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Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao Michael S.Wolfe Computational Medicine Program and Department of Pharmacology University of North Carolina–Chapel HillChapel HillNCUSA Department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

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Deforming generalized cylinders without self-intersection by means of a parametric center curve

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Computational Visual Media 2018年第4期4卷 305-321页

作者： Ruibin Ma Qingyu Zhao Rui Wang James Damon Julian Rosenman Stephen Pizer Computer Science University of North Carolina at Chapel Hill Mathematics University of North Carolina at Chapel Hill Radiation Oncology University of North Carolina at Chapel Hill

Large-scale deformations of a tubular object, or generalized cylinder, are often defined by a target shape for its center curve, typically using a parametric target curve. This task is non-trivial for free-form deformations or direct manipulation methods because it is hard to manually control the centerline by adjusting control points. Most skeleton-based methods are no better, again due to the small number of manually adjusted control points. In this paper, we propose a method to deform a generalized cylinder based on its skeleton composed of a centerline and orthogonal cross sections. Although we are not the first to use such a skeleton, we propose a novel skeletonization method that tries to minimize the number of intersections between neighboring cross sections by means of a relative curvature condition to detect intersections. The mesh deformation is first defined geometrically by deforming the centerline and mapping the cross sections. Rotation minimizing frames are used during mapping to control twisting. Secondly, given displacements on the cross sections, the deformation is decomposed into finely subdivided regions. We limit distortion at these vertices by minimizing an elastic thin shell bending energy,in linear time. Our method can handle complicated generalized cylinders such as the human colon.

关键词： generalized cylinder deformation skeleton self-intersection

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Autism spectrum disorders in adolescence and adulthood: Long-term outcomes and relevant issues for treatment and research

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Science China(Life Sciences) 2015年第10期58卷 1010-1015页

作者： Allison B.RATTO Gary B.MESIBOV Department of Psychology University of North Carolina at Chapel Hill Department of Psychiatry University of North Carolina at Chapel Hill

The advances in research and treatment of autism spectrum disorders(ASD) over the past three decades have focused largely on early childhood and school-age years. Although ASD is a lifelong condition, there has been relatively little attention paid to ASD during the adolescent and adulthood periods. As the population of those with ASD continues to rise and age, the need to provide research and treatment for this group has become increasingly evident. This paper reviews the current literature available on symptoms, functioning, and treatment of adolescents and adults with ASD, as well as the unique issues that arise for individuals with ASD after childhood. Adulthood outcomes for ASD are generally poor, even for those with average to above average cognitive ability. Further research and additional clinical resources are needed for this rapidly increasing group.

关键词： autism spectrum disorder (ASD) adolescence adulthood developmental trajectory

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Oxidation state specific analysis of arsenic species in tissues of wild-type and arsenic(+3 oxidation state)methyltransferase-knockout mice

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Journal of Environmental Sciences 2016年第11期28卷 104-112页

作者： Jenna M.Currier Christelle Douillet Zuzana Drobná Miroslav Styblo Curriculum in Toxicology University of North Carolina at Chapel Hill Department of Nutrition Gillings School of Global Public Health University of North Carolina at Chapel Hill

Arsenic methyltransferase（As3mt） catalyzes the conversion of inorganic arsenic（i As） to its methylated metabolites, including toxic methylarsonite（MAs~Ⅲ） and dimethylarsinite（DMAs~Ⅲ）. Knockout（KO） of As3 mt was shown to reduce the capacity to methylate i As in mice. However, no data are available on the oxidation states of As species in tissues of these mice. Here, we compare the oxidation states of As species in tissues of male C57BL/6 As3mt-KO and wild-type（WT） mice exposed to arsenite（iA s~Ⅲ） in drinking water. WT mice were exposed to50 mg/L As and As3mt-KO mice that cannot tolerate 50 mg/L As were exposed to 0, 15, 20, 25 or30 mg/L As. iA s~Ⅲaccounted for 53% to 74% of total As in liver, pancreas, adipose, lung, heart, and kidney of As3mt-KO mice; tri- and pentavalent methylated arsenicals did not exceed 10% of total As. Tissues of WT mice retained iA s and methylated arsenicals： iA s~Ⅲ, MAs~Ⅲand DMAs~Ⅲ represented 55%‐68% of the total As in the liver, pancreas, and brain. High levels of methylated species, particularly MAs~Ⅲ, were found in the intestine of WT, but not As3mt-KO mice,suggesting that intestinal bacteria are not a major source of methylated As. Blood of WT mice contained significantly higher levels of As than blood of As3mt-KO mice. This study is the first to determine oxidation states of As species in tissues of As3mt-KO mice. Results will help to design studies using WT and As3mt-KO mice to examine the role of iA s methylation in adverse effects of iA s exposure.

关键词： Arsenic speciation analysis Hydride generation-cryotrapping-atomic absorption spectrometry Arsenic(+ 3 oxidation state) methyltransferase As3mt knockout mice

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Cytosolic DNA sensing by cGAS:regulation,function,and human diseases

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Signal Transduction and Targeted Therapy 2021年第5期6卷 1483-1497页

作者： Le Yu Pengda Liu Lineberger Comprehensive Cancer Center The University of North Carolina at Chapel HillChapel HillNCUSA Department of Biochemistry and Biophysics The University of North Carolina at Chapel HillChapel HillNCUSA

Sensing invasive cytosolic DNA is an integral component of innate *** was identified in 2013 as the major cytosolic DNA sensor that binds dsDNA to catalyze the synthesis of a special asymmetric cyclic-dinucleotide,2/3/-cGAMP,as the secondary messenger to bind and activate STING for subsequent production of type I interferons and other immune-modulatory *** of cGAS signaling contributes to autoimmune diseases but serves as an adjuvant for anticancer immune *** the other hand,inactivation of cGAS signaling causes deficiency to sense and clear the viral and bacterial infection and creates a tumor-prone immune microenvironment to facilitate tumor evasion of immune ***,cGAS activation is tightly *** this review,we summarize up-to-date multilayers of regulatory mechanisms governing cGAS activation,including cGAS pre-and post-translational regulations,cGAS-binding proteins,and additional cGAS regulators such as ions and small *** will also reveal the pathophysiological function of cGAS and its product cGAMP in human *** hope to provide an up-to-date review for recent research advances of cGAS biology and cGAS-targeted therapies for human diseases.

关键词： diseases function cGAS

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Adrenomedullin and endocrine control of immune cells during pregnancy

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Cellular & Molecular Immunology 2014年第5期11卷 456-459页

作者： Brooke C Matson Kathleen M Caron Departments of Cell Biology & Physiology University of North Carolina at Chapel Hill Chapel Hill NC USA Genetics University of North Carolina at Chapel Hill Chapel Hill NC USA

The immunology of pregnancy is complex and incompletely understood. Aberrant immune activity in the decidua and in the placenta is believed to play a role in diseases of pregnancy, such as infertility, miscarriage, fetal growth restriction and preeclampsia. Here, we briefly review the endocrine control of uterine natural killer cell populations and their functions by the peptide hormone adrenomedullin. Studies in genetic animal models have revealed the critical importance of adrenomedullin dosage at the maternal-fetal interface, with cells from both the maternal and fetal compartments contributing to essential aspects underlying appropriate uterine receptivity, implantation and vascular remodeling of spiral arteries. These basic insights into the crosstalk between the endocrine and immune systems within the maternal- fetal interface may ultimately translate to a better understanding of the functions and consequences of dysregulated adrenomedullin levels in clinically complicated pregnancies.

关键词： adrenomedullin preeclampsia pregnancy spiral artery remodeling uNK cells

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Semi-transparent,flexible,and electrically conductive silicon mesh by capillarity-driven welding of vapor-liquid-solid-grown nanowires over large areas

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Nano Research 2020年第5期13卷 1465-1471页

作者： Thomas A.Celano Seokhyoung Kim David J.hill James F.Cahoon Department of Chemistry University of North Carolina at Chapel HillChapel HillNC 27599-3290USA

Bottom-up synthesis of semiconductor nanowires(NWs)by the vapor-liquid-solid(VLS)mechanism has enabled diverse technological applications for these *** metallic NWs,however,it has been challenging to form large-area interconnected NW ***,we generate centimeter-scale meshes of mechanically and electrically interconnected Si NWs by sequentially growing,collapsing,and joining the NWs using a capillarity-driven welding *** fabricate meshes from VLS-grown NWs ranging in diameter from 20 to 100 nm and find that the meshes are three-dimensional with a thickness ranging from^1 to^10 microns depending on the NW *** extinction measurements reveal that the networks are semi-transparent with a color that depends on the absorption and scattering characteristics of individual ***,active voltage contrast imaging of both centimeter-and micron-scale meshes reveals widespread electrical *** a sacrificial layer,we demonstrate that the mesh can be liberated from the growth substrate,yielding a highly flexible and transparent *** transport measurements both on the growth substrate and on liberated,flexible films reveal electrical conduction across a centimeter scale with a sheet resistance of^160-180 kΩ/square that does not change significantly upon *** the ability to encode complex functionality in semiconductor NWs through the VLS process,we believe these meshes of networked NWs could find application as neuromorphic memory,electrode scaffolds,and bioelectronic interfaces.

关键词： semiconductor nanowire conductive network flexible electronics welding thermal annealing active-voltage contrast

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High-throughput discovery of fluoride-ion conductors via a decoupled,dynamic,and iterative(DDI)framework

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npj Computational Materials 2022年第1期8卷 983-991页

作者： Jack D.Sundberg Daniel L.Druffel Lauren M.McRae Matthew G.Lanetti Jacob T.Pawlik Scott C.Warren Department of Chemistry The University of North Carolina at Chapel HillChapel HillNC27599United States

Fluoride–ion batteries are a promising alternative to lithium–ion batteries with higher theoretical capacities and working voltages,but they have experienced limited success due to the poor ionic conductivities of known electrolytes and ***,we report a high-throughput computational screening of 9747 fluoride-containing materials in search of fluoride-ion *** a combination of empirical,lightweight DFT,and nudged elastic band(NEB)calculations,we identified>10 crystal systems with high fluoride *** applied a search strategy where calculations are performed in any order(decoupled),computational resources are reassigned based on need(dynamic),and predictive models are repeatedly updated(iterative).Unlike hierarchical searches,our decoupled,dynamic,and iterative framework(DDI)began by calculating high-quality barrier heights for fluoride-ion mobility in a large and diverse group of *** high-quality dataset provided a benchmark against which a rapid calculation method could be *** accurate method was then used to measure the barrier heights for 6797 fluoride–ion *** final dataset has allowed us to discover many fascinating,high-performance conductors and to derive the design rules that govern their *** materials will accelerate experimental research into fluoride–ion batteries,while the design rules will provide an improved foundation for understanding ionic conduction.

关键词： fluoride dynamic repeatedly

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Acute coronary syndrome in the older adults

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Journal of Geriatric Cardiology 2016年第2期13卷 101-108页

作者： Xuming DAI Jan Busby-Whitehead Karen P Alexander Division of Cardiology University of North Carolina at Chapel Hill Chapel Hill North Carolina USA Division of Geriatric Medicine Center for Aging and Health University of North Carolina at Chapel Hill North Carolina USA Division of Cardiology Duke University Medical Center Durham North Carolina USA

Coronary heart disease remains the leading cause of death in the developed world. Advanced age is the single strongest risk factor for coronary artery disease （CAD） and independent predictor for poor outcomes following an acute coronary syndrome （ACS）. ACS refers to a spectrum of conditions compatible with acute myocardial ischemia and/or infarction due to various degrees of reduction in co- ronary blood flow as a result of plaque rupture/erosion and thrombosis formation or supply and demand mismatch.

关键词： Acute coronary syndrome Aging Coronary artery disease Older adults Risk assessment

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Intricacies of TGF-βsignaling in Treg and Th17 cell biology

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Cellular & Molecular Immunology 2023年第9期20卷 1002-1022页

作者： Junying Wang Xingqi Zhao Yisong Y.Wan Lineberger Comprehensive Cancer Center University of North Carolina at Chapel HillChapel HillNC 27599USA Department of Microbiology and Immunology University of North Carolina at Chapel HillChapel HillNC 27599USA

Balanced immunity is pivotal for health and ***4+helper T(Th)cells are central to the balance between immune tolerance and immune *** cells adopt distinct functions to maintain tolerance and clear *** of Th cell function often leads to maladies,including autoimmunity,inflammatory disease,cancer,and *** T(Treg)and Th17 cells are critical Th cell types involved in immune tolerance,homeostasis,pathogenicity,and pathogen *** is therefore critical to understand how Treg and Th17 cells are regulated in health and *** are instrumental in directing Treg and Th17 cell *** evolutionarily conserved TGF-β(transforming growth factor-β)cytokine superfamily is of particular interest because it is central to the biology of both Treg cells that are predominantly immunosuppressive and Th17 cells that can be proinflammatory,pathogenic,and immune *** TGF-βsuperfamily members and their intricate signaling pathways regulate Treg and Th17 cell function is a question that has been intensely investigated for two ***,we introduce the fundamental biology of TGF-βsuperfamily signaling,Treg cells,and Th17 cells and discuss in detail how the TGF-βsuperfamily contributes to Treg and Th17 cell biology through complex yet ordered and cooperative signaling networks.

关键词： TGF-beta regulatory T cell Th17 cell Treg

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