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Forecasting risk gene discovery in autism with machine learning and genome-scale data (vol 10, 4569, 2020)

SCIENTIFIC REPORTS 2020年第1期10卷 1-11页

作者： Brueggeman, Leo Koomar, Tanner Michaelson, Jacob J. University of Iowa Department of Psychiatry Iowa City IA USA University of Iowa Interdisciplinary Genetics Program Iowa City IA USA University of Iowa Medical Scientist Training Program Iowa City IA USA

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Proliferative and metastatic roles for Phospholipase D in mouse models of cancer

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Advances in Biological Regulation 2018年 67卷 134-140页

作者： Roth, Eric Frohman, Michael A. The Graduate Program in Molecular and Cellular Pharmacology The Medical Scientist Training Program the Department of Pharmacological Sciences Stony Brook University New York 11794 United States

Phospholipase D (PLD) activity has been proposed to facilitate multiple steps in cancer progression including growth, metabolism, angiogenesis, and mobility. The canonical enzymes PLD1 and PLD2 enact their diverse effects through hydrolyzing the membrane lipid phosphatidylcholine to generate the second messenger and signaling lipid phosphatidic acid (PA). However, the widespread expression of PLD1 and PLD2 in normal tissues and the additional distinct enzymatic mechanisms through which PA can be generated have produced uncertainty regarding the optimal settings in which PLD inhibition might ameliorate cancer. Recent studies in mouse model systems have demonstrated that inhibition or elimination of PLD activity reduces tumor growth and metastasis. One mechanism proposed for this outcome involves proliferative signaling mediated by receptor tyrosine kinases (RTK) and G protein-coupled receptors (GPCR), which is attenuated when downstream PLD signal propagation is suppressed. The reduced proliferative signaling has been reported to be compounded by dysfunctional energetic metabolism in the tumor cells under conditions of nutrient deprivation. Moreover, cancer cells lacking PLD activity display inefficiencies across multiple steps of the metastatic cascade, limiting the tumor's lethal spread. Using PLD isoform knockout mice, recent studies have reported on the net effects of inhibition and ablation in multiple cancer models through examining the role of PLD in the non-tumor cells comprising the stroma and microenvironment. The promising results of such in vivo studies, combined with the apparent low toxicity of highly-specific and potent inhibitors, highlights PLD as an attractive target for therapeutic inhibition in cancer. We discuss here the array of anti-tumor effects produced by PLD inhibition and ablation in cancer models with a focus on animal studies. © 2017 Elsevier Ltd

关键词： Angiogenesis Cancer Lipid signaling Metabolism Metastasis Phospholipase D

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ADAM10 facilitates rapid neural stem cell cycling and proper positioning within the subventricular zone niche via JAMC/RAP1Gap signaling

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Neural Regeneration Research 2022年第11期17卷 2472-2483页

作者： Nadia McMillan Gregory W.Kirschen Sanket Desai Emma Xia Stella E.Tsirka Adan Aguirre Program in Neuroscience and Medical Scientist Training Program Renaissance School of Medicine at Stony Brook UniversityStony BrookNYUSA Department of Pharmacological Sciences Renaissance School of Medicine at Stony Brook UniversityStony BrookNYUSA Department of Neurology Beth Israel Deaconess Medical Center/Harvard Medical SchoolBostonMAUSA Department of Gynecology and Obstetrics Johns Hopkins HospitalBaltimoreMDUSA

The mechanisms that regulate neural stem cell(NSC)lineage progression and maintain NSCs within diffe rent domains of the adult neural stem cell niche,the subventricular zone are not well *** NSCs are arranged at the apical ventricular wall,while mitotically activated NSCs are found in the basal,vascular region of the subventricular ***,we found that ADAM 10(a disintegrin and metalloproteinase 10)is essential in NSC association with the ventricular wall,and via this adhesion to the apical domain,ADAM10 regulates the switch from quiescent and undiffe rentiated NSC to an actively prolife rative and differentiating cell *** of JAMC(junctional adhesion molecule C)by ADAM 10 increases Rap1 GAP *** molecular machinery promotes NSC transit from the apical to the basal compartment and subsequent lineage *** the molecular mechanisms responsible for regulating the proper positioning of NSCs within the subventricular zone niche and lineage progression of NSCs could provide new targets for drug development to enhance the regenerative prope rties of neural tissue.

关键词： ADAM10 adhesion junctional adhesion molecule C neural stem cells neurogenesis olfactory bulb Rap1Gap sub-ventricular zone

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The Nrf2-ARE pathway: A potential therapeutic target for neurodegenerative diseases

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International Congress Series 2007年 1302卷 143-153页

作者： Johnson, Jeffrey A. Johnson, Delinda A. Lee, Jong-Min Li, Jiang Kraft, Andrew D. Calkins, Marcus J. Jakel, Rebekah J. Division of Pharmaceutical Sciences University of Wisconsin United States Molecular and Environmental Toxicology Training Program University of Wisconsin United States Neuroscience Training Program University of Wisconsin United States Medical Sciences Training Program University of Wisconsin United States

NF-E2-related factor 2 (Nrf2) is the primary transcription factor required for the induction of a battery of phase II detoxification genes through activation of a cis-acting enhance termed the antioxidant response element (ARE). The genes regulated by the Nrf2-ARE pathway respond to and increase resistance to oxidative stress and/or mitochondrial dysfunction. Oxidative stress or mitochondrial dysfunction have been implicated in the pathogenesis of multiple neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's Disease and amyotrophic lateral sclerosis (Lou Gehrig's disease). Both chemical and genetic models of some of these diseases in mice, as well as primary neuronal culture systems, have been used to look at the Nrf2-ARE pathway in regard to neuroprotection. Activation of this pathway protects neurons from toxic insults such as mitochondrial complex I and complex II inhibitors, glutamate, hydrogen peroxide and increased intracellular calcium. Conversely, knockout or knockdown of Nrf2 leads to increased sensitivity of neurons to toxin-induced cell death. Interestingly, this neuroprotective mechanism appears to be manifest through the astrocyte. Selective inhibition of Nrf2 function or overexpression in these non-neuronal cells has dramatic effects on the protective potential of this system. Clearly, a greater understanding of how the Nrf2-ARE pathway is intimately involved with the pathogenesis of neurodegenerative diseases and its significant neuroprotective properties could be pivotal in halting the progression of multiple neurological diseases through the development of new therapeutic approaches targeting this pathway. © 2007 Elsevier B.V. All rights reserved.

关键词： Antioxidant response element Neurodegenerative disease Nrf2 Oxidative stress

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Correction to: A machine learning approach to leveraging electronic health records for enhanced omics analysis (Nature Machine Intelligence, (2025), 7, 2, (293-306), 10.1038/s42256-024-00974-9)

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Nature Machine Intelligence 2025年

作者： Mataraso, Samson J. Espinosa, Camilo A. Seong, David Reincke, S. Momsen Berson, Eloise Reiss, Jonathan D. Kim, Yeasul Ghanem, Marc Shu, Chi-Hung James, Tomin Tan, Yuqi Shome, Sayane Stelzer, Ina A. Feyaerts, Dorien Wong, Ronald J. Shaw, Gary M. Angst, Martin S. Gaudilliere, Brice Stevenson, David K. Aghaeepour, Nima Department of Anesthesiology Perioperative and Pain Medicine Stanford University School of Medicine StanfordCA United States Department of Pediatrics Stanford University School of Medicine StanfordCA United States Department of Biomedical Data Science Stanford University School of Medicine StanfordCA United States Immunology Program Stanford University School of Medicine StanfordCA United States Medical Scientist Training Program Stanford University School of Medicine StanfordCA United States Department of Pathology Stanford University School of Medicine StanfordCA United States Department of Microbiology and Immunology Stanford University School of Medicine StanfordCA United States Department of Pathology University of California San Diego La Jolla CA United States

Correction to: Nature Machine Intelligencehttps://***/10.1038/s42256-024-00974-9, published online 16 January 2025. In the version of the article initially published, in the "COMET deep learning architecture" section of the Methods, the equations for MSE and BSE were switched and have now been corrected as shown: (Formula presented.) and (Formula presented.) Additionally, the grey background circles in Fig. 4d were incorrectly offset from the clusters and have now been corrected. These corrections have been made to the HTML and PDF versions of the article. © The Author(s) 2025.

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Correction to: Droplet Hi-C enables scalable, single-cell profiling of chromatin architecture in heterogeneous tissues (Nature Biotechnology, (2024), 10.1038/s41587-024-02447-1)

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Nature Biotechnology 2025年

作者： Chang, Lei Xie, Yang Taylor, Brett Wang, Zhaoning Sun, Jiachen Armand, Ethan J. Mishra, Shreya Xu, Jie Tastemel, Melodi Lie, Audrey Gibbs, Zane A. Indralingam, Hannah S. Tan, Tuyet M. Bejar, Rafael Chen, Clark C. Furnari, Frank B. Hu, Ming Ren, Bing Department of Cellular and Molecular Medicine University of California San Diego La JollaCA United States Biomedical Sciences Graduate Program University of California San Diego La JollaCA United States Medical Scientist Training Program University of California San Diego La JollaCA United States Department of Quantitative Health Sciences Lerner Research Institute Cleveland Clinic Foundation ClevelandOH United States Systems Biology and Bioinformatics PhD Program Case Western Reserve University School of Medicine ClevelandOH United States Bioinformatics and Systems Biology Program University of California San Diego La JollaCA United States Moores Cancer Center UC San Diego La JollaCA United States Department of Neurosurgery University of Minnesota MinneapolisMN United States Department of Medicine University of California San Diego School of Medicine La JollaCA United States Center for Epigenomics Institute for Genomic Medicine School of Medicine University of California San Diego La JollaCA United States

Correction to: Nature Biotechnologyhttps://***/10.1038/s41587-024-02447-1, published online 18 October 2024. In the version of the article initially published, in the Methods section, both mentions of "MboII" should have read "MboI (NEB, R0147M)" and have now been corrected in the HTML and PDF versions of the article. © The Author(s) 2025.

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Cryo-EM structures reveal the PP2A-B55α and Eya3 interaction that can be disrupted by a peptide inhibitor

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Journal of Biological Chemistry 2025年 110287页

作者： Shasha Shi Xueni Li Christopher Alderman Lars Wick Wei Huang North Foulon Lingdi Zhang John Rossi Wenxin Hu Shouqing Cui Hongjin Zheng Derek J. Taylor Heide L. Ford Rui Zhao Department of Biochemistry and Molecular Genetics University of Colorado Anschutz Medical Campus Aurora CO 80045 Medical Scientist Training Program University of Colorado Anschutz Medical Campus Aurora CO 80045 Molecular Biology Program University of Colorado Anschutz Medical Campus Aurora CO 80045 Cancer Biology Program University of Colorado Anschutz Medical Campus Aurora CO 80045 Department of Pharmacology Case Western Reserve University Cleveland OH 44106 Department of Pharmacology University of Colorado Anschutz Medical Campus Aurora CO 80045

We have previously shown that Eya3 recruits PP2A-B55α to dephosphorylate pT58 on Myc, increasing Myc stability and enhancing primary tumor growth of triple-negative breast cancer (TNBC). However, the molecular details of how Eya3 recruits PP2A-B55α remain unclear. Here we determined the cryo-EM structures of PP2A-B55α bound with Eya3, with an inhibitory peptide B55i, and in its unbound state. These studies demonstrate that Eya3 binds B55α through an extended peptide in the NTD of Eya3. The Eya3 peptide, PP2A-B55α substrates, and protein/peptide inhibitors including B55i bind to a similar area on the B55α surface but the molecular details of the binding differ. We further demonstrated that the B55i peptide inhibits the B55α and Eya3 interaction in vitro. The B55i peptide expressed on a plasmid increases Myc pT58 and decreases Myc protein levels in TNBC cells, suggesting the potential of B55i or similar peptides as therapies for TNBC.

关键词： Protein Phosphatase 2A (PP2A) B55 Eya3 peptide inhibitor cancer

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Effects of perinatal iron deficiency on spinal dorsal horn circuits

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The journal of pain 2025年 32卷 105434页

作者： Judy J Yoo Elizabeth K Serafin Mark L Baccei Medical Scientist Training Program and Neuroscience Graduate Program University of Cincinnati College of Medicine 231 Albert Sabin Way Cincinnati OH 45267 USA Pain Research Center Department of Anesthesiology University of Cincinnati Medical Center 231 Albert Sabin Way Cincinnati OH 45267 USA. Pain Research Center Department of Anesthesiology University of Cincinnati Medical Center 231 Albert Sabin Way Cincinnati OH 45267 USA. Electronic address: mark.baccei@uc.edu.

Clinical association studies have identified early life iron deficiency (ID) as a risk factor for the development of chronic pain. ID during the perinatal period has long-term consequences for the developing nervous system. Mounting evidence from both clinical and preclinical studies suggests that ID alters pain perception. However, nothing is yet known about how perinatal ID impacts nociceptive circuitry. The present study sought to characterize the effects of ID on the spinal superficial dorsal horn (SDH). Using ex vivo patch clamp electrophysiology in a mouse model of perinatal ID, the excitability of inhibitory and putative excitatory interneurons in the SDH was measured. It was found that early life ID did not significantly change the intrinsic excitability of either interneuron cell type in adolescence or adulthood. The investigation of synaptic inputs onto these two populations revealed that ID modulates spontaneous glutamatergic transmission within the SDH, but did not affect the excitatory drive or balance of synaptic excitation and inhibition. Interestingly, while ID altered the pattern of primary afferent inputs onto presumed glutamatergic interneurons in the mature SDH, the overall efficacy of these synapses was not affected by ID. Collectively, these results suggest that spinal nociceptive circuits are resilient to change following perinatal ID. PERSPECTIVE: This study demonstrates that perinatal iron deficiency (ID) elicits few changes to the intrinsic membrane excitability of superficial dorsal horn neurons or the efficacy of their synaptic inputs. These findings represent a critical first step towards elucidating the effects of ID on nociceptive processing in the central nervous system.

关键词： development electrophysiology nociception spinal cord synaptic transmission

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Neurocognitive and Resting-State Functional Magnetic Resonance Imaging Changes in Patients With Diffuse Gliomas After Chemoradiation Therapy

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International Journal of Radiation Oncology Biology Physics 2025年

作者： Liu, Zhihua Mitchell, Timothy J. Luo, Chongliang Park, Ki Yun Shimony, Joshua S. Fucetola, Robert Leuthardt, Eric C. Perkins, Stephanie M. Snyder, Abraham Z. Zhu, Tong Huang, Jiayi Department of Radiation Oncology Washington University School of Medicine St LouisMissouri United States Division of Public Health Sciences Washington University School of Medicine St LouisMissouri United States Medical Scientist Training Program Washington University School of Medicine St. LouisMissouri United States Department of Radiology Division of Medical Oncology Washington University School of Medicine St LouisMissouri United States Department of Neurology Washington University School of Medicine St LouisMissouri United States Department of Neurological Surgery and Division of Neurotechnology Washington University School of Medicine St LouisMissouri United States Brain Tumor Center Siteman Cancer Center Washington University School of Medicine St. LouisMissouri United States

Purpose: This prospective observational study employed resting-state functional magnetic resonance imaging (rs-fMRI) to investigate network-level disturbances associated with neurocognitive function (NCF) changes in patients with gliomas following partial-brain radiation therapy (RT). Methods and Materials: Adult postoperative patients with either isocitrate dehydrogenase (IDH)–wild-type or IDH-mutant gliomas underwent computerized NCF testing and rs-fMRI at baseline and 6 months post-RT. rs-fMRI data were assessed using seed-based functional connectivity (FC). NCF changes were quantified by the percent change in age-normalized composite scores from baseline (ΔNCFcomp). Connectivity regression analysis assessed the association between network FC changes and NCF changes, using a split-sample approach with a 26-patient training set and a 6-patient validation set, iterated 200 times. Permutation tests evaluated the significance of network selection. Results: Between September 2020 and December 2023, 43 patients were enrolled, with 32 completing both baseline and follow-up evaluations. The mean ΔNCFcomp was 2.9% (SD, 13.7%), with 38% experiencing a decline. Patients with IDH-mutant glioma had similar NCF changes compared with those with IDH–wild-type glioma. Intrahemispheric FC was similar between ipsilateral and contralateral hemispheres for 91% of patients at baseline, and 69% had similar intrahemispheric FC change posttreatment. FC changes accounted for a moderate fraction of variance in NCF changes (mean R2, 0.301;SD, 0.249), with intranetwork FC of the parietal memory network (PMN-PMN, P = .001) and internetwork FC between the PMN and the visual network (PMN-VN, P = .002) as the most significant factors. Similar findings were obtained by sensitivity analyses using only the FC data from the hemisphere contralateral to the tumor. Conclusions: Post-RT rs-fMRI changes significantly reflected NCF decline, highlighting rs-fMRI as a promising imaging biomarker for neuroco

关键词： Regression analysis

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Perioperative Stress, Inflammation, and Cancer Progression: Opportunities for Intervention in Breast and Colorectal Cancer Surgery Utilizing Beta-Adrenergic Blockade and COX-2 Inhibition

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Current Anesthesiology Reports 2018年第4期8卷 386-392页

作者： Fischer, Avital Ben-Eliyahu, Shamgar School of Medicine Medical Scientist Training Program University of California Irvine Irvine CA United States Sagol School of Neuroscience School of Psychological Sciences Tel Aviv University Tel Aviv 69978 Israel

Purpose of review: This review explores the blockade of cyclooxygenase (COX)-2/prostaglandin and catecholamine/beta(β)-adrenergic signaling as opportunities to enhance the curative potential of surgical excision of breast and colorectal cancer malignancies. Recent findings: Phase-II randomized placebo-controlled biomarker clinical trials, employing perioperative administration of the COX-2 inhibitor etodolac and the β-adrenergic antagonist propranolol, have shown improved biomarkers associated with both breast and colorectal cancer progression. Tumor epithelial-to-mesenchymal transition (EMT) status and tumor transcription activity levels of GATA-1, GATA-2, EGR3, and STAT-3 were reduced, while anti-cancer immune parameters within the tumor microenvironment improved perioperatively. Increased tumor-associated B cells and NK cells and reduced tumor-associated monocytes were noted. Reduced systemic pro-inflammatory markers IL-6 and CRP were indicated, starting before surgery. Summary: Improved biomarkers of tumor-associated (i) anti-metastatic transcriptional activity, (ii) anti-metastatic immune function, and (iii) reduced systemic inflammatory indices were observed following the combined administration of etodolac and propranolol. These findings support future investigation with larger clinical trials to test long-term cancer outcomes. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

关键词： Beta-adrenergic blockade Breast cancer Cancer progression Colorectal cancer COX-2 inhibition Perioperative stress Surgery

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