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Cell replacement therapy for central nervous system diseases

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Neural Regeneration Research 2015年第9期10卷 1356-1358页

作者： danju Tso randall d.mckinnon department of Surgery (Neurosurgery) Rutgers-Robert Wood Johnson Medical School

The brain and spinal cord can not replace neurons or supporting glia that are lost through trau- matic injury or disease. In pre-clinical studies, however, neural stem and progenitor cell transplants can promote functional recovery. Thus the central nervous system is repair competent but lacks endogenous stem cell resources. To make transplants clinically feasible, this field needs a source of histocompatible, ethically acceptable and non-tumorgenic cells. One strategy to generate pa- tient-specific replacement cells is to reprogram autologous cells such as fibroblasts into pluripotent stem cells which can then be differentiated into the required cell grafts. However, the utility of pluripotent cell derived grafts is limited since they can retain founder cells with intrinsic neoplastic potential. A recent extension of this technology directly reprograms fibroblasts into the final graft- able cells without an induced pluripotent stem cell intermediate, avoiding the pluripotent caveat. For both types of reprogramming the conversion efficiency is very low resulting in the need to amplify the cells in culture which can lead to chromosomal instability and neoplasia. Thus to make reprogramming biology clinically feasible, we must improve the efficiency. The ultimate source of replacement cells may reside in directly reprogramming accessible cells within the brain.

关键词： in vivo direct reprogramming spinal cord injury trauma personalized medicine induced pluripotent stem cell embryonic stem cells

Suicide transport blockade of motor neuron survival generates a focal graded injury and functional deficit

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Neural Regeneration Research 2021年第7期16卷 1281-1287页

作者： Allison S.Liang Joanna E.Pagano Christopher A.Chrzan randall d.mckinnon department of Neurosurgery Rutgers-Robert Wood Johnson Medical SchoolPiscatawayNJUSA Member The Cancer Institute of New JerseyNew BrunswickNJUSA

We describe a pre-clinical spinal cord motor neuron injury model that is minimal invasive, reproducible, focal and easily applied to small rodents.Retrograde axonal transport of a pro-apoptotic phosphatidylinosotol 3'-kinase inhibitor, wortmannin, via the sciatic nerve results in loss of ipsilateral lumbar motor neurons proportional to the level of drug administered.Motor neuron loss was detected by choline acetyltransferase(ChAT) immunostaining and with a transgenic thy1-eGFP marker.The short half-life of wortmannin generates minimal wound spread, and wortmannin does not affect axon transport, as determined by co-injection of a pseudorabies virus tracer.Using quantitative transcript analysis, we found that ChAT transcripts significantly decreased at 14 days post-delivery of 1 μg wortmannin, relative to sham controls, and remained low after 90 days.Smaller effects were observed with 200 ng and 100 ng wortmannin.Wortmannin also generated a transient and significant increase in astrocyte Gfap transcripts after 14 days with a return to control levels at 90 days.Treated mice had hind limb spasticity and a forced motor function defect that was quantified using a water exit test.Controls rapidly exit a shallow water tray, and wortmannin treated animals were up to 12-fold slower, a phenotype that persisted for at least 3 months.Thus the focal delivery of wortmannin to motor neurons generates a reproducible and scalable injury that can facilitate quantitative studies on neural regeneration and repair.The efficacy of sciatic nerve suicide transport can also explain neurotoxin-mediated selective loss of motor neurons in diseases such as amyotrophic lateral sclerosis.All procedures were performed at Rutgers under established Institutional Animal Care and Use protocols(eIACUC_TR201800022, approved on March 20, 2018).

关键词： amyotrophic lateral sclerosis injury motor function motor neuron PI3'kinase sciatic nerve suicide transport wortmannin

Backdoor intrusion: retrotoxicity can explain targeted motor neuron death in amyotrophic lateral sclerosis

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Neural Regeneration Research 2021年第7期16卷 1448-1448页

作者： randall d.mckinnon department of Neurosurgery and Member The Cancer Institute of New JerseyRutgers-Robert Wood Johnson Medical SchoolPiscatawayNJUSA

To the editor: Amyotrophic lateral sclerosis(ALS) is a fatal disease of unknown cause that selectively targets brain and spinal cord motor neurons(MNs).The lifetime risk is 1 in 2000, and most cases are sporadic although up to 10% of patients are predisposed by familial mutations in MN protection or repair genes(Bruijn et al., 2004).Risk factors include agrochemical exposure and trauma(Walters et al., 2019), although why they target MN is perplexing.Farmers are at a greater risk than non-farming rural residents(Kang et al, 2014), and ALS clusters occur in abrasion prone activities conducted on agrochemical treated fields such as baseball and soccer(Chio et al., 2005).

关键词： al. editor Walter

Prehospital transdermal glyceryl trinitrate for ultra- acute ischaemic stroke: data from the RIGHT- 2 randomised sham- controlled ambulance trial

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Stroke & Vascular Neurology 2024年第1期9卷 38-49,I0035-I0046页

作者： Jason Philip Appleton Lisa J Woodhouse Craig S Anderson Sandeep Ankolekar Lesley Cala Mark dixon Timothy J England Kailash Krishnan Grant Mair Keith W Muir John Potter Christopher I Price Marc randall Thompson G Robinson Christine Roffe Else C Sandset Jeffrey L Saver Angela Shone Aloysius Niroshan Siriwardena Joanna M Wardlaw Nikola Sprigg Philip M Bath Stroke University Hospitals Birmingham NHS Foundation TrustBirminghamUK Institute of Applied HealthResearch University of Birmingham College of Medical and Dental SciencesBirminghamUK Stroke Trials Unit Mental Health and Clinical NeurosciencesUniversity of NottinghamNottinghamUK Faculty of Medicine The George Institute for Global HealthSydneyNew South WalesAustralia The George Institute China at Peking University Health Science Center BeijingChina Neurology Royal Prince Alfred HospitalSydney Health PartnersSydneyNew South WalesAustralia department of Neurology King's College Hospital NHS Foundation TrustLondonUK Faculty of Health and Medical Sciences University of Western AustraliaCrawleyWestern AustraliaAustralia East Midlands Ambulance Service NHS Trust NottinghamUK Stroke Queen's Medical CentreNottingham University Hospitals NHS TrustNottinghamUK Centre for Clinical Brain Sciences Dementia Research InstituteUniveristy of EdinburghEdinburghUK Institute of Neurology and Psychology University of GlasgowGlasgowUK Bob Champion Research and Education Building University of East AngliaNorwichUK Institute of Neuroscience Newcastle UniversityNewcastle upon TyneUK department of Neurology Leeds Teaching Hospitals NHS TrustLeedsUK department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre University of LeicesterLeicesterUK Stroke Research in Stoke Institute for Science and Technology in MedicineKeele UniversityStoke-on TrentUK department of Neurology Oslo University HospitalOsloNorway Research and development Norwegian Air Ambulance FoundationOsloNorway department of Neurology and Comprehensive Stroke Center David Geffen School of MedicineUCLALos AngelesCaliforniaUSA Research and Graduate Services University of NottinghamNottinghamUK Community and Health Research Unit University of LincolnLincolnUK

Background The effect of transdermal glyceryl trinitrate(GTN,a nitrovasodilator)on clinical outcome when administered before hospital admission in suspected stroke patients is unclear.Here,we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2(RIGHT-2).Methods RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4hours of onset.The primary outcome was a shift in scores on the modified Rankin scale(mRS)at day 90.Secondary outcomes included death;a global analysis(Wei-Lachin test)containing Barthel Index,EuroQol-5d,mRS,telephone interview for cognitive status-modified and Zung depression scale;and neuroimaging-determined‘brain frailty’markers.data were reported as n(%),mean(Sd),median[IQR],adjusted common OR(acOR),mean difference or Mann-Whitney difference(MWd)with 95%CI.Results 597 of 1149(52%)patients had a final diagnosis of ischaemic stroke;age 75(12)years,premorbid mRS>2107(18%),Glasgow Coma Scale 14(2)and time from onset to randomisation 67[45,108]min.Neuroimaging‘brain frailty’was common:median score 2[2,3](range 0–3).At day 90,GTN did not influence the primary outcome(acOR for increased disability 1.15,95%CI 0.85 to 1.54),death or global analysis(MWd 0.00,95%CI-0.10 to 0.09).In subgroup analyses,there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1hour of symptom onset and in those with more severe stroke.Conclusions In patients who had an ischaemic stroke,ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.WHAT IS ALREAdY KNOWN ON THIS TOPIC⇒Transdermal glyceryl trinitrate(GTN)was associat-ed with less death and dependency in those with acute stroke treated within 6hours of stroke

关键词： Glasgow nitrate random

Visual rating and the use of image analysis for assessing canopy density in a pecan provenance collection during leaf fall

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林业研究:英文版 2023年第6期34卷 1843-1854页

作者： Cristina Pisani Clive H.Bock Jennifer randall United States department of Agriculture−Agricultural Research Service (USDA-ARS)Southeastern Fruit and Tree Nut Research Station(SEFTNRS)ByronGA 31008USA department of Entomology Plant Pathology and Weed ScienceNew Mexico State UniversityLas CrucesNM 88003USA

A collection representing the native range of pecan was planted at the US dA-ARS Southeastern Fruit and Tree Nut Research Station,Byron,GA.The collection(867 trees)is a valuable genetic resource for characterizing important horticultural traits.Canopy density during leaf fall is important as the seasonal canopy dynamics provides insights to environmental cues and breeding potential of germplasm.The ability of visual raters to estimate canopy density on a subset of the provenance collection(76 trees)as an indicator of leaf shed during autumn along with image analysis values was explored.Mean canopy density using the image analysis software was less compared to visual estimates(11.9%vs 18.4%,respectively).At higher canopy densities,the raters overestimated foliage density,but overall agreement between raters and measured values was good(ρc=0.849 to 0.915),and inter-rater reliability was high(R^(2)=0.910 to 0.953).The provenance from Missouri(MOL),the northernmost provenance,had the lowest canopy density in November,and results show that the higher the latitude of the provenance,the lower the canopy density.Based on regression,the source provenance latitude explained 0.609 of the variation using image analysis,and0.551 to 0.640 when based on the rater estimates of canopy density.Visual assessment of pecan canopy density due to late season leaf fall for comparing pecan genotypes provides accurate and reliable estimates and could be used in future studies of the whole provenance collection.

关键词： Carya illinoinensis Accuracy Reliability Canopy Foliage density Leaf area density Leaf area index

The Soft X-ray Imager(SXI)on the SMILE Mission

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Earth and Planetary Physics 2024年第1期8卷 5-14页

作者： S.Sembay A.L.Alme d.Agnolon T.Arnold A.Beardmore A.Belén Balado Margeli C.Bicknell C.Bouldin G.Branduardi-Raymont T.Crawford J.P.Breuer T.Buggey G.Butcher R.Canchal J.A.Carter A.Cheney Y.Collado-Vega H.Connor T.Crawford N.Eaton C.Feldman C.Forsyth T.Frantzen G.Galgóczi J.Garcia G.Y.Genov C.Gordillo H-P.Gröbelbauer M.Guedel Y.Guo M.Hailey d.Hall R.Hampson J.Hasiba O.Hetherington A.Holland S-Y.Hsieh M.W.J.Hubbard H.Jeszenszky M.Jones T.Kennedy K.Koch-Mehrin S.Kögl S.Krucker K.d.Kuntz C.Lakin G.Laky O.Lylund A.Martindale J.Miguel Mas Hesse R.Nakamura K.Oksavik N.Østgaard H.Ottacher R.Ottensamer C.Pagani S.Parsons P.Patel J.Pearson G.Peikert F.S.Porter T.Pouliantis B.H.Qureshi W.Raab G.Randal A.M.Read N.M.M.Roque M.E.Rostad C.Runciman S.Sachdev A.Samsonov M.Soman d.Sibeck S.Smit J.Søndergaard R.Speight S.Stavland M.Steller TianRan Sun J.Thornhill W.Thomas K.Ullaland B.Walsh d.Walton C.Wang S.Yang School of Physics and Astronomy University of LeicesterLeicesterLE17RHUK Space Park Leicester University of LeicesterLeicesterLE17RHUK Mullard Space Science Laboratory University College LondonDorkingRH56NTUK Centre for Electronic Imaging Open UniversityMilton KeynesMK76 AAUK Birkeland Centre for Space Science Department of Physics and TechnologyUniv.of BergenN-5007 BergenNorway University of Vienna A-1010 ViennaAustria Space Research Institute Austrian Academy of SciencesA-8042 GrazAustria National Institute of Aerospace Technology MadridSpain ESTEC European Space Agency2201 AZ NoordwijkNetherlands State Key Laboratory of Space Weather National Space Science CentreBeijing 100190China University of Applied Sciences and Arts Northwestern Switzerland CH-5210 WindischSwitzerland Koegl Space GmbH CH-8157 DielsdorfSwitzerland Space Acoustics GmbH CH-8157 DielsdorfSwitzerland Zurich University of Applied Sciences 8400 WinterhurSwitzerland Genov Solutions N-5172 LoddefjordNorway STM Engineering N-5165 LaksevagNorway John Hopkins University Applied Physics Laboratory MD 20723USA NASA/Goddard Space Flight Centre MD 20771USA Center for Space Physics Boston UniversityBostonMA 02215USA department of Theoretical Physics and Astrophysics Masaryk University60177 BrnoCzech Republic Institute of Physics E¨otvo¨s Lor´and University1053 BudapestHungary Aerospace Information Research Institute Chinese Academy of SciencesBeijing 100045China Centro de Astrobiologia(CAB) CSIC-INTAMadridSpain

The Soft X-ray Imager(SXI)is part of the scientific payload of the Solar wind Magnetosphere Ionosphere Link Explorer(SMILE)mission.SMILE is a joint science mission between the European Space Agency(ESA)and the Chinese Academy of Sciences(CAS)and is due for launch in 2025.SXI is a compact X-ray telescope with a wide field-of-view(FOV)capable of encompassing large portions of Earth’s magnetosphere from the vantage point of the SMILE orbit.SXI is sensitive to the soft X-rays produced by the Solar Wind Charge eXchange(SWCX)process produced when heavy ions of solar wind origin interact with neutral particles in Earth’s exosphere.SWCX provides a mechanism for boundary detection within the magnetosphere,such as the position of Earth’s magnetopause,because the solar wind heavy ions have a very low density in regions of closed magnetic field lines.The sensitivity of the SXI is such that it can potentially track movements of the magnetopause on timescales of a few minutes and the orbit of SMILE will enable such movements to be tracked for segments lasting many hours.SXI is led by the University of Leicester in the United Kingdom(UK)with collaborating organisations on hardware,software and science support within the UK,Europe,China and the United States.

关键词： Soft X-ray Imaging micropore optics large area CCd

High-throughput predictions of metal-organic framework electronic properties:theoretical challenges,graph neural networks,and data exploration

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npj Computational Materials 2022年第1期8卷 1053-1062页

作者： Andrew S.Rosen Victor Fung Patrick Huck Cody T.O’donnell Matthew K.Horton donald G.Truhlar Kristin A.Persson Justin M.Notestein randall Q.Snurr department of Materials Science and Engineering University of CaliforniaBerkeleyCA94720USA Miller Institute for Basic Research in Science University of CaliforniaBerkeleyBerkeleyCA94720USA Materials Science division Lawrence Berkeley National LaboratoryBerkeleyCA94720USA department of Chemical and Biological Engineering Northwestern UniversityEvanstonIL60208USA Center for Nanophase Materials Sciences Oak Ridge National LaboratoryOak RidgeTN37831USA Energy Technologies Area Lawrence Berkeley National LaboratoryBerkeleyCA94720USA department of Chemistry Chemical Theory Centerand Minnesota Supercomputing InstituteUniversity of MinnesotaMinneapolisMN55455USA Molecular Foundry Lawrence Berkeley National LaboratoryBerkeleyCA94720USA

With the goal of accelerating the design and discovery of metal–organic frameworks(MOFs)for electronic,optoelectronic,and energy storage applications,we present a dataset of predicted electronic structure properties for thousands of MOFs carried out using multiple density functional approximations.Compared to more accurate hybrid functionals,we find that the widely used PBE generalized gradient approximation(GGA)functional severely underpredicts MOF band gaps in a largely systematic manner for semi-conductors and insulators without magnetic character.However,an even larger and less predictable disparity in the band gap prediction is present for MOFs with open-shell 3d transition metal cations.With regards to partial atomic charges,we find that different density functional approximations predict similar charges overall,although hybrid functionals tend to shift electron density away from the metal centers and onto the ligand environments compared to the GGA point of reference.Much more significant differences in partial atomic charges are observed when comparing different charge partitioning schemes.We conclude by using the dataset of computed MOF properties to train machine-learning models that can rapidly predict MOF band gaps for all four density functional approximations considered in this work,paving the way for future high-throughput screening studies.To encourage exploration and reuse of the theoretical calculations presented in this work,the curated data is made publicly available via an interactive and user-friendly web application on the Materials Project.

关键词： charges electronic centers

Optimal designs for Genomic Selection in Hybrid Crops

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Molecular Plant 2019年第3期12卷 390-401页

作者： Tingting Guo Xiaoqing Yu Xianran Li Haozhe Zhang Chengsong Zhu Sherry Flint-Garcia Michael d.McMullen James B.Holland Stephen J.Szalma randall J.Wisser Jianming Yu department of Agronomy Iowa State UniversityAmesIA50011USA department of Statistics Iowa State UniversityAmesIA50011USA USdA-ARS and division of Plant Sciences University of MissouriColumbiaMO65211USA USdA-ARS and department of Crop and Soil Sciences North Carolina State UniversityRaleighNC27695USA department of Plant and Soil Sciences University of DelawareNewarkDE19716USA

Improved capacity of genomics and biotechnology has greatly enhanced genetic studies in different areas. Genomic selection exploits the geno type-to-phe no type relationship at the whole-ge nome level and is being implemented in many crops? Here we show that design-thinking and data-mining techniques can be leveraged to optimize genomic prediction of hybrid performance? We phenotyped a set of 276 maize hybrids generated by crossing founder inbreds of nested association mapping populations for flowering time, ear height, and grain yield? With 10 296 310 SNPs available from the parental inbreds, we explored the pat? terns of genomic relati on ships and phenotypic variation to establish training samples based on clustering, graphic n etwork analysis, and genetic mating scheme ? Our analysis showed that training set desig ns outperformed random sampling and earlier methods that either minimize the mean of prediction error variance or maximize the mean of generalized coefficient of determination. Additional analyses of 2556 wheat hybrids from an early-stage hybrid breeding system and 1439 rice hybrids from an established hybrid breeding system validated the approaches. Together, we dem on strated that effective genomic predicti on models can be established with a training set 2%-13% of the size of the whole set, enabling an efficient exploration of enormous inf ere nee space of gen etic combi nations.

关键词： data mining molecular breeding genomic relationship genomic selection optimal design

designing chimeric enzymes inspired by fungal cellulosomes

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Synthetic and Systems Biotechnology 2020年第1期5卷 23-32页

作者： Sean P.Gilmore Stephen P.Lillington Charles H.Haitjema randall de Groot Michelle A.O'Malley department of Chemical Engineering University of CaliforniaSanta BarbaraSanta BarbaraCA93106United States MC 5080 University of CaliforniaSanta BarbaraCA93106-5080United States

Cellulosomes are synthesized by anaerobic bacteria and fungi to degrade lignocellulose via synergistic action of multiple enzymes fused to a protein scaffold.Through templating key protein domains(cohesin and dockerin),designer cellulosomes have been engineered from bacterial motifs to alter the activity,stability,and degradation efficiency of enzyme complexes.Recently a parts list for fungal cellulosomes from the anaerobic fungi(Neocallimastigomycota)was determined,which revealed sequence divergent fungal cohesin,dockerin,and scaffoldin domains that could be used to expand the available toolbox to synthesize designer cellulosomes.In this work,multi-domain carbohydrate active enzymes(CAZymes)from 3 cellulosome-producing fungi were analyzed to inform the design of chimeric proteins for synthetic cellulosomes inspired by anaerobic fungi.In particular,Piromyces finnis was used as a structural template for chimeric carbohydrate active enzymes.Recombinant enzymes with retained properties were engineered by combining thermophilic glycosyl hydrolase domains from Thermotoga maritima with dockerin domains from Piromyces finnis.By preserving the protein domain order from P.finnis,chimeric enzymes retained catalytic activity at temperatures over 80°C and were able to associate with cellulosomes purified from anaerobic fungi.Fungal cellulosomes harbor a wide diversity of glycoside hydrolases,each representing templates for the design of chimeric enzymes.By conserving dockerin domain position within the primary structure of each protein,the activity of both the catalytic domain and dockerin domain was retained in enzyme chimeras.Taken further,the domain positioning inferred from native fungal cellulosome proteins can be used to engineer multi-domain proteins with non-native favorable properties,such as thermostability.

关键词： Cellulosome dockerin Scaffoldin Anaerobic fungi Thermophile Enzyme