at mature stage and was specifically repressed after the onset of leaf senescence. AtVQ25-overexpressing plants and atvq25 mutants displayed precocious and delayed leaf senescence, respectively. Importantly, we identified AtWRKY53 as an interacting partner of AtVQ25. We determined that interaction between AtVQ25 and AtWRKY53 prevented AtWRKY53from binding to W-box elements on the AtWRKY53promoter and thus counteracted the selfrepression of AtWRKY53. In addition, our RNA-sequencing data revealed that the AtVQ25-AtWRKY53 module is related to the salicylic acid(SA) pathway. Precocious 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 senescence. Collectively, 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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Fine-needle aspiration technique under endoscopic ultrasound guidance:A technical approach for RNA profiling of pancreatic neoplasms

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World Journal of Gastrointestinal Oncology 2024年第6期16卷 2663-2672页

作者： Sabina Sherafedinovna Seyfedinova Olga Aleksandrovna Freylikhman Polina Sergeevna Sokolnikova Konstantin Aleksandrovich Samochernykh Anna Aleksandrovna Kostareva Olga Viktorovna Kalinina Evgeniy Gennadievich Solonitsyn research Laboratory of Digestive Cancer Almazov Medical Research CentreSaint-Petersburg 197341Russia research Laboratory of molecular and cellular Modeling and Gene Therapy Almazov Medical Research CentreSaint-Petersburg 197341Russia Head of Russian Neurosurgical Institute Named after Prof.A.L.Polenova Russian Neurosurgical Institute Named after Prof.A.L.PolenovaSaint-Petersburg 191014Russia Head of Institute of molecular Biology and Genetics Almazov National Medical Research CentreSaint-Petersburg 197341Russia research Laboratory of Autoimmune and Autoinflammatory Diseases Almazov National Medical Research CentreSaint-Petersburg 197341Russia

BACKGROUND Early diagnosis of pancreatic ductal adenocarcinoma(PDAC)has been a longstanding challenge.The prognosis of patients with PDAC depends on the stage at diagnosis.It is necessary to identify biomarkers for the detection and differentiation of pancreatic tumors and optimize PDAC sample preparation procedures for DNA and RNA analysis.Most molecular studies are done using paraffin-embedded blocks;however,the integrity of DNA and RNA is often compromised in this format.Moreover,RNA isolated from human pancreatic tissue samples is generally of low quality,in part,because of the high concentration of endogenous pancreatic RNAse activity present.AIM To assess the potential of endoscopic ultrasound-guided fine-needle aspiration(EUS-FNA)to obtain specimens from pancreatic neoplasms for subsequent RNA molecular profiling,including next-generation sequencing(NGS).METHODS Thirty-four EUS-FNA samples were included in this study:PDAC(n=15),chronic pancreatitis(n=5),pancreatic cysts(n=14),mucinous cysts(mucinous cystic neoplasia/intraductal papillary mucinous neoplasia)n=7,serous cystic neoplasms n=5,and pseudocysts n=2.Cyst material consisted of cyst fluid and cyst wall samples obtained by through-the-needle biopsy(TTNB).Samples were stored at -80℃ until analysis.RNA purity(A260/230,A260/280 ratios),concentration,and integrity(RIN)were assessed.Real-time polymerase chain reaction was conducted on all samples,and small RNA libraries were prepared from solid mass samples.RESULTS RNA was successfully extracted from 29/34(85%)EUS-FNA samples:100% pancreatic adenocarcinoma samples,100% chronic pancreatitis samples,70% pancreatic fluid cyst samples,and 50%TTNB samples.The relative expression of GAPDH and HPRT were obtained for all successfully extracted RNA samples(n=29)including lowquality RNA specimens.Low concentration and nonoptimal RIN values(no less than 3)of RNA extracted from EUS-FNA samples did not prevent NGS library preparation.The suitability of cyst fluid samples for RNA profiling varied.The quality of RNA extr

关键词： Endoscopic ultrasound-guided,fine-needle aspiration Pancreatic cancer Pancreatic cysts RNA extraction Through-the-needle biopsy Next-generation sequencing

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Wood of trees:cellular structure,molecular formation,and genetic engineering

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Journal of Integrative Plant Biology 2024年第3期66卷 443-467页

作者： Yingying Zhu Laigeng Li State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems and College of Ecology Lanzhou UniversityLanzhou 730000China National Key Laboratory of Plant molecular Genetics CAS Center for Excellence in Molecular Plant SciencesChinese Academy of SciencesShanghai 200032China

Wood is an invaluable asset to human society due to its renewable nature,making it suitable for both sustainable energy production and material manufacturing.Additionally,wood derived from forest trees plays a crucial role in sequestering a significant portion of the carbon dioxide fixed during photosynthesis by terrestrial plants.Nevertheless,with the expansion of the global population and ongoing industrialization,forest coverage has been substantially decreased,resulting in significant challenges for wood production and supply.Wood production practices have changed away from natural forests toward plantation forests.Thus,understanding the underlying genetic mechanisms of wood formation is the foundation for developing high-quality,fast-growing plantation trees.Breeding ideal forest trees for wood production using genetic technologies has attracted the interest of many.Tremendous studies have been carried out in recent years on the molecular,genetic,and cell-biological mechanisms of wood formation,and considerable progress and findings have been achieved.These studies and findings indicate enormous possibilities and prospects for tree improvement.This review will outline and assess the cellular and molecular mechanisms of wood formation,as well as studies on genetically improving forest trees,and address future development prospects.

关键词： cambium cell wall Populus wood formation xylem

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Hippo-YAP/TAZ signaling in breast cancer:Reciprocal regulation of microRNAs and implications in precision medicine

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Genes & Diseases 2024年第2期11卷 760-771页

作者： Farzad Sadri Seyede fatemeh Hosseini Zohreh Rezaei Mohammad Fereidouni Student research Committee Birjand University of Medical SciencesBirjand ***Iran Tabas School of Nursing Birjand University of Medical SciencesBirjand ***Iran Department of Biology University of Sistan and BaluchestanZahedan ***Iran cellular and molecular research Center Birjand University of Medical SciencesBirjand ***Iran

Breast cancer is a molecularly heterogeneous disease and the most common female malignancy.In recent years,therapy approaches have evolved to accommodate molecular diversity,with a focus on more biologically based therapies to minimize negative consequences.To regulate cell fate in human breast cells,the Hippo signaling pathway has been associated with the alpha subtype of estrogen receptors.This pathway regulates tissue size,regeneration,and healing,as well as the survival of tissue-specific stem cells,proliferation,and apoptosis in a variety of organs,allowing for cell differentiation.Hippo signaling is mediated by the kinases MST1,MST2,LATS1,and LATS2,as well as the adaptor proteins SAV1 and MOB.These kinases phosphorylate the downstream effectors of the Hippo pathway,yes-associated protein(YAP),and transcriptional coactivator with PDZ-binding motif(TAZ),suppressing the expression of their downstream target genes.The Hippo signaling pathway kinase cascade plays a significant role in all cancers.Understanding the principles of this kinase cascade would prevent the occurrence of breast cancer.In recent years,small noncoding RNAs,or microRNAs,have been implicated in the development of several malignancies,including breast cancer.The interconnections between miRNAs and Hippo signaling pathway core proteins in the breast,on the other hand,remain poorly understood.In this review,we focused on highlighting the Hippo signaling system,its key parts,its importance in breast cancer,and its regulation by miRNAs and other related pathways.

关键词： Breast cancer Hippo signaling Large tumor suppressor kinase 1 microRNAs PDZ-binding motif Yes-associated protein

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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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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 range.Certainly,the body necessitates a stable supply of energy mainly provided by glucose for various bodily functions.High or low blood glucose levels would impair the physiological functions of various organs of the body.Prolonged high blood glucose(i.e.,

关键词： HYPOGLYCEMIA

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Characterization of the infectivity of an Indonesian Zika virus strain in mammalian cell lines

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Asian Pacific Journal of Tropical Biomedicine 2024年第5期14卷 215-224页

作者： Justus Thomas Obiajulu Sievers Anom Bowolaksono R.Tedjo Sasmono Graduate School of Biology Department of BiologyFaculty of Mathematics and Natural SciencesUniversitas IndonesiaDepok 16424Indonesia Eijkman research Center for molecular Biology National Research and Innovation AgencyCibinong 16911Indonesia cellular and molecular Mechanisms in Biological System research Group Department of BiologyFaculty of Mathematics and Natural SciencesUniversitas IndonesiaDepok 16424Indonesia

Objective:To characterize the infection patterns and growth characteristics of the Zika virus(ZIKV)strain JMB-185 from Indonesia in various mammalian cell lines.Methods:ZIKV was grown in human(A549,HEK293,HepG2,Huh7,Jurkat,and THP-1)and non-human mammalian(RAW264.7,Vero,and Vero76)cell lines.Viral replication kinetics were measured using plaque assay,while intra-and extracellular viral RNA concentrations were assessed using RT-PCR.Flow cytometry was used to quantify the infected cells and cell viability was measured using an MTT assay.The ability of ZIKV to infect cell lines was visualized using a fluorescence immunostaining assay.Results:This ZIKV strain preferentially infected the lung,kidney,and liver cell lines A549,HEK293,Huh7,Vero,and Vero76,but not the immune cells Jurkat,RAW264.7,and THP-1.By contrast,the ZIKV showed no sign of infection in HepG2 cells,while maintaining viral titer over 3 days post-infection,with no infection recorded in immunostaining,no increase in viral RNA,and no indication of cell deterioration.Conclusions:The Indonesian ZIKV strain has a similar infection profile as other strains,except for its poor infectivity on HepG2 cells.Information on the growth characteristics of Indonesia ZIKV will help expand our understanding of the biology of ZIKV which will be useful for various applications including antiviral discovery.

关键词： Zika virus Infectivity Replication Cell lines In vitro

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