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Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics

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Protein & Cell 2024年第5期15卷 364-384页

作者： Huifen Lu Ying Jing Chen Zhang Shuai Ma Weiqi Zhang Daoyuan Huang Bin Zhang Yuesheng Zuo Yingying Qin Guang-Hui Liu Yang Yu Jing Qu Si Wang Advanced Innovation center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational medicine center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for Stem Cell and Regenerative medicine Beijing 100101China CAS Key laboratory of Genomic and precision medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China Institute for Stem cell and Regeneration CASBeijing 100101China China National center for Bioinformation Beijing 100101China The Fifth People’s Hospital of Chongqing Chongqing 400062China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Sino-Danish center for Education and Research Beijing 101408China Department of Obstetrics and Gynecology Center for Reproductive MedicinePeking UniversityThird HospitalBeijing 100191China Clinical Stem Cell Research center Peking UniversityThird HospitalBeijing 100191China center for Reproductive medicine Cheeloo College of MedicineShandong UniversityJinan 250012China Key laboratory of Reproductive Endocrinology of Ministry of Education National Research Center for Assisted Reproductive Technology and Reproductive GeneticsShandong Key Laboratory of Reproductive MedicineShandong Provincial Clinical Research Center for Reproductive HealthJinan 250012China Key laboratory of Organ Regeneration and Reconstruction Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Biomarker Consortium Beijing 100101China

The ovary is indispensable for female reproduction,and its age-dependent functional decline is the primary cause of ***,the molecular basis of ovarian aging in higher vertebrates remains poorly ***,we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate *** a global view,somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region,likely constituting a hostile microenvironment that facilitates ovarian ***,we uncovered that inflammation,the senescent-associated secretory phenotype,senescence,and fibrosis are the likely primary contributors to ovarian aging(PCOA).Of note,we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2(Metallothionein 2)highly expressing spot(MT2^(high))characterized by high levels of inflammation,potentially serving as an aging hotspot in the primate ***,with advanced age,a subpopulation of MT2^(high)accumulates,likely disseminating and amplifying the senescent signal *** study establishes the first primate spatiotemporal transcriptomic atlas,advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.

关键词： spatial transcriptome primate ovary aging senescence inflammation

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KHK-A promotes fructose-dependent colorectal cancer liver metastasis by facilitating the phosphorylation and translocation of PKM2

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2959-2976页

作者： Chaofan Peng Peng Yang Dongsheng Zhang Chi Jin Wen Peng Tuo Wang Qingyang Sun Zhihao Chen Yifei Feng Yueming Sun Department of General Surgery the First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029China Colorectal Institute of Nanjing Medical University Nanjing 210029China The First School of Clinical medicine Nanjing Medical UniversityNanjing 210029China Jiangsu Province Engineering Research center of Colorectal Cancer precision medicine and Translational medicine Nanjing 210029China

Excessive fructose diet is closely associated with colorectal cancer(CRC)***,fructose’s specific function and precise mechanism in colorectal cancer liver metastasis(CRLM)is rarely ***,this study reported that the fructose absorbed by primary colorectal cancer could accelerate CRLM,and the expression of KHK-A,not KHK-C,in liver metastasis was higher than in paired primary ***,KHK-A facilitated fructose-dependent CRLM in vitro and in vivo by phosphorylating PKM2 at ***2 phosphorylated by KHK-A inhibited its tetramer formation and pyruvic acid kinase activity but promoted the nuclear accumulation of *** and aerobic glycolysis activated by nuclear PKM2 enhance CRC cells’migration ability and anoikis resistance during CRLM ***-46 treatment,targeting the phosphorylation of PKM2,inhibited the pro-metastatic effect of ***,c-myc activated by nuclear PKM2 promotes alternative splicing of KHK-A,forming a positive feedback loop.

关键词： CRC CRLM Fructose KHK-A PKM2

Electrically Driven Nonresonant Single Molecular Switches

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CCS Chemistry 2024年第2期6卷 465-472页

作者： Rui Wang Ajun Tang Zhi Li Yunpeng Li Dahui Qu Hongxiang Li Key laboratory for Advanced Materials and Joint International Research laboratory of precision Chemistry and Molecular Engineering Feringa Nobel Prize Scientist Joint Research CenterFrontiers Science Center for Materiobiology and Dynamic ChemistryInstitute of Fine ChemicalsSchool of Chemistry and Molecular EngineeringEast China University of Science and TechnologyShanghai 200237

Electrical switching of a single-molecule junction provides a practical module to perform sophisticated operations in electronic ***,designing an all-electrically-driven molecular switch is a great ***,we experimentally and theoretically investigated the charge transport characteristics of isoindigo(ISO)-molecules at the single-molecule level using the scanning tunneling microscope break junction *** find that the single-molecule junctions of ISO-molecules display bias voltage-driven switching *** switches are realtime,reversible,and nondestructive under low-bias *** results show that the mechanism of the switch is not the transition from nonresonant charge transport to resonant charge transport,but it is the shift of the frontier orbital energy levels of ISO-molecules and the change of the interfacial electronic coupling with bias *** results will advance the design of high-performance bias voltage-driven molecular switches.

关键词： single-molecule junction isoindigo molecular switch bias voltage nonresonant charge transport molecular electronics

Enhanced precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

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Engineering 2024年第5期36卷 178-192页

作者： Ruogu Qi Shanshan Wang Jiayi Yu Tianming Lu Zhiqiang Bi Weibo Liu Yuanyuan Guo Yong Bian Jianliang Shen Xuesong Zhang Wenhao Hu School of medicine Nanjing University of Chinese MedicineNanjing 210023China laboratory Animal center Nanjing University of Chinese MedicineNanjing 210023China Key laboratory of Carcinogenesis and Translational Research Ministry of Education/BeijingDepartment of Radiation OncologyBeijing Cancer HospitalBeijing 100142China Department of Orthopedics The Fourth Medical CenterThe Chinese People’s Liberation Army General HospitalBeijing 100853China State Key laboratory of Ophthalmology Optometry and Vision ScienceSchool of Biomedical EngineeringWenzhou Medical UniversityWenzhou 325027China

Multiple myeloma(MM)is the second most prevalent hematological *** MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic *** study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@*** results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in ***,this material demonstrated a capability for drug release triggered by low pH ***,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM ***,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic ***,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

关键词： Multiple myeloma Bortezomib Drug delivery Dual targeting Controlled release

Anthrax lethal toxin and tumor necrosis factor-a synergize on intestinal epithelia to induce mouse death

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Protein & Cell 2024年第2期15卷 135-148页

作者： Xinhe Gao Teng Teng Yifei Liu Tingting Ai Rui Zhao Yilong Fu Peipei Zhang Jiahuai Han Yingying Zhang State Key laboratory of Cellular Stress Biology School of Life SciencesFaculty of Medicine and Life SciencesXiamen UniversityXiamen 361102China Research Unit of Cellular Stress of CAMS Xiang'an Hospital of Xiamen UniversityCancer Research Center of Xiamen UniversitySchool of MedicineFaculty of Medicine and Life SciencesXiamen UniversityXiamen 361102China laboratory Animal center Faculty of Medicine and Life SciencesXiamen UniversityXiamen 361102China

Bacillus anthracis lethal toxin(LT)is a determinant of lethal *** function in myeloid cells is required for bacterial dissemination,and LT itself can directly trigger dysfunction of the cardiovascular *** interplay between LT and the host responses is important in the pathogenesis,but our knowledge on this interplay remains *** necrosis factor-a(TNF-a)is a pleiotropic pro-inflammatory cytokine induced by bacterial *** LT accumulates and cytokines,predominantly TNF,amass during *** infection,co-treatment of TNF+LT in mice was used to mimic in vivo conditions for LT to function in inflamed *** marrow transplantation and genetically engineered mice showed unexpectedly that the death of intestinal epithelial cells(IECs)rather than that of hematopoietic cells led to LT+TNF-induced *** of p38a mitogen-activated protein kinase(MAPK)signaling by LT in IECs promoted TNF-induced apoptosis and necroptosis of IECs,leading to intestinal damage and mouse ***,p38a inhibition by LT enhanced TNF-mediated cell death in human colon epithelial HT-29 *** intestinal damage is one of the leading causes of lethality in anthrax patients,the IEC damage caused by LT+TNF would most likely be a mechanism underneath this clinical manifestation and could be a target for interventions.

关键词： lethal toxin TNF p38a intestinal epithelial cell cell death

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Both gain-and loss-of-function variants of KCNA1 are associated with paroxysmal kinesigenic dyskinesia

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Journal of Genetics and Genomics 2024年第8期51卷 801-810页

作者： Wan-Bing Sun Jing-Xin Fu Yu-Lan Chen Hong-Fu Li Zhi-Ying Wu Dian-Fu Chen Department of Medical Genetics and center for Rare Diseases and Department of Neurologyand Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation in Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Nanhu Brain-computer Interface Institute HangzhouZhejiang 314050China MOE Frontier Science center for Brain Science and Brain-machine Integration School of Brain Science and Brain MedicineZhejiang UniversityHangzhouZhejiang 310012China

KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelα*** variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia(PKD),but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD *** the whole exome sequencing followed by Sanger sequencing,we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese *** proband of one family(c.496G>A,p.A166T)manifests as episodic ataxia type 1,and the other two(c.877G>A,p.V293I and c.1112C>A,p.T371A)manifest as *** pathogenicity of these variants is confirmed by functional studies,suggesting that p.A166T and p.T371A cause a loss-of-function of the channel,while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic *** reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein,we find that these variants tend to cluster around the pore domain,which is similar to ***,our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype–phenotype correlations of KCNA1 channelopathy.

关键词： Paroxysmal kinesigenic dyskinesia KCNA1 Loss-of-function Gain-of-function Channelopathy Episodicataxiatype1

Deep learning framework for comprehensive molecular and prognostic stratifications of triple-negative breast cancer

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Fundamental Research 2024年第3期4卷 678-689页

作者： Shen Zhao Chao-Yang Yan Hong Lv Jing-Cheng Yang Chao You Zi-Ang Li Ding Ma Yi Xiao Jia Hu Wen-Tao Yang Yi-Zhou Jiang Jun Xu Zhi-Ming Shao Key laboratory of Breast Cancer in Shanghai Department of Breast SurgeryFudan University Shanghai Cancer CenterShanghai 200032China Institute for AI in medicine School of Artificial IntelligenceNanjing University of Information Science and TechnologyNanjing 210044China Department of Pathology Fudan University Shanghai Cancer CenterShanghai 200032China Greater Bay Area Institute of precision medicine Guangzhou 511466China Department of Radiology Fudan University Shanghai Cancer CenterShanghai 200032China

Triple-negative breast cancer(TNBC)is the most challenging breast cancer *** stratification and target therapy bring clinical benefit for TNBC patients,but it is difficult to implement comprehensive molecular testing in clinical ***,using our multi-omics TNBC cohort(N=425),a deep learning-based framework was devised and validated for comprehensive predictions of molecular features,subtypes and prognosis from pathological whole slide *** framework first incorporated a neural network to decompose the tissue on WSIs,followed by a second one which was trained based on certain tissue types for predicting different ***-omics molecular features were analyzed including somatic mutations,copy number alterations,germline mutations,biological pathway activities,metabolomics features and immunotherapy *** was shown that the molecular features with therapeutic implications can be predicted including the somatic PIK3CA mutation,germline BRCA2 mutation and PD-L1 protein expression(area under the curve[AUC]:0.78,0.79 and 0.74 respectively).The molecular subtypes of TNBC can be identified(AUC:0.84,0.85,0.93 and 0.73 for the basal-like immune-suppressed,immunomodulatory,luminal androgen receptor,and mesenchymal-like subtypes respectively)and their distinctive morphological patterns were revealed,which provided novel insights into the heterogeneity of TNBC.A neural network integrating image features and clinical covariates stratified patients into groups with different survival outcomes(log-rank P<0.001).Our prediction framework and neural network models were externally validated on the TNBC cases from TCGA(N=143)and appeared robust to the changes in patient *** potential clinical translation,we built a novel online platform,where we modularized and deployed our framework along with the validated *** can realize real-time one-stop prediction for new *** summary,using only pathological WSIs,our proposed framework

关键词： Triple-negative breast cancer Deep learning Digital pathology Patient stratification Online platform

Genomic analysis of Nypa fruticans elucidates its intertidal adaptations and early palm evolution

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Journal of Integrative Plant Biology 2024年第4期66卷 824-843页

作者： Weihong Wu Xiao Feng Nan Wang Shao Shao Min Liu Fa Si Linhao Chen Chuanfeng Jin Shaohua Xu Zixiao Guo Cairong Zhong Suhua Shi Ziwen He State Key laboratory of Biocontrol and Guangdong Provincial Key laboratory of Plant Resources School of Life SciencesSun Yat-sen UniversityGuangzhou 510275China Greater Bay Area Institute of precision medicine School of Life SciencesFudan UniversityGuangzhou 511462China Hainan Academy of Forestry(Hainan Academy of Mangrove) Haikou 571100China

Nypa fruticans(Wurmb),a mangrove palm species with origins dating back to the Late Cretaceous period,is a unique species for investigating long-term adaptation strategies to intertidal environments and the early evolution of ***,we present a chromosome-level genome sequence and assembly for *** integrated the genomes of *** and other palm family members for a comparative genomic analysis,which confirmed that the common ancestor of all palms experienced a whole-genome duplication event around 89 million years ago,shaping the distinctive characteristics observed in this *** also inferred a low mutation rate for the *** genome,which underwent strong purifying selection and evolved slowly,thus contributing to its stability over a long evolutionary ***,ancient duplicates were preferentially retained,with critical genes having experienced positive selection,enhancing waterlogging tolerance in ***,we discovered that the pseudogenization of Early Methionine-labelled 1(EM1)and EM6 in *** underly its crypto-vivipary characteristics,reflecting its intertidal *** study provides valuable genomic insights into the evolutionary history,genome stability,and adaptive evolution of the mangrove *** results also shed light on the long-term adaptation of this species and contribute to our understanding of the evolutionary dynamics in the palm family.

关键词： crypto-vivipary genome stability long-term adaptation mangrove Nypa fruticans palm

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Control of defensive behavior by the nucleus of Darkschewitsch GABAergic neurons

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National Science Review 2024年第4期11卷 70-83页

作者： Huiying Zhao Jinrong Liu Yujin Shao Xiang Feng Binhan Zhao Li Sun Yijun Liu Linghui Zeng Xiao-ming Li Hongbin Yang Shumin Duan Yan-qin Yu Department of Neurology of Second Affiliated Hospital and School of Brain Science and Brain medicine Zhejiang University School of Medicine Nanhu Brain-Computer Interface Institute Liangzhu laboratory MOE Frontier Science Center for Brain Science and Brain-Machine Integration State Key Laboratory of Brain-Machine Intelligence Zhejiang University NHC and CAMS Key laboratory of Medical Neurobiology Zhejiang University Key laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province School of Medicine Hangzhou City University

The nucleus of Darkschewitsch(ND), mainly composed of GABAergic neurons, is widely recognized as a component of the eye-movement controlling system. However, the functional contribution of ND GABAergic neurons(NDGABA) in animal behavior is largely unknown. Here, we show that NDGABA neurons were selectively activated by different types of fear stimuli, such as predator odor and foot *** and chemogenetic manipulations revealed that NDGABA neurons mediate freezing ***, using circuit-based optogenetic and neuroanatomical tracing methods, we identified an excitatory pathway from the lateral periaqueductal gray(l PAG) to the ND that induces freezing by exciting ND inhibitory outputs to the motor-related gigantocellular reticular nucleus, ventral part(Gi V). Together,these findings indicate the NDGABA population as a novel hub for controlling defensive response by relaying fearful information from the l PAG to Gi V, a mechanism critical for understanding how the freezing behavior is encoded in the mammalian brain.

关键词： nucleus of Darkschewitsch GABAergic population defensive behavior freezing neural circuitry