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Enhancing human pluripotent stem cell differentiation to cardiomyocytes through cardiac progenitor reseeding and cryopreservation

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iScience 2025年第5期28.0卷

作者： Feeney, Austin K. Simmons, Aaron D. Peplinski, Claire J. Zhang, Xiaotian Palecek, Sean P. Department of Biomedical Engineering University of Wisconsin-Madison Madison 53706 WI United States Medical Scientist Training Program University of Wisconsin School of Medicine and Public Health Madison 53726 WI United States Department of Chemical and Biological Engineering University of Wisconsin-Madison Madison 53706 WI United States

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have the potential to transform the understanding of heart development and heart failure treatment. However, hPSC-CM differentiation efficiency is plagued by batch-to-batch and line-to-line variability. Here, we describe a method to improve CM purity by 10–20% (absolute) without negatively affecting contractility, sarcomere structure, multinucleation, junctional Cx43, or CM number by detaching and reseeding progenitors between the EOMES+ mesoderm and ISL1+/NKX2-5+ cardiac progenitor stages. Moreover, we demonstrate that EOMES+ mesoderm and ISL1+/NKX2-5+ cardiac progenitors are cryopreservable with similar improvements in CM purity after resuming differentiation, facilitating storage of large batches of hPSC-CM progenitors for on-demand CM production. Reseeding during differentiation also enables transition to defined extracellular matrices, including fibronectin, vitronectin, and laminin-111, which all supported hPSC-derived EOMES+ mesoderm and ISL1+/NKX2-5+ cardiac progenitor differentiation to CMs. In summary, we present a method to increase hPSC-CM differentiation purity and demonstrate that specific CM progenitors are amenable to cryopreservation. © 2025 The Authors

关键词： Biological sciences Biological sciences research methodologies Technical aspects of cell biology

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Charcot-Marie-Tooth disease: A gene-dosage effect

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HOSPITAL PRACTICE 1997年第5期32卷 83-&页

作者： Lupski, JR Medical Scientist Training Program Baylor College of Medicine Houston USA.

A broad spectrum of inherited neuropathy has been traced to three myelin genes, yet in the two most common disorders, there is no mutated gene. Instead, a gene has an extra or missing copy, as part of a 1.5-megabase DNA duplication or deletion. Eventually, duplications may emerge as a large fraction of all mutations. The discoveries have implications even for acquired disorders-including carpal tunnel syndrome.

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Clusterin induced by OPC phagocytosis blocks IL-9 secretion to inhibit myelination in a model of Alzheimer's disease

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Heliyon 2025年第1期11卷 e41635页

作者： Beiter, Rebecca M. Raghavan, Tula P. Suchocki, Olivia Ennerfelt, Hannah E. Rivet-Noor, Courtney R. Merchak, Andrea R. Phillips, Jennifer L. Bathe, Tim Lukens, John R. Prokop, Stefan Dupree, Jeffrey L. Gaultier, Alban Center for Brain Immunology and Glia Department of Neuroscience Charlottesville 22908 VA United States Graduate Program in Neuroscience Charlottesville 22908 VA United States Department of Neurobiology UMass Chan Medical School Worcester 01655 MA United States Medical Scientist Training Program University of Virginia School of Medicine Charlottesville 22908 VA United States Center for Translational Research in Neurodegenerative Disease College of Medicine University of Florida Gainesville 32610 FL United States Department of Pathology College of Medicine University of Florida Gainesville 32610 United States McKnight Brain Institute College of Medicine University of Florida Gainesville 32610 FL United States Department of Anatomy and Neurobiology Virginia Commonwealth University Richmond 23298 VA United States

Background: Variants in the CLUSTERIN gene have been identified as a risk factor for late-onset Alzheimer's disease and are linked to decreased white matter integrity in healthy adults. However, the specific role for clusterin in myelin maintenance in the context of Alzheimer's disease remains unclear. Methods: We employed a combination of immunofluorescence and transmission electron microscopy techniques, primary culture of OPCs, and an animal model of Alzheimer's disease. Results: We found that phagocytosis of debris such as amyloid beta, myelin, and apoptotic cells, increases clusterin expression in oligodendrocyte progenitors. We further discovered that exposure to clusterin inhibits differentiation of oligodendrocyte progenitors. Mechanistically, clusterin blunts production of IL-9 and addition of exogenous IL-9 can rescue clusterin-inhibited myelination. Lastly, we demonstrate that clusterin deletion in mice prevents myelin loss in the 5XFAD model. Discussion: Our data suggest that clusterin could play a key role in Alzheimer's disease myelin pathology. © 2025 The Authors

关键词： Alzheimer's disease Astrocyte Clusterin IL-9 Myelin Oligodendrocyte progenitor cells

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VeriFact: Verifying Facts in LLM-Generated Clinical Text with Electronic Health Records

arXiv

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arXiv 2025年

作者： Chung, Philip Swaminathan, Akshay Goodell, Alex J. Kim, Yeasul Reincke, S. Momsen Han, Lichy Deverett, Ben Sadeghi, Mohammad Amin Ariss, Abdel-Badih Ghanem, Marc Seong, David Lee, Andrew A. Coombes, Caitlin E. Bradshaw, Brad Sufian, Mahir A. Hong, Hyo Jung Nguyen, Teresa P. Rasouli, Mohammad R. Kamra, Komal Burbridge, Mark A. McAvoy, James C. Saffary, Roya Ma, Stephen P. Dash, Dev Xie, James Wang, Ellen Y. Schmiesing, Clifford A. Shah, Nigam Aghaeepour, Nima Department of Anesthesiology Perioperative and Pain Medicine Stanford Medicine United States Department of Biomedical Data Science Stanford Medicine United States Department of Pediatrics Stanford Medicine United States Department of Medicine Stanford Medicine United States Department of Emergency Medicine Stanford Medicine United States Immunology Program Stanford Medicine United States Medical Scientist Training Program Stanford Medicine United States Clinical Excellence Research Center Stanford Medicine United States Technology and Digital Solutions Stanford Health Care United States

Methods to ensure factual accuracy of text generated by large language models (LLM) in clinical medicine are lacking. VeriFact is an artificial intelligence system that combines retrieval-augmented generation and LLM-as-a-Judge to verify whether LLM-generated text is factually supported by a patient’s medical history based on their electronic health record (EHR). To evaluate this system, we introduce VeriFact-BHC, a new dataset that decomposes Brief Hospital Course narratives from discharge summaries into a set of simple statements with clinician annotations for whether each statement is supported by the patient’s EHR clinical notes. Whereas highest agreement between clinicians was 88.5%, VeriFact achieves up to 92.7% agreement when compared to a denoised and adjudicated average human clinician ground truth, suggesting that VeriFact exceeds the average clinician’s ability to fact-check text against a patient’s medical record. VeriFact may accelerate the development of LLM-based EHR applications by removing current evaluation bottlenecks. © 2025, CC BY.

关键词： Electronic health record

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Intrauterine contraceptive device-associated actinomycotic abscess and Actinomyces detection on cervical smear

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OBSTETRICS AND GYNECOLOGY 1996年第1期87卷 142-149页

作者： Fiorino, AS From the Medical Scientist Training Program Albert Einstein College of Medicine Bronx New York USA

Objective: To summarize clinical features and treatments in reported cases of actinomycotic pelvic abscess occurring in women using intrauterine contraceptive devices (IUD), and to review detection of Actinomyces by cervical smear. Data Sources: The English-language medical literature accessed through MEDLINE. Methods of Study Selection: We identified 92 cases of actinomycotic abscesses associated with IUD use in 63 case reports. In addition, 31 studies of Actinomyces detection were found, 16 of which were studies of Papanicolaou smear-based detection. Data Abstraction and Synthesis: Data regarding clinical presentation and treatment were culled from case reports, whereas detection rates of Papanicolaou smear and other methods were obtained from studies of Actinomyces detection. The average patient was 37 years old, had been using an IUD for 8 years, and presented with abdominal pain, weight loss, vaginal discharge, and fever. Laboratory studies commonly revealed anemia, leukocytosis, and an elevated erythrocyte sedimentation rate. Most of these patients underwent operative procedures, usually hysterectomy and salpingo-oophorectomy. High-dose penicillin was found to be an effective antibiotic. Detection rates of organisms on Papanicolaou smear were somewhat variable;use of other detection methods, including endometrial biopsy, culture, and immunofluorescence, did not improve this variability. Conclusions: Pelvic actinomycosis associated with the use of IUDs can mimic pelvic malignancy;for that reason, it is often treated surgically. However, if the diagnosis of actinomycosis can be obtained preoperatively, antibiotic treatment may lead to complete resolution. The Papanicolaou smear may be useful in evaluating such patients.

关键词： Abscess Actinomyces Actinomycosis Adult Female Humans Intrauterine Devices Pelvis Research Support U.S. Gov't P.H.S. Vaginal Smears

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A pancreatic player in dementia:pathological role for islet amyloid polypeptide accumulation in the brain

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Neural Regeneration Research 2023年第10期18卷 2141-2146页

作者： Angelina S.Bortoletto Ronald J.Parchem Center for Cell and Gene Therapy Stem Cell and Regenerative Medicine CenterDepartment of NeuroscienceDepartment of Molecular and Cellular BiologyTranslational Biology and Molecular Medicine ProgramMedical Scientist Training ProgramBaylor College of MedicineHoustonTXUSA

Type 2 diabetes mellitus patients have a markedly higher risk of developing *** multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes *** amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are *** this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of *** discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced *** are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at ***,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating *** such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.

关键词： Alzheimer’s disease amylin amyloid dementia diabetes human islet amyloid polypeptide islet amyloid polypeptide protofibrils type 2 diabetes mellitus vascular dementia

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Protection of CD33-modified hematopoietic stem cell progeny from CD33-directed CAR T cells in rhesus macaques

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Blood Advances 2025年第10期9卷 2367-2378页

作者： Petty, Nicholas E. Radtke, Stefan Kanestrom, Greta Fields, Emily Humbert, Olivier Fiorenza, Salvatore Llewellyn, Mallory J. Laszlo, George S. Thomas, Justin Burger, Zach Swing, Kyle Zhu, Haiying Jerome, Keith R. Turtle, Cameron J. Walter, Roland B. Kiem, Hans-Peter Translational Science and Therapeutics Division Fred Hutchinson Cancer Center Seattle WA United States Medical Scientist Training Program University of Washington School of Medicine Seattle WA United States Division of Hematology and Oncology Department of Medicine University of Washington School of Medicine Seattle WA United States Department of Laboratory Medicine and Pathology University of Washington School of Medicine Seattle WA United States Vaccine and Infectious Disease Division Fred Hutchinson Cancer Center Seattle WA United States

The treatment of monogenetic disorders, such as hemoglobinopathies and lysosomal storage diseases, has markedly improved with the advent of cell and gene therapies, particularly allogeneic or gene-modified autologous stem cell transplantations. However, therapeutic efficacy is reliant on maintaining engraftment above a critical threshold. To maintain such engraftment levels, we and others have pursued approaches to shield edited cells from antibody or chimeric antigen receptor (CAR) T-cell–mediated selection. Here, we focused on CD33, which is expressed early on hematopoietic stem and progenitor cells (HSPCs) as well as on myeloid progenitors. Rhesus macaques were engrafted with HSPCs edited to ablate CD33 using either CRISPR/CRISPR-associated protein 9 or adenine base editor. Both editing strategies showed similar post-transplant recovery kinetics and yielded equivalent levels of engraftment. We then created a V-set domain–specific CAR construct (CAR33), validated its functionality in vitro, and treated both animals with autologous CAR33 T cells. CAR33 T cells expanded after infusion and caused specific depletion of CD33^WT but not CD33^null progeny, leading to a transient enrichment for gene-edited cells in the blood. No depletion was seen in the bone marrow stem cell compartment with CD34⁺CD90⁺ HSCs expressing lower levels of CD33 in comparison to monocytes. Thus, we show proof of concept and safety of an epitope editing–based enrichment/protection strategy in macaques. © 2025 American Society of Hematology.

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Auditory Understanding of Speech and Non-speech. 1

Auditory Understanding of Speech and Non-speech. 1

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作者： Uddin, Sophia.0(orcid)0000-0002-7285-42620 The University of Chicago.bInterdisciplinary Scientist Training Program: Computational Neuroscience.0

学位级别：Ph.D.

There is a longstanding debate about the specificity and encapsulation of the mechanisms behind humans' ability to understand speech. Some scholars argue that these abilities arise from evolutionarily specialized language modules, while others hold that they are a result of the interaction between cognitive-general mechanisms and extensive experience. In the present work, we use meaningful non-speech sounds, e.g. dog barks and train whistles, in the context of spoken sentences, to probe the extent to which language understanding mechanisms can quickly and easily adapt to non-speech. We find that behaviorally, listeners can recognize and understand non-speech sounds in sentence context quickly and easily, with processing costs much smaller than those that would be expected from a "translation" or covert naming process. Moreover, neurally, the N400 and P600 potentials are remarkably similar between non-speech sounds and matched spoken words, suggesting similar processing that is, in both cases, equally sensitive to sentential constraint and congruency with the preceding sentence context. These results closely mirrored the results from a final study in which we examined neural responses to spoken words said by a different talker. Analysis of relationships between working memory and scalp topography, as well as source analysis, indicated that both the comprehension of a different talker and the comprehension of an environmental sound involve early recruitment of working memory in the N1 and P2 time windows. These processes are mediated by parietal and temporal speech areas that have previously been identified in studies of talker normalization. Though the degree of recruitment of these resources may be greater and/or last longer for non-speech sounds than for a changing talker, the underlying mechanisms appear to be qualitatively the same. These results are discussed in light of a new model of auditory understanding, in which working memory, attention, and experience in

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Chronic impairment of neurovascular coupling and cognitive decline in young survivors of severe traumatic brain injury

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GeroScience 2025年 1-13页

作者： Magyar-Sumegi, Zsofia Dina Csendes, Mark Lendvai-Emmert, Dominika Sebestyen, Gabriella Tamas, Viktoria Bandi, Szabolcs Czigler, Andras Yabluchanskiy, Andriy Tarantini, Stefano Ungvari, Zoltan Czeiter, Endre Amrein, Krisztina Orsi, Gergely Perlaki, Gabor Buki, Andras Toth, Peter Department of Neurosurgery Medical School University of Pecs Pecs Hungary Department of Psychiatry and Psychotherapy Medical School University of Pecs Pecs Hungary Doctoral School of Clinical Neurosciences Medical School University of Pecs Pecs Hungary Vascular Cognitive Impairment Neurodegeneration and Healthy Brain Aging Program Department of Neurosurgery University of Oklahoma Health Sciences Center Oklahoma City OK United States Doctoral College Health Sciences Division/Institute of Preventive Medicine and Public Health International Training Program in Geroscience Semmelweis University Budapest Hungary HUN-REN–PTE Clinical Neuroscience MR Research Group University of Pecs Pecs Hungary Molecular Medicine Research Group Szentagothai Research Centre University of Pecs Pecs Hungary Department of Neurosurgery Faculty of Medicine and Health Orebro University Orebro Sweden

Severe traumatic brain injury (TBI) leads to chronic cognitive decline, imposing a significant societal burden. The regulation of cerebral blood flow (CBF) is critical for cognitive function, and acute disruptions in CBF regulation predict poor TBI outcomes. However, the long-term effects of TBI on CBF regulation and their association with cognitive function remain poorly understood. This study aimed to investigate whether severe TBI results in chronic CBF dysregulation and whether this contributes to long-term cognitive deficits. Additionally, we examined the role of TBI-induced insulin-like growth factor 1 (IGF-1) deficiency in cerebrovascular dysfunction. We assessed cognitive function, basal CBF (via phase contrast MRI), CBF autoregulation (via transcranial Doppler), and neurovascular coupling (NVC) in 33 TBI survivors (mean age 37.6 years, ~ 10 years post-injury) and 21 age-matched healthy controls. Serum IGF-1 levels were also measured. TBI survivors exhibited significant impairments in memory and executive function compared to controls. While basal CBF and autoregulation remained intact, NVC responses were chronically impaired and correlated with cognitive deficits. However, IGF-1 levels did not differ between groups and were not associated with NVC impairment or cognitive function. Our findings indicate that severe TBI results in chronic impairment of neurovascular coupling, which likely contributes to long-term cognitive deficits. These results highlight the need for further research to identify underlying neurovascular mechanisms and develop interventions to restore NVC and cognitive function in TBI survivors. © The Author(s) 2025.

关键词： Autoregulation Brain injury CBF Cognitive impairment IGF-1 Neurovascular hyperemia

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THIAMINE IN NEURAL MEMBRANES ENZYMIC HYDROLYSIS OF THIAMINE DIPHOSPHATE

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JOURNAL OF NEUROCHEMISTRY 1972年第4期19卷 1039-+页

作者： BARCHI, RL BRAUN, PE Department of Biochemistry University of Pennsylvania Philadelphia Pa. 19104. Trainee of the Medical Scientist Training Program.

Abstract— The membrane-associated diphosphatase from rat brain which catalyses the hydrolysis of thiamine diphosphate and nucleoside diphosphate is described. The parallel sub-cellular distribution of thiamine diphosphatase and nucleoside diphosphatase activity and the equal inhibition of both activities by adenosine methylenediphosphonate, a non-hydrolysable structural analogue of ADP, suggests that a single enzyme is involved. The divalent cation requirement and basic kinetic properties of this enzyme have been determined. This nucleoside diphosphatase is not activated by ATP.

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