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Common AAV gene therapy vectors show nonselective transduction of ex vivo human brain tissue

Molecular Therapy Methods & Clinical Development 2025年第2期33卷

作者： JP McGinnis Joshua Ortiz-Guzman Maria Camila Guevara Sai Mallannagari Benjamin D.W. Belfort Suyang Bao Snigdha Srivastava Maria Morkas Emily Ji Angela Addison Evelyne K. Tantry Sarah Chen Ying Wang Zihong Chen Kalman A. Katlowitz Jeffrey J. Lange Melissa M. Blessing Carrie A. Mohila M. Cecilia Ljungberg Guillermo Aldave Benjamin R. Arenkiel Department of Neurosurgery Baylor College of Medicine Houston TX 77030 USA Jan and Dan Duncan Neurological Research Institute Texas Children’s Hospital Houston TX 77030 USA Department of Molecular and Human Genetics Baylor College of Medicine Houston TX 77030 USA Medical Scientist Training Program Baylor College of Medicine Houston TX 77030 USA Development Disease Models & Therapeutics Graduate Program Baylor College of Medicine Houston TX 77030 USA Stowers Institute for Medical Research Kansas City MO 64110 USA Department of Pathology Texas Children’s Hospital Baylor College of Medicine Houston TX 77030 USA Department of Pediatrics Texas Children’s Hospital Baylor College of Medicine Houston TX 77030 USA Department of Neurosurgery Texas Children’s Hospital Baylor College of Medicine Houston TX 77030 USA

The ability to deliver a therapeutic sequence to a specific cell type in the human brain would make possible innumerable therapeutic options for some of our most challenging diseases; however, studies on adeno-associated virus (AAV) vector tropism have generally relied on animal models with limited translational utility. For this reason, establishing the tropism of common adeno-associated virus (AAV) vectors in living human brain tissue serves as an important baseline for further optimization, as well as a determination of human brain cell types transduced by clinically approved gene therapy vectors AAV2 and AAV9. We have adapted an ex vivo organotypic model to evaluate AAV transduction properties in living slices of human brain tissue. Using fluorescent reporter expression and single-nucleus RNA sequencing, we found that common AAV vectors show broad transduction of normal cell types, with protein expression most apparent in astrocytes; this work introduces a pipeline for identifying and optimizing AAV gene therapy vectors in human brain samples.

关键词： gene therapy human brain AAV AAV tropism human brain organotypic slice culture

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Heart Block Caused by Cardiac Metastasis From Merkel Cell Carcinoma: A Case Report

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Mayo Clinic Proceedings: Innovations, Quality and Outcomes 2019年第4期3卷 510-516页

作者： Kazemi, Nazanin Yeganeh Jain, Christopher Bois, Melanie C. Behfar, Atta Olivier, Kenneth Markovic, Svetomir N. Medical Scientist Training Program Mayo Clinic Rochester MN United States Department of Cardiovascular Medicine Mayo Clinic Rochester MN United States Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN United States Department of Radiation Oncology Mayo Clinic Rochester MN United States Department of Oncology Mayo Clinic Rochester MN United States

Merkel cell carcinoma (MCC) is a rare, rapidly proliferating skin cancer that commonly metastasizes to regional lymph nodes. We present the case of a 73-year-old woman with a history of MCC and non-Hodgkin B-cell lymphoma who presented with second-degree heart block (Mobitz type II) caused by an interatrial mass. Temporary pacing was required before biopsy, which revealed metastatic MCC. Treatment included permanent pacing, anti–programmed cell death ligand 1 immunotherapy, and radiation to the heart resulting in notable decrease in tumor size and normalized cardiac rhythm. © 2019 Mayo Foundation for medical Education and Research

关键词： CM, cardiac metastases CT, computed tomography FDG, [18F]-fluorodeoxyglucose MCC, Merkel cell carcinoma MCPyV, Merkel cell polyomavirus MRI, magnetic resonance imaging PD-L1, programmed cell death ligand 1 PET, positron emission tomography

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Glioblastoma stem cells:Molecular characteristics and therapeutic implications

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World Journal of Stem Cells 2014年第2期6卷 230-238页

作者： Nermin Sumru Bayin Aram Sandaldjian Modrek Dimitris George Placantonakis Department of Neurosurgery New York University School of Medicine Stem Cell Biology Training Program New York University School of Medicine Medical Scientist Training Program New York University School of Medicine Kimmel Center for Stem Cell Biology New York University School of Medicine Brain Tumor Center New York University School of Medicine

Glioblastoma Multiforme(GBM)is a grade IV astrocytoma,with a median survival of 14.6 *** GBM,stem-like cells,namely glioblastoma stem cells(GSCs),have the ability to self-renew,differentiate into distinct lineages within the tumor and initiate tumor xenografts in immunocompromised animal *** importantly,GSCs utilize cell-autonomous and tumor microenvironment-mediated mechanisms to overcome current therapeutic *** are,therefore,very important therapeutic *** the functional criteria defining GSCs are well defined,their molecular characteristics,the mechanisms whereby they establish the cellular hierarchy within tumors,and their contribution to tumor heterogeneity are not well *** review is aimed at summarizing current findings about GSCs and their therapeutic importance from a molecular and cellular point of view.A better characterization of GSCs is crucial for designing effective GSCtargeted therapies.

关键词： Glioblastoma Glioblastoma stem cells Selfrenewal Differentiation Molecular markers Therapy resistance

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Bilateral pseudo-internuclear ophthalmoplegia in a patient with myasthenia gravis

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American Journal of Ophthalmology Case Reports 2018年 12卷 76-78页

作者： McClard, Cynthia K. Lyons, Lance J. Yalamanchili, Sushma School of Medicine Baylor College of Medicine Houston TX United States School of Medicine Baylor College of Medicine Medical Scientist Training Program Houston TX United States Department of Ophthalmology UTMB Galveston TX United States Department of Ophthalmology Methodist Eye Associates Blanton Eye Institute Houston Methodist Hospital Houston TX United States

Purpose: To report a case of myasthenia gravis presenting with a false localizing sign, a bilateral pseudo internuclear ophthalmoplegia. Observations: A 61 year-old male presented with a five-week history of painless binocular oblique diplopia that was associated with fatigue, vocal hoarseness and bilateral ptosis, the latter two of which worsened through the course of the day. Exam was remarkable for an apparent bilateral internuclear ophthalmoplegia (INO). MRI of the brain with and without contrast and MRA of the head and neck were within normal limits. Lab work was positive for anti-AChR binding, blocking, and modulating antibodies, as well as anti-striated muscle and anti-titin antibodies. The patient was initiated on therapy for myasthenia gravis. Conclusion and importance: Although myasthenia gravis often presents with ptosis or diplopia, rarely patients may develop pseudo-INO secondary to extraocular muscle weakness. True INO occurs with damage to the medial longitudinal fasciculus, a myelinated tract of fibers that controls yoked horizontal eye movements. Clinicians should be suspicious of the false localizing sign of a pseudo-INO associated with myasthenia gravis when more common causes of INO have been excluded. © 2018

关键词： False localizing signs Myasthenia gravis Ocular myasthenia gravis Pseudo internuclear ophthalmoplegia

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Melanoma in a patient with previously unrecognized Birt-Hogg-Dubé syndrome

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JAAD Case Reports 2019年第11期5卷 947-952页

作者： Nowsheen, Somaira Hand, Jennifer L. Gibson, Lawrence E. el-Azhary, Rokea A. Mayo Clinic Medical Scientist Training Program Mayo Clinic Rochester MN United States Department of Dermatology Mayo Clinic Rochester MN United States Department of Pediatrics and Adolescent Medicine Mayo Clinic Rochester MN United States Department of Clinical Genomics Mayo Clinic Rochester MN United States Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN United States

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Reinforcement Learning for Control of Evolutionary and Ecological Processes

arXiv

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arXiv 2023年

作者： Bagley, Bryce Allen Khoshnan, Navin Petritsch, Claudia K. Mathematical Medicine Group Stanford University United States Petritsch Laboratory Department of Neurosurgery Stanford Medical School United States Physician-Scientist Training Program Stanford Medical School United States

As Evolutionary Dynamics moves from the realm of theory into application, algorithms are needed to move beyond simple models. Yet few such methods exist in the literature. Ecological and physiological factors are known to be central to evolution in realistic contexts, but accounting for them generally renders problems intractable to existing methods. We introduce a formulation of evolutionary games which accounts for ecology and physiology by modeling both as computations and use this to analyze the problem of directed evolution via methods from Reinforcement Learning. This combination enables us to develop first-of-their-kind results on the algorithmic problem of learning to control an evolving population of cells. We prove a complexity bound on eco-evolutionary control in situations with limited prior knowledge of cellular physiology or ecology, give the first results on the most general version of the mathematical problem of directed evolution, and establish a new link between AI and *** Codes 93 (Primary) 68Txx, 92Dxx, 92Cxx (Secondary) © 2023, CC BY-NC-ND.

关键词： Anthropogenic

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Multimodal analyses reveal genes driving electrophysiological maturation of neurons in the primate prefrontal cortex

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Neuron 2025年

作者： Gao, Yu Dong, Qiping Arachchilage, Kalpana Hanthanan Risgaard, Ryan D. Syed, Moosa Sheng, Jie Schmidt, Danielle K. Jin, Ting Liu, Shuang Sandoval, Soraya O. Knaack, Sara Eckholm, Magnus T. Chen, Rachel J. Guo, Yu Doherty, Dan Glass, Ian Levine, Jon E. Wang, Daifeng Chang, Qiang Zhao, Xinyu Sousa, Andre M.M. Waisman Center University of Wisconsin-Madison Madison 53705 WI United States Department of Pediatrics University of Washington School of Medicine Seattle 98195 WA United States Department of Neuroscience University of Wisconsin-Madison Madison 53705 WI United States Wisconsin National Primate Research Center University of Wisconsin-Madison Madison 53705 WI United States Department of Biostatistics and Medical Informatics University of Wisconsin-Madison Madison 53705 WI United States Department of Computer Sciences University of Wisconsin-Madison Madison 53706 WI United States Department of Medical Genetics University of Wisconsin-Madison Madison 53705 WI United States Department of Neurology University of Wisconsin-Madison Madison 53705 WI United States Neuroscience Training Program University of Wisconsin-Madison Madison 53705 WI United States

The prefrontal cortex (PFC) is critical for myriad high-cognitive functions and is associated with several neuropsychiatric disorders. Here, using Patch-seq and single-nucleus multiomic analyses, we identified genes and regulatory networks governing the maturation of distinct neuronal populations in the PFC of rhesus macaque. We discovered that specific electrophysiological properties exhibited distinct maturational kinetics and identified key genes underlying these properties. We unveiled that RAPGEF4 is important for the maturation of resting membrane potential and inward sodium current in both macaque and human. We demonstrated that knockdown of CHD8, a high-confidence autism risk gene, in human and macaque organotypic slices led to impaired maturation, via downregulation of key genes, including RAPGEF4. Restoring the expression of RAPGEF4 rescued the proper electrophysiological maturation of CHD8-deficient neurons. Our study revealed regulators of neuronal maturation during a critical period of PFC development in primates and implicated such regulators in molecular processes underlying autism. © 2025 Elsevier Inc.

关键词： CHD8 functional genomics neurodevelopmental disorder neuronal maturation non-human primate Patch-seq prefrontal cortex prenatal development RAPGEF4 single-nucleus multiome

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Prospective evaluation of data-driven models to predict daily risk of Clostridioides difficile infection at 2 large academic health centers (vol 2, pg 1, 2022)

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INFECTION CONTROL & HOSPITAL EPIDEMIOLOGY 2023年第10期44卷 1705-1705页

作者： Kamineni, Meghana Otles, Erkin Oh, Jeeheh Rao, Krishna Young, Vincent B. Li, Benjamin Y. West, Lauren R. Hooper, David C. Shenoy, Erica S. Guttag, John G. Wiens, Jenna Makar, Maggie Electrical Engineering and Computer Science Department Massachusetts Institute of Technology Cambridge Massachusetts Medical Scientist Training Program University of Michigan Medical School Ann Arbor Michigan Department of Industrial and Operations Engineering University of Michigan College of Engineering Ann Arbor Michigan Division of Computer Science and Engineering University of Michigan College of Engineering Ann Arbor Michigan Department of Internal Medicine Division of Infectious Diseases University of Michigan Medical School Ann Arbor Michigan Infection Control Unit Massachusetts General Hospital Boston Massachusetts Division of Infectious Diseases Massachusetts General Hospital Boston Massachusetts Harvard Medical School Boston Massachusetts

Many data-driven patient risk stratification models have not been evaluated prospectively. We performed and compared the prospective and retrospective evaluations of 2 Clostridioides difficile infection (CDI) risk-prediction models at 2 large academic health centers, and we discuss the models’ robustness to data-set shifts.

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Cooperative Gsx2-DNA binding requires DNA bending and a novel Gsx2 homeodomain interface (Jun, gkae522, 2024)

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NUCLEIC ACIDS RESEARCH 2024年第13期52卷 8037-8037页

作者： Webb, Jordan A. Farrow, Edward Cain, Brittany Yuan, Zhenyu Yarawsky, Alexander E. Schoch, Emma Gagliani, Ellen K. Herr, Andrew B. Gebelein, Brian Kovall, Rhett A. Department of Molecular and Cellular Biosciences University of Cincinnati College of Medicine Cincinnati OH 45267 USA. Graduate Program in Molecular and Developmental Biology Cincinnati Children's Hospital Research Foundation Cincinnati OH 45229 USA. Medical-Scientist Training Program University of Cincinnati College of Medicine Cincinnati OH 45229 USA. Division of Developmental Biology Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue MLC 7007 Cincinnati OH 45229 USA. Division of Immunobiology Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati OH 45229 USA. Department of Medical Education University of Cincinnati College of Medicine Cincinnati OH 45229 USA. Department of Chemistry Xavier University Cincinnati OH 45207 USA. Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH 45229 USA.

The conserved Gsx homeodomain (HD) transcription factors specify neural cell fates in animals from flies to mammals. Like many HD proteins, Gsx factors bind A/T-rich DNA sequences prompting the following question: How do HD factors that bind similar DNA sequences in vitro regulate specific target genes in vivo? Prior studies revealed that Gsx factors bind DNA both as a monomer on individual A/T-rich sites and as a cooperative homodimer to two sites spaced precisely 7 bp apart. However, the mechanistic basis for Gsx-DNA binding and cooperativity is poorly understood. Here, we used biochemical, biophysical, structural and modeling approaches to (i) show that Gsx factors are monomers in solution and require DNA for cooperative complex formation, (ii) define the affinity and thermodynamic binding parameters of Gsx2/DNA interactions, (iii) solve a high-resolution monomer/DNA structure that reveals that Gsx2 induces a 20° bend in DNA, (iv) identify a Gsx2 protein-protein interface required for cooperative DNA binding and (v) determine that flexible spacer DNA sequences enhance Gsx2 cooperativity on dimer sites. Altogether, our results provide a mechanistic basis for understanding the protein and DNA structural determinants that underlie cooperative DNA binding by Gsx factors.

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Long-term olfactory loss post-COVID-19:Pathobiology and potential therapeutic strategies

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2024年第2期10卷 148-155页

作者： Sarah Kim John B.Finlay Tiffany Ko Bradley J.Goldstein Department of Head and Neck Surgery&Communication Sciences Duke UniversityDurhamNorth CarolinaUSA Medical Scientist Training Program Duke UniversityDurhamNorth CarolinaUSA Department of Neurobiology Duke UniversityDurhamNorth CarolinaUSA

An acute loss of smell emerged as a striking symptom present in roughly half of the people infected with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)virus in the early phases of the COVID-19 *** most COVID-19 patients,olfaction recovers over the course of a few ***,a lasting partial or complete loss of smell,often associated with distorted olfactory perceptions termed parosmia,has emerged as a widespread problem impacting at least 5%-10%of those who experience anosmia due to *** inability to offer effective therapies to this hyposmic or anosmic population,comprising millions of patients,highlights an enormous unmet need for the medical ***,we summarize the current understanding of the pathobiology causing acute olfactory loss due to SARS-CoV-2 infection,focusing on how the virus interacts with the peripheral olfactory system,a major site of viral *** also explore the problem of long-COVID olfactory dysfunction,which may accompany other persistent systemic disorders collectively termed postacute sequelae of ***,we discuss an emerging model focused on unresolved immune cell activity driving ongoing ***,we review current and future therapeutic approaches aimed at restoring olfactory function.

关键词： hyposmia inflammation long-COVID parosmia

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