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Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

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Neural Regeneration Research 2025年第3期20卷 715-724页

作者： Xin Yang Yu-Wen Alvin Huang John Marshall Department of Molecular Biology Cell Biology and BiochemistryBrown UniversityProvidenceRIUSA Department of Neurology Warren Alpert Medical School of Brown UniversityProvidenceRIUSA Center for Translational Neuroscience Robert J.and Nancy D.Carney Institute for Brain Science and Brown Institute for Translational ScienceBrown UniversityProvidenceRIUSA

Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and *** activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term ***,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term *** this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and *** with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 *** TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific *** TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

关键词： Angelman syndrome autism brain-derived neurotrophic factor depression neurodegenerative disorder neurodevelopmental disorder postsynaptic density protein-95 synaptic plasticity TrkB

Lax-Oleinik-Type Formulas and Efficient Algorithms for Certain High-Dimensional Optimal Control Problems

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Communications on Applied Mathematics and Computation 2024年第2期6卷 1428-1471页

作者： Paula Chen Jerome Darbon Tingwei Meng Division of Applied Mathematics Brown UniversityProvidenceRIUSA Department of Mathematics UCLALos AngelesCAUSA

Two of the main challenges in optimal control are solving problems with state-dependent running costs and developing efficient numerical solvers that are computationally tractable in high *** this paper,we provide analytical solutions to certain optimal control problems whose running cost depends on the state variable and with constraints on the *** also provide Lax-Oleinik-type representation formulas for the corresponding Hamilton-Jacobi partial differential equations with state-dependent ***,we present an efficient,grid-free numerical solver based on our representation formulas,which is shown to scale linearly with the state dimension,and thus,to overcome the curse of *** existing optimization methods and the min-plus technique,we extend our numerical solvers to address more general classes of convex and nonconvex initial *** demonstrate the capabilities of our numerical solvers using implementations on a central processing unit(CPU)and a field-programmable gate array(FPGA).In several cases,our FPGA implementation obtains over a 10 times speedup compared to the CPU,which demonstrates the promising performance boosts FPGAs can *** numerical results show that our solvers have the potential to serve as a building block for solving broader classes of high-dimensional optimal control problems in real-time.

关键词： Optimal control Hamilton-Jacobi partial differential equations Grid-free numerical methods High dimensions Field-programmable gate arrays(FPGAs)

Differential expression profile of circular RNAs in mouse peritoneum with peritoneal fibrosis and the potential regulatory role of novel_circ_0007527

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Genes & Diseases 2024年第3期11卷 59-62页

作者： Yingfeng Shi Yan Hu Hui Chen Jinqing Li Min Tao Xun Zhou Qin Zhong Andong Qiu Shougang Zhuang Na Liu Department of Nephrology Shanghai East HospitalTongji University School of MedicineShanghai 200120China School of Life science and Technology Advanced Institute of Translational MedicineTongji UniversityShanghai 200092China Department of Medicine Rhode Island Hospital and Alpert Medical SchoolBrown UniversityProvidenceRI 02912USA

CircRNAs,a novel type of endogenous non-coding RNAs(ncRNAs),are typically produced by back-splicing from exons of protein-coding genes,which are characterized by a covalently closed structure with neither 5'to 3'polarity nor a poly(A)tail.'On the one hand,circRNAs are involved in the regulation of a variety of important biological processes,such as apoptosis,proliferation,migration,and inflammatory responses.'On the other hand,the relationship between circRNAs and several fibrotic diseases has been reported.2 However.

关键词： endogenous peritoneal diseases

Distinct and Additive Effects of Alcohol and Thiamine Deficiency in the Developing Brain: Relevance to Fetal Alcohol Spectrum Disorder

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Journal of Behavioral and Brain science 2024年第6期14卷 161-186页

作者： Suzanne M. de la Monte Elizabeth Silbermann Ming Tong Departments of Pathology (Neuropathology) Neurology and Neurosurgery Brown University Providence RI USA Department of Medicine Brown University Providence RI USA Rhode Island Hospital Providence RI USA Women & Infants Hospital Providence RI USA Warren Alpert medical School of brown university Providence RI USA Portland VA medical Center Oregon Health & Science University Portland OR USA

Background: Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are linked to brain insulin resistance and oxidative stress. However, the role of thiamine deficiency as a distinct or additive factor in the pathogenesis of the neurodevelopmental and metabolic derangements in FASD has not been determined. Methods: Control and ethanol-exposed human PNET2 cerebellar neuronal cells and rat cerebellar slice cultures were treated with vehicle or pyrithiamine (Pyr) to assess independent and additive effects of thiamine deficiency on ethanol-mediated neurotoxicity, mitochondrial dysfunction, insulin resistance, inhibition of neuronal and glial genes, and oxidative stress. Results: Pyr treatments (0 - 200 µM) caused dose-dependent cell loss (Crystal Violet assay) and reduced mitochondrial function (MTT assay) in PNET2 neuronal cultures. Ethanol alone (100 mM) significantly reduced PNET2 neuronal viability, MTT activity, and ATP production. Over the broad dose range of Pyr treatment, ethanol significantly reduced ATP content and cell number and increased mitochondrial mass (MitoTracker Green). Ex vivo cerebellar slice culture studies revealed ethanol-induced developmental architectural disruption that was substantially worsened by Pyr. The adverse effects of ethanol were linked to increased lipid peroxidation and inhibition of asparatyl-asparaginyl-β-hydroxylase (ASPH) expression. The independent and additive effects of Pyr were associated with increased cytotoxicity, lipid peroxidation, Caspase 3 activation, and Tau accumulation. Conclusions: During development, alcohol exposure and thiamine deficiency exert distinct but overlapping molecular pathologies that ultimately impair the structure and function of cerebellar neurons. While both insults drive cell loss and mitochondrial dysfunction with increased lipid peroxidation, ethanol’s additional inhibitory effects on ASPH reflect impairments in insulin and IGF signaling. In contrast, Pyr’s main adverse e

关键词： Fetal Alcohol Spectrum Disorder Thiamine Deficiency Cerebellum Slice Culture Pyrithiamine

Selective synthesis of the B_(11)H_(14)^(-) and B_(12)H_(12)^(2-) borane derivatives and the general mechanisms of the B-H bond condensation

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science China Chemistry 2024年第3期67卷 876-881页

作者： Yi Jing Xinghua Wang Hui Han Xin-Ran Liu Xing-Chao Yu Xi-Meng Chen Donghui Wei Lai-Sheng Wang Xuenian Chen College of Chemistry Green Catalysis CenterZhengzhou UniversityZhengzhou 450001China School of Chemistry and Chemical Engineering Henan Key Laboratory of Boron Chemistry and Advanced Energy MaterialsHenan Normal UniversityXinxiang 453007China Department of Chemistry Brown UniversityProvidenceRI 02912USA

Polyhedral boranes are a class of well-known boron molecular clusters with unique physical and chemical properties,and great efforts have been made in the past decades to find more effective synthetic ***,the established synthetic methods suffer from low efficiency and low selectivity because the mechanism of the B-H bond condensation reaction,critical for the synthesis of the polyhedral boranes,is not well *** we report highly selective and efficient synthetic methods of the salts of the tetradecahydridoundecaborate(1-)(B_(11)H^(-)_(14)) and dodecahydrido-dodecaborates(2-)(B_(12)H_(12)^(2-)) anions by employing commercially available and inexpensive starting *** theoretical and experimental investigations are carried out to elucidate the reaction *** have found that the nature of the B-H bond condensation is the dihydrogen bonding interaction in which the positively charged hydrogens(bridged hydrogens) play a crucial *** current study has not only led to more effective and selective synthetic methods for B_(11)H^(-)_(14) and B_(12)H_(12)^(2-) but also unveiled the nature of the B-H bond condensation and the general formation mechanisms of polyhedral *** finding will facilitate the development of more effective synthetic methods for polyhedral boranes and spur their wide application.

关键词： Boranes polyhedral boranes dihydrogen bond nucleophilicity

Spatial relationship of tertiary lymphoid structures and tumor-associated neutrophils in bladder cancer and prognostic potential for anti-PD-L1 immunotherapy

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Cancer Communications 2024年第4期44卷 499-503页

作者： Xuechun Wang Anna Juncker-Jensen Gang Huang Mate Levente Nagy Xuemin Lu Liang Cheng Xin Lu Department of Biological sciences Boler-Parseghian Center for Rare and Neglected DiseasesHarper Cancer Research InstituteUniversity of Notre DameNotre DameINUSA NeoGenomics Laboratories Inc.Aliso ViejoCAUSA Department of Pathology and Laboratory Medicine Brown University Warren Alpert Medical SchoolLifespan Academic Medical CenterLegorreta Cancer Center at Brown UniversityProvidenceRIUSA Tumor Microenvironment and Metastasis Program Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolisINUSA

Dear Editor,Tertiary lymphoid structures(TLSs)are organized clus-ters of immune cells found in non-lymphoid tissues of chronic inflammation,including solid tumors[1].High endothelial venules(HEVs)positive for peripheral node addressin(PNAd)are present in TLSs and may pro-vide highway entry for ***-residing TLSs may be formed by the concerted actions of cytokines and chemokines,a finding supported by the relation between a 12-chemokine signature and TLSs[2].

关键词： bladder lymphoid inflammation

Efficient Finite Difference WENO Scheme for Hyperbolic Systems withNon-conservativeProducts

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Communications on Applied Mathematics and Computation 2024年第2期6卷 907-962页

作者： Dinshaw S.Balsara Deepak Bhoriya Chi-Wang Shu Harish Kumar Physics Department University of Notre DameNotre DameUSA ACMS Department University of Notre DameNotre DameUSA Division of Applied Mathematics Brown UniversityProvidenceUSA Department of Mathematics Indian Institute of TechnologyDelhiIndia

Higher order finite difference weighted essentially non-oscillatory(WENO)schemes have been constructed for conservation *** multidimensional problems,they offer a high order accuracy at a fraction of the cost of a finite volume WENO or DG scheme of the comparable *** makes them quite attractive for several science and engineering ***,to the best of our knowledge,such schemes have not been extended to non-linear hyperbolic systems with non-conservative *** this paper,we perform such an extension which improves the domain of the applicability of such *** extension is carried out by writing the scheme in fluctuation *** use the HLLI Riemann solver of Dumbser and Balsara(***.304:275-319,2016)as a building block for carrying out this *** of the use of an HLL building block,the resulting scheme has a proper supersonic *** use of anti-diffusive fluxes ensures that stationary discontinuities can be preserved by the scheme,thus expanding its domain of the *** new finite difference WENO formulation uses the same WENO reconstruction that was used in classical versions,making it very easy for users to transition over to the present *** conservation laws,the new finite difference WENO is shown to perform as well as the classical version of finite difference WENO,with two major advantages:(i)It can capture jumps in stationary linearly degenerate wave families exactly.(i)It only requires the reconstruction to be applied *** examples from hyperbolic PDE systems with non-conservative products are shown which indicate that the scheme works and achieves its design order of the accuracy for smooth multidimensional *** Riemann problems and several novel multidimensional problems that are drawn from compressible Baer-Nunziato multiphase flow,multiphase debris flow and twolayer shallow water equations are also shown to document the robustness of the *** some

关键词： Hyperbolic PDEs Numerical schemes Non-conservative products Stiff source terms Finite difference WENO

Reveal the lost entanglement for accelerated atoms in the high-dimensional spacetime

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science China(Physics,Mechanics & Astronomy) 2024年第6期67卷 48-57页

作者： Jiatong Yan Baocheng Zhang Qingyu Cai School of Mathematics and Physics China University of GeosciencesWuhan 430074China Physics Department Brown UniversityProvidenceRhode Island 02912USA Center for Theoretical Physics Hainan UniversityHaikou 570228China School of Information and Communication Engineering Hainan UniversityHaikou 570228China Peng Huanwu Center for Fundamental Theory Hefei 230026China

When atoms are accelerated in the vacuum,entanglement among atoms will degrade compared with the initial situation before the *** this study,we propose a novel and interesting view that the lost entanglement can be recovered completely when the high-dimensional spacetime is exploited,in the case that the acceleration is not too large,since the entanglement loss rate caused by the large acceleration is faster than the recovery *** also calculate the entanglement change caused by the anti-Unruh effect and found that the lost entanglement could just be recovered part by the anti-Unruh effect,and the anti-Unruh effect could only appear for a finite range of acceleration when the interaction time scale is approximately shorter than the reciprocal of the energy gap in two dimensional *** limit case of zero acceleration is also investigated,which gives an analytical interpretation for the increase or recovery of entanglement.

关键词： entanglement acceleration high-dimensional spacetime

Emerging role of cellular senescence in normal lung development and perinatal lung injury

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Chinese medical Journal Pulmonary and Critical Care Medicine 2024年第1期2卷 10-16页

作者： Phyllis A.Dennery Hongwei Yao Department of Molecular Biology Cell Biology&BiochemistryDivision of Biology and MedicineBrown UniversityProvidenceRI 02912USA Department of Pediatrics Warren Alpert Medical School of Brown UniversityProvidenceRI 02903USA

Cellular senescence is a status of irreversible growth arrest,which can be triggered by the p53/p21cip1 and p16INK4/Rb pathways via intrinsic and external *** cells are typically enlarged and flattened,and characterized by numerous molecular *** latter consists of increased surfaceome,increased resid-ual lysosomal activity at pH 6.0(manifested by increased activity of senescence-associated beta-galactosidase[SA-𝛽-gal]),senescence-associated mitochondrial dysfunction,cytoplasmic chromatin fragment,nuclear lamin b1 exclusion,telomere-associated foci,and the senescence-associated secretory *** features vary depending on the stressor leading to senescence and the type of *** senescence plays pivotal roles in organismal aging and in the pathogenesis of aging-related ***,senescence can also both promote and inhibit wound healing *** recently report that senescence as a programmed pro-cess contributes to normal lung *** senescence is also observed in Down Syndrome,as well as in premature infants with bronchopulmonary dysplasia and in a hyperoxia-induced rodent model of this ***,this senescence results in neonatal lung *** this review,we briefly discuss the molecular features of *** then focus on the emerging role of senescence in normal lung development and in the pathogenesis of bronchopulmonary dysplasia as well as putative signaling pathways driving ***,we discuss potential therapeutic approaches targeting senescent cells to prevent perinatal lung diseases.

关键词： Senescence Normal lung development Bronchopulmonary dysplasia Down syndrome Senolytics