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SH2B1 Tunes Hippocampal ERK Signaling to Influence Fluid Intelligence in Humans and Mice

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Research 2024年第3期2023卷 369-389页

作者： Xiujuan Du Yuhua Yan Juehua Yu Tailin Zhu Chu-Chung Huang Lingli Zhang Xingyue Shan Ren Li Yuan Dai Hui LV Xiao-Yong Zhang Jianfeng Feng Wei-Guang Li Qiang Luo Fei Li Developmental and Behavioral Pediatric Department Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and Ministry of Education-Shanghai Key Laboratory for Children's Environmental HealthXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China Developmental and Behavioral Pediatric Department Shanghai Xinhua Children's HospitalShanghai 200092China National Clinical Research Center for Aging and Medicine at Huashan Hospital Institute of Science and Technology for Brain-lnspired IntelligenceMinistry of Education-Key Laboratory of Computational Neuroscience and Brain-lnspired IntelligenceFudan UniversityShanghai 200433China State Key laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science Institutes of Brain Science and Human Phenom InstituteFudan UniversityShanghai 200032China Shanghai Key laboratory of Brain Functional genomics(Ministry of Education) School of Life SciencesEast China Normal UniversityShanghai 200062China Department of Rehabilitation Medicine Huashan HospitalInstitute for Translational Brain ResearchState Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain ScienceFudan UniversityShanghai 200032China Center for Experimental Studies and Research The First Affliated Hospital of Kunming Medical UniversityKunming 650032China Shanghai Research Center for Brain Science and Brain-lnspired Intelligence Shanghai201210China Institute of Cognitive Neuroscience School of Psychology and Cognitive ScienceEast China Normal UniversityShanghai 200062China.

Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.

关键词： metabolism impaired reversed

Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity

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Signal Transduction and Targeted Therapy 2024年第1期9卷 259-270页

作者： Yan Sun Xiu-Na Yang Shuang-Shuang Yang Yi-Zhu Lyu Bing Zhang Kai-Wen Liu Na Li Jia-Chen Cui Guang-Xiang Huang Cheng-Lin Liu Jie Xu Jian-Qing Mi Zhu Chen Xiao-Hu Fan Sai-Juan Chen Shuo Chen Shanghai Institute of Hematology National Research Center for Translational MedicineState Key Laboratory of Medical GenomicsRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China Department of Hematology Second Hospital of Dalian Medical UniversityDalian 116023China National Facility for Protein Science Shanghai Shanghai Advanced Research InstituteChinese Academy of SciencesShanghai 201210China Legend Biotech China Nanjing 211112China Shanghai Immune Therapy Institute Shanghai Cancer InstituteState Key Laboratory of Oncogenes and Related GenesRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200127China Wondercel Biotechnology Shenzhen 518052China

Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity,safeguarding receptor activation,and facilitating amplification of signal transduction across the cellular ***,cell-surface antigeninduced multimerization(dubbed AIM herein)has not yet been consciously leveraged in chimeric antigen receptor(CAR)engineering for enriching T cell-based *** co-developed ciltacabtagene autoleucel(cilta-cel),whose CAR incorporates two B-cell maturation antigen(BCMA)-targeted nanobodies in tandem,for treating multiple *** we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated *** analysis of BCMA–nanobody complexes revealed atomic details of antigen–antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in ***-induced nanobody CAR multimerization enhanced cytotoxicity,alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release,towards myeloma-derived *** results provide a framework for contemplating the AIM approach in designing next-generation CARs.

关键词： cytotoxicity Antigen elevated

Unveiling the emerging role of curcumin to alleviate ochratoxin A-induced muscle toxicity in grass carp(Ctenopharyngodon idella):in vitro and in vivo studies

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Journal of Animal Science and Biotechnology 2024年第4期15卷 1638-1656页

作者： Piao Zhao Lin Feng Weidan Jiang Pei Wu Yang Liu Hongmei Ren Xiaowan Jin Lu Zhang Haifeng Mi Xiaoqiu Zhou Animal Nutrition Institute Sichuan Agricultural UniversityChengdu 611130SichuanChina Fish Nutrition and Safety Production University Key laboratory of Sichuan Province Sichuan Agricultural UniversityChengdu 611130SichuanChina Key laboratory of Animal Disease‑Resistance Nutrition Ministry of EducationMinistry of Agriculture and Rural AffairsKey Laboratory of Sichuan ProvinceChengdu 611130SichuanChina Tongwei Co. Ltd.Healthy Aquaculture Key Laboratory of Sichuan ProvinceChengdu 610041SichuanChina

Background Ochratoxin A(OTA),a globally abundant and extremely hazardous pollutant,is a significant source of contamination in aquafeeds and is responsible for severe food *** developmental toxicity of OTA and the potential relieving strategy of natural products remain *** study screened the substance curcumin(Cur),which had the best effect in alleviating OTA inhibition of myoblast proliferation,from 96 natural products and investigated its effect and mechanism in reducing OTA myotoxicity in vivo and in *** A total of 720 healthy juvenile grass carp,with an initial average body weight of 11.06±0.05 g,were randomly assigned into 4 groups:the control group(without OTA and Cur),1.2 mg/kg OTA group,400 mg/kg Cur group,and 1.2 mg/kg OTA+400 mg/kg Cur *** treatment consisted of 3 replicates(180 fish)for 60 *** Firstly,we cultured,purified,and identified myoblasts using the tissue block culture *** preliminary screening and re-screening of 96 substances,we examined cell proliferation-related indicators such as cell viability and ultimately found that Cur had the best ***,Cur could alleviate OTA-inhibited myoblast differentiation and myofibrillar development-related proteins(Myo G and MYHC)in vivo and in vitro and improve the growth performance of grass ***,Cur could also promote the expression of OTA-inhibited protein synthesis-related proteins(S6K1 and TOR),which was related to the activation of the AKT/TOR signaling ***,Cur could downregulate the expression of OTA-enhanced protein degradation-related genes(murf1,foxo3a,and ub),which was related to the inhibition of the Fox O3a signaling *** In summary,our data demonstrated the effectiveness of Cur in alleviating OTA myotoxicity in vivo and in *** study confirms the rapidity,feasibility,and effectiveness of establishing a natural product screening method targeting myoblasts to alleviate fungal toxin toxicity.

关键词： Curcumin Grass carp Myotoxic Ochratoxin A Protein deposition

Anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab for first-line treatment in advanced natural killer T cell lymphoma

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1665-1674页

作者： Jie Xiong Shu Cheng Xiao Gao Shan-He Yu Yu-Ting Dai Xin-Yun Huang Hui-Juan Zhong Chao-Fu Wang Hong-Mei Yi Hao Zhang Wei-Guo Cao Rong Li Wei Tang Yan Zhao Peng-Peng Xu Li Wang Wei-Li Zhao Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Nuclear Medicine Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Pathology Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Otolaryngology Shanghai Rujin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Radiation Shanghai Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Hematology Navy Medical Center of PLAShanghaiChina Pole de Recherches Sino-Francais en Science du Vivant et Genomique Laboratory of Molecular PathologyShanghaiChina

Natural killer T cell lymphoma(NKTCL)is highly aggressive,with advanced stage patients poorly responding to intensive *** explore effective and safe treatment for newly diagnosed advanced stage NKTCL,we conducted a phase ll study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab(NCT04096690).Twenty-two patients with a median age of 51 years(range,24-74)were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days,followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 *** complete response and overall response rate after induction treatment were 59%(95%Cl,43-79%)and 68%(95%Cl,47-84%),*** a median follow-up of 30 months,the 2 year progression-free and overall survival rates were 68%(95%Cl,45-83%)and 86%(95%Cl,63-95%),*** most frequently grade 3/4 adverse events were neutropenia(32%,n=7)and hypofibrinogenemia(18%,n=4),which were manageable and led to no discontinuation of *** proportion score of PD-L1,peripheral blood high-density lipoprotein cholesterol,and apolipoprotein A-l correlated with good response,while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab *** conclusion,the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed,advanced stage *** lipid profle and immunosuppressive signature contributed to treatment resistance,providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

关键词： killer metabolism lymphoma

Loss of SHROOM3 affects neuroepithelial cell shape through regulating cytoskeleton proteins in cynomolgus monkey organoids

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Zoological Research 2024年第2期45卷 233-241页

作者： Peng Li Ting Zhang Ruo Wu Jun-Yu Zhang Yan Zhuo Shan-Gang Li Jiao-Jian Wang Wen-Ting Guo Zheng-Bo Wang Yong-Chang Chen State Key laboratory of Primate Biomedical Research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnan 650500China Yunnan Key laboratory of Primate Biomedical Research KunmingYunnan 650500China

Neural tube defects(NTDs)are severe congenital neurodevelopmental disorders arising from incomplete neural tube *** folate supplementation has been shown to mitigate the incidence of NTDs,some cases,often attributable to genetic factors,remain *** SHROOM3 gene has been implicated in NTD cases that are unresponsive to folate supplementation;at present,however,the underlying mechanism remains *** tube morphogenesis is a complex process involving the folding of the planar epithelium of the neural *** determine the role of SHROOM3 in early developmental morphogenesis,we established a neuroepithelial organoid culture system derived from cynomolgus monkeys to closely mimic the in vivo neural plate *** of SHROOM3 resulted in shorter neuroepithelial cells and smaller *** morphological changes were attributed to the insufficient recruitment of cytoskeletal proteins,namely fibrous actin(F-actin),myosin II,and phospho-myosin light chain(PMLC),to the apical side of the neuroepithelial ***,these defects were not rescued by folate *** sequencing revealed that differentially expressed genes were enriched in biological processes associated with cellular and organ *** summary,we established an authentic in vitro system to study NTDs and identified a novel mechanism for NTDs that are unresponsive to folate supplementation.

关键词： Neural tube defects SHROOM3 Neuroepithelial Organoids Cynomolgus monkey

Direct reprogramming of fibroblasts into functional hepatocytes via CRISPRa activation of endogenous Gata4 and Foxa3

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Chinese Medical Journal 2024年第11期137卷 1351-1359页

作者： Jiacheng Li Ruopu Li Xue Bai Wenlong Zhang Yu Nie Shengshou Hu State Key laboratory of Cardiovascular Disease Fuwai Hospital and Cardiovascular InstituteNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China Department of Obstetrics and Gynecology Beijing Advanced Innovation Center for GenomicsThird HospitalSchool of Life SciencesPeking UniversityBeijing 100871China

Background:The ability to generate functional hepatocytes without relying on donor liver organs holds significant therapeutic promise in the fields of regenerative medicine and potential liver disease *** regularly interspaced short palindromic repeats(CRISPR)activator(CRISPRa)is a powerful tool that can conveniently and efficiently activate the expression of multiple endogenous genes simultaneously,providing a new strategy for cell fate *** main purpose of this study is to explore the feasibility of applying CRISPRa for hepatocyte reprogramming and its application in the treatment of mouse liver ***:The differentiation of mouse embryonic fibroblasts(MEFs)into functional induced hepatocyte-like cells(iHeps)was achieved by utilizing the CRISPRa synergistic activation mediator(SAM)system,which drove the combined expression of three endogenous transcription factors-Gata4,Foxa3,and Hnf1a-or alternatively,the expression of two transcription factors,Gata4 and *** vivo,we injected adeno-associated virus serotype 6(AAV6)carrying the CRISPRa SAM system into liver fibrotic Col1a1-Cre^(ER);Cas9^(fl/fl)mice,effectively activating the expression of endogenous Gata4 and Foxa3 in *** endogenous transcriptional activation of genes was confirmed using real-time quantitative polymerase chain reaction(RT-qPCR)and RNA-seq,and the morphology and characteristics of the induced hepatocytes were observed through *** level of hepatocyte reprogramming in vivo is detected by immunofluorescence staining,while the improvement of liver fibrosis is evaluated through Sirius red staining,alpha-smooth muscle actin(α-SMA)immunofluorescence staining,and blood alanine aminotransferase(ALT)***:Activation of only two factors,Gata4 and Foxa3,via CRISPRa was sufficient to successfully induce the transformation of MEFs into *** iHeps could be expanded in vitro and displayed functional characteristics similar to th

关键词： Liver fibrosis CRISPRa cell reprogramming Transcriptional activation Hepatocytes

HvMPK4 phosphorylates HvWRKY1 to enhance its suppression of barley immunity to powdery mildew fungus

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Journal of Genetics and genomics 2024年第3期51卷 313-325页

作者： Pengya Xue Ling Zhang Renchun Fan Yanan Li Xinyun Han Ting Qi Lifang Zhao Deshui Yu Qian-Hua Shen State Key laboratory of Plant cell and Chromosome Engineering Institute of Genetics and Developmental BiologyInnovation Academy for Seed DesignChinese Academy of SciencesBeijing 100101China CAS Center for Excellence in Biotic Interactions College of Advanced Agricultural SciencesUniversity of Chinese Academy of SciencesBeijing 100049China Department of Nutritional Sciences&Toxicology University of CaliforniaBerkeleyCA 94720USA Lushan Botanical Garden Chinese Academy of ScienceJiujiangJiangxi 332900China

Mitogen-activated protein kinase(MAPK)cascades play important roles in disease resistance in model plant ***,the functions of MAPK signaling pathways in crop disease resistance are largely *** we report the function of HvMKK1-HvMPK4-HvWRKY1 module in barley immune ***4 is identified to play a negative role in barley immune response against Bgh,as virus-induced gene silencing of HvMPK4 results in enhanced disease resistance whilst stably overexpressing HvMPK4 leads to super-susceptibility to Bgh ***,the barley MAPK kinase HvMKK1 is found to specifically interact with HvMPK4,and the activated HvMKK1^(DD) variant specifically phosphorylates HvMPK4 in ***,the transcription factor HvWRKY1 is identified to be a downstream target of HvMPK4 and phosphorylated by HvMPK4 in vitro in the presence of HvMKK1^(DD).Phosphorylation assay coupled with mutagenesis analyses identifies S122,T284,and S347 in HvWRKY1 as the major residues phosphorylated by ***1 is phosphorylated in barley at the early stages of Bgh infection,which enhances its suppression on barley immunity likely due to enhanced DNA-binding and transcriptional repression *** data suggest that the HvMKK1-HvMPK4 kinase pair acts upstream of HvWRKY1 to negatively regulate barley immunity against powdery mildew.

关键词： Barley MPK4 WRKY1 Phosphorylation Disease resistance Powdery mildew

Comparative genomics reveal shared genomic changes in syngnathid fishes and signatures of genetic convergence with placental mammals

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National Science Review 2020年第6期7卷 964-977页

作者： Yan-Hong Zhang Vydianathan Ravi Geng Qin He Dai Hui-Xian Zhang Feng-Ming Han Xin Wang Yu-Hong Liu Jian-Ping Yin Liang-Min Huang Byrappa Venkatesh Qiang Lin CAS Key laboratory of Tropical marine Bio-resources and Ecology South China Sea Institute of Oceanology Innovation Academy of South China Sea Ecology and Environmental Engineering Chinese Academy of Sciences Comparative and Medical genomics laboratory Institute of Molecular and Cell Biology Southern marine Science and Engineering Guangdong laboratory (Guangzhou) Biomarker Technologies Corporation University of Chinese Academy of Sciences

Syngnathids(seahorses, pipefishes and seadragons) exhibit an array of morphological innovations including loss of pelvic fins, a toothless tubular mouth and male pregnancy. They comprise two subfamilies:Syngnathinae and Nerophinae. Genomes of three Syngnathinae members have been analyzed *** this study, we have sequenced the genome of a Nerophinae member, the Manado pipefish(Microphis manadensis), which has a semi-enclosed brood pouch. Comparative genomic analysis revealed that the molecular evolutionary rate of the four syngnathids is higher than that of other teleosts. The loss of all but one P/Q-rich SCPP gene in the syngnathids suggests a role for the lost genes in dentin and enameloid formation in teleosts. Genome-wide comparison identified a set of 118 genes with parallel identical amino acid substitutions in syngnathids and placental mammals. Association of some of these genes with placental and embryonic development in mammals suggests a role for them in syngnathid pregnancy.

关键词： Manado pipefish whole-genome sequencing transposable elements placenta-like structure convergent evolution

Enhanced biocompatibility of ZnS:Mn quantum dots encapsulated with Aloe vera extract for therapeutic applications

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Chinese Physics B 2016年第8期25卷 412-416页

作者： Anilkumar M Bindu K R Sneha Saj A Anila E I cell culture laboratory Department of Botany UC College Optoelectronic and Nanomaterials' Research laboratory Department of Physics UC College Department of Physics SSV College

Toxicity of nanoparticles remains to be a major issue in their application to the biomedical field. Aloe vera（AV） is one of the most widely exploited medicinal plants that have a multitude of amazing properties in the field of *** extract of Aloe vera can be used as a novel stabilising agent for quantum dots to reduce toxicity. We report the synthesis, structural characterization, antibacterial activity and cytotoxicity studies of ZnS：Mn quantum dots synthesized by the colloidal precipitation method, using methanol extract of Aloe vera（AVME） as the capping agent. The ZnS：Mn quantum dots capped with AVME exhibit superior performances in biocompatibility and antibacterial activity compared with ZnS：Mn quantum dots without encapsulation.

关键词： quantum dot transmission electron microscopy biocompatibility