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Function and dysfunction of GEMIN5:understanding a novel neurodevelopmental disorder

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Neural Regeneration Research 2024年第11期19卷 2377-2386页

作者： Charles H.Nelson Udai B.Pandey Department of Pediatrics Division of Child NeurologyChildren’s Hospital of PittsburghUniversity of Pittsburgh Medical CenterPittsburghPAUSA Children’s Neuroscience Institute Children’s Hospital of PittsburghUniversity of Pittsburgh Medical CenterPittsburghPAUSA

The recent identification of a neurodevelopmental disorder with cerebellar atrophy and motor dysfunction(NEDCAM)has resulted in an increased interest in GEMIN5,a multifunction RNA-binding protein.As the largest member of the survival motor neuron complex,GEMIN5 plays a key role in the biogenesis of small nuclear ribonucleoproteins while also exhibiting translational regulatory functions as an independent protein.Although many questions remain regarding both the pathogenesis and pathophysiology of this new disorder,considerable progress has been made in the brief time since its discovery.In this review,we examine GEMIN5 within the context of NEDCAM,focusing on the structure,function,and expression of the protein specifically in regard to the disorder itself.Additionally,we explore the current animal models of NEDCAM,as well as potential molecular pathways for treatment and future directions of study.This review provides a comprehensive overview of recent advances in our understanding of this unique member of the survival motor neuron complex.

关键词： cerebellar atrophy GEMIN5 neurodevelopmental disorder neurological disease SMN complex

Sino-U.S. partnerships in research, education, and patient care：The experience of the university of pittsburgh and UPMC

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Science China(Life Sciences) 2017年第10期60卷 1150-1156页

作者： S.Levine Margaret C.McDonald Charles E.Bogosta university of pittsburgh Schools of the Health Sciences Pittsburgh PA 15261 USA university of pittsburgh Medical Center (UPMC) Pittsburgh PA 15219 USA

In 2011, the university of pittsburgh School of Medicine(UPSOM) and Tsinghua university formed a partnership to further the education of Tsinghua medical students. These students come to UPSOM as visiting research scholars for two years of their eight-year MD curriculum. During this time, the students, who have completed four years at Tsinghua, work full-time in medical school laboratories and research programs of their choice, essentially functioning as graduate students. In their first two months in pittsburgh, the scholars have a one-week orientation to biomedical research, followed by two-week rotations in four labs selected on the basis of the scholars' scientific interests, after which they choose one of these labs for the remainder of the two years.Selected labs may be in basic science departments, basic science divisions of clinical departments, or specialized centers that focus on approaches like simulation and modeling. The Tsinghua students also have a brief exposure to clinical medicine. UPSOM has also formed a similar partnership with Central South university Xiangya School of Medicine in Changsha, Hunan Province. The Xiangya students come to UPSOM for two years of research training after their sixth year and, thus, unlike the Tsinghua students,have already completed their clinical rotations. UPSOM faculty members have also paved the way for UPMC(university of pittsburgh Medical Center), UPSOM's clinical partner, to engage with clinical centers in China. Major relationships involving advisory, training, managerial, and/or equity roles exist with Xiangya International Medical Center, KingMED Diagnostics, First Chengmei Medical Industry Group, and Macare Women's Hospital. Both UPSOM and UPMC are actively exploring other clinical and academic opportunities in China.

关键词： medical education research training partnership

Impact of microplastics and nanoplastics on liver health:Current understanding and future research directions

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World Journal of Gastroenterology 2024年第9期30卷 1011-1017页

作者： Chun-Cheng Chiang Hsuan Yeh Ruei-Feng Shiu Wei-Chun Chin Tzung-Hai Yen School of Medicine University of PittsburghPittsburghPA 15213United States pittsburgh Liver Research Center University of PittsburghPittsburghPA 15213United States Division of Experimental Pathology Department of PathologyUniversity of PittsburghPittsburghPA 15213United States Division of Endocrinology Department of PediatricsUniversity of PittsburghPittsburghPA 15213United States Center of Excellence for The Oceans National Taiwan Ocean UniversityKeelung 20224Taiwan Institute of Marine Environment and Ecology National Taiwan Ocean UniversityKeelung 20224TaiwanChina Department of Materials Science and Engineering University of California MercedMercedCA 95343United States Department of Nephrology Clinical Poison CenterChang Gung Memorial HospitalTaoyuan 333TaiwanChina College of Medicine Chang Gung UniversityTaoyuan 333TaiwanChina

With continuous population and economic growth in the 21st century,plastic pollution is a major global issue.However,the health concern of microplastics/nanoplastics(MPs/NPs)decomposed from plastic wastes has drawn public attention only in the recent decade.This article summarizes recent works dedicated to understanding the impact of MPs/NPs on the liver-the largest digestive organ,which is one of the primary routes that MPs/NPs enter human bodies.The interrelated mechanisms including oxidative stress,hepatocyte energy re-distribution,cell death and autophagy,as well as immune responses and inflammation,were also featured.In addition,the disturbance of microbiome and gut-liver axis,and the association with clinical diseases such as metabolic dysfunction-associated fatty liver disease,steatohepatitis,liver fibrosis,and cirrhosis were briefly discussed.Finally,we discussed potential directions in regard to this trending topic,highlighted current challenges in research,and proposed possible solutions.

关键词： Microplastics Nanoplastics Liver Reactive oxidative species Cell death Autophagy Innate immunity Metabolic dysfunction-associated fatty liver disease Gut-liver axis

Sulfation of chondroitin and bile acids converges to antagonize Wnt/β-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1241-1256页

作者： Pengfei Xu Yue Xi Jong-Won Kim Junjie Zhu Min Zhang Meishu Xu Songrong Ren Da Yang Xiaochao Ma Wen Xie Center for Pharmacogenetics and Department of Pharmaceutical Sciences University of PittsburghPittsburghPA 15261USA Department of Hepatobiliary and Pancreatic Surgery Zhongnan Hospital of Wuhan UniversitySchool of Pharmaceutical SciencesWuhan UniversityWuhan 430071China Department of Pharmacology&Chemical Biology University of PittsburghPittsburghPA 15261USA

Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology.3’-Phosphoadenosine 5’-phosphosulfate(PAPS)synthase 2(PAPSS2)is the primary enzyme to generate the universal sulfonate donor PAPS.The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli(APC)mutation-promoted colonic carcinogenesis has not been reported.Here,we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages,and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer.Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout(Apc^(Δgut-Het)Papss2^(Δgut))mice were created,and the phenotypes were compared to the spontaneous intestinal tumorigenesis of Apc^(Δgut-Het)mice.Apc^(Δgut-Het)Papss2^(Δgutmice) were more sensitive to gut tumorigenesis,which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor(FXR)-transducin-like enhancer of split 3(TLE3)gene regulatory axis.Chondroitin sulfate supplementation in Apc^(Δgut-Het)Papss2^(Δgutmice) alleviated intestinal tumorigenesis.In summary,we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin signaling.Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.

关键词： Colon cancer APC Wnt/b-catenin PAPSS2 Chondroitin sulfate Sulfation Bile acids FXR

The oxidative DNA damage response： A review of research undertaken with Tsinghua and Xiangya students at the university of pittsburgh

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Science China(Life Sciences) 2017年第10期60卷 1077-1080页

作者： S.Levine Luxi Sun Rong Tan Ying Gao Lu Yang Hao Chen Yaqun Teng Li Lan UPMC Hillman Cancer Center pittsburgh PA 15213 USA Department of Microbiology and Molecular Genetics University of Pittsburgh School of Medicine Pittsburgh PA 15219 USA School of Medicine Tsinghua University Beijing 100084 China Xiangya Hospital Central South University Changsha 410008 China

Endogenous stress and exogenous toxicants(chemicals and UV light) alter genetic information either directly or indirectly through the production of reactive oxygen species(ROS), thereby driving genomic instability in cells and promoting tumorigenesis. All living cells try to faithfully preserve and transmit their genomic information from one generation to the next using DNA repair mechanisms to repair oxidative DNA damage to prevent cancer or premature aging. Oxidative DNA damage comprises a mixture of DNA lesions including base damage, DNA single strand breaks(SSBs), and DNA double strand breaks(DSBs). This review summarizes some of the studies on DNA damage response at a defined genome locus that are performed by students from the Tsinghua university School of Medicine and the School of Medicine of Central South university(Xiangya Hospital) at the university of pittsburgh School of Medicine. A summary of their work highlights the continuous contribution of the students to a particular research program and exemplifies the achievements of this China-U.S. collaborative training program.

关键词： DNA damage chromatin telomere DNA repair

High-yield and rapid isolation of extracellular vesicles by flocculation via orbital acoustic trapping:FLOAT

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Microsystems & Nanoengineering 2024年第1期10卷 313-323页

作者： Joseph Rufo Peiran Zhang Zeyu Wang Yuyang Gu Kaichun Yang Joseph Rich Chuyi Chen Ruoyu Zhong Ke Jin Ye He Jianping Xia Ke Li Jiarong Wu Yingshi Ouyang Yoel Sadovsky Luke P.Lee Tony Jun Huang Department of Mechanical Engineering and Materials Science Duke UniversityDurhamNCUSA Department of Biomedical Engineering Duke UniversityDurhamNCUSA Department of Obstetrics Gynecologyand Reproductive SciencesMagee-Womens Research InstituteUniversity of PittsburghPittsburghPAUSA Department of Microbiology and Molecular Genetics School of MedicineUniversity of PittsburghPittsburghPAUSA Renal Division and Division of Engineering in Medicine Department of MedicineBrigham and Women’s HospitalHarvard Medical SchoolBostonMAUSA Department of Bioengineering Department of Electrical Engineering and Computer ScienceUniversity of CaliforniaBerkeleyBerkeleyCAUSA Department of Biophysics Institute of Quantum BiophysicsSungkyunkwan UniversitySuwonKorea

Extracellular vesicles(EVs)have been identified as promising biomarkers for the noninvasive diagnosis of various diseases.However,challenges in separating EVs from soluble proteins have resulted in variable EV recovery rates and low purities.Here,we report a high-yield(>90%)and rapid(<10 min)EV isolation method called FLocculation via Orbital Acoustic Trapping(FLOAT).The FLOAT approach utilizes an acoustofluidic droplet centrifuge to rotate and controllably heat liquid droplets.By adding a thermoresponsive polymer flocculant,nanoparticles as small as 20 nm can be rapidly and selectively concentrated at the center of the droplet.We demonstrate the ability of FLOAT to separate urinary EVs from the highly abundant Tamm-Horsfall protein,addressing a significant obstacle in the development of EV-based liquid biopsies.Due to its high-yield nature,FLOAT reduces biofluid starting volume requirements by a factor of 100(from 20 mL to 200µL),demonstrating its promising potential in point-of-care diagnostics.

关键词： trapping utilize separating

Cell replacement with stem cell-derived retinal ganglion cells from different protocols

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Neural Regeneration Research 2024年第4期19卷 807-810页

作者： Ziming Luo Kun-Che Chang Spencer Center for Vision Research Byers Eye InstituteStanford University School of Medicine Department of Ophthalmology Louis J.Fox Center for Vision RestorationUniversity of Pittsburgh School of Medicine Department of Neurobiology Center of NeuroscienceUniversity of Pittsburgh School of Medicine

Glaucoma,characterized by a degenerative loss of retinal ganglion cells,is the second leading cause of blindness worldwide.There is currently no cure for vision loss in glaucoma because retinal ganglion cells do not regenerate and are not replaced after injury.Human stem cell-derived retinal ganglion cell transplant is a potential therapeutic strategy for retinal ganglion cell degenerative diseases.In this review,we first discuss a 2D protocol for retinal ganglion cell differentiation from human stem cell culture,including a rapid protocol that can generate retinal ganglion cells in less than two weeks and focus on their transplantation outcomes.Next,we discuss using 3D retinal organoids for retinal ganglion cell transplantation,comparing cell suspensions and clusters.This review provides insight into current knowledge on human stem cell-derived retinal ganglion cell differentiation and transplantation,with an impact on the field of regenerative medicine and especially retinal ganglion cell degenerative diseases such as glaucoma and other optic neuropathies.

关键词： cell clumps cell suspension cell transplantation differentiation direct-induced protocol glaucoma optic neuropathy regenerative medicine retinal ganglion cell retinal organoids stem cells

Omics approaches in asthma research:Challenges and opportunities

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Chinese Medical Journal Pulmonary and Critical Care Medicine 2024年第1期2卷 1-9页

作者： Molin Yue Shiyue Tao Kristina Gaietto Wei Chen Department of Biostatistics School of Public HealthUniversity of PittsburghPittsburghPA 15224USA Division of Pediatric Pulmonary Medicine UPMC Children’s Hospital of PittsburghUniversity of PittsburghPittsburghPA 15224USA

Asthma,a chronic respiratory disease with a global prevalence of approximately 300 million individuals,presents a significant societal and economic burden.This multifaceted syndrome exhibits diverse clinical phenotypes and pathogenic endotypes influenced by various factors.The advent of omics technologies has revolutionized asthma research by delving into the molecular foundation of the disease to unravel its underlying mechanisms.Omics technologies are employed to systematically screen for potential biomarkers,encompassing genes,transcripts,methylation sites,proteins,and even the microbiome components.This review provides an insightful overview of omics applications in asthma research,with a special emphasis on genetics,transcriptomics,epigenomics,and the microbiome.We explore the cutting-edge methods,discoveries,challenges,and potential future directions in the realm of asthma omics research.By integrating multi-omics and non-omics data through advanced sta-tistical techniques,we aspire to advance precision medicine in asthma,guiding diagnosis,risk assessment,and personalized treatment strategies for this heterogeneous condition.

关键词： Asthma Genomics Transcriptomics Epigenomics Metagenomics Multi-omics integration

On the inviscid limit of the compressible Navier-Stokes equations near Onsager's regularity in bounded domains

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Science China Mathematics 2024年第1期67卷 1-22页

作者： Robin Ming Chen Zhilei Liang Dehua Wang Runzhang Xu Department of Mathematics University of PittsburghPittsburghPA 15260USA School of Mathematics Southwestern University of Finance and EconomicsChengdu 611130China College of Mathematical Sciences Harbin Engineering UniversityHarbin 150001China

The viscous dissipation limit of weak solutions is considered for the Navier-Stokes equations of compressible isentropic flows confined in a bounded domain.We establish a Kato-type criterion for the validity of the inviscid limit for the weak solutions of the Navier-Stokes equations in a function space with the regularity index close to Onsager’s critical threshold.In particular,we prove that under such a regularity assumption,if the viscous energy dissipation rate vanishes in a boundary layer of thickness in the order of the viscosity,then the weak solutions of the Navier-Stokes equations converge to a weak admissible solution of the Euler equations.Our approach is based on the commutator estimates and a subtle foliation technique near the boundary of the domain.

关键词： inviscid limit Navier-Stokes equations Euler equations weak solutions bounded domain Katotype criterion Onsager’s regularity