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Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice

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Neural Regeneration Research 2020年第1期15卷 136-144页

作者： Andrew RClark Chia George Hsu m A Hassan Talukder mark noble John CElfar Center for Orthopaedic Research and Translational Science Penn State Hershey College of MedicineMilton S.Hershey Medical CenterHersheyPAUSA Department of Orthopaedics The University of Rochester Medical CenterRochesterNYUSA Department of medicine Aab Cardiovascular Research InstituteUniversity of Rochester School of Medicine and DentistryRochesterNYUSA Department of Biomedical Genetics The University of Rochester Medical CenterRochesterNYUSA

Oral 4-aminopyridine(4-AP)is clinically used for symptomatic relief in multiple sclerosis and we recently demonstrated that systemic 4-AP had previously unknown clinically-relevant effects after traumatic peripheral nerve injury including the promotion of re-myelination,improvement of nerve conductivity,and acceleration of functional *** hypothesized that,instead of oral or injection administration,transdermal 4-AP(TD-4-AP)could also improve functional recovery after traumatic peripheral nerve *** with surgical traumatic peripheral nerve injury received TD-4AP or vehicle alone and were examined for skin permeability,pharmacokinetics,functional,electrophysiological,and nerve morphological properties.4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to TD-4-AP *** a single dose of TD-4-AP administration demonstrated rapid transient improvement in motor function,chronic TD-4-AP treatment significantly improved motor function and nerve conduction and these effects were associated with fewer degenerating axons and thicker myelin sheaths than those from vehicle *** findings provide direct evidence for the potential transdermal applicability of 4-AP and demonstrate that 4-AP delivered through the skin can enhance in-vivo functional recovery and nerve conduction while decreasing axonal *** animal experiments were approved by the University Committee on Animal Research(UCAR)at the University of Rochester(UCAR-2009-019)on march 31,2017.

关键词： 4-aminopyridine electron microscopy functional recovery nerve conduction velocity peripheral nerve injury pharmacokinetics transdermal administration

Development of magnesium-Dominant Soils Under Irrigated Agriculture in Southern Kazakhstan

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Pedosphere 2009年第3期19卷 331-343页

作者： A. KARImOV m. QADIR A. noble F. VYSHPOLSKY K. ANZELm International Water management Institute (IWmI) Central Asia Regional Office Tashkent 700000 (Uzbekistan) International Center for Agricultural Research in the Dry Areas (ICARDA) Aleppo 5466 (Syria) International Water management Institute (IWmI) Colombo 2075 (Sri Lanka) International Water management Institute (IWmI) c/o WorldFish Center Penang 11960 (Malaysia) Water Conservation Laboratory The Kazakh Research Institute of Water Management Ministry of Agriculture Taraz480022 (Kazakhstan) Southern Kazakhstan Hydrogeology and Land Reclamation Expedition Shymkent (Kazakhstan)

Irrational irrigation practices in the Arys Turkestan Canal command area in the southern part of Kazakhstan have led to the formation of soils with poor physical and chemical properties. To study whether irrigation and leaching practices and/or groundwater rise have contributed to the accumulation of mg2+ on the cation exchange complex of these soils, historical changes in soil and groundwater quality were used as source data and the Visual mINTEQ model was applied to analyze the chemical composition of water and soils in the study area. The imposed irrigation regime and the leaching of light sierosem soils led to the dissolution and subsequent leaching of inherent gypsum and organic matter from the soil profile. Further, the domination of bicarbonate in the irrigation water promoted weathering of the carbonate minerals present as calcite. The higher concentrations of mg2+ in comparison to Ca2+ in the irrigation water resulted in the replacement of Na+ by mg2+ on the cation exchange complex. In the lower part of the command area, shallow groundwater has contributed to the accumulation of Na+ and to a large extent of mg2+ on the cation exchange sites.

关键词： exchangeable magnesium high-magnesium soil and water Kazakhstan land degradation

Human equivalent dose of oral 4-aminopyridine differentiates nerve crush injury from transection injury and improves post-injury function in mice

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Neural Regeneration Research 2020年第11期15卷 2098-2107页

作者： Chia George Hsu m A Hassan Talukder Li Yue Loel CTurpin mark noble John C.Elfar Center for Orthopaedic Research and Translational Science Penn State Hershey College of MedicineMilton S.Hershey Medical CenterHersheyPAUSA Department of medicine Aab Cardiovascular Research InstituteUniversity of Rochester School of Medicine and DentistryRochesterNYUSA Department of Orthopedics The Warren Alpert Medical School of Brown University/Rhode Island HospitalProvidenceRIUSA Department of Neuroscience The University of Rochester Medical CenterRochesterNYUSA Department of Biomedical Genetics The University of Rochester Medical CenterRochesterNYUSA

4-Aminopyridine(4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated that local, transdermal or injectable forms of 4-AP improve myelination, nerve conduction velocity, muscle atrophy, and motor function after traumatic peripheral nerve injury in mice. While oral 4-AP is most commonly used in the clinic, it is unknown whether human equivalent oral doses of 4-AP have effects on traumatic peripheral nerve injury differentiation, myelination, muscle atrophy, functional recovery, and post-injury inflammatory processes in animals. mice with sciatic nerve crush or denervation injury received oral or intraperitoneal 4-AP(10 μg) or vehicle alone and were examined for pharmacokinetics, motor function, muscle mass, intrinsic muscle force, nerve morphological and gene expression profiles. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to 4-AP dose. Acute single dose of oral 4-AP administration induced a rapid transient improvement in motor function that was different in traumatic peripheral nerve injury with or without nerve continuity, chronic daily oral 4-AP treatment significantly enhanced post crush injury motor function recovery and this effect was associated with improved myelination, muscle mass, and ex vivo muscle force. Polymerase chain reaction array analysis with crushed nerve revealed significant alterations in gene involved in axonal inflammation and regeneration. These findings provide convincing evidence that regardless of the route of administration, 4-AP can acutely differentiate traumatic peripheral nerve injury with or without nerve continuity and can enhance in vivo functional recovery with better preservation of myelin sheaths, muscle mass, and muscle force. The animal experiments were approved by the University Committee on Animal Research(UCAR) at the University

关键词： 4-aminopyridine electron microscopy of nerves functional recovery gene expression muscle force muscle mass oral administration pharmacokinetics sciatic nerve crush injury sciatic nerve denervation injury

Probing the architecture of the mycobacterium marinum arylamine N-acetyltransferase active site

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Protein & Cell 2010年第4期1卷 384-392页

作者： Areej m.Abuhammad Edward D.Lowe Elizabeth Fullam martin noble Elspeth F.Garman Edith Sim Department of Pharmacology University of OxfordMansfield RoadOxford OX13QTUK Department of Biochemistry University of OxfordSouth Parks RoadOxford OX13QUUK

Treatment of latent tuberculosis infection remains an important goal of global TB *** this end,targets that are essential for intracellular survival of mycobacterium tuberculosis are particularly *** N-acetyltransferase(NAT)represents such a target as it is,along with the enzymes encoded by the associated gene cluster,essential for mycobacterial survival inside macrophages and involved in cholesterol *** is likely to be the fuel for *** inside *** the nat gene and inhibiting the NAT enzyme prevents survival of the microorganism in macrophages and induces cell wall alterations,rendering the mycobacterium sensitive to antibiotics to which it is normally *** date,NAT from ***(mmNAT)is considered the best available model for NAT from ***(TBNAT).The enzyme catalyses the acetylation and propionylation of arylamines and *** is a good acetyl and propionyl acceptor for both mmNAT and *** mmNAT structure has been solved to 2.1Åresolution following crystallisation in the presence of hydralazine and is compared to available NAT *** the mode of ligand binding,features of the binding pocket can be identified,which point to a novel mechanism for the acetylation reaction that results in a 3-methyltriazolo[3,4-a]phthalazine ring compound as product.

关键词： mycobacterium tuberculosis mycobacterium marinum tuberculosis arylamine N-acetyltransferase 3D crystal structure binding pocket

Hydrochemical evolution of groundwater in northwestern part of the Indo-Gangetic Basin,India:A geochemical and isotopic approach

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Geoscience Frontiers 2023年第6期14卷 450-463页

作者： Shive Prakash Rai Kossitse Venyo Akpataku Jacob noble Abhinav Patel Suneel Kumar Joshi Department of Geology Institute of ScienceBanaras Hindu UniversityVaranasi 221005India Laboratory of Organic Chemistry and Environmental Sciences Department of ChemistryUniversity of KaraPO Box 404KaraTogo Laboratory of Applied Hydrology and Environment University of LoméP.O.Box 1515LomeTogo Isotope and Radiation Application Division Bhabha Atomic Research CentreMumbai 400085India Hydrological Investigations Division National Institute of HydrologyRoorkee 247667India

The present study aims to understand the hydrochemical evolution of groundwater in the Ghaggar River Basin,representing a zone of excessive abstraction of groundwater in the northwestern Indo-Gangetic *** study comprises a regional scale and high-resolution sampling of groundwater during preand post-monsoon seasons of 2013 and their analyses for major ions,δ^(18)O,δ^(2)H,and 3 *** in hydrochemical and isotopic data is found both in spatial and vertical *** significant vertical variation of TDS,NO_(3)and K^(+)allowed the classification of the aquifer system into two major groups:shallow(depthm bgl)and deep(depth>80 m bgl).The depthwise variations ofδ^(18)O andδ^(2)H support this categorization of the *** Ca-HCO_(3)and Ca-mg-Na-HCO_(3)water facies with higher values of 3 H in the proximal part of the basin characterize recharge areas under humid *** dominance of mg-Na-HCO_(3)and Na-HCO_(3)facies in shallow and deep aquifers in central part of the basin,illustrate the intermediate to advanced stages of hydrochemical evolution in the *** of brackish Ca-mg-Cl-SO_(4)and Na-Cl-SO_(4)water types in the discharge areas is due to the prevailing geological conditions and anthropogenic *** modelling supports the reverse cation exchange and mixing during lateral and vertical flows,weathering of silicate minerals,dissolution of crustal salts,and evaporative enrichment are the natural processes governing the evolution of groundwater chemistry along the *** developed process-based conceptual model will aid in the formulation of a suitable plan for groundwater resource management in the region.

关键词： Hydrogeochemical evolution Groundwater salinity Cation exchange Fluoride Anthropogenic impact Ghaggar River Basin

Large-scale fabrication of highly ordered sub-20 nm noble metal nanoparticles on silica substrates without metallic adhesion layers

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microsystems & Nanoengineering 2018年第1期4卷 380-389页

作者： Hai Le-The Erwin Berenschot Roald m.Tiggelaar Niels R.Tas albert van den Berg Jan C.T.Eijkel BIOS Lab-on-a-Chip Group MESA+Institute for NanotechnologyMIRA Institute for Biomedical Technology and Technical MedicineMax Planck Center for Complex Fluid DynamicsUniversity of TwenteEnschede 7522 NBThe Netherlands mesoscale Chemical Systems Group MESA+Institute for NanotechnologyUniversity of TwenteEnschede 7522 NBThe Netherlands NanoLab Cleanroom MESA+Institute for NanotechnologyUniversity of TwenteEnschede 7522 NBThe Netherlands

Periodic noble metal nanoparticles offer a wide spectrum of applications including chemical and biological sensors,optical devices,and model catalysts due to their extraordinary *** sensing purposes and catalytic studies,substrates made of glass or fused-silica are normally required as supports,without the use of metallic adhesion ***,precise patterning of such uniform arrays of silica-supported noble metal nanoparticles,especially at sub-100 nm in diameter,is challenging without adhesion *** this paper,we report a robust method to large-scale fabricate highly ordered sub-20 nm noble metal nanoparticles,i.e.,gold and platinum,supported on silica substrates without adhesion layers,combining displacement Talbot lithography(DTL)with dry-etching *** photoresist nanocolumns at diameters of~110 nm are patterned on metal-coated oxidized silicon wafers using DTL,and subsequently transferred at a 1:1 ratio into anti-reflection layer coating(BARC)nanocolumns with the formation of nano-sharp tips,using nitrogen plasma *** BARC nanocolumns are then used as a mask for etching the deposited metal layer using inclined argon ion-beam *** find that increasing the etching time results in coneshaped silica features with metal nanoparticles on the tips at diameters ranging from 100 nm to sub-30 nm,over large areas of 3×3 cm^(2).moreover,subsequent annealing these sub-30 nm metal nanoparticle arrays at high-temperature results in sub-20 nm metal nanoparticle arrays with~10^(10) uniform particles.

关键词： metallic ordered columns

Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus

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World Journal of Gastroenterology 2013年第48期19卷 9282-9293页

作者： Fergus noble Luke Nolan Adrian C Bateman James P Byrne Jamie J Kelly Ian S Bailey Donna m Sharland Charlotte N Rees Timothy J Iveson Tim J Underwood Andrew R Bateman Cancer Sciences Unit Faculty of Medicine University of Southampton Southampton SO16 6YD United Kingdom Department of Surgery University Hospital Southampton NHS Foundation Trust Southampton SO16 6YD United Kingdom Department of Cellular Pathology University Hospital Southampton NHS Foundation Trust Southampton SO16 6YD United Kingdom Cancer Care University Hospital Southampton NHS Foundation Trust Southampton SO16 6YD United Kingdom

AIm:To assess tumour regression grade(TRG)and lymph node downstaging to help define patients who benefit from neoadjuvant ***:Two hundred and eighteen consecutive patients with adenocarcinoma of the esophagus or gastro-esophageal junction treated with surgery alone or neoadjuvant chemotherapy and surgery between 2005and 2011 at a single institution were *** neoadjuvant chemotherapy consisting of platinum,fluoropyrimidine and anthracycline was considered for operable patients(World Health Organization performance status≤2)with clinical stage T2-4 *** to neoadjuvant chemotherapy(NAC)was assessed using TRG,as described by mandard et *** addition lymph node downstaging was also *** node downstaging was defined by cN1 at diagnosis:assessed radiologically(computed tomography,positron emission tomography,endoscopic ultrasonography),then pathologically recorded as N0 after surgery;ypN0 if NAC given prior to surgery,or pN0if surgery *** were followed up for 5 years post *** was defined radiologically,with or without pathological *** association was examined between t TRG and lymph node downstaging with disease free survival(DFS)and a comprehensive range of clinicopathological ***:Two hundred and eighteen patients underwent esophageal resection during the study interval with a mean follow up of 3 years(median follow up:2.552,95%CI:2.022-3.081).There was a 1.8%(n=4)inpatient mortality *** hundred and thirty-six(62.4%)patients received NAC,with 74.3%(n=101)of patients demonstrating some signs of pathological tumour regression(TRG 1-4)and 5.9%(n=8)having a complete pathological *** four point one percent(n=60)had downstaging of their nodal disease(cN1 to ypN0),compared to only 15.9%(n=13)that underwent surgery alone(pre-operatively overstaged:cN1 to pN0),(Pmean DFS;TRG 1-2:5.1years,

关键词： Esophageal cancer Gastro-esophageal cancer Neoadjuvant Regression

Innovations in Value-Addition of Agricultural By-Products in Uganda

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Journal of Environmental Protection 2019年第11期10卷 1493-1506页

作者： Denis Nsubuga noble Banadda Nicholas Kiggundu Department of Agricultural and Biosystems Engineering Makerere University Kampala Uganda Department of Agricultural and Biosystems Engineering 1340 Elings Hall Ames Iowa USA

The purpose of this review was to profile the existing innovations in the value addition of agricultural by-products and suggest innovations that could yield more value-added products from the available agricultural by-products in Uganda. These by-products were from crops, livestock, fish and forestry sub-sectors. The review indicated 7.8 million tons from the crops’ subsector, 6.69 million skins and hides, 2280 million tons of cow dung and 390,550 tons of chicken dung from the livestock subsector, 36,000 tons from the fish subsector and 440,000 m3 of sawdust and offcuts from the forestry sub-sector. Current innovations in value-addition of agricultural by-products included the making of briquettes, organic fertilizers, biogas, biochar, pellets and organic pesticides from the crop subsector. Cow dung from the livestock is used for plastering walls of houses, used as fertilizer and used for the production of biogas. Chicken droppings are as well used as fertilizer and for production of biogas. Fish frames and skins are mainly consumed in smoked form whereas trimmings are usually rolled into fish balls and then fried for people to eat while the fats are used for frying the fish balls. Sawdust has been mixed with cement to make wood-cement composite bricks that reduce the overall weight of the building. It is also being used as feed in the Indigenous micro-Organisms (ImO) technology in the production of pigs. Proposed innovations include the use of bones to produce soft tissue, buttons, knife handles and bone meal. Blood can be used in making adhesives and fertilizers while fish oil is a major dietary source of long chain omega-3 polyunsaturated fatty acids and so can be utilized to enrich different food products.

关键词： Value Addition Agricultural Waste By-Products Innovations in Agriculture Agricultural Value Chains

Refining aquifer heterogeneity and understanding groundwater recharge sources in an intensively exploited agrarian dominated region of the Ganga Plain

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Geoscience Frontiers 2024年第4期15卷 134-147页

作者： Abhinav Patel Shive Prakash Rai Nijesh Puthiyottil Abhinesh Kumar Singh Jacob noble Rajesh Singh Dharmappa Hagare U.D.Saravana Kumar Nachiketa Rai Kossitse Venyo Akpataku Department of Geology Institute of ScienceBanaras Hindu UniversityVaranasiUttar Pradesh 221005India Isotope and Radiation Application Division Bhabha Atomic Research CentreTrombayMumbai 400085India Environmental Hydrology Division National Institute of HydrologyRoorkeeUttarakhand 247667India School of Engineering Design and Built EnvironmentWestern Sydney UniversityAustralia Isotope Hydrology Section Division of Physical and Chemical SciencesInternational Atomic Energy Agency(IAEA)ViennaAustria Department of Earth Sciences Indian Institute of TechnologyRoorkeeUttarakhand 247667India Laboratory of Organic Chemistry and Environmental Science Department of ChemistryUniversity of KaraPO Box 404KaraTogo

Densely populated region of Ganga Plain is facing aquifer vulnerability through waterborne pollutants and groundwater stress due to indiscriminate abstraction,causing environmental and socio-economic *** address long-term groundwater resilience,it is crucial to understand aquifer heterogeneity and connectivity,groundwater recharge sources,effects of groundwater abstraction *** this con-text,present study aims to understand factors responsible for vertical and spatial variability of groundwater chemistry and to identify groundwater recharge sources in an intensively exploited agrarian region of the Ganga *** of chemometric,statistical,and isotopic analysis categorises the alluvial aquifer into zone 1(G1;ground surface to 100 m)and zone 2(G2;>100 m-210 m).The group G1 samples are characterized by a wide variation in hydrochemical species,noted with pockets of F-and NO3-rich groundwater,and fresh to more evolved water types,while group G2 groundwater is characterized by a sharp increase in freshwater types and limited variation in their isotopic and hydrochemical *** G1 groundwater chemistry is governed by soil mineralogy,local anthropogenic inputs(SO42-,Cl-,and NO3-),and manifested by multiple recharge sources(local precipitation,river,canal water,pond).The G2 group is dominated by geogenic processes and mainly recharged by the local *** signatures confirm more evolved water type for group G1 in northwestern region,while fresh-water type covers the rest of the study *** rich groundwater is attributed to sodic water under alkaline conditions and enrichedδ18O values emphasizing role of evaporation in F-mobilization from micas and amphiboles abundant in the *** findings provide insight into potential groundwater vulnerability towards inorganic contaminants,and ground water recharge *** outcome of this study will help to develop aquifer resilience towards indiscriminate groundwater extrac

关键词： Stable isotopes Hydrogeochemical attributes Groundwater recharge sources Ganga Plain