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strategies for translating proteomics discoveries into drug discovery for dementia

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Neural Regeneration Research 2024年第1期19卷 132-139页

作者： Aditi Halder eleanor Drummond school of Medical sciences and Brain&Mind Center University of SydneyNSWSydneyAustralia Department of Aged Care Prince of Wales HospitalSydneyNSWAustralia

Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia *** there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing *** such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug *** this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired *** highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this *** propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.

关键词： Alzheimer's disease biomarkers drug development drug discovery druggability frontotemporal dementia interactome proteomics tau tauopathies therapeutics

Insights from a proteomic atlas of human Alzheimer's disease brain tissue

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Neural Regeneration Research 2025年第3期20卷 799-800页

作者： Tomas Kavanagh eleanor Drummond Brain and Mind Centre and school of Medical sciences University of SydneyCamperdownNSWAustralia

There is an urgent need to identify new drug targets for Alzheimer's disease(AD). While new immunotherapies show promise, clinical benefit appears low, and side effects are high. A greater understanding of the disease mechanisms driving AD is an essential factor that will facilitate the identification of new, effective drug targets.

关键词： Alzheimer clinical driving

Development,validation,and transportability of several machine-learned,non-exercise-based VO_(2max)prediction models for older adults

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Journal of sport and Health science 2024年第5期13卷 611-620页

作者： Benjamin T.schumacher Michael J.LaMonte Andrea Z.LaCroix eleanor M.simonsick steven P.Hooker Humberto Parada Jr. John Bellettiere Arun Kumar Herbert Wertheim school of Public Health and Human Longevity science University of California San DiegoLa JollaCA 92093USA Department of Epidemiology and Environmental Health School of Public Health and Health ProfessionsUniversity at BuffaloState University of New YorkBuffaloNY 14214USA Translational Gerontology Branch Intramural Research ProgramNational Institute on AgingNational Institutes of HealthBaltimoreMD 21225USA College of Health and Human services San Diego State UniversitySan DiegoCA 92182USA Division of Epidemiology and Biostatistics School of Public HealthSan Diego State UniversitySan DiegoCA 92182USA University of California san Diego Moores Cancer Center La JollaCA 92093USA Computer science and Engineering and Halicioglu Data science Institute University of California San DiegoLa JollaCA 92093USA

Background:There exist few maximal oxygen uptake(VO_(2max))non-exercise-based prediction equations,fewer using machine learning(ML),and none specifically for older *** direct measurement of VO_(2max)is infeasible in large epidemiologic cohort studies,we sought to develop,validate,compare,and assess the transportability of several ML VO_(2max)prediction ***:The Baltimore Longitudinal study of Aging(BLsA)participants with valid VO2_(max)tests were included(n=1080).Least absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine(sVM)algorithms were trained to predict VO_(2max)*** developed these algorithms for:(a)the overall BLsA,(b)by sex,(c)using all BLsA variables,and(d)variables common in aging ***,we quantified the associations between measured and predicted VO_(2max)and ***:The age was 69.0±10.4 years(mean±sD)and the measured VO_(2max)was 21.6±5.9 mL/kg/*** absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine yielded root mean squared errors of 3.4 mL/kg/min,3.6 mL/kg/min,3.4 mL/kg/min,3.6 mL/kg/min,and 3.5 mL/kg/min,*** quartiles of measured VO_(2max)showed an inverse gradient in mortality *** VO_(2max)variables yielded similar effect estimates but were not robust to ***:Measured VO_(2max)is a strong predictor of *** ML can improve the accuracy of prediction as compared to simpler approaches but estimates of association with mortality remain sensitive to *** studies should seek to reproduce these results so that VO_(2max),an important vital sign,can be more broadly studied as a modifiable target for promoting functional resiliency and healthy aging.

关键词： Cardiorespiratory fitness Prediction algorithms Epidemiology Mortality

Capturing 2D van der Waals magnets with high probability for experimental demonstration from materials science literature

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InfoMat 2023年第4期5卷 39-47页

作者： Haiyang song Yinghe Zhao eleanor Turner YuWu Yuan Li Menghao Wu Guang Feng Huiqiao Li Tianyou Zhai state Key Laboratory of Materials Processing and Die&Mould Technology School of Materials Science and EngineeringHuazhong University of Science and TechnologyWuhanthe People's Republic of China Department of Chemical&Biological Engineering Monash UniversityClayton CampusClaytonVictoriaAustralia school of Physics Huazhong University of Science and TechnologyWuhanthe People's Republic of China state Key Laboratory of Coal Combustion School of Energy and Power EngineeringHuazhong University of Science and TechnologyWuhanthe People's Republic of China

2D van der Waals(vdW)magnets have opened intriguing prospects for next-generation spintronic *** learning techniques and density functional theory calculations enable the discovery of 2D vdW magnets to be accelerated;however,current computational frameworks based on these state-ofthe-art approaches cannot offer probability analysis on whether a 2D vdW magnet can be experimentally ***,a new framework can be established to overcome this *** the framework,2D vdW magnets with high probability for experimental demonstration are captured from materials science *** key to the successful establishment is the introduction of the theory of mutual *** validation of predictions substantiates the high reliability of the *** example,half of the 302D vdW magnets discovered in the literature published prior to 2017 have been experimentally demonstrated in the subsequent *** framework has the potential to become a revolutionary force for progressing experimental discovery of 2D vdW magnets.

关键词： 2D vdW magnets mutual information neural networks

Effects of PGC-1αoverexpression on the myogenic response during skeletal muscle regeneration

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sports Medicine and Health science 2022年第3期4卷 198-208页

作者： Tyrone A.Washington Wesley s.Haynie eleanor R.schrems Richard A.Perry Jr. Lemuel A.Brown Breanna M.Williams Megan E.Rosa-Caldwell David E.lee Jacob L.Brown Exercise Muscle Biology Laboratory Exercise Science Research CenterDepartment of HealthHuman Performance and RecreationUniversity of ArkansasFayettevilleAR72701USA Cachexia Research Laboratory Exercise Science Research CenterDepartment of HealthHuman Performance and RecreationUniversity of ArkansasFayettevilleAR72701USA

The ability of skeletal muscle to regenerate from injury is crucial for locomotion,metabolic health,and quality of *** proliferator-activated receptor-γcoactivator-1α(PGC1A)is a transcriptional coactivator required for mitochondrial *** mitochondrial biogenesis is associated with improved muscle cell differentiation,however PGC1A's role in skeletal muscle regeneration following damage requires further *** purpose of this study was to investigate the role of skeletal muscle-specific PGC1A overexpression during regeneration following damage.22 C57BL/6J(WT)and 26 PGC1A muscle transgenic(A1)mice were injected with either phosphate-buffered saline(PBs,uninjured control)or Bupivacaine(MAR,injured)into their tibialis anterior(TA)muscle to induce skeletal muscle *** muscles were extracted 3-or 28-days postinjury and analyzed for markers of regenerative myogenesis and protein ***1a mRNA was~10–20 fold greater in A1 *** of protein synthesis,AKT and 4EBP1,displayed decreases in A1 mice compared to WT at both timepoints indicating a decreased protein synthetic *** mRNA was~75%lower compared to WT 3 days *** mice exhibited decreased cross-sectional area of the TA muscle at 28 days post-injection with bupivacaine compared to all other ***1A overexpression modifies the myogenic response during regeneration.

关键词： PGC-1α skeletal muscle Muscle regeneration satellite cells Protein turnover p38 MAPK

It takes more than tau to tangle:using proteomics to determine how phosphorylated tau mediates toxicity in neurodegenerative diseases

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Neural Regeneration Research 2021年第11期16卷 2211-2212页

作者： Geoffrey Pires eleanor Drummond Center for Cognitive Neurology Department of NeurologyNew York University School of MedicineNew YorkNYUSA Alzheimer’s and Prion Diseases Team Paris Brain InstituteCNRSUMR 7225INSERM 1127Sorbonne University UM75ParisFrance

Two of the most common causes of dementia are Alzheimer’s disease(AD)and frontotemporal dementia(FTD).AD is an irreversible,progressive neurodegenerative disorder that is clinically characterized by severe memory loss and behavioral impairment that eventually interferes with everyday *** is neuropathologically defined by the presence of extracellularβ-amyloid plaques and intracellular accumulation of neurofibrillary tangles(NFTs)that primarily contain aggregated,hyperphosphorylated tau(pTau).Intriguingly,pTau is also the central protein in multiple subtypes of FTD(*** degeneration,progressive supranuclear palsy,Pick’s disease).FTD is an umbrella term for a group of neurological conditions that primarily affect the temporal and frontal regions of the *** in the tau gene(MAPT)can cause familial FTD,providing further evidence of the integral role of tau in ***,tau regulates microtubule structure and dynamics,as well as axonal transport through interaction with *** is also involved in neuronal development and *** AD and FTD,tau becomes hyperphosphorylated and undergoes major conformational changes,causing it to aggregate into the characteristic neuropathological lesions that define AD and *** the known involvement of tau in these diseases,exactly how tau mediates toxicity is still unclear.

关键词： tau involvement media

The use of localized proteomics to identify the drivers of Alzheimer's disease pathogenesis

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Neural Regeneration Research 2017年第6期12卷 912-913页

作者： eleanor Drummond Thomas Wisniewski Center for Cognitive Neurology Department of Neurology New York University School of Medicine Departments of Neurology Pathology and Psychiatry New York University School of Medicine

Alzheimer’s disease（AD）is broadly defined by dementia and the presence of specific neuropathological features in the brain（amyloid plaques,neurofibrillary tangles（NFTs）and congophilic amyloid angiopathy）.However,the rate of disease progression,type of cognitive impairment,and extent of neuropathology vary widely in patients with AD（Murray et al.,2011）.

关键词： amyloid pathogenesis proteomics localized impairment plaques Murray targeted progression brains

CRIsPR/Cas: a Nobel Prize award-winning precise genome editing technology for gene therapy and crop improvement

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Journal of Zhejiang University-science B(Biomedicine & Biotechnology) 2021年第4期22卷 253-284页

作者： Chao LI eleanor BRANT Hikmet BUDAK Baohong ZHANG Oil Crops Research Institute Chinese Academy of Agricultural SciencesKey Laboratory for Biology and Genetic Improvement of Oil CropsMinistry of Agriculture and Rural AffairsWuhan 430062China Agronomy Department University of FloridaGainesvilleFL 32611USA Montana Bio Agriculture Inc.MissoulaMT 59802USA Department of Biology East Carolina UniversityGreenvilleNC 27858USA

since it was first recognized in bacteria and archaea as a mechanism for innate viral immunity in the early 2010 s,clustered regularly interspaced short palindromic repeats(CRIsPR)/CRIsPR-associated protein(Cas)has rapidly been developed into a robust,multifunctional genome editing tool with many *** the discovery of the initial CRIsPR/Cas-based system,the technology has been advanced to facilitate a multitude of different *** include development as a base editor,prime editor,epigenetic editor,and CRIsPR interference(CRIsPRi)and CRIsPR activator(CRIsPRa)gene *** can also be used for chromatin and RNA targeting and *** applications have proved revolutionary across numerous biological fields,especially in biomedical and agricultural *** a diagnostic tool,CRIsPR has been developed to aid the detection and screening of both human and plant diseases,and has even been applied during the current coronavirus disease 2019(COVID-19)***/Cas is also being trialed as a new form of gene therapy for treating various human diseases,including cancers,and has aided drug *** terms of agricultural breeding,precise targeting of biological pathways via CRIsPR/Cas has been key to regulating molecular biosynthesis and allowing modification of proteins,starch,oil,and other functional components for crop *** to this,CRIsPR/Cas has been shown capable of significantly enhancing both plant tolerance to environmental stresses and overall crop yield via the targeting of various agronomically important gene *** to the future,increasing the efficiency and precision of CRIsPR/Cas delivery systems and limiting off-target activity are two major challenges for wider application of the *** review provides an in-depth overview of current CRIsPR development,including the advantages and disadvantages of the technology,recent applications,and future considerations.

关键词： Genome editing Clustered regularly interspaced short palindromic repeats(CRIsPR)/CRIsPR-associated protein(Cas) Coronavirus disease 2019(COVID-19) Cancer Precision breeding Crop improvement Gene knock-out/in Gene repair/replacement

Rectal biopsy for Hirschsprung's disease:a review of techniques,pathology,and complications

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世界儿科杂志:英文版 2016年第2期12卷 135-141页

作者： eleanor Dorothy Muise Robert Anthony Cowles section of Pediatric surgery Department of SurgeryYale University School of MedicineNew HavenCTUSA

Background:Hirschsprung's disease(HD)is one of the most common congenital anomalies of colorectal function,affecting approximately 1 in 5000 live births,with a 4:1 male *** is characterized by aganglionosis that is most often limited to the rectosigmoid,but can extend proximally along the colon and,in rare instances,reach into the small intestine.A clinical history of delayed passage of meconium beyond 48 hours after birth,physical exam findings of abdominal distention and vomiting,and a contrast enema demonstrating a transition zone are highly suggestive of *** sources:We searched databases including PubMed,Google scholar,and scopus for the following key words:Hirschsprung's disease,rectal biopsy,pathology,ganglion cell,nerve trunk hypertrophy,pediatric constipation,and selected publications written in English that were relevant to the scope of this ***:Based on the data presented in the literature,we reviewed 1)biopsy techniques for the diagnosis of Hirschsprung's disease,addressed inadequate biopsies,and complications from rectal biopsy,and 2)pathologic and histologic interpretation of biopsy specimens for the diagnosis of Hirschsprung's ***:A well-executed rectal biopsy with expert pathologic evaluation of the specimen remains the gold standard for the diagnosis of Hirschsprung's disease and is the subject of this review.

关键词： ganglion cell Hirschsprung's disease nerve trunk hypertrophy pediatric constipation rectal biopsy