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Annals of the Child Neurology Society 2025年

作者： Donald L. Gilbert Deana Crocetti Paul S. Horn Steve W. Wu David A. Huddleston Jacqueline M. Ehrman Karlee Y. Migneault Stewart H. Mostofsky Division of Neurology Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Ohio USA Center for Neurodevelopmental and Imaging Research Kennedy Krieger Institute Baltimore Maryland USA Departments of Neurology and Psychiatry Johns Hopkins University School of Medicine Baltimore Maryland USA Medical Scientist Training Program University of Cincinnati College of Medicine Cincinnati Ohio USA

Objective The aim of this study was to identify a quantitative, brain-based measure reflecting impaired response inhibition in children with attention-deficit/hyperactivity disorder (ADHD). Methods In this cross-sectional study, we used transcranial magnetic stimulation (TMS) to evoke potentials in hand muscle during both a simple reaction time and a response inhibition task in 8-to-12-year-old children, 41 with ADHD (42% girls, 76% white, mean age 10.3 years) and 38 typically developing controls (53% girls, 74% white, mean age 9.8 years). We used mixed-model linear regressions of evoked potential amplitudes to compare motor cortex excitability at (1) task-onset (“START”: 550 ms prior to action); (2) preparing-to-go (“GO”: 150 ms prior to action); and (3) selecting-to-stop (“STOP”: 150 ms after stop cue). We hypothesized that task-related up-modulation of motor cortex excitability (motor evoked potential amplitudes) would depend both on task (STOP > GO > START) and on diagnosis (controls > patients). Results Motor cortex up-modulation was significantly greater for STOP trials than during GO or START. Children with ADHD had both worse response inhibition performance (longer stop-signal reaction times) and significantly less task effect on motor cortex up-modulation. The largest diagnostic difference in motor cortex activation occurred during STOP trials. Reduced up-modulation during stopping was also associated with higher parent-rated symptom severity. Interpretation Our findings suggest that motor cortex up-modulation of excitability, assessed indirectly by TMS motor evoked potentials, reflects the cognitive load during response inhibition tasks and may be a quantitative, brain-based indicator of impaired response inhibition in children with ADHD.

关键词： attention-deficit/hyperactivity disorder children motor cortex response inhibition transcranial magnetic stimulation task-related up-modulation (TRUM)

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Radiation-Induced Cardiotoxicity

Advances in Oncology

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Advances in Oncology 2021年 1卷 1-13页

作者： Samuel Zorn David Rayan Sherry-Ann Brown Carmen Bergom Medical Scientist Training Program Medical College of Wisconsin Milwaukee WI USA Department of Medicine Medical College of Wisconsin Hub for Collaborative Medicine 8701 Watertown Plank Rd 8th Floor Milwaukee WI 53226 USA Froedtert Hospital-Center for Advanced Care Heart and Vascular Center 8900 Doyne Avenue Milwaukee WI 53226 USA Department of Radiation Oncology Washington University School of Medicine 660 S. Euclid Ave Campus Box 8224 St Louis MO 63110 USA Department of Radiation Oncology Medical College of Wisconsin Milwaukee WI USA

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Investigation of Cas9 antibodies in the human eye (vol 13, 1053, 2022)

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NATURE COMMUNICATIONS 2022年第1期13卷 1053-1053页

作者： Toral, Marcus A. Charlesworth, Carsten T. Ng, Benjamin Chemudupati, Teja Homma, Shota Nakauchi, Hiromitsu Bassuk, Alexander G. Porteus, Matthew H. Mahajan, Vinit B. Stanford University Molecular Surgery Program Department of Ophthalmology Byers Eye Institute Palo Alto USA (GRID:grid.168010.e) (ISNI:***) University of Iowa Medical Scientist Training Program and Graduate Program in Molecular Medicine Iowa City USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) Stanford University Department of Pediatrics Palo Alto USA (GRID:grid.168010.e) (ISNI:***) Stanford University Molecular Surgery Program Department of Ophthalmology Byers Eye Institute Palo Alto USA (GRID:grid.168010.e) (ISNI:***) University of Oxford Medical Sciences Division Oxford UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) Stanford University Molecular Surgery Program Department of Ophthalmology Byers Eye Institute Palo Alto USA (GRID:grid.168010.e) (ISNI:***) Stanford University Department of Genetics Palo Alto USA (GRID:grid.168010.e) (ISNI:***) Stanford University Department of Genetics Palo Alto USA (GRID:grid.168010.e) (ISNI:***) Stanford University School of Medicine Institute for Stem Cell Biology and Regenerative Medicine Palo Alto USA (GRID:grid.168010.e) (ISNI:***) University of Tokyo Division of Stem Cell Therapy Distinguished Professor Unit Institute of Medical Science Tokyo Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X) University of Iowa Departments of Pediatrics and Neurology and The Iowa Neuroscience Institute (INI) Iowa City USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) Stanford University Molecular Surgery Program Department of Ophthalmology Byers Eye Institute Palo Alto USA (GRID:grid.168010.e) (ISNI:***) Veterans Affairs Palo Alto Health Care System Palo Alto CA Palo Alto USA (GRID:grid.280747.e) (ISNI:0000 0004 0419 2556)

Preexisting immunity against Cas9 proteins in humans represents a safety risk for CRISPR–Cas9 technologies. However, it is unclear to what extent preexisting Cas9 immunity is relevant to the eye as it is targeted for early in vivo CRISPR–Cas9 clinical trials. While the eye lacks T-cells, it contains antibodies, cytokines, and resident immune cells. Although precise mechanisms are unclear, intraocular inflammation remains a major cause of vision loss. Here, we used immunoglobulin isotyping and ELISA platforms to profile antibodies in serum and vitreous fluid biopsies from human adult subjects and Cas9-immunized mice. We observed high prevalence of preexisting Cas9-reactive antibodies in serum but not in the eye. However, we detected intraocular antibodies reactive to S. pyogenes-derived Cas9 after S. pyogenes intraocular infection. Our data suggest that serum antibody concentration may determine whether specific intraocular antibodies develop, but preexisting immunity to Cas9 may represent a lower risk in human eyes than ***-existing antibodies against Cas9 proteins represent a potential issue for gene therapies, including those targeting the eye. Here the authors assess the presence of intraocular antibodies, and show that Cas9 antibodies were prevalent in human serum but not the eye, unless prior bacterial infection occurred.

关键词： CRISPR-Cas systems Visual system Translational immunology

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55564 Interactive mindfulness and dialogue sessions are integral components of research training.

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Journal of Clinical and Translational Science 2021年第S1期5卷 64-65页

作者： Kit Knier Adriana Morales Gomez Joanna Yang Yowler Chris Pierret Linda M. Scholl Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Rochester MN USA Mayo Clinic Medical Scientist Training Program Mayo Clinic Rochester MN USA Department of Research Mayo Clinic Jacksonville FL USA Department of Biochemistry and Molecular Biology Mayo Clinic Rochester MN USA Office of Applied Scholarship and Education Science Mayo Clinic College of Medicine Mayo Clinic Rochester MN USA

ABSTRACT IMPACT: This work demonstrates the integration of interactive mindfulness and dialogue sessions in curricula is both desired by students and effective in conferring resilience, a protective factor that may aid in maintaining wellbeing of trainees interested in pursuing graduate studies in biomedical research and science. OBJECTIVES/GOALS: To support student futures in the field of biomedicine, Mayo Clinic Graduate School of Biological Sciences utilized digital platforms to deliver a summer research program in the summer of 2020. One goal of this program, in addition to scholastic outcomes and research experience, was to support and improve the wellbeing of college student participants. METHODS/STUDY POPULATION: Following the cancellation of in-person summer research programs, students were invited to attend a digital Summer Foundations in Research program. The 4-week program included 4 small group dialogue sessions led by trained facilitators and 4 large group mindfulness seminars followed with 3 Q/A style small group sessions. Surveys were delivered on days 1, 27, and 3 months following the program. Wellbeing measures included Brief Resilience, Perceived Stress, and Satisfaction with Life Scales. Students were prompted to indicate how worthwhile they found course components and comment on why they rated each component the way they did. Wellbeing results were assessed using paired t-tests with Bonferroni correction for multiple comparisons. Thematic analysis was used to interpret qualitative results. RESULTS/ANTICIPATED RESULTS: Students improved across all wellbeing measures at the program conclusion, including resilience (mean difference(SE) pre- to post-program +0.22(0.06) p=0.0007), perceived stress (-1.71(0.66) p=0.0116), and life satisfaction (+1.57(0.52) p=0.0037). Gains in resilience were maintained 3 months out (pre-program to 3 month survey +0.28(0.06) p<0.0001). To our surprise, mindfulness was the highest rated component of the research program

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Micromagnetic Neural Stimulation and Spintronic Neural Sensing

Micromagnetic Neural Stimulation and Spintronic Neural Sensi...

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Magnetic Conference - Short Papers (INTERMAG Short Papers), IEEE International

作者： Renata Saha Denis Tonini Matthew S. Hopper Abhinav Goyal Jason Yuen Yoonbae Oh Zachary Sanger Sadegh Faramarzi Maple Shiao Dusty Van Helden Robert P. Bloom Onri J. Benally Kai Wu Susan A. Keirstead Theoden I. Netoff Walter C. Low John Osborn Kevin E. Bennet Kendall H. Lee Hojin Shin Jian-Ping Wang Department of Electrical and Computer Engineering University of Minnesota Minneapolis MN United States Department of Neurologic Surgery Mayo Clinic Rochester MN United States Medical Scientist Training Program Mayo Clinic Rochester MN United States IMPACT - the Institute for Mental and Physical Health and Clinical Translation Barwon Health Deakin University School of Medicine Geelong VIC Australia Department of Biomedical Engineering Mayo Clinic Rochester MN United States Department of Biomedical Engineering University of Minnesota Minneapolis MN United States Stem Cell Institute University of Minnesota Minneapolis MN United States Department of Surgery University of Minnesota Minneapolis MN United States Department of Neurosurgery University of Minnesota Minneapolis MN United States Division of Engineering Mayo Clinic Rochester MN United States

ISBN: (数字)9798350362213

ISBN: (纸本)9798350362220

We report our team's recent magnetic biomedical brain-related research work: 1) micromagnetic neural stimulation $(\boldsymbol{\mu} \mathbf{MS})$ ; 2) calculation of magnetic field generated by neural cells and tissues and spintronic neural sensing. First, the designing, fabrication, and testing of two micromagnetic implants - the Magnetic Pen (MagPen), a solenoid-shaped single $\boldsymbol{\mu} \mathbf{coil}$ prototype, and the Magnetic Patch (MagPatch), a rectangular helix-shaped planar $\boldsymbol{\mu} \mathbf{coil}$ array prototype, is discussed. The efficacy of micromagnetic activation using MagPen has been successfully tested over many rodent models. The MagPen prototype had its caveat in terms of mm-size, lack of multidimensional spatial control and activation at the cellular-level. To bridge this research gap, the MagPatch array was designed and fabricated to study $\boldsymbol{\mu} \mathbf{MS}$ at the single-cell resolution. Second, we used FEM exemplary models and open-source computational libraries and calculated the magnetic fields generated by individual neurons and neuronal networks at micrometer distances. Our results show that the magnetic field generated by a single-neuron action potential can be detected by ultra-high sensitivity sub-pT magnetic field sensors, which opens the door to future in vivo decoding of neuronal activities through neural networks. Room temperature, high endurance, small volume and low power make spintronic sensors one of the promising candidates for neural sensing. On this aspect, the recent experimental progress for the spintronic sensors for neural sensing has been reviewed, with a specific discussion on our effort on spintronic stack design, device fabrication and detection.

关键词： Temperature sensors Fabrication Magnetic sensors Computational modeling Prototypes Micromagnetics Magnetic fields

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Gene set proximity analysis: expanding gene set enrichment analysis through learned geometric embeddings

arXiv

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arXiv 2022年

作者： Cousins, Henry Hall, Taryn Guo, Yinglong Tso, Luke Tzeng, Kathy Tzy-Hwa Cong, Le Altman, Russ Department of Biomedical Data Science Stanford University School of Medicine StanfordCA United States Medical Scientist Training Program Stanford University School of Medicine StanfordCA United States Optum Labs UnitedHealth Group MinneapolisMN United States Department of Genetics Stanford University School of Medicine StanfordCA United States Department of Pathology Stanford University School of Medicine StanfordCA United States Department of Medicine Stanford University School of Medicine StanfordCA United States Department of Bioengineering Stanford University StanfordCA United States

Gene set analysis methods rely on knowledge-based representations of genetic interactions in the form of both gene set collections and protein-protein interaction (PPI) networks. Explicit representations of genetic interactions often fail to capture complex interdependencies among genes, limiting the analytic power of such methods. Here we propose an extension of gene set enrichment analysis to a latent feature space reflecting PPI network topology, called gene set proximity analysis (GSPA). Compared with existing methods, GSPA provides improved ability to identify disease-associated pathways in disease-matched gene expression datasets, while improving reproducibility of enrichment statistics for similar gene sets. GSPA is statistically straightforward, reducing to classical gene set enrichment through a single user-defined parameter. We apply our method to identify novel drug associations with SARS-CoV-2 viral entry. Finally, we validate our drug association predictions through retrospective clinical analysis of claims data from 8 million patients, supporting a role for gabapentin as a risk factor and metformin as a protective factor for COVID-19 hospitalization. © 2022, CC BY-NC-ND.

关键词： SARS

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Developmental brain abnormalities and acute encephalopathy in a patient with myopathy with extrapyramidal signs secondary to pathogenic variants in micu1

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JIMD Reports 2020年第1期53卷 2-28页

作者： Wilton, Katelynn M. Morales-Rosado, Joel A. Selcen, Duygu Muthusamy, Karthik Ewing, Sarah Agre, Katherine Nickels, Katherine Klee, Eric W. Ho, Mai-Lan Morava, Eva Medical Scientist Training Program Mayo Clinic Alix College of Medicine Mayo Clinic Rochester United States Center for Individualized Medicine Mayo Clinic Rochester United States Department of Health Science Research Division of Biomedical Statistics and Informatics Mayo Clinic Rochester United States Department of Neurology Mayo Clinic Rochester United States Department of Clinical Genomics Mayo Clinic Rochester United States Department of Radiology Nationwide Children’s Hospital Columbus OH United States

Mitochondria play a variety of roles in the cell, far beyond their widely recognized role in ATP generation. One such role is the regulation and sequestration of calcium, which is done with the help of the mitochondrial calcium uniporter (MCU) and its regulators, MICU1 and MICU2. Genetic variations in MICU1 and MICU2 have been reported to cause myopathy, developmental disability and neurological symptoms typical of mitochondrial disorders. The symptoms of MICU1/2 deficiency have generally been attributed to calcium regulation in the metabolic and biochemical roles of mitochondria. Here, we report a female child with heterozygous MICU1 variants and multiple congenital brain malformations on MRI. Specifically, she shows anterior perisylvian polymicrogyria, dysmorphic basal ganglia, and cerebellar dysplasia in addition to white matter abnormalities. These novel findings suggest that MICU1 is necessary for proper neurodevelopment through a variety of potential mechanisms, including calciummediated regulation of the neuronal cytoskeleton, Miro1-MCU complexmediated mitochondrial movement, or enhancing ATP production. This case provides new insight into the molecular pathogenesis of MCU dysfunction and may represent a novel diagnostic feature of calcium-based mitochondrial disease. © 2020 The Authors.

关键词： Acute disseminated encephalomyelitis Genetic MICU1 MICU1 deficiency Mitochondria MPXPS

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Vitamin A Directly Enhances TET2 Activity and Suppresses Clonal Hematopoiesis

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Blood 2024年 144卷 4051-4051页

作者： John P Brabson Tiffany Leesang Yoon Sing Yap Daniela A Barbieri Joey Pinzone Minh Quang Lam Peter D Lyon Maria E Figueroa Namrata S. Chandhok Felipe Beckedorff Aristeidis Telonis Luisa Cimmino Cancer Epigenetics Program Sylvester Comprehensive Cancer Center University of Miami-Miller School of Medicine Miami FL Department of Biochemistry & Molecular Biology University of Miami-Miller School of Medicine Miami FL Medical Scientist Training Program University of Miami-Miller School of Medicine Miami FL Sylvester Comprehensive Cancer Center University of Miami-Miller School of Medicine Miami FL Department of Human Genetics University of Miami-Miller School of Medicine Miami FL University of Miami-Miller School of Medicine Miami FL

Introduction : TET2 haploinsufficiency is a driving event in up to 30% of individuals with clonal hematopoiesis (CH), a pre-malignant blood condition that can increase the risk of developing a hematological malignancy. Loss of TET2 function imparts aberrant self-renewal to hematopoietic stem and progenitor cells (HSPCs) and a pro-inflammatory myeloid lineage expansion. Studies have shown that restoring Tet2 activity using genetic models, or treatment with the TET catalytic cofactor ascorbate, can reverse the clonal advantage and myeloid bias of Tet2 -deficient pre-malignant HSPCs, and slow the development of myeloid leukemia. Preliminary clinical studies have shown that increased supplementation with ascorbate can improve survival in patients with clonal cytopenia or low risk myeloid malignancy. These data suggest that enhancing TET2 activity represents a viable therapeutic strategy for the prevention of CH progression. To identify additional pharmacological interventions that could enhance and restore TET2 activity to suppress CH progression, we tested the efficacy of retinoic acid as a TET2 activator, given it had previously been shown in ESCs to upregulate Tet2 transcription and 5hmC formation, and is a known positive regulator of hematopoietic stem cell quiescence and myeloid differentiation. Results : We show that all-trans retinoic acid (ATRA) induces TET2 transcription in myeloid leukemia cells and primary murine and human HSPCs. In combination with ascorbate, ATRA synergistically enhances TET2 -mediated DNA hydroxymethylation when assayed by base-resolution 5hmC-sequencing in myeloid leukemia cells, with enrichment at enhancers and CEBP, ETS and FOS/JUN transcription factor binding motifs. RNA- and ATAC-sequencing showed that genes with increased 5hmC levels upon ATRA treatment alone or in combination with ascorbate overlap with gene expression changes and altered chromatin accessibility linked to terminal myeloid differentiation and reduced inflammatory sig

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Case Report of Fibro-Adipose Vascular Anomaly (FAVA) with Activating Somatic PIK3CA Mutation

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Case reports in genetics 2022年第1期2022卷 9016497页

作者： Jordan H Driskill Helena Hwang Alexandra K Callan Dwight Oliver Medical Scientist Training Program The University of Texas Southwestern Medical Center Dallas TX 75390 USA. Department of Pathology The University of Texas Southwestern Medical Center Dallas TX 75390 USA. Department of Orthopaedic Surgery The University of Texas Southwestern Medical Center Dallas TX 75390 USA.

Fibro-adipose vascular anomaly (FAVA) is a recently described complex and painful benign lesion found in young adults and the pediatric population composed of intramuscular vascular, fibrous, and adipose tissues. A previous report has identified the presence of somatic mosaic mutations in the gene for the catalytic subunit of phosphatidylinositol 3-kinase () in cases of FAVA. Herein, we present a case of FAVA found in a 23-year-old male patient who presented with chronic wrist pain associated with a mass, and we identified an associated somatic activating mutation (H1047R) in . We briefly review the relevant literature surrounding the identification and histology of FAVA, the known mutational spectrum, downstream signaling pathways, and relevant treatment modalities. Our case highlights the association between FAVA and somatic mosaic activating mutations.

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Angiotensin AT 1 R Expressing Cells Within the Ventral Hypothalamus Modulate Integrative Control of Cardiometabolic Functions

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iScience 2025年

作者： Jhonatan Pasos Valerie A. Wagner Samuel B.R. Lawton Alyssa M. Madison Kush Nandani Natalia M. Mathieu Connie C. Grobe John J. Reho Bonnie P. Freudinger Alexander J. Sherman Daniel T. Brozoski Lisa L. Morselli Colin M.L. Burnett Jeffrey L. Segar Pablo Nakagawa Curt D. Sigmund Justin L. Grobe Department of Physiology Medical College of Wisconsin Milwaukee WI 53226 USA Universidad CES Medellin Antioquia Colombia Medical Scientist Training Program Medical College of Wisconsin Milwaukee WI 53226 USA Department of Pediatrics Division of Neonatology Medical College of Wisconsin Milwaukee WI 53226 USA Comprehensive Rodent Metabolic Phenotyping Core Medical College of Wisconsin Milwaukee WI 53226 USA Engineering Core Medical College of Wisconsin Milwaukee WI 53226 USA Department of Medicine / Division of Endocrinology and Molecular Medicine Medical College of Wisconsin Milwaukee WI 53226 USA Cardiovascular Center Medical College of Wisconsin Milwaukee WI 53226 USA Department of Medicine / Division of Cardiovascular Medicine Medical College of Wisconsin Milwaukee WI 53226 USA Department of Biomedical Engineering Medical College of Wisconsin Milwaukee WI 53226 USA Neuroscience Research Center Medical College of Wisconsin Milwaukee WI 53226 USA

Subtypes of Agouti-related peptide (AgRP) neurons can be distinguished based upon expression of angiotensin II receptors. The Type 1 subtype, which expresses the angiotensin type 1 receptor ( Agtr1a ), was examined for its role in the integrative control of cardiometabolic functions. Mice expressing Cre-recombinase via the Agtr1a locus received bilateral microinjection of an AAV vector encoding Cre-dependent expression of caspase-3 into the arcuate nucleus of mice housed at 22°C or 30°C. Ablation of Agtr1a + cells caused increased food intake, adiposity, resting metabolic rate and shifts in nutrient partitioning, elevated temperature preference, loss of core temperature defense, and changes in blood pressure and heart rate. Many phenotypes were ameliorated by housing animals at thermoneutrality. Thus, Agtr1a + cells in the ventral hypothalamus (including the Type 1 AgRP neuron) influence cardiometabolic control through modulation of thermoregulatory responses to cold. Some functions of these cells appear to oppose canonical roles of other AgRP neuron subtypes.

关键词： Agouti-related peptide Angiotensin Energy metabolism Thermoregulation

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