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AAV-mediated silencing of Sox4 leads to long-term amelioration of liver phenotypes in mouse models of Alagille syndrome

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Gastroenterology 2025年

作者： Duncan Fox Jun Xie Jennifer L. Burwinkel Josh M. Adams Kashish Chetal Marzieh Keivandarian Yaniv Faingelernt Sanjay Subramanian Mario F. Lopez Anna L. Peters Nathan Salomonis Neda Zarrin-Khameh Guangping Gao Stacey S. Huppert Hamed Jafar-Nejad Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas Genetics and Genomics Graduate Program Baylor College of Medicine Houston Texas Department of Genetic and Cellular Medicine UMass Chan Medical School Worcester Massachusetts Horae Gene Therapy Center UMass Chan Medical School Worcester Massachusetts Department of Microbiology UMass Chan Medical School Worcester Massachusetts Viral Vector Core UMass Chan Medical School Worcester Massachusetts Division of Gastroenterology Hepatology and Nutrition Cincinnati Children’s Hospital Medical Center Cincinnati Ohio Program in Developmental Biology Baylor College of Medicine Houston Texas Division of Biomedical Informatics Cincinnati Children's Hospital Medical Center Cincinnati Ohio Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Ohio Department of Pathology and Immunology Baylor College of Medicine and Ben Taub Hospital Houston Texas

BACKGROUND & AIMS In patients with Alagille syndrome (ALGS), bile duct paucity often leads to severe cholestatic phenotypes for which liver transplantation remains the only definitive treatment. No FDA-approved mechanism-based strategies exist to enhance biliary development in ALGS or other diseases with bile duct paucity. We aimed to identify a therapeutic target to address this unmet need. METHODS Preclinical ALGS mouse models lacking one copy of Jag1 with or without conditional deletion of one or both copies of Sox9 were used. Sox4 levels were reduced genetically or with adeno-associated virus 8 (AAV8) vectors driving a Sox4 -silencing sequence. Liver histology, biliary tree ink injection, serum chemistry, RNAscope (on mouse and human livers), mouse liver single-cell RNA-sequencing (scRNA-Seq), and reanalysis of published human liver bulk RNA-Seq were performed. RESULTS Conditional removal of one copy of Sox4 in mouse liver significantly improved the ALGS liver phenotypes in a Sox9 -dependent manner. An increase in Sox4/SOX4 expression in early postnatal Jag1 -heterozygous mouse livers and ALGS patient livers was observed. scRNA-Seq revealed the appearance of an intermediate hepatobiliary cluster co-expressing Sox4 and Sox9 in Jag1- heterozygous livers. AAV8-mediated Sox4 knockdown, ubiquitously or driven by the hepatocyte-specific TBG promoter, led to long-term improvement of ALGS liver phenotypes upon injection at postnatal day 1 (P1). AAV8 injection at P15—after the appearance of liver necrosis—led to the incorporation of some transduced cells into bile ducts and phenotypic improvement. CONCLUSIONS Preclinical studies provide proof of principle for postnatal AAV-mediated Sox4 knockdown in TBG + cells as a therapeutic approach for ALGS liver disease.

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A Novel Protein with Similarities to Rb Binding Protein 2 Compensates for Loss of Chk1 Function and Affects Histone Modification in Fission Yeast

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Molecular and Cellular Biology 2004年第9期24卷 3660-3669页

作者： Shakil Ahmed Carmela Palermo Shanhong Wan Nancy C. Walworth 1 Department of Pharmacology Robert Wood Johnson Medical School 2 Graduate Program in Cellular and Molecular Pharmacology Graduate School of Biomedical Sciences University of Medicine and Dentistry of New Jersey and Rutgers The State University of New Jersey 2 Graduate Program in Cellular and Molecular Pharmacology Graduate School of Biomedical Sciences University of Medicine and Dentistry of New Jersey and Rutgers The State University of New Jersey3 Cancer Institute of New Jersey Piscataway New Jersey

The conserved protein kinase Chk1 mediates cell cycle progression and consequently the ability of cells to survive when exposed to DNA damaging agents. Cells deficient in Chk1 are hypersensitive to such agents and enter mitosis in the presence of damaged DNA, whereas checkpoint-proficient cells delay mitotic entry to permit time for DNA repair. In a search for proteins that can improve the survival of Chk1-deficient cells exposed to DNA damage, we identified fission yeast Msc1, which is homologous to a mammalian protein that binds to the tumor suppressor Rb (RBP2). Msc1 and RBP2 each possess three PHD fingers, domains commonly found in proteins that influence the structure of chromatin. Msc1 is chromatin associated and coprecipitates a histone deacetylase activity, a property that requires the PHD fingers. Cells lacking Msc1 have a dramatically altered histone acetylation pattern, exhibit a 20-fold increase in global acetylation of histone H3 tails, and are readily killed by trichostatin A, an inhibitor of histone deacetylases. We postulate that Msc1 plays an important role in regulating chromatin structure and that this function modulates the cellular response to DNA damage.

关键词： PROTEIN kinases CELL cycle DNA damage DNA repair HISTONES CHROMATIN

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Neuromodulation of the peripheral nervous system:Bioelectronic technology and prospective developments

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BMEMat(biomedical Engineering Materials) 2024年第1期2卷 88-114页

作者： Hayoung Song Moohyun Kim Enji Kim Jakyoung Lee Inhea Jeong Kyeonghee Lim Seoung Young Ryu Myoungjae Oh Younhee Kim Jang-Ung Park Department of Materials Science and Engineering Yonsei UniversitySeoulSouth Korea Center for Nanomedicine Institute for Basic Science(IBS)SeoulSouth Korea Department of Neurosurgery Yonsei University College of MedicineSeoulSouth Korea Graduate Program of Nano Biomedical Engineering(NanoBME) Advanced Science InstituteYonsei UniversitySeoulSouth Korea

The peripheral nervous system(PNS)is a fascinatingly complex and crucial component of the human body,responsible for transmitting vital signals throughout the body's intricate network of *** efficient functioning is paramount to our health,with any dysfunction often resulting in serious medical conditions,including motor disorders,neurological diseases,and psychiatric *** strides in science and technology have made neuromodulation of the PNS a promising avenue for addressing these health *** involves modifying nerve activity using a range of techniques,such as electrical,chemical,optical,and mechanical *** plays a critical role in this effort,allowing for precise,controlled,and sustained stimulation of the *** paper provides an overview of the PNS,discusses the current state of neuromodulation devices,and presents emerging trends in the field,including advances in wireless power transfer and materials,that are shaping the future of neuromodulation.

关键词： bioelectronics neuromodulation peripheral nervous system

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Implementation of the relay server for the Ubiquitous Integrated Biotelemetry System for Emergency Care (UIBSEC) based on 3.5G HSDPA technology

Implementation of the relay server for the Ubiquitous Integr...

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29th Annual International Conference of IEEE-EMBS, Engineering in medicine and Biology Society, EMBC'07

作者： Min, Yang Jung Jaemin, Kang Il, Hyung Shin Yoonseo, Koo Gil, Joon Suh Hee, Chan Kim Interdisciplinary Program Graduate School Seoul National University Seoul Korea Republic of Department of Emergency Medicine Seoul National University Seoul Korea Republic of Department of Biomedical Engineering Institute of Medical and Biological Engineering Seoul National University Seoul Korea Republic of

ISBN: (纸本)1424407885

When an emergent case occurs, to give proper and immediate emergency treatment to a patient is as important as to transfer him or her to the hospital as early as possible. For this circumstance where first aid usually happens in an ambulance, we developed the Ubiquitous Integrated Biotelemetry System for Emergency Care (UIBSEC) based on wireless 3.5G HSDPA module in order to provide more proper and active medical care to a patient. For this system we performed experimental tests on the HSDPA module to measure practical performance values with respect to throughput and RTT (round-trip-time) and compared the result with the theoretical specifications. In the course of developing this system we created the C#-based Network Solution Library (NSL) which helps drastically reducing the overhead. We applied this library to components of the UIBSEC - two kinds of clients and one central server - and confirmed that it works smoothly in wireless networks and it is useful in the future development process of network applications. © 2007 IEEE.

关键词： Servers

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Equilibrative nucleoside transporter 3 supports microglial functions and protects against the progression of Huntington's disease in the mouse model

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Brain, Behavior, and Immunity 2024年 120卷 413-429页

作者： Lu, Ying-Sui Hung, Wei-Chien Hsieh, Yu-Ting Tsai, Pei-Yuan Tsai, Tsai-Hsien Fan, Hsiu-Han Chang, Ya-Gin Cheng, Hui-Kuei Huang, Shen-Yan Lin, Hsin-Chuan Lee, Yan-Hua Shen, Tzu-Hsiang Hung, Bing-Yu Tsai, Jin-Wu Dzhagalov, Ivan Cheng, Irene Han-Juo Lin, Chun-Jung Chern, Yijuang Hsu, Chia-Lin Institute of Microbiology and Immunology National Yang Ming Chiao Tung University Taipei Taiwan Taiwan International Graduate Program in Molecular Medicine National Yang Ming Chiao Tung University and Academia Sinica Taipei Taiwan Institute of Brain Science National Yang Ming Chiao Tung University Taipei Taiwan Institute of Biomedical Sciences Academia Sinica Taipei Taiwan Taiwan International Graduate Program in Interdisciplinary Neuroscience National Yang Ming Chiao Tung University and Academia Sinica Taipei Taiwan Biomedical Industry Ph.D. Program National Yang Ming Chiao Tung University Taipei Taiwan Brain Research Center National Yang Ming Chiao Tung University Taipei Taiwan School of Pharmacy College of Medicine National Taiwan University Taipei Taiwan

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by involuntary movements, cognitive deficits, and psychiatric symptoms. Currently, there is no cure, and only limited treatments are available to manage the symptoms and to slow down the disease's progression. The molecular and cellular mechanisms of HD's pathogenesis are complex, involving immune cell activation, altered protein turnover, and disturbance in brain energy homeostasis. Microglia have been known to play a dual role in HD, contributing to neurodegeneration through inflammation but also enacting neuroprotective effects by clearing mHTT aggregates. However, little is known about the contribution of microglial metabolism to HD progression. This study explores the impact of a microglial metabolite transporter, equilibrative nucleoside transporter 3 (ENT3), in HD. Known as a lysosomal membrane transporter protein, ENT3 is highly enriched in microglia, with its expression correlated with HD severity. Using the R6/2 ENT3^−/− mouse model, we found that the deletion of ENT3 increases microglia numbers yet worsens HD progression, leading to mHTT accumulation, cell death, and disturbed energy metabolism. These results suggest that the delicate balance between microglial metabolism and function is crucial for maintaining brain homeostasis and that ENT3 has a protective role in ameliorating neurodegenerative processes. © 2024 The Authors

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WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity

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Nature Communications 2025年第1期16卷 1-19页

作者： Alissa J. Trzeciak Zong-Lin Liu Adam S. Krebs Waleska Saitz Rojas Anya J. O’Neal Zhaoquan Wang Allie Lipshutz Michael S. Glickman Justin S. A. Perry Justin Nelson Anna-Katerina Hadjantonakis Michael Overholtzer Thomas Vierbuchen Mohamed Gatie Ann K. Baako Isabella C. Miranda Christopher N. Parkhurst Jazib Uddin Jian Xie Chou-Long Huang Pedro H. V. Saavedra Arohan R. Subramanya Jon Iker Etchegaray Christopher D. Lucas Immunology Program Memorial Sloan Kettering Cancer Center New York NY USA Louis V. Gerstner Jr. Graduate School of Biomedical Sciences Memorial Sloan Kettering Cancer Center New York NY USA Department of Immunology and Microbial Pathogenesis Weill Cornell Medicine New York NY USA Division of Infectious Diseases Memorial Sloan Kettering Cancer Center New York NY USA Developmental Biology Program Sloan Kettering Institute for Cancer Research New York NY USA Cell Biology Program Sloan Kettering Institute for Cancer Research New York NY USA Division of Pulmonary and Critical Care Medicine Weill Cornell Medicine New York NY USA Jill Roberts Institute for Research in Inflammatory Bowel Disease Weill Cornell Medicine New York NY USA Department of Medicine Division of Nephrology Carver College of Medicine University of Iowa Iowa City IA USA Department of Biology Northeastern University Boston MA USA Dept of Medicine Renal-Electrolyte Division University of Pittsburgh School of Medicine Pittsburgh PA USA Aging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City OK USA University of Edinburgh Centre for Inflammation Research Queen’s Medical Research Institute Edinburgh BioQuarter UK Institute for Regeneration and Repair Edinburgh BioQuarter UK

Tissue-resident macrophages (TRM) are critical for mammalian organismal development and homeostasis. Here we report that with-no-lysine 1 (WNK1) controls myeloid progenitor fate, withCsf1riCre-mediatedWnk1deletion in mice (WNK1-deficient mice) resulting in loss of TRMs and causing perinatal mortality. Mechanistically, absence of WNK1 or inhibition of WNK kinase activity disrupts macrophage colony-stimulating factor (M-CSF)-stimulated macropinocytosis, thereby blocking mouse and human progenitor and monocyte differentiation into macrophages and skewing progenitor differentiation into neutrophils. Treatment with PMA rescues macropinocytosis but not macrophage differentiation of WNK-inhibited progenitors, implicating that M-CSF-stimulated, macropinocytosis-induced activation of WNK1 is required for macrophage differentiation. Finally, M-CSF-stimulated macropinocytosis triggers WNK1 nuclear translocation and concomitant increased protein expression of interferon regulatory factor (IRF)8, whereas inhibition of macropinocytosis or WNK kinase activity suppresses IRF8 expression. Our results thus suggest that WNK1 and downstream IRF8-regulated genes are important for M-CSF/macropinocytosis-mediated regulation of myeloid cell lineage commitment during TRM development and homeostasis.

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Socioeconomic gradients and inequalities in all-cause mortality and cardiovascular diseases: A retrospective cohort study using Korean NHANES-mortality linkage data

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Public Health 2025年 244卷

作者： Chaiho Jeong Kyu-Na Lee Jin-Hyung Jung Tae-Seo Sohn Hyuk-Sang Kwon Kyungdo Han Seung-Hwan Lee Division of Endocrinology and Metabolism Department of Internal Medicine Uijeongbu St. Mary's Hospital College of Medicine The Catholic University of Korea Seoul Republic of Korea Department of Public Health Graduate School The Catholic University of Korea Seoul Republic of Korea Samsung Biomedical Research Institute Sungkyunkwan University School of Medicine Suwon Republic of Korea Division of Endocrinology and Metabolism Department of Internal Medicine Yeouido St. Mary's Hospital College of Medicine The Catholic University of Korea Seoul Republic of Korea Department of Statistics and Actuarial Science Soongsil University Seoul Republic of Korea Division of Endocrinology and Metabolism Department of Internal Medicine Seoul St. Mary's Hospital College of Medicine The Catholic University of Korea Seoul Republic of Korea Department of Medical Informatics College of Medicine The Catholic University of Korea Seoul Republic of Korea

Objectives Rapid economic growth in South Korea provides a valuable context for investigating how socioeconomic status (SES) impacts mortality and cardiovascular disease (CVD) risk in an emerging high-income Asian country. The objective of this study was to examine these associations in a general population and a subgroup with type 2 diabetes mellitus (T2DM). Study design Retrospective cohort study. Methods Data from the Korea National Health and Nutrition Examination Survey (KNHANES) linked to mortality records was used. A total of 48,190 participants including 6,382 patients with T2DM from the 2011–2020 KNHANES cohort were included and followed until death, a cardiovascular event (myocardial infarction or ischemic stroke), or the study endpoint. Results Participants in the lowest income quintile had higher risks of mortality (Hazard ratio [HR]: 1.44, 95 % CI: 1.19–1.76) and CVD (HR: 1.35, 95 % CI: 1.05–1.74) compared to the highest quintile. Unemployed individuals had a higher mortality risk (HR: 1.34, 95 % CI: 1.19–1.51) than employed ones. Non-homeowners also had a higher mortality risk (HR: 1.46, 95 % CI: 1.20–1.77) than multi-homeowners. Participants with elementary school education or less had higher risks of mortality (HR: 1.59, 95 % CI: 1.32–1.93) and CVD (HR: 1.71, 95 % CI: 1.31–2.24) compared to college graduates. Among those with T2DM, unemployment (HR: 1.43, 95 % CI: 1.16–1.77) and low education (HR: 1.53, 95 % CI: 1.07–2.17) were associated with higher mortality. Conclusions This analysis revealed significant associations of low SES with increased risks of mortality and CVD. Similar associations were observed in T2DM population for mortality outcomes.

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The prospects and limitations of liquid biopsy utilization for clinical practice in Taiwan

The journal of liquid biopsy

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The journal of liquid biopsy 2025年 7卷 100290页

作者： Huei-Ying Li Chun-Chuan Chang Yu-Hsuan Yang Chi-Yuan Yao Jason Chia-Hsun Hsieh Shao-Hsuan Chang Medical Microbiota Center of the First Core Laboratory National Taiwan University Taipei Taiwan. Professional Master's Program of Biotechnology Management National Taiwan University Taipei Taiwan. Graduate Institute of Medical Genomics and Proteomics National Taiwan University Taipei Taiwan. Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan. Division of Oncology Department of Internal Medicine Linkou Chang Gung Memorial Hospital Taoyuan Taiwan. College of Medicine Chang Gung University Taoyuan Taiwan. Department of Biomedical Engineering Chang Gung University Taoyuan Taiwan.

Objective:Liquid biopsy is a promising, non-invasive diagnostic tool for cancer, offering rapid and cost-effective genomic analysis. It provides a less invasive alternative to traditional tissue biopsies, with potential benefits in monitoring disease progression and detecting minimal residual disease (MRD). However, its clinical integration faces challenges, including utility assessment and workflow adaptation. This study evaluates the value of liquid biopsy in Taiwan from a clinical physician's perspective. Methods:A survey was conducted with 16 physicians specializing in thoracic medicine and hematologic oncology. Participants responded to a 5-point Likert scale to evaluate the timing of liquid biopsy adoption, willingness to incorporate it into clinical practice, and agreement on its role in managing specific clinical conditions. Results:Forty percent of physicians preferred liquid biopsy when tissue samples were unavailable. The inclusion of liquid biopsy under National Health Insurance (NHI) was a key factor in its adoption. Hematologic oncologists showed a stronger preference for liquid biopsy, particularly for MRD testing, compared to their counterparts in thoracic medicine (hematologic oncology vs. thoracic medicine: 4.2 ± 0.83 vs. 3.1 ± 0.60; p value = 0.01). Younger physicians valued turnaround time, while senior physicians prioritized test brand, with a focus on report speed. Conclusion:Physicians are generally less inclined to replace tissue biopsies with liquid biopsy, but hematologic oncologists show more flexibility. Test brand plays a role in physician decision-making, and the inclusion of liquid biopsy under NHI coverage is vital for its broader adoption in Taiwan.

关键词： Cancer diagnosis Clinical adoption Liquid biopsy Minimal residual disease (MRD) National health insurance

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Overcoming the Blood-Brain Tumor Barrier with Docetaxel-Loaded Mesoporous Silica Nanoparticles for Treatment of Temozolomide-Resistant Glioblastoma

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ACS Applied Materials and Interfaces 2024年第17期16卷 21722-21735页

作者： Hsu, Tsung-I Chen, Yi-Ping Zhang, Rong-Lin Chen, Zih-An Wu, Cheng-Hsun Chang, Wen-Chang Mou, Chung-Yuan Chan, Hardy Wai-Hong Wu, Si-Han Ph.D. Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University and National Health Research Institutes Taipei110 Taiwan International Master Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University Taipei110 Taiwan Graduate Institute of Nanomedicine and Medical Engineering Taipei Medical University Taipei110 Taiwan International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei110 Taiwan Nano Targeting & Therapy Biopharma Inc. Taipei110 Taiwan Graduate Institute of Medical Sciences College of Medicine Taipei Medical University Taipei110 Taiwan Department of Chemistry National Taiwan University Taipei106 Taiwan

While temozolomide (TMZ) has been a cornerstone in the treatment of newly diagnosed glioblastoma (GBM), a significant challenge has been the emergence of resistance to TMZ, which compromises its clinical benefits. Additionally, the nonspecificity of TMZ can lead to detrimental side effects. Although TMZ is capable of penetrating the blood-brain barrier (BBB), our research addresses the need for targeted therapy to circumvent resistance mechanisms and reduce off-target effects. This study introduces the use of PEGylated mesoporous silica nanoparticles (MSN) with octyl group modifications (C8-MSN) as a nanocarrier system for the delivery of docetaxel (DTX), providing a novel approach for treating TMZ-resistant GBM. Our findings reveal that C8-MSN is biocompatible in vitro, and DTX@C8-MSN shows no hemolytic activity at therapeutic concentrations, maintaining efficacy against GBM cells. Crucially, in vivo imaging demonstrates preferential accumulation of C8-MSN within the tumor region, suggesting enhanced permeability across the blood-brain tumor barrier (BBTB). When administered to orthotopic glioma mouse models, DTX@C8-MSN notably prolongs survival by over 50%, significantly reduces tumor volume, and decreases side effects compared to free DTX, indicating a targeted and effective approach to treatment. The apoptotic pathways activated by DTX@C8-MSN, evidenced by the increased levels of cleaved caspase-3 and PARP, point to a potent therapeutic mechanism. Collectively, the results advocate DTX@C8-MSN as a promising candidate for targeted therapy in TMZ-resistant GBM, optimizing drug delivery and bioavailability to overcome current therapeutic limitations. © 2024 The Authors. Published by American Chemical Society.

关键词： Tumors

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Registration of finger vein image using skin surface information for authentication

Registration of finger vein image using skin surface informa...

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Image Processing: Machine Vision Applications II

作者： Noh, SeungWoo Kong, Hyoun-Joong Park, SangYun Kim, JiMan Lee, Seung-Rae Kim, Taejeong Kim, Hee Chan Interdisciplinary Program Bioengineering Major Graduate School Seoul National University Seoul Korea Republic of Interdisciplinary Program Biomedical Engineering Major Graduate School Seoul National University Seoul Korea Republic of Institute of Medical and Biological Engineering Medical Research Center Seoul National University Seoul Korea Republic of Department of Electrical Engineering and Computer Sciences Seoul National University Seoul Korea Republic of Department of Biomedical Engineering College of Medicine Seoul National University Seoul Korea Republic of

ISBN: (纸本)9780819475015

The finger vein image acquired with an acquisition system should be properly aligned to proceed with comparing algorithm. However it is not easy to find control the points since the images are naturally blurred with an inherent scattering property. To overcome this problem, we propose a novel finger vein registration method utilizing skin surface information (i.e. wrinkles and outlines). We assumed that finger crooking was insignificant. Images were sampled with intended translation and rotation. Each time, two images were acquired successively by switching the light source;one with infrared light and the other with white light. Degree of rotation and translation of sampled image were calculated using outline features in the white light image and then the infrared image was transformed according to the calculated data. To validate our method, correlation values were computed between identical subjects and different subjects. High correlation values were shown between identical subjects whereas low values were shown between different subjects. © 2009 SPIE.

关键词： Authentication

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