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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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Structural and Biophysical Analysis of the Calcium-Activated Chloride Channel Regulator 1 (CLCA1) VWA Domain Suggests Mode of TMEM16A Engagement

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SSRN 2019年

作者： Berry, Kayla N. Brett, Tom J. Immunology Program and Medical Scientist Training Program Department of Internal Medicine Division of Pulmonary and Critical Care Department of Cell Biology and Physiology Department of Biochemistry and Molecular Biophysics Washington University School of Medicine St. LouisMO63110 United States

The secreted protein calcium-activated chloride channel regulator 1 (CLCA1) utilizes a von Willebrand Factor type A domain (VWA) to bind to and potentiate the calcium activated chloride channel TMEM16A. To gain insight into this unique potentiation mechanism, we determined the 2.0 Å crystal structure of human CLCA1 VWA bound to Ca2+, the first CLCA family structure reported. The structure reveals the metal ion dependent adhesion site (MIDAS) in a high-affinity "open" conformation, engaging in crystal contacts that likely mimic how CLCA1 engages TMEM16A. The CLCA1 VWA contains a disulfide bond between α3 and α4 in close proximity to the MIDAS that is invariant in the CLCA family and unique in VWA structures. Further biophysical studies indicate that CLCA1 VWA is preferably stabilized by Mg2+ over Ca2+ and that a6 atypically extends from the VWA core. Finally, an analysis of TMEM16A structures suggests residues likely to mediate interaction with CLCA1 VWA. © 2019, The Authors. All rights reserved.

关键词： Glycoproteins

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Regulation of sister chromatid cohesion by nuclear PD-L1

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细胞研究（英文版） 2020年第7期30卷 590-601页

作者： Jia Yu Bo Qin Ann M.Moyer Somaira Nowsheen Xinyi Tu Haidong Dong Judy C.Boughey Matthew P.Goetz Richard Weinshilboum Zhenkun Lou Liewei Wang Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic Rochester MN 55905 USA Department of Oncology Mayo Clinic Rochester MN 55905USA Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN 55905 USA Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic School of Medicine and the Mayo Clinic Medical Scientist Training Program Mayo Clinic Rochester MN 55905 USA Departments of Urology and Immunology Mayo Clinic Rochester MN 55905 USA Department of Surgery Mayo Clinic Rochester MN 55905 USA

programmed death ligand-1 (PD-L1 or B7-H1) is well known for its role in immune checkpoint regulation,but its function inside the tumor cells has rarely been *** we report that nuclear PD-L1 is important for cancer cell sister chromatid *** found that depletion of PD-L1 suppresses cancer cell proliferation,colony formation in vitro,and tumor growth in vivo in immunedeficient NSG mice independent of its role in immune ***,PD-L1 functions as a subunit of the cohesin complex,and its deficiency leads to formation of multinucleated cells and causes a defect in sister chromatid ***,PD-L1 compensates for the loss of Sororin,whose expression is suppressed in cancer cells overexpressing ***-L1 competes with Wing Apart-Like (WAPL) for binding to PDS5B,and secures proper sister chromatid cohesion and *** findings suggest an important role for nuclear PD-L1 in cancer cells independent of its function in immune checkpoint.

关键词： Cell division Oncogenes

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Regulation of stem and progenitor cells in the adrenal cortex

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Current Opinion in Endocrine and Metabolic Research 2019年 8卷 66-71页

作者： Finco, Isabella Mohan, Dipika R. Hammer, Gary D. Lerario, Antonio Marcondes Department of Internal Medicine Division of Metabolism Endocrinology and Diabetes University of Michigan Ann Arbor MI United States Medical Scientist Training Program University of Michigan Ann Arbor MI United States Doctoral Program in Cancer Biology University of Michigan Ann Arbor MI United States Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI United States Rogel Cancer Center University of Michigan Ann Arbor MI United States Department of Cell & Developmental Biology University of Michigan Ann Arbor MI United States

The adrenal cortex is an endocrine organ comprised of three histological zones, the outermost zona glomerulosa, the intermediate zona fasciculata, and the innermost zona reticularis. High plasticity of the adrenal gland is supported by pools of stem and progenitor cells that are deployed to sustain physiological and homeostatic demands. In recent decades, exciting new discoveries elucidating the identity, function, and fate of these cell populations have emerged. In this review, we describe paracrine and endocrine signaling loops that are crucial for adrenal biology, focusing on recent studies unpacking the enigmatic nature of adrenal stem and progenitor cell populations. © 2019 Elsevier Ltd

关键词： Adrenal cortex Endocrine signaling Progenitor cells Signaling pathways Stem cells

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New strategies for applying targeted therapies to adrenocortical carcinoma

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Current Opinion in Endocrine and Metabolic Research 2019年 8卷 72-79页

作者： Mohan, Dipika R. Lerario, Antonio Marcondes Finco, Isabella Hammer, Gary D. Medical Scientist Training Program University of Michigan Ann Arbor MI United States Doctoral Program in Cancer Biology University of Michigan Ann Arbor MI United States Department of Internal Medicine Division of Metabolism Endocrinology and Diabetes University of Michigan Ann Arbor MI United States Department of Molecular and Integrative Physiology University of Michigan Ann Arbor MI United States Department of Cell & Developmental Biology University of Michigan Ann Arbor MI United States University of Michigan Rogel Cancer Center University of Michigan Ann Arbor MI United States

Adrenocortical carcinoma (ACC) is a rare, aggressive, and frequently deadly cancer. Up to 75% of all patients will eventually develop metastatic disease, and our current medical therapies for ACC provide limited — if any — survival benefit. These statistics highlight a crucial need for novel approaches. Recent studies performing comprehensive molecular profiling on ACC have illuminated that ACC comprises three clinically distinct molecular subtypes, bearing differential regulation of the cell cycle, epigenetics, Wnt/β-catenin signaling, PKA signaling, steroidogenesis, and immune cell biology. Furthermore, these studies have spurred the development of molecular subtype–based biomarkers, contextualized outcomes of recent clinical trials, and advanced our understanding of the underlying biology of adrenocortical homeostasis and cancer. In this review, we describe these findings and their implications for new strategies to apply targeted therapies to ACC. © 2019 Elsevier Ltd

关键词： ACC Adrenocortical carcinoma Biomarkers Genomics Targeted therapy

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Abstract #4370 Immune responses at the maternal-fetal interface following restraint stress in late gestation

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Brain, Behavior, and Immunity 2019年 81卷 45-46页

作者： Antonson, A.M. Rajasekera, T.A. Chen, H.J. Gur, T.L. The Ohio State University Institute for Behavioral Medicine Research 460 Medical Center Drive Rm 113 Columbus OH 43210 United States NIDCR CTOC T32 Training Fellowship United States Medical Scientist Training Program United States Department of Psychiatry and Behavioral Health United States

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Rb analog Whi5 regulates G1 to S transition and cell size but not replicative lifespan in budding yeast

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Translational Medicine of Aging 2019年 3卷 104-108页

作者： Crane, Matthew M. Tsuchiya, Mitsuhiro Blue, Ben W. Almazan, Jared D. Chen, Kenneth L. Duffy, Siobhan R. Golubeva, Alexandra Grimm, Annaiz M. Guard, Alison M. Hill, Shauna A. Huynh, Ellen Kelly, Ryan M. Kiflezghi, Michael Kim, Hyunsung D. Lee, Mitchell Lee, Ting-I. Li, Jiayi Nguyen, Bao M.G. Whalen, Riley M. Yeh, Feng Y. McCormick, Mark Kennedy, Brian K. Delaney, Joe R. Kaeberlein, Matt Department of Pathology University of Washington Seattle WA United States Department of Genome Sciences University of Washington Seattle WA United States Medical Scientist Training Program University of Washington Seattle WA United States Department of Biochemistry and Molecular Biology University of New Mexico Albuquerque NM United States Buck Institute for Research on Aging Novato CA United States Department of Biochemistry and Molecular Biology Medical University of South Carolina Charleston SC United States

An increase in cell size with age is a characteristic feature of replicative aging in budding yeast. Deletion of the gene encoding Whi5 results in shortened duration of G1 and reduced cell size, and has been previously suggested to increase replicative lifespan. Upon careful analysis of multiple independently derived haploid and homozygous diploid whi5Δ mutants, we find no effect on lifespan, but we do confirm the reduction in cell size. We suggest that instead of antagonizing lifespan, the elongated G1 phase of the cell cycle during aging may actually play an important role in allowing aged cells time to repair accumulating DNA damage. © 2019 The Authors

关键词： Cell cycle regulation Replicative aging Saccharomyces cerevisiae

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