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metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism

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Genes & Diseases 2022年第4期9卷 1129-1142页

作者： Brendan P.Norman Andrew S.Davison juliette H.Hughes Hazel Sutherland peter j.m.wilson Neil G.Berry Andrew T.Hughes Anna m.milan jonathan C.jarvis Norman B.Roberts Lakshminarayan R.Ranganath George Bou-Gharios james A.Gallagher Institute of Life Course and medical Sciences University of LiverpoolWilliam Henry Duncan Building6 West Derby StreetLiverpoolL78TXUK Department of Clinical Biochemistry&metabolic medicine Liverpool Clinical LaboratoriesRoyal Liverpool University HospitalPrescot StreetLiverpoolL78XPUK School of Sport&Exercise Sciences Liverpool John Moores UniversityTom Reilly BuildingByrom StreetLiverpoolL33AFUK Department of Chemistry University of LiverpoolCrown StreetLiverpoolL697ZDUK

Alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of active enzyme homogentisate 1,2-dioxygenase (HGD). The primary consequence of HGD deficiency is increased circulating homogentisic acid (HGA), the main agent in the pathology of AKU disease. Here we report the first metabolomic analysis of AKU homozygous Hgd knockout (Hgd−/−) mice to model the wider metabolic effects of Hgd deletion and the implication for AKU in humans. Untargeted metabolic profiling was performed on urine from Hgd−/− AKU (n = 15) and Hgd+/− non-AKU control (n = 14) mice by liquid chromatography high-resolution time-of-flight mass spectrometry (Experiment 1). The metabolites showing alteration in Hgd−/− were further investigated in AKU mice (n = 18) and patients from the UK National AKU Centre (n = 25) at baseline and after treatment with the HGA-lowering agent nitisinone (Experiment 2). A metabolic flux experiment was carried out after administration of 13C-labelled HGA to Hgd−/−(n = 4) and Hgd+/−(n = 4) mice (Experiment 3) to confirm direct association with HGA. Hgd−/− mice showed the expected increase in HGA, together with unexpected alterations in tyrosine, purine and TCA-cycle pathways. metabolites with the greatest abundance increases in Hgd−/− were HGA and previously unreported sulfate and glucuronide HGA conjugates, these were decreased in mice and patients on nitisinone and shown to be products from HGA by the 13C-labelled HGA tracer. Our findings reveal that increased HGA in AKU undergoes further metabolism by mainly phase II biotransformations. The data advance our understanding of overall tyrosine metabolism, demonstrating how specific metabolic conditions can elucidate hitherto undiscovered pathways in biochemistry and metabolism.

关键词： Alkaptonuria Biotransformation metabolism metabolomics mice

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Towards implementation of alloy-specific thermo-fluid modelling for laser powder-bed fusion of mg alloys

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journal of magnesium and Alloys 2024年第6期12卷 2327-2344页

作者： mohammad Hoseini-Athar mikael Ersson peter Hedström Department of material Science and Engineering KTH Royal Institute of TechnologyStockholmSE-10044 Sweden

multi-physics thermo-fluid modeling has been extensively used as an approach to understand melt pool dynamics and defect formation as well as optimizing the process-related parameters of laser powder-bed fusion(L-PBF).However,its capabilities for being implemented as a reliable tool for material design,where minor changes in material-related parameters must be accurately captured,is still in *** the present research,first,a thermo-fluid computational fluid dynamics(CFD)model is developed and validated against experimental *** the predicted material properties of the pure mg and commercial ZK60 and WE43 mg alloys,parametric studies are done attempting to elucidate how the difference in some of the material properties,i.e.,saturated vapor pressure,viscosity,and solidification range,can influence the melt pool *** is found that a higher saturated vapor pressure,associated with the ZK60 alloy,leads to a deeper unstable keyhole,increasing the keyhole-induced porosity and evaporation mass *** viscosity and wider solidification range can increase the non-uniformity of temperature and velocity distribution on the keyhole walls,resulting in increased keyhole instability and formation of ***,the WE43 alloy showed the best behavior in terms of defect formation and evaporation mass loss,providing theoretical support to the extensive use of this alloy in *** summary,this study suggests an approach to investigate the effect of materials-related parameters on L-PBF melting and solidification,which can be extremely helpful for future design of new alloys suitable for L-PBF.

关键词： mg alloys Laser powder-bed fusion(L-PBF) melt pool dynamics Computational fluid dynamics Fluid flow

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Adaptation in brain structure and respiratory and olfactory structures across environmental gradients in African and North American muroid rodents

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Integrative Zoology 2024年第1期19卷 165-181页

作者： peter j.TAYLOR Aluwani NENGOVHELA Christiane DENYS Graham R.SCOTT Catherine m.IVY Department of Zoology School of Natural and Mathematical SciencesUniversity of VendaThohoyandouSouth Africa Afromontane Unit Department of Zoology and EntomologyUniversity of the Free StatePhuthaditjhabaSouth Africa Department of mammalogy National MuseumBloemfonteinSouth Africa Institut de Systématique EvolutionBiodiversité(ISYEB)Muséum National d’Histoire NaturelleCNRSSorbonne UniversitéEPHEUniversitéDes AntillesParisFrance Department of Biology McMaster UniversityHamiltonOntarioCanada Guglielmo and Shoemaker Labs Advanced Facility for Avian ResearchUniversity of Western OntarioLondonOntarioCanada

morphometric studies of 3D micro CT-scanned images can provide insights into the evolution of the brain and sensory structures but such data are still scarce for the most diverse mammalian order of *** reviewed and new data,we tested for convergence to extreme aridity and high elevation in the sensory and brain morphology of rodents,from morphometric data from micro-CT X-ray scans of 174 crania of 16 species of three distantly re-lated African murid(soft-furred mice,Praomyini,laminate-toothed rats,Otomyini,and gerbils,Gerbillinae)clades and one North American cricetid(deer mice and white-footed mice,Peromyscus)*** studies demon-strated convergent evolution acting on the oval window area of the cochlea(enlarged in extremely arid-adapted species of Otomyini and Gerbillinae)and on endocranial volume(reduced in high elevation taxa of Otomyini and Peromyscus).However,contrary to our predictions,we did notfind evidence of convergence in brain struc-ture to aridity,or in the olfactory/respiratory system(turbinate bones)to high *** structure differed,particularly in the petrosal lobules of the cerebellum and the olfactory bulbs,between Otomyini and Gerbillinae,with extreme arid-adapted species in each clade being highly divergent(not convergent)from other species in the same *** observed greater“packing”of the maxillary turbinate bones,which have important respiratory functions,in Peromyscus mice from high and low elevations compared to the high-elevation African Praomyini,but more complex patterns within Peromyscus,probably related to trade-offs in respiratory physiology and heat exchange in the nasal epithelium associated with high-elevation adaptation.

关键词： 3D morphometrics Africa brain size North America Rodentia sensory evolution

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Stable diffusion gradients in microfluidic conduits bounded by fluid walls

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microsystems & Nanoengineering 2024年第3期10卷 357-367页

作者： Federico Nebuloni Cyril Deroy peter R.Cook Edmond j.Walsh Department of Engineering Science Osney Thermo-Fluids InstituteUniversity of OxfordOxford OX20ESUK Sir William Dunn School of Pathology University of OxfordOxford OX13REUK

Assays mimicking in vitro the concentration gradients triggering biological responses like those involved in fighting infections and blood clotting are essential for biomedical *** assays prove especially attractive as they allow precise control of gradient shape allied to a reduction in *** microfluidic devices are fabricated using solid plastics that prevent direct access to responding ***-walled microfluidics allows the manufacture of circuits on standard Petri dishes in seconds,coupled to simple operating methods;cell-culture medium sitting in a standard dish is confined to circuits by fluid walls made of an immiscible *** develop and experimentally validate an analytical model of diffusion between two or more aqueous streams flowing at different rates into a fluid-walled conduit with the cross-section of a circular *** solid walls,fluid walls morph during flows as pressures fall,with wall shape changing down the *** model is validated experimentally for Fourier numbersminar *** enables a priori prediction of concentration gradients throughout a conduit,so allowing rapid circuit design as well as providing bioscientists with an accurate way of predicting local concentrations of bioactive molecules around responsive and nonresponsive cells.

关键词： walls diffusion attractive

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Effect of age on the standardized ileal amino acid digestibility of soybean meal and canola meal in broilers

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Animal Nutrition 2024年第1期16卷 11-22页

作者： mukti Barua m.Reza Abdollahi Faegheh Zaefarian Timothy j.Wester Channarayapatna K.Girish peter V.Chrystal Velmurugu Ravindran monogastric Research Center School of Agriculture and EnvironmentMassey UniversityPalmerston North 4442New Zealand Department of Animal Science and Nutrition Faculty of Veterinary MedicineChattogram Veterinary and Animal Sciences UniversityKhulshiChattogram 4225Bangladesh Nutrition and Care Animal NutritionEvonik(SEA)Pte.Ltd609927 Singapore Complete Feed Solutions Howick 2145AucklandNew Zealand

Standardized ileal digestibility coefficients(SIDC)of nitrogen(N)and amino acids(AA)in two protein sources(soybean meal[SBm]and canola meal[Cm])were investigated at six broiler ages(d 7,14,21,28,35,and 42).Two assay diets were formulated to contain either SBm(413 g/kg)or Cm(553 g/kg)as the sole dietary AA *** dioxide(5 g/kg)was added as an indigestible marker.A total of 696 male broilers at 1 d old were allotted to 12 replicate cages per age *** assay diet was offered to birds for 4 d prior to the ileal digesta collection on d 7(14 birds/cage),14(12 birds/cage),21(10 birds/cage),28(8 birds/cage),35(8 birds/cage)and 42(6 birds/cage),*** apparent digestibility coefficients were standardized using age-specific basal endogenous AA *** the SBm group,though the SIDC of N tended to be influenced(quadratic;P=0.075)by age,no linear or quadratic response of age effect was observed on the average SIDC of indispensable(IAA)and total AA(TAA).An age effect(quadratic;Pm with the highest value recorded at d 7,followed by a decrease from d 14 to 28,which increased beyond d *** SIDC of some individual AA(Arg,Thr,Trp,Cys,Pro)were affected(Pmanner by *** the Cm,the SIDC of N,average SIDC of IAA,DAA and TAA were influenced(quadratic;Pm d 7 to 14,declined at d 21,and then increased beyond d *** average SIDC of IAA was low between d 7 and 28 and increased *** SIDC of individual AA were affected(linear or quadratic;Pmagnitudes by *** age influence on the SIDC AA was variable,depending on the protein source and *** results demonstrate that age-specific SIDC AA data might need consideration in broiler feed formulations.

关键词： Age Amino acid Broiler Digestibility Protein source

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Identific tion of quantitative trait loci and associated candidate genes for pregnancy success in Angus–Brahman crossbred heifers

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journal of Animal Science and Biotechnology 2024年第1期15卷 162-170页

作者： Quinn A.Hoorn Gabriel A.Zayas Eduardo E.Rodriguez Laura m.jensen Raluca G.mateescu peter j.Hansen Department of Animal Sciences Donald Henry Barron Reproductive and Perinatal Biology Research Programand the Genetics InstituteUniversity of FloridaGainesvilleFLUSA School of Applied Systems Biology La Trobe UniversityBundooraVIC 3083Australia

Background In beef cattle, more than 50% of the energy input to produce a unit of beef is consumed by the female that produced the calf. Development of genomic tools to identify females with high genetic merit for reproductive function could increase the profitability and sustainability of beef *** Genome-wide association studies(GWAS) were performed using a single-step genomic best linear unbiased prediction approach on pregnancy outcome traits from a population of Angus–Brahman crossbred heifers. Furthermore, a validation GWAS was performed using data from another farm. Heifers were genotyped with the Bovine GGP F250 array that contains 221,077 SNPs. In the discovery population, heifers were bred in winter breeding seasons involving a single round of timed artificial insemination(AI) followed by natural mating for 3 months. Two phenotypes were analyzed: pregnancy outcome to first-service AI(PAI;n = 1,481) and pregnancy status at the end of the breeding season(PEBS;n = 1,725). The heritability was estimated as 0.149 and 0.122 for PAI and PEBS, respectively. In the PAI model, one quantitative trait locus(QTL), located between 52.3 and 52.5 mb on BTA7, explained about 3% of the genetic variation, in a region containing a cluster of γ-protocadherin genes and SLC25A2. Other QTLs explaining between 0.5% and 1% of the genetic variation were found on BTA12 and 25. In the PEBS model, a large QTL on BTA7 was synonymous with the QTL for PAI, with minor QTLs located on BTA5, 9, 10, 11, 19, and 20. The validation population for pregnancy status at the end of the breeding season were Angus–Brahman crossbred heifers bred by natural mating. In concordance with the discovery population, the large QTL on BTA7 and QTLs on BTA10 and 12 were *** In summary, QTLs and candidate SNPs identified were associated with pregnancy outcomes in beef heifers, including a large QTL associated with a group of protocadherin genes. Confirmation of these associations

关键词： Beef cattle Fertility GWAS QTL

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Spatial and temporal patterns of sarcoptic mange in wombats using the citizen science tool,WomSAT

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Integrative Zoology 2024年第3期19卷 387-399页

作者： Sujatha mAYADUNNAGE Hayley jade STANNARD peter WEST julie m.OLD School of Science Western Sydney UniversityHawkesburyNSWAustralia School of Agricultural Environmental and Veterinary SciencesCharles Sturt UniversityWagga WaggaNSWAustralia Department of Primary Industries Orange Agricultural InstituteOrangeNSWAustralia

There is currently limited information regarding the levels of infection and distribution of sarcoptic mange in the wombat population throughout *** analyzed cases of sarcoptic mange in bare-nosed wombats reported into WomSAT,a website and mobile phone application where citizen scientists can upload sightings of wombats,burrows,and sarcoptic mange *** used maxent software to predict locations and the environmental factors associated with sarcoptic mange occurrence in bare-nosed wombats.A total of 1379 sarcoptic mange-infected and 3043 non-sarcoptic mange-infected wombats were reported by 674 and 841 citizen scientists,*** all the wombats reported to WomSAT from 2015 to 2019,31.2%were infected with sarcoptic *** mange in bare-nosed wombats was reported in 502 suburbs across four *** South Wales had the highest number of sarcoptic mange cases reported to *** was no statistically significant seasonal variation of sarcoptic mange levels in bare-nosed *** model showed that Euclidean distance to urban areas was the highest contributing factor for sarcoptic mange *** distance to urban areas decreased,the suitability for sarcoptic mange *** precipitation was the next contributing factor in the model,with higher rainfall of 400–700 mm correlating to an increase in sarcoptic mange *** the data collected to date have provided the largest-scale contemporary distribution of sarcoptic mange in wombats,data should continue to be collected by citizen scientists as it is an easy and low-cost method of collecting data over large *** suggest targeting the identified hotspot areas and more site-specific studies for studying and mitigating sarcoptic mange in bare-nosed wombats.

关键词： bare-nosed wombats habitat suitability maxent modeling

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The Global Energy and Water Exchanges(GEWEX)Project in Central Asia:The Case for a Regional Hydroclimate Project

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Advances in Atmospheric Sciences 2024年第5期41卷 777-783页

作者： michael BRODY maksim KULIKOV Sagynbek ORUNBAEV peter j.VAN OEVELEN International Agricultural University Tashkent 111200Uzbekistan George mason University FairfaxVirginia 22030USA University of Central Asia Bishkek 720001Kyrgyz Republic American University of Central Asia Bishkek 720060Kyrgyz Republic International GEWEX project George Mason UniversityFairfaxVirginia 22030USA

Central Asia consists of the former Soviet Republics,Kazakhstan,Kyrgyz Republic,Tajikistan,Turkmenistan,and *** region’s climate is continental,mostly semi-arid to *** is a significant part of the region’s *** its nature of intensive water use,agriculture is extremely vulnerable to climate *** growth and irrigation development have significantly increased the demand for water in the *** climate change issues include melting glaciers and a shrinking snowpack,which are the foundation of the region’s water resources,and a changing precipitation *** glaciers are located in Kyrgyzstan and Tajikistan,leading to transboundary water resource *** already has extremely high *** indicate that Central Asia has been warming and precipitation might be *** warming is expected to increase,but its spatial and temporal distribution depends upon specific global *** of future precipitation show significant uncertainties in type,amount,and *** Hydroclimate Projects(RHPs)are an approach to studying these *** steps to develop an RHP began in 2021 with a widely distributed online survey about these climate *** was followed up with an online workshop and then,in 2023,an in-person workshop,held in Tashkent,*** for the Global Energy and Water Exchanges(GEWEX)project for the region include both observations and modeling,as well as development of better and additional precipitation observations,all of which are topics for the next workshop.A well-designed RHP should lead to reductions in critical climate uncertainties in policy-relevant timeframes that can influence decisions on necessary investments in climate adaptation.

关键词： GEWEX Central Asia climate change agriculture

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Frequency-dependent viscoelasticity effects on the wave attenuation performance of multi-layered periodic foundations

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Applied mathematics and mechanics(English Edition) 2024年第3期45卷 407-424页

作者： m.SAFI m.VAKILIFARD m.j.mAHmOODI Faculty of Civil Water&Environmental EngineeringShahid Beheshti UniversityTehran ***Iran Faculty of mechanical and Energy Engineering Shahid Beheshti UniversityTehran ***Iran

In this paper,layered periodic foundations(LPFs)are numerically examined for their responses to longitudinal and transverse modes in the time and frequency *** different unit-cells,i.e.,2-layer,4-layer,and 6-layer unit-cells,comprising concrete/rubber,concrete/rubber/steel/rubber,and concrete/rubber/steel/rubber/lead/rubber materials,respectively,are taken into ***,the viscoelasticity behavior of the rubber is modeled with two factors,i.e.,a frequency-independent(FI)loss factor and a linear frequency-dependent(FD)loss *** the extraction of the complex dispersion curves and the identification of the band gaps(BGs),the simulations of wave transmission in the time and frequency domains are performed using the COmSOL *** parametric studies evaluate the effects of the rubber viscoelasticity models on the dispersion curves and the wave transmission for the longitudinal and transverse *** results show that considering the rubber viscoelasticity enhances the wave attenuation ***,the transverse-mode damping is more sensitive to the viscoelasticity model than its longitudinal *** 6-layer unit-cell LPF exhibits the lowest BG,ranging from 4.8 Hz to 6.5 Hz.

关键词： layered metamaterial periodic foundation complex dispersion curve wave transmission diagram

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Cannabinoids and endocannabinoids as therapeutics for nervous system disorders:preclinical models and clinical studies

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Neural Regeneration Research 2024年第4期19卷 788-799页

作者： R.Scott Duncan Sean m.Riordan matthew C.Gernon peter Koulen Department of Ophthalmology School of MedicineUniversity of Missouri Department of Biomedical Sciences School of MedicineUniversity of Missouri

Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human *** have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human *** of these include central nervous system(CNS)diseases and dysfunctions such as forms of epilepsy,multiple sclerosis,Parkinson’s disease,pain and neuropsychiatric *** addition,the endogenously produced cannabinoid lipids,endocannabinoids,are critical for normal CNS function,and if controlled or modified,may represent an additional therapeutic avenue for CNS *** review discusses in vitro cellular,ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS *** addition,the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS *** and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.

关键词： anandamide cannabidiol cannabinoid endocannabinoid epilepsy multiple sclerosis neurodegeneration neuroprotection tetrahydrocannabinol

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