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Synaptosome microrNAs:emerging synapse players in aging and Alzheimer’s disease

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Neural regeneration research 2023年第6期18卷 1275-1276页

作者： Subodh kumar Center of Emphasis in Neuroscience Department of Molecular and Translational Medicine Paul L.Foster School of Medicine Texas Tech University Health Sciences CenterEl PasoTXUSA

Synaptosome:Synapses are the most critical portion of neuron connections,necessary for cellular organization of the *** integrity is uttermost important for healthy brain *** perturbation in the synapse structure and/or function initiates neurological *** are the prime targets that are smashed in almost all neurodegenerative *** vital components of synapse are essential for neurotransmission,synaptic plasticity and overall synapse *** dysfunctions are well studied in Alzheimer’s disease(AD)and other neurodegenerative diseases(Gowda et al.,2021).The best way to study the synapse dysfunctions in neurological diseases is the biochemical analysis of“synaptosome”.

关键词： Alzheimer diseases

Non-viral iPSCs:a safe way for therapy?

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Protein & Cell 2012年第4期3卷 241-245页

作者： Weiqi Zhang Di Guan Jing Qu Weizhou Zhang Guang-Hui Liu National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Laboratory of Gene regulation and Signal Transduction Department of PharmacologySchool of MedicineUniversity of CaliforniaSan DiegoLa JollaCA 92093USA

Patients-derived induced pluripotent stem cells(iPSCs)pro-vide an invaluable tool to study mechanisms of human dis-eases and also a limitless cellular source for clinical trans-plantation(Takahashi et al.,2007;Yu et al.,2007;Liu et al.,2011a,2011b;Zhang et al.,2012).retrovirus-or lenti-virus-based delivery systems have been serving as main-stream methods to generate patients-derived ***-ever,genomic integrations of reprogramming factors in virally generated iPSCs not only cause insertional mutagenesis but also lead to residual expression of reprogramming factors in iPSCs and their derivatives.

关键词： al. clinical programming

CHOP THEr APY INDUCED MITOCHONDrIAL rEDOX STATE ALTErATION IN NON-HODGkIN'S LYMPHOMA XENOGrAFTS

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Journal of Innovative Optical Health Sciences 2013年第2期6卷 29-35页

作者： H.N.XU H.ZHAO T.A.MIr S.C.LEE M.FENG r.CHOE J.D.GLICkSON L.Z.LI Department of radiology University of Pennsylvania PhiladelphiaPAUSA Britton Chance Laboratory of redox Imaging Johnson research Foundation Department of Biochemistry and Biophysics University of Pennsylvania PhiladelphiaPAUSA Biostatistics and Data Management Core The Children's Hospital of Philadelphia(CHOP) PhiladelphiaPAUSA Department of Biomedical Engineering University of rochester RochesterNYUSA Abramson cancer Center University of Pennsylvania PhiladelphiaPAUSA Institute of Translational Medicine and Therapeutics University of Pennsylvania PhiladelphiaPAUSA

We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and *** redox state can be imaged by the redox scanner that collects the fuorescence signals from both the oxidized-fAavoproteins(Fp)and the reduced form of nicotinamide adenine dinucleotide(NADH)in snap frozen tissues and has been previously employed to study tumor aggressiveness and treatment ***,with the redox scanner we investigated the effects of chemotherapy on mouse xenografts of a human diffuse large *** lymphoma cell line(DLCL2).The mice were treated with CHOP therapy,i.e,cyclophosphamide(C)+hydroxydoxorubicin(H)+Oncovin(O)+prednisone(P)with CHO administration on day 1 and prednisone administration on days *** Fp content of the treated group was significantly decreased(p=0.033)on day 5,and the mitochondrial redox state of the treated group was slightly more reduced than that of the control group(p=0.048).The decrease of the Fp heterogeneity(measured by the mean st andard deviation)had a border-line statistical significance(p=0.071).The result suggests that the mitochondrial metabolism of lymphoma cells was slightly suppressed and the lymphomas became less aggressive after the CHOP therapy.

关键词： NA DH flavoprotein DLCL2 therapeutic effect tumor metabolism

Targeting orthotopic gliomas with renal-clearable luminescent gold nanoparticles

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Nano research 2017年第4期10卷 1366-1376页

作者： Chuanqi Peng Xiaofei Gao Jing Xu Bujie Du Xuhui Ning Shaoheng Tang robert M. Bachoo Mengxiao Yu Woo-Ping Ge Jie Zheng Department of Chemistry and Biochemistry The University of Texas at Dallas Richardson TX 75080 USA Children's research Institute Department of Pediatrics Department of Neuroscience Harold C. Simmons Comprehensive Cancer Center UT Southwestem Medical Center Dallas TX 75390 USA Simmons cancer Center Annette G. Strauss Center for Neuro-Oncology Department of Internal Medicine Department of Neurology and Neurotherapeutics UT Southwestern Medical Center Dallas TX 75390 USA

A major clinical translational challenge in nanomedicine is the potential of toxicity associated with the uptake and long-term retention of non-degradable nanoparticles （NPs） in major organs. The development of inorganic NPs that undergo renal clearance could potentially resolve this significant biosafety concern. However, it remains unclear whether inorganic NPs that can be excreted by the kidneys remain capable of targeting tumors with poor permeability. Glioblastoma multiforme, the most malignant orthotopic brain tumor, presents a unique challenge for NP delivery because of the blood-brain barrier and robust blood-tumor barrier of reactive microglia and macroglia in the tumor microenvironment. Herein, we used an orthotopic murine glioma model to investigate the passive targeting of glutathione-coated gold nanoparticles （AuNPs） of 3 nm in diameter that undergo renal clearance and 18-nm AuNPs that fail to undergo renal clearance. remarkably, we report that 3-nm AuNPs were able to target intracranial tumor tissues with higher efficiency （2.3× relative to surrounding non-tumor normal brain tissues） and greater specificity （3.0×） than did the larger AuNPs. Pharmacokinetics studies suggested that the higher glioma targeting ability of the 3-nm AuNPs may be attributed to the longer retention time in circulation. The total accumulation of the 3-nm AuNPs in major organs was significantly less （8.4×） than that of the 18-nm AuNPs. Microscopic imaging of blood vessels and renal-clearable AuNPs showed extravasation of NPs from the leaky blood-tumor barrier into the tumor interstitium. Taken together, our results suggest that the 3-nm AuNPs, characterized by enhanced permeability and retention, are able to target brain tumors and undergo renal clearance.

关键词： enhanced permeability and retention brain tumor passive targeting gold nanoparticles renal clearance

Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease

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Microsystems & Nanoengineering 2017年第1期3卷 382-388页

作者： Ziliang carter Lin Allister F.McGuire Paul W.Burridge Elena Matsa Hsin-Ya Lou Joseph C.Wu Bianxiao Cui Department of Applied Physics Stanford UniversityStanfordCA 94305USA Department of Chemistry Stanford UniversityStanfordCA 94305USA Stanford cardiovascular Institute Stanford UniversityStanfordCA 94305USA Department of Pharmacology and Center for Pharmacogenomics Northwestern UniversityChicagoIL 60611USA

The measurement of the electrophysiology of human pluripotent stem cell-derived cardiomyocytes is critical for their biomedical applications,from disease modeling to drug ***,a method that enables the high-throughput intracellular electrophysiology measurement of single cardiomyocytes in adherent culture is not *** address this area,we have fabricated vertical nanopillar electrodes that can record intracellular action potentials from up to 60 single beating *** access is achieved by highly localized electroporation,which allows for low impedance electrical access to the intracellular ***,we demonstrate that this method provides the accurate measurement of the shape and duration of intracellular action potentials,validated by patch clamp,and can facilitate cellular drug screening and disease modeling using human pluripotent stem *** study validates the use of nanopillar electrodes for myriad further applications of human pluripotent stem cell-derived cardiomyocytes such as cardiomyocyte maturation monitoring and electrophysiology-contractile force correlation.

关键词： cardiomyocytes drug screening electrophysiology human pluripotent stem cells multielectrode array

Integrative modeling of transmitted and de novo variants identifies novel risk genes for congenital heart disease

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Quantitative Biology 2021年第2期9卷 216-227页

作者： Mo Li Xue Zeng Chentian Jin Sheng Chih Jin Weilai Dong Martina Brueckner richard Lifton Qiongshi Lu Hongyu Zhao Department of Biostatistics Yale School of Public HealthNew HavenCT 06510USA Department of Genetics Yale UniversityNew HavenCT 06510USA Department of Molecular Cellular&Developmental BiologyYale UniversityCT 06510USA Department of Genetics Washington University School of MedicineSt LouisMO 63110USA Department of Pediatrics Yale UniversityNew HavenCT 06510USA Laboratory of Human Genetics and Genomics Rockefeller UniversityNew YorkNY 10065USA Department of Biostatistics and Medical Informatics University of Wisconsin-MadisonMadisonWl 53792USA Program of Computational Biology and Bioinformatics Yale UniversityNew HavenCT 06510USA

Background:Whole-exome sequencing(WES)studies have identified multiple genes enriched for de novo mutations(DNMs)in congenital heart disease(CHD)***,risk gene identification based on DNMs alone remains statistically challenging due to heterogenous etiology of CHD and low mutation rate in each ***:In this manuscript,we introduce a hierarchical Bayesian framework for gene-level association test which jointly analyzes de novo and rare transmitted *** integrative modeling of multiple types of genetic variants,gene-level annotations,and reference data from large population cohorts,our method accurately characterizes the expected frequencies of both de novo and transmitted variants and shows improved statistical power compared to analyses based on DNMs ***:Applied to WES data of 2,645 CHD proband-parent trios,our method identified 15 significant genes,half of which are novel,leading to new insights into the genetic bases of ***:These results showcase the power of integrative analysis of transmitted and de novo variants for disease gene discovery.

关键词： rare variants gene-level association test congenital heart disease de novo mutation

The statistical practice of the GTEx Project: from single to multiple tissues

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Quantitative Biology 2021年第2期9卷 151-167页

作者： Xu Liao Xiaoran Chai Xingjie Shi Lin S.Chen Jin Liu Center for Quantitative Medicine Health Services&Systems ResearchDuke-NUS Medical SchoolSingapore 169857Singapore Beijing Advanced Innovation Center for Genomics(ICG) Biomedical Pioneering Innovation Center(BIOPIC)School of Life SciencesPeking UniversityBeijing 100871China Yong Loo Lin School of Medicine National University of SingaporeSingapore 119228Singapore Department of Statistics Nanjing University of Finance and EconomicsNanjing 210023China Department of Public Health Sciences The University of ChicagoChicagoIL 60637USA

Background:The Genotype-Tissue Expression(GTEx)Project has collected genetic and transcriptome profiles from a wide spectrum of tissues in nearly 1,000 ceased indiv iduals,providing an opportunity to study the regulatory roles of genetic variants in transcriptome activities from both cross-tissue and tissue-specific ***,transeriptome activities(e.g.,transcript abundance and alternative splicing)can be treated as mediators between genotype and phenotype to achieve phenotypic *** the genotype associated transcriptome status,researchers can better understand the biological and molecular mechanisms of genetic risk variants in complex ***:In this article,we first explore the genetic architecture of gene expression traits,and then review recent methods on quantitative trait locus(QTL)and co-expression network *** further exemplify the usage of associations between genotype and transcriptome status,we briefly review methods that either directly or indirectly integrate expression/splicing QTL information in genome wide association studies(GWASs).Conclusions:The GTEx Project provides the largest and useful resouree to investigate the associations between genotype and transcriptome *** integration of results from the GTEx Project and existing GWASs further advances our understanding of roles of gene expression changes in bridging both the genetic variants and complex traits.

关键词： the Genotype-Tissue Expression Project quantitative trait loci(QTL) transcriptome-wide association studies genome-wide association studies

The history of oxygen sensing: 2016 Lasker Award for Basic Medical research

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Science Bulletin 2016年第21期61卷 1665-1668页

作者： Giada Zurlo Qing Zhang Lineberger Comprehensive cancer Center Department of Pathology and Laboratory Medicine University of North Carolina School of Medicine

The importance of adequate oxygenation has been known for a long time. Oxygen has been early recognized as a critical substrate for cell metabolism： mitochondrial oxidative phosphorylation, which consumes oxygen, is up to 15 times more efficient in ATP production than anaerobic glycolysis. However, how animals sense and adapt to changes in oxygen availability have remained a big enigma until when the research of Drs. William kaelin, Peter ratcliffe and Gregg Semenza has allowed the discovery of the molecular mechanisms underlying cellular adaptive response to low levels of oxygen, condition known as hypoxia （see the timeline below）. For this great contribu- tion to medical science, they have been awarded the 2016 Albert Lasker Basic Medical research Award.

关键词： HIF EPO

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3063-3072页

作者： Yi Zhu Na Li Mingyang Huang Xi Chen Yu AAn Jianping Li Shangang Zhao Jan-Bernd Funck Jianhong cao Zhenyan He Qingzhang Zhu Zhuzhen Zhang Zhao VWang Lin Xu kevin W.Williams Chien Li kevin Grove Philipp E.Scherer Touchstone Diabetes Center Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Division of cardiology Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Division of Hypothalamic research Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Quantitative Biomedical research Center Department of Population and Data Sciencesthe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Department of Pediatrics the University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Novo Nordisk research Center SeattleWA 98109USA Children’s Nutrition research Center Department of PediatricsBaylor College of MedicineHoustonTX 77030USA Department of Cell Biology the University of Texas Southwestern Medical Center at DallasDallasTX 75390USA

Adipose tissue is a promising target for treating obesity and metabolic ***,pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization,especially in obese *** have previously shown that during cold exposure,connexin43(Cx43)gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple *** reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose *** an adipose tissue-specific Cx43 overexpression mouse model,we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of theβ_(3)-adrenergic receptor agonist Mirabegron and ***,combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced *** light of these findings,we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage ***,Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.

关键词： GJA1 Adipose tissue Gap junction Connexin43 FGF21 β3-Adrenergic receptor agonist Obesity Type 2 diabetes